The WHO Antenatal Care Randomised Controlled Trial: rationale and study design

l,,rriirlri. ,pr,l l",r,r,.rl. Ll'rl.,trr(rt\q l'as 1:' st'Ptl 2 :;-i|'

Tlie WHO Antenatal Care Randomised Controlied

Trial: rationale and study desigu

'. Y. Al-N'lazrou'l'rrolii, U Farnt)tq'. Berendesr for the

ir GrouPal Care Trial Research

are listed at the end of the PaPer

os'ario' Arscrrti'ln' sHosl)ilnl Cirlcro-

Ot)slfiriao'.4r'ic[i'n'Arlns'Hni'rlttn'Ctrlrrt'KJtcrrXncttUltii'crstlv'KLorr Xrtt't;, ,',',-1,,,,'i, ';'r'1

\'rlr()rrr;/ /':iliilr;l' oi Cirii'l H.'rtliL 'trr'l

;;:ffi;::. l.;;;;;;;'rLr r\irr/D\rii' trir:ri'':'; tir' u-( '

SumErary' The \Norld Heal

tiorls in develoPing countrles

controlled trial to eva

consisting oi tests' clini

demonstrated to be

outcomes These actilitiesfour visits during the cours

or the traditiolal Protra

.{rr,i ; css /,r, corrcsPortrrcr tcc: Dr, } ose .l i' Tfu

tJ,?li.Y \il,l;: |^"fiT:,ô tl"iHfilProcrnmne of Research' DeteloPm(

lili,i';:"il'",ilsation' 12r I Geneva 27' s'^ itzerl'\nd'

r 19qS BlrckNell S(iencc Ltd'

28 l. Villar er al.

women Pres('lrting for AûC nt these clinics over an average period of

lsmonths rtill hivc been recruiteJ '{s tvomen attcnding thc control

clinicsreceir'ethetcststandardtreirtment,.rsolrrentlyofferedinthcseclinics, in<iivir'lual iniormed consent is requested onlv from lvomen

attending the inten'ention clinics Authorities of the corresPonding health

districts ind all participating clinics have Provided written institutional

in(ormed consent before randomisation'

The Primary outcome oI the trial in relation to ndternol conditions is

the ratetf a morbidity indicator index' defined as the Pr6ence o( at least

one of the follorving conditions for which ANC is relevant: (a) Pre-

".t"*pd" o, eclamplia during pregnancy or.within 24 h of detivery; G)

DostDartum anaem; {traemoglobin < 90 g/L); or (c) severe urinary tEct

In-f-".'tionl pu"lon"plrritis' deiined as 'ln ePisode . requiring antibiohc

treatment and/or hosPitalisarion The primaw /ctnl outcome is the rate

of lorv birthr{eight (< l50O t) AdYerse matemal and fetal outcomes are

exPected for = 10L of th" tinttol group- Several matemal and perinatal

secondary outcomes are also consiJered' A comPrehensive cost-effective

ness anaivsis and viomen's and Provident' satisfaction evaluation are

performed concrrrrer,ttlv \(ith the;ial Health{are programmes should

Le riSorouslv evaluated bv randomised . controlled trials' rvhich are

feasit'leindcveloPingcountriesandihouldbecontiuctedbciorein:ro(iu(:iq netv iie'ltnl'l:t5 1!r heillih i'ntcr\ enti('ns'

Introduction

Antenatal care (Ai.\IC) Programmes, as currently Practised' originate from models

.lcveloped in the earlv dccades oi

Kinedom. TIre core of thcse earlv

,rne"u.-rluared, although, as medical k

tests for screening for disease and Prim

;;;;;".added"toroutineANC,"'*lY, j[t"":l":;1,:",:"1'H;î:?:;:Y';:d only a ferv attemPts have been made

aLrl visits.2{ain a substantlll numlrer of visits for the

mothers-to-be (as manv as 16) r'itlr Iittle or no distinction betwcen high- arrtl lorv-

,trt r,r'o*"n. Rec!'ntl\', cost-bcncfit asPects of antenatal cnrc lrave been acldresst'd

in r"uornl countries, and attemPts are heing made to redtlce costs for ciients and

ifr" n"nfrn-.nt"."rvices.r To a large t'rtt'rrt' developing countries lrave adoPted' rt

i".-,r, in ,ft*ty, tlre antcnatal Programnrt:t ol the de!€loPed countrics with t)nly

-ilt "alr"ti*". Horvcver, tirc cirt'oftcn consists of irregularlv spaceci risits

"r'ith

iong ttuiiing time atrd p:oor iectllrack to tlrc lvomcrr' and thcre is little cttrnnruni-

cattn betwien tlrc ANC clinics nnd the oL'stetric dePartments lncl nraternitv units

' leqs ilh.!'r!cil 5.i(n(c Lt.l t',r,llrrlri' n !' t !t!'ti i:t' tti'l':v l:' )uFPl : 17-:$

l.]lr, l.VlJO rl,ric,trlirli rart RC7: rrlli(),lIli('rl,l.1 sltlriy dcri.qtr 29

Tl',. '. aliclitr' (rf tlr('c()rltcnt and thr rati

i i:,its nttds to trt' cvaluated This \Las earl

stated, 'llv sontc ctlritrus chancc, ANC lras c

r:rost scrcenirlg Protcdures hate tx'cn sub

'ihc cntotivc ntnrosphcrc slrould bc rcmove\l

;,:;;i ;..n ';r: ""ll

int '-"tigatc<i

t'r' randomiscd coutr()llcJ trials' i More reccntll"

tir( US t'trblr. l{caltlt Scn'ice l*p"it t'anet (nr thc C()ntcnt tri l'rcrr'rtal Care troted

i:1 its rcvle\\' that the literaturc on Frcnatal carc ictifitics rr'as olicn Iimited and

tiral manv studies \\'erc tonOuti"i rt'ithout nraximal scicntific ri8('ur'r Sirnilar

annafuaiont ,.'g1g lrritcd at bv a EuroPcan Panel"

The necd for randonrised controlled triils on procedures and examinations

i*f ri"a i. ."**tly Practised ANC has been identified; as u'ell as the evaluation

of the content, nunrber and timing of prenatal care visits for lvomen with differing

."in"i".i .,*'"1 risks Such tria'is can establish nrininral levels of care for r^ omen

ar l()\\' risk ti'\rou,:ll comP.trilr'; less frequent or less ilrtense Prenatal care with

si.rn.iard care."- "'"'s,i.."nroi..randomisedconrro,ecr,,'*,$;:);r#;',::i:iJi,:,r#'i1

Division of ReProductive Health

rtith research insttutions in develoPint

rogranlme of ANC rthich emPhasise

oscrtial elenrenls oi cart thal hale t'een d

:ra,;r cfi(ctiIe than a i;aillit'l"ai '\\'estc

,r:rd fetai morhiditr" The relative cos" ol

and 1\omen's satisfaction lfith the nert- -

The trial includes random allocation of ANC clinics (clusters) to either a

traditional programme ol care (i e tlre "V\'estern' model as currently in place) or a

rationally designed Protramme foorsing on the esseniial elements of proven

efficac'. The purpose of the Present ptpJ' it to discuss the rationale' design and

methoiological features of the trial'

Hypotheses that a ne$' model of ANC which includes

lvn to be effective in imProvint maternal'

ore efficient than the traditional Packate

nd perinatal end Points among sintleton

oresnancies and is not more exPensl\'e' End points are listed in detail in Table 1'

ih""fo[o.ting secondary hypotheses s ill also be exPlored:

oThereisadifferentialeffectoftheinterventiondePendintontlrecharacteristicsof the ANC clinics i e clinic size and prenatal care protider (obstetrician-

Svnaecologist, general practitioner' midwife)'

rlgg8Bllckr^,cllscienceLtd.Pa.dinlrird'r'iPtrrrr'rt'rlEpidcrrriolqy'12'Suppl2'27-5S

30 l. Viltar er al'

frUt" f. O'tto

^ i:[ :1 i:rffi r"'l''stv<il*1:ir inder'

B. secondarv outcomes $ed diseas- durhB pregnancy.

tlDut EeaEnmt dudnt P€8nanc'vj

for matemal comPlications

"ll1'J'o, a,,"'t"nne 8ro\rth retardationb

il,il "i "'i"t"

oaiierY ( < 3i neeks)

il;;i G;;;*'s lnd Prelieli'erv nrprure or membranes

< 35 \(eeks

35-36 treeks

*.i,-" "i.Jitn' 'rtldicited Frelerm deli*erv

< l5 rrc'eks

fr6h stilbi h)

from hosPital

a Proc6s outcomdn"1" oi "n,"nu,"l ,vith Pregnanc.v comPlications'

Rate of elective an

DaYs of hosPital

D. Economic outcomE

Cost-effe(tivenss

Satisfaction outcomes

Rate of rvomen satishe'l lr'ith the two ANC models

li"i*rr,i"* *trtit"ion/dissatisf 'lctioniollolving conditions

delivelv;.Proteinuriadtlivelv; Proteinuria(1) pre'eclampsia * "cliTi]:l"-::';". i],-i;;r" on qualitative ex minarion 19

p:lli:it]Sl^1[:l]8"":'-""1* jil :i ji "::':x:u:;','x$:.T[',:dl

jtl'ffi:*'j$$**.*:x,1":il*jilfl"ti::;-li,:r.*'J;1":'"'-i,,1;H}i:'JT"','ll1:*f,:'lUlnll' :.*":fliilf;:I";;":J#;;ii;- n"''ibroti.'' siven to treat

lrf if to.otl.. uno"'iu;nl'gtiffi':l*':tJ::J,'il1)period not availoble' use the hcst'obstctric estinrrte; bclorv

q::**gol^ffi*lHt'*llll'u.*'io" ror 'ctnl

distiL\s or ccPhaloPelvic disProPortron'

10th

, l!)o$ Blnt{scll Slrcrl(c Ll('l Pn'rii'lr'' nx'l I'('i'xrl'tl [l'i'L',"ir""til' 12' guPPl :' ]i-ii'

Tltt' WHO itttctntal cnre RCT: ralionnl( n tl slrrdrT dtsl'grr 31

r Tht're is; ciiffcrentiai eifNt of thc intervention anronc nrultiple pregnancies'

It is not e\Pccted that thc study ra'ill have adequate Po\^'er io test these h{o

secondarv hvFrotheses in other than an exPloraton manner'

6ric1 IrislonT of lirc plnrrrrirrg llnsc ot' the trinl

This initiativc oricinated <iuring'1991 out o[ the interest of thc UNDP/UNFPA/

trials u'hich the Programme is uniqueh'

The logistics an.l thc cost of such a massir'

an international effort' ovember 1991 1r'ith a grouP of obstetri-

conomists to set the frameu'ork for the

randomised controlled trial evaluating a

+L - h.^r ^.nr \\' a s preDa rec. a,*t " t"a,"":Jl'::l ::li'fl :;

tt":'*Hil':i;

lljl-"jl.:."î.-.,,-:;;,;1.t""=. and an initiati'e for raising the tunds (or the: .\,FLa)""'! ' '- --

r;,air.',as Lr uncrrec Reuc'"' Loi th:iff iffi:J::lXi',n;t1,T I[i:l;

agencies have Priorty cotmtries and

needs of the shrdy Protocol' e 8 a con

with most of these initial issue

d and met for the

and the tYPe and

Thaiiand on 1 MaY

after four and a half vears of PreParation'

four countries ra'ere recruitin8 women into

a l99S Blackwell S.icncc Ltd Pn"lhlri( n'rd P 'riintlt

Efid'niolog! 71 SuPPl 2' 27-58

32 /. Villar et al'

bv : 200 staff, working in the clinics

aid religiously tlifferent' share the

effective intewentions for health care'

ad been recruited and data collection

the PreParatory Period could

We think that the tedious and

ral investigators' meetings' have been

n of the trial' We never would have

t of a Pragmatic trial' and the sense of

The i'alue of meetings and site visits

mes regarded as a 'luxu1y' rather than

ised triais.rr

action among some highly motiYated

'we cannot i'ait so long to have the

should be made to avoid the seduction

h intervention before it has been proved

countries where resources are Scarce'

Is are vaiuable because cf ihe Potential

effective metlical Praciices \\'e also h'rd

ation of conducting pilot str'rdies' n'hich

ence on PostPoning or eliminating a

.t: As it is said, 'once the Senie escaPes

d usually impossible to put him (or her)

e rvith Ar\C.

Methods

Trinl organlsation

ata coordinating units are located at IVHO in

nd safety monitoring committee was

of the kial; it reviews periodically

is informed monthly of thc (ollowing

an,.i fetal deaths bv trial arm' as rvell as

r' lq98 ilhc}tlvell S(icrr'J Ll't I'krl"'lrit r',rJ ,'r'irr'r"rl E''r'l''rnrulo'iy r2' SuPPI 2' 27-i8

I

I

Thc WHO anttnntal utrc RCT: rntitunb nnd sltlhT ricsigrr 33

rc:iuitmcnt rat!5 and Percelltage of hig,h-risk u olr1elr in tlre itrtcrvention arm \rllo

.i() not rcccivc thc baiic neu ANC modcl Tlre ..l'rta coordinatinil urlit produccs

the5.-,reports 1-. r,r'gll .rs rePorts to monitor thc qu'rlitv o[ data collected' such as

f"r."^,Jg. oi nrissing .'all',es fo' the main t'tttct'nrc variattlcs and numbcr of

antenataivisits by triai arm. lt also c<)nducts intcriN arlal1'ses oi primart' orttcomes

at specified numbcrs oi \^'omcn that c()mPlc'te'l lhc stuJv'll Tlrc frrst of sr'rch

in,rilrn nnniur"a rr.as conducted rr'hen 'l200tl 6lrttrPleletl wo cn's 1g66161s rr'erP

ar':ilable in Ccneva.

Trial doanrtcntntiofi and thc collnllorali'oe fftit'Ltlk

.{ detailed protocol u'as prepared in English and Spanish' supported by tw3

smaller documents written in a cookbooi style (also in English and spanish).

These trr'o smaller documents are the Mow'il "f Opcrotiorrs and the Marrrrnl o/

Clirirni .artieilio rshich are used at the clinics ancl local slu'iv offices for the dar'

ro-daY imPlementation oi the trial'

An ANC checklist and all data collec

into Spanish and Arabic. A bimonthlv s

cenrally produced. lt highlighs study

commonlY asked questions, uPdates

shares information about studv sites a- ttointuir,ing the coliaboration and the unif(rmritv of a multicenEe' multi

:ui:urai, ranoinrised controlled trial is in itself a nrajcr chellenge The trial

coordinatins unit in Geneva *.,"Tl;ff il:iilliil:il:':l'ij[ iffi"f :i

tioni u'ith queries related to data monitorint'

ths in Geneva, and site visits eYery 3months to

l,ocally, periodic n'orkshops for the inten'ention

Broup's staff are conducted to revielr' the protocol including.a periodic clinical

check-list evaluation and summary form assessment This eJfort has created a

i"aing of "n

international team a"i contributed to high morale among trial staff'

Selection of study sites: criterir and statistical considerltiotls

The clinics in eaclr study site have been selected because they serve similar

p"pJ,i"* with regard io socio-demographic factors' and have study-relevant

mortality and morbidity rates of the same o'der of magnitude' An ANC

;r%t;;*" following traditional standards delivered through the public sector

rvas already available to Pregnant rr'omen Each clinic orcluster u'as exPected to

ô"ug" ia*Iy between 450-and 500 nert ANC rvomen during the study Period'

Hor.,""r,"r, ". tire number of clusters has a greater impact on statistical power than

the sizes of the clusters, smaller antenatalllinics, Potentially supplying as fevv as

f 199E Btackh'ell Socnce Ltd Pdcdiatti" nn'l R titt'llol EPide'niotosy 12' SuPPl 2' 27-58

24months.il i'iii^-.""" and control clinics will be in the same SeograPhical area' but serving

.ti.iin.t neishbourhcrds.;1;;;;1;;;* thes€ ANc clinics rvill be traceable at deliverv

.

i. ff"';u;;;;;echanism rvill have access ro the hospitals which are the referral place

c) ANC system Military hosPitals or

, lvill not include cliniG where direcl

alreadv in place rvith norms and predefined

imPlenent nelv simPle tests or activiti€s as required b'"--the

activities should be Provided by the instihrtion(s)' as the]/

ntv' Tftest ferv nerv ictivities r't'ill rePlace several curentlv

34 l. V illar et al'

Table Z Criteria for clinic selection for the WHO antenatal care randomised controlled

Jrr'i i. ai." is the unii of randomis"rtion)

@nelv patients in a period not longer tlran

imolemented.il'"riJJ,.ti tn.rd ha'e an alreadv rvorking and economically supported minimum stall

,"qJJ rot p"ti""l.--!-B"t th" Ptot-ol'

300 rvorren,'.vere acce;ied- TIre criieria for each l'\C clinic "rithin

a studv sitc to

i" l.,.ira"a for randomisation' are presented in Table 2 . ,

All women attending prenatal care for the first time after the start of the shrdv

",;;;.; the s"lected-cii.ics, regardless of their gestational age, medical or

obstetric characteristics or

enroled for Prenatal care at

are referred for deliverv at

ired, or referred iJ identified at risk of

r at the usual refenal hospitals as well'

ntion clinics, women are classified by a

si form) as

e. alised in

it tory (Pre

three or more conseotivc sPontaneous

;;, ;i; ;, hospr tal ar'tmission ror hvPertension ;J"tff '; i:1:f Hg::'";

or > 40 years; Rh(-) iso-immunisation;

ic blood Pressure 90 mmHg or more at

ons (insulin-dependent diabetes mellitus;

stitrrce abuse, including alcohol; and anv

orher severe medicnl disense or condition) Answers were recorded as a binary

ilgesB!.r!\w,rllSLicn(!Ltd.P'I,tli'rrri'n,I'iP"i'nrrrriEt'r'ii"'i('[rsvl:'SuPFI2'27-i3

Thc WHO i,tttL.l,ttttttl carl IiCT; rntiL)nnlc fitt(l slrrd.rT dtsiqrr 35

variahle (vcs/no). \f omell lrith a Positivc re'sPolls( t() any oi thc questions rr'erc not

cc.rnsicicrc'd elig,iblc for thc Irasic conr;x.rnctrt of thL'nc\\' Progranrmc but renrainc{ ill

thc interventi<in grouP r('ceivilrg the carc ctrrrcsltolrdilrg tr'r thc dctecled contlition or

risk fackrr. lt should tc n('tBl that the risk classificaticrn form is an intL'8ral Pnrt of

the interventiorr ('Nerv B.rsic Progranrmc' and 'S1--cial Care') and should not t't'

corrsidercd as an cntrv critcri(nl ti' tllc triil. Figltre 1 provitlcs a fl()$'chart showing

thc path that rr'orrtcn follorr' in the th o aInrs oi tht' trial \{omerr u'ho did trot agree

tc, particip.rtc in thc trial rtcre asked to Protidc the inforrnation needed to conrPlete

the 'classifyine' f<.rmr for'oascline dcsoiptive PurPos(s onl)''

all ,.'onrcn ettending, the studv clinics regardless o[ thc care received and the

number of Yisits rvere included in the assessm€nt of trial outcomes (intention-to-

treat). Again, the trial comPares two systems of care; the basic Programme is a

compon;t of the care offered to the inten'ention group \{omen B'ill be followed

untii discharge lrom the hosPitals Post partum, including those rvho refuse to

p.rrticipate in- or <tiscontintre the ne\\' Prograrnnrc becausc of.either medical or

personal situations. Hortever, given tlre equivalcuce naiure of the trial' subjects

ivho reruse to ParticiPate to anv extent at all in the inten'ention will not be

regarded as belonging to the inten'ention grouP for the primary analysis'

siondary analvses-r.-iu include all enrolled subiects to the extent that their follor.r-

up data are ar ailable. Women u'ho refuse to initiate or continue the neu' ANC

progr"^nl" are offered the 'traditional' ANC at the same clinic or referred to an

altei,rati.e clinic i, ii is locoted nearbr-and does not represeni an! in'onterrience

io; tlrt t\ on1en. Tire prop<xtion oi r" omcn reiusinq tire llel\' ProEirammc (droP-

outs), or \r-ho discontinue the trial Protocol after randomisation (transfer rate) are

regarded as a Process outcome.

Trial desigtt

The study currently under way is a multicentre randomised trial of two different

models oi ANC. The nerv model of care u'ill be compared rT'ith the existint form of

I ..$ r-l

Figure 1. S

Controlledrandomisntiprovide thepurposes only.

( l99E Blacknell Sde ^<e

Ltd P,ralioln.a,1 Pc,tnlol Elid?mioloSv 72, SuPPl 2' 27-58

36 /. Vill,rr et al.

ntly ireclurvill

are r;ndomised (cluster randomisation)

each of four sites and rvithin clinic

ite were the number of Pretnant women

e year Previous to the study' the tyPe of

ministrative health svstem to rvhich they

each of three studv sites and 17 in the

fourth site.

DescriPtion of the stutlv siles

Khon Kaen Province' Thailand

kok) is the:entre oi ihe north-:astern Dnrt

their babies at the health-care facility

ANC scheme follows the traclitional

Table 3. Allocittion of clinics across sites

Numbcr of rindolnised units

per stIatumrCountry

ThailnndArgentirlnCuba

Khrrl K.lcn ProvtnceRosarioHavlna

2 largt', 5 meditlnr, { small

I hrge, 15 srn.rll'12 smallJ nrediunr, S small

Itrtttahnc'/v P:rtients n veir' tvPe oi clitric

t(hi.h th,.v lrr.h)ns.(iree-st.rnding/ hosPitnl nssociirtcJ) 'lnd hciltlr-c'rre j)-stem to rrhich thcy b('lt)n8'

t l(E)S Dt.r(L\(rll l.icniu I t.l i''r'r'li,''ri x"l l'r''nxtl't' ir'rhnrir'l'\v l2'SttPfl l'::-5St)

TIrr' tt'fjO n tL'ttniil cnrc I(CT: r'tliontlt nd sirrrfil dcsigrr 37

irar.r:r.rtoc;it rnel scr.rlosr tlsts ftrr s"'plrilis (trstr'rllr' \'Dlll-) arc routinel\'

ix'ril1611{. Tr.,rl tlrrsts.,i l.o"',,,',, ttrxrlid .tt.c l]i\'cn l(! Frcgnilll rt<rmcn tluritlg'tirc antcrrat.rl },.'ri<rl. UncontPiicattC dqlivcrics rrc attcndt'd and cttnductcd by

,',u.s.., t.ll.r.1". courr,licatci dclivcrics art' lrranagctl t'v mcdical officcrs or

,.li"rr",l n. apProPrinll. Facilitic's for Cacsar"atr sNti(nr arc availablc in all tlrrcc

6ft-hed aurl .ii :tr-tC crr::rrnunit) h()sililals nrrd itr sort'tc trf tlrr:1Ghcd hospitals'

\urscs ir(!t't't tirc c(n'l1l:rullitY hosFit'lli all(i ulitlrr'i\es ftrrnr thc lrcalth cclltres nle

.cht,dtllt,.i [l,r a lrtl;lrc r.rsit it' Pt.:i},;rrtur)] \\.()t,11(.It itr tircir rtsl.rcctive areas for

riving lrcalth t'.luc;,tiott alld rrall.lsclllcllt oi thr-';rostpartunr 1:crioC

Rosario, Argentina

Rosario, the second largest city in the countrt" is located = 300km from Buenos

Aircs. lt has a krtal pp;'ut61i(11 of ovcr one million inh'lbitants Health care

i:riludin,: ,\\C i: pr,'r:irlecl t'\' .r nri\ oi i'iilate' Irttlllr' hc'alih ald social st'curitv

.c:'.i[cs. .\iut(\sl all dcli\.cries irl lhr- '-'rrt'.riic s\':t('l.l'l (rccr'r: ir: iirc ]rosr''itals'

intcnatal clinics includcd in the stud! arc thtrsc'.lttached to trt't' hosltitals as rvell

o, fr""-r,nnd,ng clinics. all belonginc to the pul'lic svstem'. ldcall\" tlre traditional

'\!cstern' svstelll is recornnrended, rr'ith a t:lininrutl of file antenatal tisits Per

rtc,nran. \'lost of the fu\C is provided bv olrstctric/Evnaecologv specialists'

ll:i ani. Culr.r

!la!an.r is the caFital of Cuba' The tiial i' irlrPlcrrcntei in threc municipalities of

ti\c citY, Centro Habana, Habana Vieia antl Habana del Este Poh'clinics located.in

ii"*;t"". provide ANC to all Pregnant rsometr resident ill these nruniciPalities

and all deliveries are referred io iertiary care hospitals nr 'NC is Provided by

ceneral Dractitioners or obstetric sPecialists' complemetrted b1' a conrprehensive

i-t". i t"Ja, medical and nutriiional services The amount and content of care

i; .qrl."i* i" afre best Ar.NC in deseloPed countries' tr'hich.has contributed to the

Iort levels of negative Pregnancv outcomes in this PoPulation'

Jeddah, Saudi Arabia

Jeddah is ihe second lartst city in the Kingdom oI Saudi Arabia and is the maior

r;;;". The populatio'n of the city is estimated to be 15. million u'ith 17800

a"ti.1"ri", p"i y"r.. Health care is provided by the Ministry of Health'

*"t'"^r*tlf aiencies such as tlte Lniversitl' hosPital' military hosPitals and

itro t 1' tt " priuui" sector. Tlre Mirristr of Healih renders its sen ices through eight

f.".pt;"f, oitd o n"uuo,k of 37 Prirnan'Health Care Centres (PHCC) distributed

throughout the city. Obstetric sun ic"s a'e available in t\vo Seneral hosPitals and

trr:o #temiry hospitals' ANC sen'ices arc available in all the PHCCs as u'ell as in

( lgqs Blackwcll Scicn.c Lld Pnr''lintri" nnd P{'rittitnt F'Pi'lct"idofv 72' SuPPl 2' 17-5E

38 J. Villnr et al

t rvomen follows to a larte extent

and frequencv of sisits' AII care is

s. A lbrmal scoring s)'stem is used to

nsultant clinics located in cither larger

deliveries takes Place in hosPitals'

Interuefltiol1

The rrial inr,olves a diject comParison of trvo programnres.of ANC. one is the

;ffi;; ;.\r; ;;rently offered'in the selected sitesihich follorvs the 'traditional'

model. A detailed rlescriPtion of baseline A'\C was obtained before the

,r.0"r,tr",t...*eotheristhenelv.Plosram6grvhichincludesscientificallv

"."i""i"I, .ii*tt'e-oriented activities

r5'16

ActiYities included in the new Protramme. fall within three general areas:

(") ;;;;;; ".io"' r"' Iteattlt condltilns likelv to increase the risk of speciiic

oiu"rr" ora-.onr"t of pregnancy; (b) th'

tl\ese outcomes beneficiallv; (c)

pro'clents, especiallv e:llergen':es'

As rtith anv other sireening

conform to the common critena for scr er' screening ior

nerv medical risks in ANC is a continu of the screening

I nunrerical risk-

clinics, is not inclucled because of its lo'v

ck of evidence of the effectiveness of such

d controlled trialsrq Therapeutic inten'en-

ff:i,$:ff: lvere serected irom

It is inevitable in a multinational trial such as this that the actual

trial is'Pragmatic' irl its orientation rather than 'explan'rtory"a) Horvcver' in order

to standardise the interyention' all stutlv sites use a.Mnrrrr'rl rrf Clirricrrl Actii'itics

an,l a clirrical activities'checkiisf (Fig.i) that translateLl irrto local languagc is

atltletl ttr all medic'rl '"to'J' in the iitenention clinics' arr.l completed at each

ANC visit.Neverthcless, tr trutnber of elot-unrented deviations from the formal protocol

have occttrre.l in tlle studY sites ln Th'liland' ihe uterirrt' hciSht chart Nirs not

implemented, althouqh the actual measuremcnts lvere taken 'rnd recordetl in the

, l\r"S Bl.r.hvcll I icrl.( LtJ lir'1"'rl'r' r'r'i 'I"li"'ri'rl

l':t'i'l'1rrx'/r"(v 12' SuPfi :' :;-is

Tlrc WHO nnlollj.lal cnrc RCT: rfilittnnlc n ii sllrrltT dt'sigr:

I}ASI(',lNTENATAI, C^RE CII ECKI,IST

( llE - t: f l lL 1t-tl t lflLt C-tkflf.l, Ol'f lt l ltRL tlliolil tTt t l'rll t.t l)Lb l( ,rE\tt i,/r ./,s! ra1d,"!,,.a{r{ /r' n'. o/ r^d

39

( hnk trrdd tio _SuJl Suhj!(r rio_ -:--

$dn Bp@ibt. lu ant@tot .nc non

Figure 2. Basic anteratal care checklist included in all medical records of women attending

an]enatal care clinics randomised to the inten'ention artn of the trial Care providers

complete this form at each visit following standard procedures lt is exPe(ted that this

me(hanism lacilitates the inPlementation of dle intervention and reduces Protocol deviations'

C 1998 Blickrrcll Scie ^ce

Ltd. Pa.,lialtic nttd Pcirnh Elidcntiology 72, Suppl 2,27-58

FtlL$ \'tsrl ,,.,d/ro,tr',.t!trrrt.o tatfih.ti"td r.*ddttn iJ Fllintn'n tur" lI fite t i!" Ltur tt\tt ttr,anrt,tlal. ut4 .t ull *t^ itit tP t'

'h ntu'

l,ATt:llt :nd inl rlh

a i,\v^,,r r.,r 'nd,:t'* cllirln ln lltr h:rk F.?rrnm

(nnr.ll\ E\d.Jnd Ilh rqrr

()t.r&, ($hun.l rr:6trf,rtio utrrin. h.ilhr

(r ^ .rs lr$ E oorEn d stl *dtl rb )

R.Di3 nrnil'i16l. &t d'6.f trnD|nnis 5TB ' ud6<ir

t.:. rd rruinoL dilrrr'

ic ro[r..d$!r 6.nuri6irlt mrjaid for co.r::Gn.iq hd l'.. fd dcrB*6

I

SICOID VISIT rrd SUDSEQL:EIT YTSITS Gc'tato nlu$ a?ri 'ol\t<Lt:l,^TE: 16 ll il

al'n(. cilnEr6lq atii!

rr.\ri r.tctiN.i.r: ?!:iiJncr ctr:.. h.th fdrl hr&r n':

f r n. lrtr td Drd.m rd. tu[l'fu!.om t [l tt' 6 'drErlr. fol'..cdllDDl.i.nuton

R..mDddrnoi tor.hcr!cn.'6

THIRD vlSITr lld DATEI

ir'!nurrorod (!..6d.io(,

R..6hh.nd.tm! fr l-rdDn rcntrarnion

FOITRTH VISIT: .dd DATE: ,

D.t..tion of btrc.ch pwnEno. & r.f.ml lor.r!.m.lr'Rd

CohDld. ANC !.r(r<omn.nd i' b. broughl tohotpn,

40 l. Villar et al.

medical records, and all women had a haemoglobin test at the fust visit which was

not recommended in the protocol ln Saudi Arabia, all Rh(-) tvomen were not

eligible tbr tlre basic comPonent of ANC, and the recommended routine vaBinal

"ti*ir,o,ion rvas not culturally acceptable ln Argentina' many phvsicians in the

inten'ention clinics requestcd one ultrasound assessment' even if there rvas no

medical indic^tion, ,.'hich was not recommended in the trial; if the woman had

,roi a"Ur"r"d by rveek 41 o[ g€station, the next visit was conducted at the ANC

clinic rather than in the hospital as required in the Proto€ol; physicians in one unit

randomised to the intervention ErouP imPlemented a glucose tolerance screening

test, although this was not included in the Protocol'A final

-explanation is needed in resPect of the imPlementation of the trial

in Cuba. Because of the universal availability of family doctors' it is possible

that, although rvomen had a reduced number of visits at the clinic' they rvould

;."piu."'tt""r" visits by Soing to the family doctor's of6ce' lve have instructed

these doctors to refer iU pregnant women to the A'NC clinic' but there is still the

possibilir,v of rvomen demanding care that cannot be refused Fortunately' there is

a routine data-collection system in B'hich family doctors have to record anv formal

ANC visit and such a visit is also registered in the \roman's 'd\C card All visits

recorded on this cJrd nie nbstracted iI the time of ,.1eliven bv the inl'estigators.

Tlrerefore'iftherearee\trauisitsrof.rmilv(ioctors,ihe\,rr.illbeincludedinthenumber of visits made to clinics other than the original antenatal clinic'

Moskitrg ol in te roen t ion

Considerable efforts are made to mask treatment status for deliverv and neonatal

care providers. The staff responsible ior data collection after birth at the hospiial

le,el are unarvare o[ the treatment status oi r\,omen ilr the Study' In Argentina, all

deliveries occurring in the ParticiPating hospitals' even those from other clinics in

the city, are reco.-ded, miking it very difficult for hospital clerk to identif'v

intervJntion status. The study site in Thailand is an excePtion' as delivery occurs

atthesameinstihrtionsrvherewomenattend(orANC.Therefore,itispossiblethatstaffinthedelivervroomkntrrvthetleatmentstatusandPerhaPsactdifferently based on their belief ol the effect of ANC' The Primary outcomes are

little influenced by intraParh'rnr care, horvever, and it is exPected tlut this effect

willbeminimal.lVervillncvertheless.rtt('mPttoevaluatethiseffect,ifpresent,using trvo mechanistns:

(a) lnfornration on intraPartunr events Partiall)r unrelated to ANC' such as

emergency Caesarean section atttl iorceps tlelivery, rvill be collected'

Comparisons rvill be made bet\\'eelr the two treatment grouPs'

(b) Trenis in Pcrinatal outcomcs u'ill be lrbsewed at all ParticiPating hosPitals ior

their total PoPulation.

, lqrs Bl.rllw(ll ici(!\.r Lr(|. nr,1i,,r,n .rnJ t'ri LP"l "i'l+tt 12, Srrpfl 1 11-55

Tlrc h/HO a luntai crrll l(C'l'; t'tllt.rttnlr i i siraiy ricsi;]rr {1

Ollcoltc,rt(?srr,('s

Antcn.ltal carc is a conrplcx sqt of aciiYitics (t'.rsicallv a nrttliiplt,tsic scrtltritrg

proccdurc) aiDl('d at rcducing nratcrnal antl fclrl rrrorbielitr' 'rttd m(trtalitv b\'

iccrcasing, tlrc likclihotxl that a Prcgnant rltltrtatr uill crpcrience scrit'tts

ctxrplicatio.s rlurinS prcsnanc* or childl'irth, and lr\: irllPr()\'irlg t1c mntcrtral

and fetal outcontcs oi \ronlcl'l \\'ith colrplicntioll:. lt is clear tlrlt' iI orrli n]ilte:'nal

dcath and Prc-latrour fet.rl death are consi.le'teti (outc()nlcs th;rt A\C shorrltl

ideallv prei'cnt), the sanrple sizc rc<1uirt'cl r'rtltl..l ['t' crtrenrc]r' largc arr..1

unrealistic; thus, surroSatc measulrls and a molL''itlitv itrclcx ate used to trtcasure'

intcr!ention eifect.

As far as poteniial fctal outcomes are collcernc|.l, ollc aitcrnative is Perinatal

mortality, r.'hich can be considered as a Elobal indicator of fetal/nertborn health'

Ho*e.,er, perinatal death is also related to certailr aetiological factors such as

congenital malfonllations, intrapartu:n coDl|li''ltiorrs ()r tvPc of neotratat care

upon rthich ANC has linritt'd elfect Furthe'rrrrtrre A\C h'rs littic eff('ct orr

pcrinatal nrort.rlitY among norrr,ai biriirrlcigirt iniants For lr\allrPlc, in the'C)xl<rrci

region, UK, from l9&l to 1987, onh 61i of all irrtrapartum or }rostPartunl deaths

r.'!re term sintleton babies uithout congenital malfornrations or evidence of

severe infection. In this region, oi all perinatal deaths, onll' 47? of nertboms rr'ho

died rvere considered to have a complicated antenatal historv.:r Neonatal irte.sive

care units do remarkabh'rtell in 'rescuing frorn death' \'en' Preternr infants rl

Excludinq cotrgcnital maltomlatiolt alrtl introrrartuill dL'atll. it is tcn ulllil'eit that

.r-\C r{ili inllrrcnrc }rerirat.rl nrortalitr'\\'itlrout ci\rllsinS ths iatc oi'-'rclcml deii!en'

or intrauterine gror.ith retardation (1UGR). Bv reducing the inct.lctrce of IUGR:'an.i

Frcterm deliven', ANC can influence fetal, irrkaP.rrtutl and r]e(nlatal death

There are legitimate concerns arising from tlre use of lorl' birtlrh'eight as t'

primary outcome of a proiect such as the Present one, u-ithout differentiating

Letween preterm delivery and IUGR rthich require gestational age estimation'

Althougtr an accePtable ievel of reliability-can be obtained in the estimation of

Sestati;nal age in developing courtries,r{ rve believe that imPlementing a

io-rnon system of Eestational age or nervborn assessment ra'ithin a very large

trial in four countries is impractical.

Trials that are exPected to have modest imProvements or no imProvements in

relatively rare outcomes can use combined indices (e g matemal morbidity index)

or surrogate measures instead of the ideal outcomes' We have chosen as the

primary-outcome of the trial in relation to maternal conditions the rate of maternal

morbiiity indicator index. This is defined as the Preserlce of at least one of the

follou'ing severe conditions for u'hich ANC is likely to be relevant:

(a) pre-eclampsia or eclampsia during prcgnancv or u'ithin 2'l hours of deliverv;

proteinuria is defined as 2.0 g or more in 24 hours or 2+ or more otl qualitative

examination (diPstick);

i 1q98 Blackwellsciene Ltd- Jrnc,rialri. r,r.l Pl.riralnl Eli,lt),Li)lo.g, 12, SuPPI 2,27-iS

42 /. Villrr et al'

(b) postPartum inaemia ( in); and

i;j ;;";" urirary tract in defined 'rs anv episode of these

corr(litiolls requiring a t or hosPitalisation'

These comPonents are relatively independent from each other and I^'e exPect

that only a small percentage of one of these

]".aii"itt.'rtit ""'*eigtttei ittae variable' but

"].i.i,rt"t" three conlitions rvil as secondary

outconres. The primary outconre in relati be the rate of

i"* "U'tr,fl-"tgi,

t< i;oog), as a surrogate measure -for Perinatal mortality'

;::";;; ";;.""re variabl-es inclucle other matemal and Perinatal events such as

the rate of incomplete tetanus tmmunisation' t'reech Presentation at birth' the rate

of treated svphiiis or a PostPartum hospital stay for maternal complications of

1 rveek or more (Table 1).

Thc economic e-tnluntiotr

There is an ecouomic evalua[ion alongsicle this randomised controlled trial' A

U"*it..i a"=."p,iolr oi its nieii]o!1oh-t3i-\' is Fresented elservhcre in this Supple-

i,"*ii gr,"i],:. lhe .'coltonric eveiuation airiis to assess rvhetlrer the ntrr'

Drosranlme is more c'rsceilet:ive th

itoilan,',aing the service an.-1 ior healt

ivill estimate the unit cos[s oi care tha

particiPatilg in the clirlical trial Unit c

il;;;; "^:it type of care (collected in calculate the

,o,ot aoro oi tt"otth c']re given lo \rome the trial The

t care duringt'Pes o[

delir'Pregnan rvillcare. ln.ostr, ony consultation and PrescriPtio ' the

and lost income. All costs incurred unt Post

Assessmett of tonrcn's nntl proaiLlts' pcrcept'totts of rynlity ol care

of grcat inPortance and consielerable efforts are

lcd itescripttn of its nethodology is presented

.l" Lr sirort, tltis comPonent ains to comPare the

sr.rbiective perccptiotr of the tlualitv of

reasons bellintl it, il'l \\'olllcll altelrdi

control units. The sttt..1v 'rlso ain]s kt

nurses anrl othcr ililicd !-crsorrDcl) !''"runits lncl lhe r]ew .'lntclliltal Pac

, le')s ijl.r.l$.ll S.rcn.! l-I.i. I'.r,lftlrit 'tl"i l'lti'Iitrl [,,,'i(1'In'1"'ir/ 12' Strl'PI 2' lt-is

l}r' lVFl() l,ttlt'nttt.,lcnrr' RCT: tiliittil.' tl' 1sllr'iv r{r'str'l +i

considcrations, thc stlbieati\'(' dinrcnsiotl atrrrrtrs htrtlr rls('rs alld provi''ic:s is a

crucial slcnrcrrt ttr trc takr'D itrto account b('(()r('rc('oll'tnlcn(linS thc atlol'titrrr oI the

rrcrt ANC Pxckailc- This c()DrPollcnl rtill also lrroville uscftri inftrrrrr'rtitrtr alrr'rut

thc obstacli+ that m.1\' 1,n1'q t(r he ovcrconlc drrtille rcPlicati('tl antl s('rlint uF'

Results are particulariv rele'r'allt for a nlulticr'lrtrr' trial, cnrricd out ill crtrelnclv

differcnt coritcxts. The sttr.lv i5 organist'd into t\\'o st.lscs lrr thc first phase' 'ruethrro.:raplric aPPr()ach ftrllou'ttl techniclucs sttcir :rs itrcus SrttuPs alr.l irr-.lcpth

irrtcn iesis uith hc.rlth Pcrsolurl.'l atttl rvontcn, iu ortler tir 'lsscss thc iranre tll

culturallv rclaterl valucs in e[erv countn. Tll(' fill'lillgs \\'erc incQrPor'lted ilr thc

,eco,1d sta,r" (qual)titatiYc), aud rtill also L'e used kr itltcrPr('t tllc results of tlre

quantitatire cu'nPonents. The second plrase uses a standardised' close-ended

questio,r,raire to alt ANC Providers ParticiPating in the trial in every country' and

another questionnaire to a random sample of ra'omen attcnding the clinics'

Qualitatir"e data u'ill be anah'sed bv applving the'grounded theo4' approach'"

that e\ables an illductive illtcrPretation oi tllc illfortllatioll Quanlitative data rtillhe a:ralvsed using stalrdard statistical tcchrli(lues'

Basclinc surz,ev

A formal sun'ey describing ANC Practices uas inrplemented in all eligible clinics

immediatelv before randornisation to obtain a detailed description of clirric and

serr.ice clraracteristics Lrefore the interventiolls. lnfort:ratiolt is availatrle on thc'

clinicai uracticcs .rnd servicc. ()l tire clinics. Tlrere ar.' i\\'o c()l'r'lPo:lents oi this A\Csuncr':cliniclevclatrdPatienilevel.Atthecli:ricletcl,c't'teiornrr''asconrpleter'lfor each clinic particiPating in the study in each coutrtrl. bY the studv field director

and t5e clinic ftcal person. The s.,n,ev coordinators liaised with the clinic staff and

authorities to obtain the most uP-to-date description oi the clinic The visit was not

communicated to the clinic staff in advance and a 'tvpical day' of the clinic u'as

chosen to avoid selection bias of patients and procedures' The principal

investigator of each countrv prepared the agenda for tlle visits'

The-patient component of the survev rtas also conducted before randomisation

and after completing the 'clinic level' form. lt *'as carried out by the dinic focal

pe.son undei the iupen'ision of the shrdy field director and implemented

simultaneously in all ciinics at a given study site An index day n'as chosen by the

sh:dy field director to conduct the sun'ey. The clinic focal person used the dinic

Iogblok to determine the medical record numbers corresponding to the

co-nsecutive visits of women before the index day A minimum of 64 consecutive

records of pregnant women B'ere aimed at each clinic (cluster)' At the Patientlerel, 2913 meJical records u'ere revierr-ed. The desiSn and methodology of tltis

sun'ev is described elsctvhcre irr tl s Supplement ls

Tables 4 and 5 Present the characteristics of the 53 clinics randomised to tlre

inten,entionandcontrolgroups,usingdatafromtlreantenatalcarecontentsun,ey

r I99S Btnckh'ell Scicn ca Lld PnL\liol/i. nt l Prri'r''ill Et"i'd'r"i'lost' 12, Suppl l' 17-i9

44 l. Villtr et al'

Table ,1. Ch,rr.rcteristics oi the clinics randonrised irl the IVHO

,*"Ji "i ,ft1 nrtennt'ri inrc (-ontcrrt slrr\ t'v lt tl.r" t11n;': level"

Antenatal Care Trinl:

Cllaractcristicslnten'ention(27 clinics)

Control(26 clinics)

Number of clinics

Type and PlaceP blic hcnllh syslcl't

MuniciPal or Provinci'rllvlinistry of Health

LocatiotrU rbanRur,rl

Type of ANC clinicP.rrt oi a Poll'clinicP.rrt oi .r hosPital

Higlr-risk clinii ar'.rilablc in s'rnre btrildirrg

Separate antenatal consultati()n roon1

Lotv-risk r"omenHigh-risk rr'omen

Piitete .'irtssitrs r('r)n1

\-'i\\' [iiltiarts/'nlolrin (n1l.,'1:1 |

Openins tinle (hoursr' rr t'-k) t n"ean)

Resources availableFornral risk score classi[icatiotl

Nutritional assessment

Uterire heiEiht measurcment

Bloo.l !ttets.,te r'leasurcDlellts

Dentnl exalni11itionPreslr.rncy Lest

Ith (- ) antibodicsHaenroglobirFasting blood glucose test

Uterine height chart

illaternal rveight gain chart

V,rginaI sPectrlumH.rnLlJre'ltl DoPPIer

Fetal sietl'r()sc()Pe

Tetanus ttrxoir.l

Schcdulc visits ti)r r()ltlirt 'JrcColtinttitv oi clre

I{anrrL d('s rnllilrl,ld lo i1'1lt_r'isl tr'r'rttutt

Cardiok\coiir.rphOr.rl gluct-rse ltstGlucose iolcrancc teitrorrltlrrrr'd

1il2

21

6

:07

21

l472

20

6

19

7

23

72

l9

33.2

23.5

13

i9

lt.9

12

2626

1619

24

2526

266

12

l619

26

l6i620

262{tt'

12T271t-

16

2i272726

59

27

22

27

27

27

21

t55l5

, I!',ti lll,rch"! tl S(icnct' Ll(l i'r,di'tl'x n'xl !"t!t't l li'f it ti"ln':y t:' S PFI 2' l7-5H

Tlrc I'VHO nt t'nnl.ll rnrc RCT; '1iii()"rllt'

rt'lrl sllrilt/ dcs+j'r .15

Tabl( 4. corllirlx.rl

Charnct{]ristics

Ultrason(,gr.1Phic sclnniDB

B.Ctcri<11 culturc irr trrine

Ailha-f ctoProtuin sctettring

\utrition su['Pl!'nrentsAntibrotic.Iodine suPPlcmcnts

lirl('r\ \'trti(rn1l; (litrics)

(i)ntrol(16 clinics)

!unrlrrr (,, (lilrics

lron,/f olic acid supPlements

Extemal version for breech Presentation

26

l614

:0li

7

26l6

t;lo1i2ll3l

?7r5

;A;;,*,"d ln-fl ,l* ParticiPnnt clinics before ralld(rllrsati(rn'

ai the clitric level Clinics nrc mosill urharr ('lr=-l'l)' ill bcl(rnqirlq k) the Pul'lic

f-r".i,it ti.,"* ""0 }rart of fl Polvclini; (ir = jq) (l \Lithirr '1

hosrliiai rri = l'lr' \'lost oi

iir"r..f**, or" "Ll",o,"it' tt't'rn"rr to other levels of cart rr'ithin tlre sarre

I"riir"S, a proPortion has tlre possibilitv of admittins \romen or delivering some

t^ ir," .,?t"J f"J try, although t'tte m"io'iq' of rr'onreu in the studi' sites' excePt in

Thailand, deliver in large hospitals Fatiliti"t o'" modcst' l\'ith ferr' having' for

exanrple, private clressing rooms lor women and onh' half l\are separate

.on.'.if,^rio^ rooms. \4ost clinics are of nric.i'liL'size rtith 3l-38 ne".. Prcsnarlt

\ro:ne11 a nrorrtlr (Tal'lc +t Ti1e distrihtrtior tr: tltc:'c cllilriiicrisiics \\'as silllilai

t,eirr'een lhe clinics that suhsequentll rr-ere;an''lott''istl to thc in:crtentiotr (rt = 27)

or control (rr = 26) ErouPs ffable 4)'

Resources available at these clinics are also Iisted in Table { and are sinrilarly

distributed behr-een groups Clinics should be able to provide adequate AI'\C with

these resources even in high-risk pregnancies t'ess tlmn half of the clinics have formal

risk-score classification systefis reflectin

of these screening strategies; uterine hei

vet not recorded in standard charts redu

Lreech presentation at term is only pract

practice is now recognised u' un "ff"ttit"

p'"r'entive measure for breech delivery'

"'TJ;;;;;.f r""u"ur" tend to'be similar to those required for- the

imDlementation of routine, 'WLte*' type of ANC' Most of the clinics in both

:ff;i#;ipt",o"-typr'ii" antiuoay testing of all.pregnant women' but

screening procedures fo. otit"' int"ttio" ii'"ut"'- "'" offered only to high-risk

r,' onren (Table 5).

Phvsicians (€ither obstetric and Sv

tioners) are available in all clinics for tl

the inten'ention group and 13 of the

ANC as u'ell. Half of the clinics in bo

a lqgs Blackr.'cll Scic ^ce

Lld Pocdtoti( nt P'ri't'rlnl El'idcrriolosu 12' SuPFI 2' l7-Ss

45 I. Villar et al'

Table 5. Resources available '1t the clinics ranclomised in the i{HO 'Antenatal Care Trial:

results of the nntenatal c'1re content at the clinic level'

Resourceslnterverrtion(27 clinics)

Control(26 clinits)

Nr.rmber of clinics

Screening (or infecdous diseases

Hepatitis B

Low riskHigh risk

ToxoplasmosisLow riskHigh risk

Conococcal investiSationLow riskHigh risk

Trichonomiasis/YeastLorv riskHigh risk

Sv[.irilis antirodvLcrrr' riskHigh risk

Human resourcesSpecialistGener.rl PSpecialisi als

lvlidrviieProfessional nurse

Empirical nurse

Bi(rchemistLaboratory technician

UltrasonograPher.{dministrative staif

2226

l022

3

76

627

:377

17

209

'ti1S

2

214

19

16E

7

20

E

6

l6

26

12:111

1313l,l

16

15

bloocl or trrine sar:rples, rvhile the other clinics are routinely visited by staff from

the central laboratories for samples to be drawn or collected' Social workers are

not ernploved irr these clinics (Table 5)-

Etlricnl isslrcs

This trint has L.|ten appmved by the scientific and Ethical Review croup of the

UNDP/IJNFPA/wHO,/worlli Bank SPecinl Programme of Researclr' Develop-

''Conclucted in nll ParticiPant clinics before randomisation'

, le S Uhckrrrll SLicN( Ltl. t',& ririllr. ,,r,, Ptnt,it Eni.h",li,t$u 11 SuPlti :' l7-i3

Tnc l(,9O rl'li'rlnlnJ iarc RCT: r 'tiiotialt itttri sl'lrril/ iir'si:lri 'l;

Irrt, tluctitltr' the WHO Secrctarilt

i'i..tt nntt thc lnstitutional Rcvic\\'

ct'trtres a ntl co;rsponding health

their babies'(b) Most u'omen attendinS prenatal ca-'

do not receive' nor rtill theY in

continue Performint those tests

randomisation status'

g 1998 Blackr\'ell S'ien ce Ltd' Po.llirlti' o'1d Ptri'rnlnl EPnicnri('los? 12' SuPPt 2' 27-58

48 l. Villtr et al.

rvould receive the 'best stan(lard treatment'as currently offered in these clinics'

The collectetl tlata .rre usetl no differentlv from their routine use by clinical

departnrcnts or cotrntry health authorities for analysis of risk or outcome

inforrnation. .\n ex.rnrple of this strategv has recentlv been published for a trial

of s.r""ning for colorectal cancer in a healthy population in Denmark'3r

Furthermore, because of the cluster allocation, pre-randomisation informed

consent oi individual rvomen is not logisticallv feasible to obtain. The inlomred

conserlt in the intervention clinics is obtained Post-randomisation as it is the cl'inic

that is the unit of randomisation-

There has been a recent inten'ention trial in rvhich a written informed consent

is only obtained from the person legallv responsible for the unit of randomisation'

In tliat particular cluster randomisation trial, \'hich was of vitamin Asupplementation to children, consent lvas obtained lrom all of the 29 'village

de..elopnrettt committee' chairmen, and on-ly verbal consent was obtained from

the caietakers of ParticiPating children.32 In another trial that evaluated a

combination oi ANC and trr'o models of deliven, but rvith t'omen as the unit of

randomisation,'r informed consent \Yas sought onlv irom the exPerimental grouP'

The consent .lcsign rte are usins in this trial is related to the ProPosed design

bv Zelena)Jrrri hns r:a!':ttl\. l.recn ciiticallv re., ie,.. ed (t/lc silgla rotrrlotttis.'d rcttscttf

Jrsi,.:,rl i,r icre:cr:cg irr ir,tlir itiuai ;an icrnri:atlcrn in cJlrcer treatmenl iriais'1

Although titcse autllors ,.'iiscouragetl it ior cancer theraPeutic trials, rvlrere

individrrals are the urlit oi ranelomisation, r{e believe that most of the limitations

identifiecl bv then either tlo not apply or .rre unavoidable because of the

characteristics of communitv trials, especialiy rthere different EeograPhical units

are randonrised. Tllis concePt seems to be shared by experts in the field

(D. Altnr:rn, person.rl connrurrication to J. VilLrr; Oxford, UK, 1996)'

Discussion

This large, complex, randomised community trial has been implemented with the

assistan;e of collaborating cetrtres in developing countries and a selected group of

international scientists acting as .rdvisers. [t is the unanimous opinion of all

concerncd that this ri:lorous evaluation has been long overdue' The nerv A'r\C

p.rckage repre;ent:i,r maior dep rture irom the Present recommetrded form of

iare, ,vtrich is strorglv rootc(l ilr obstctric culture. We rvill not be able to determine

\r,hethcr anv Fotertial bencirt irom tht' intervention is rclated to the fre(lnencv, the

ovcrall content or.r specific nctivitY of the neh'PackaBe. If the results of the study

clerronstrate thit thc llc!\' tntxlel is sit:rilar or evcn better thalr the tradition.rl

mo.lel, this rantlonrise'tl controllctl ,..lesign would be basic tr.r the accePtance of the

proposL{ rrel\' programnlc. Nonetheless, there are disappointing rePorts that

rtxults oI ran.lrtnrisccl trials shouing clear beneficial elfects have not been

incorporited into prncticL'cvctr loltg liter the form.rl publication of the trials.3i':5

, Itrrs lilr.f\\(ll LLr('t!(. l-lJ j'r,1j,i,lrn-,,,,J l\'rintrl Ei,ti'ttti,'ln:u l2,Srtrfl- l.:;-13

Thc INHO ntluntnl cnrc .liCT; ..rtionnlL, nntl slntly tlcsign 49

Onc area of concern in a trial such as ours tllnl can seriousl], aficct its rEults isq hether or rrot clinicians are comolf in6 u,ith th('nor raodcl of ANC. Obviously,if the tu'o 6;roup; reccive more or lq;s tlre s,rnr(' tvpe of care the trial will be ofIimited valuc. This could r6ult from tlrc intcrtcntiul trouF being providcd u'ithcare additional to that recommcnded in trre tri,ll pr(')t(rcol because stalf see thestandard ANC nrore fatourabir'. Converselr', the stafi o[ thr'control group mayadopt the heu-' model ('therapeutic c()rrtamil,ttio!]') and reLiucc the number ofvisits. One trial on thc routine use of cpisiotorrrt h.rs incieed encountered thisproblem.sT The follorr,ing meclranisms arc in place in tlre prcsent trial to reduceand evaluate inten'ention compliance: exterEi\-e initial training with interventionprotocols; continuous monitorint of protocol conpliance by visits to the clinics atleast every fortnight by the study field director or local principal investigator; andhequent site visits to the study sites by trial coordinators. Compliance rvith theintervention was evalu.lted using the'ANC checklist' (Fig. 2) implemented in theinberlention eroup. This checkiist has comDl!'ted in a randorn sanrFlc oi Yisits bY

the clinician rsponsible tbr the visit, an e\ternal observer and bv using dataobtained from the medical records. Agreement anrong these three 'checklists'\r'as calculated.

Furthermore, u'e have informed care providers in the control clinics in detailthat they are part of a randomised controlled trial, and rve have explained itsnature and have encouraged them to adhere to their standard -ANC protocols andreferral practices. This is |en'important for a comrnr:nitY trial expectins to trul\,c()mpare t\l-o dj.iferent forms of care rather tilan a rigorous .{\C protocol(inien ention) r's. an ANC r\'ithoui a protocol.i' Clinics in both arms of the trialalso receivcd scheduled visits for monitoring patient recruitment and thecompleteness of medical records.

A trial rrith characteristics such as ours provides many opportunities forintroducing bias. We have rnade considerable efforts during the preparation of theprotocol and the implementation to follou, recommended guidelines forrandomised controlled trials in reproductive health3e and for the futue reportingof such trials.o An unpredictable allocation sequence was centrally prepardusing a computerZeneratd random sequence and kept at the cenEal unit untilthe time of treahnent implementation, thus eliminating the possibility oI allocationdeciphering which is more likely to occur in unmasked trials. Cl.inic staff were notaware of group stahrs (allocation concealment) until the time of initiation of thetraining workshops and patient recruitment, thus preventing selection bias, as

after this time there is no longer the possibility of refusing to accept anyparticipant into the sh:dy-

Ho$,evel, there are, in theory, at least t$,o instances in lr,hich clinic staff cansubvert the randomisation process. Firstl)', they can discourage high-risk patientsrthom they may know are considering attending an intervention clinic, iI theyperceive that these women will have poorer outcomes if enrolled in the new,

! l9S Blackr{ell Science Ltd. Pocdtattic nnl Ptnna|r',l.l E idcniology 72, Suppl. 2, 27-56


simplified ANC model secondlv' individu'rl ed only in

i;'J;';';"*'"; clinics i. tire inten'enti ge of the

;;;;;.;;;;is#ent rherefore' clinicians c according

a" *i."iii"y b"",*ve will be the omen can rehtse to ParticiPate

i" in"'""* *.Oa "fcare

and re f,odcl in this or another clinic'

ln both instances the intervent be 'healthie/ than the control

group and Produce better Perinatal outcome- For the'first situation there "*,,1x,11"$:::;,:":ii::'fl::,HJ:::

,nd tit.,rtion, rve are going to analyse the

particiPates excludingthe shrdy.

Horvever, it is likely that rvomen rvho refuse to ParticiPatewill miss more data on

outcome variables than the total PoPulaiion and contribute less to the final

:nalvsis. Thev rvill, nesertlrcless' hai'e is detailed a baseline risk-tlescription as the

ffifi;;P,;ro,'ing fot totnpu'ison lvith those \^'omen s'ho agreed to be in

the ner* model meniation of the inten ention Ho\t'e'er'

ose protidine care tltrring iabottr anti

sPital d.lia clerks are masked to group

t bias. lt u'ould be possible"ls recentlv

masked, as this is a sub,ective Processias during analvsis is to

as r,;r'll as detailed and

the lar':est trial on this

. analvses rvill be conducted'

ibias and recoSnising that large trials are

ations,{3 it is possible that we will observe

n'ention al bias

is empiri ls Yield

larger estimates o[ treatment effect than double- 17V"\'aa

Randomised controlled trials evaluating drug and non-drug forms of medical

care are particularly important for tJeveloping countries' where resources allo-

cated to health are scarce and should be used for the imPlementation of cost-

efiecti,re forms of care This allorvs prioritis'rtion of lrealth-care services to optimise

the use of resources These trials als

against the transfer oI incffective

south. ConverselY, resttlts of ran

developing countries have inflrretrccrl P

iotn .i,,ingr, nrulticentred rantlomisctl controlletl trials rvould have lvoided the

rvidespreact use of perinatat technobgies of dubious "ffectiveness

!5 1''11

, logs ill.r(krscll Sdenc!' t-ld lh,',iirrlri' 'r,,rl PnDut f!&1'tlln'!tt l2' SrrFFl :':7-is

Tllc WHO nnt l!fll carc RCT: rntionnlc nnd strrr l dcslgrr 51

Tirerc is norr clear cvidcncr.'that h('alth L.'rioritl irltcrventiolls cnn b('evah'talt'dbt,developing countrt re;clrcltcrs ill the conte\t ol largc rancionriscd c()ntrolled

trials and rcstrlrs put'lished in learling iournals.:'{"-i" Dcspitc tlrese success stories,

conducting large-scalc, cutiins-ctl3e health serlicc rtscarch in developing

coL:ntrics is a lirrmitlable trsk. Donol agencics .lrc llot totltlll convincc.l t'i thc

lrcr..el ior thesc trials ftrr the r'\'alultioll of nrt'tiic.l] ilt tcr\'('n ti()l'ls. Partictrlarlv tht'

non-clrug forms oi cart' that s(--l.n 'lqgicalh' gotrd llris ilttitudt is Prescnt evell ifthe trials are relrtiveh' itrcxirensivc bl' industri.ilised coutltries' stand.rrcis ltr the

case of the current conrplex trial, several largc agcncies h.ld to be enroiled to

complete its total budget oi USS 2.5 million for 3 vears and includirrg more than

24 000 women in four countries. Furthermore, the cost of field 'a'ork, overheads

and researchers' salaries is often hard to explain to potential donors rthen thev use

the current logic of international research funding.5r lt is clear tirat the reu ard ofqroup menrbership, satisfling both iniellectuai curiositv atr..j comnlitnrent to

reDroductile Ireilith, nltlxrugit \-erv it)llx)rinnr to;rll rr; us. llis t(' he comnlemented

bv tangiblc rerrirrd s ior those in thc trenches oi primar\ data collection, ii rTell-

designed, relevant trialsi2 are to be successful.

Acknowledgements

Thrs is a collaboratitc eflort her\reen the I-\DP/U\-FP,\ /'\\'HO/'\\ orld Eank Special

Pro-qramme of Ileseerch, Drrteloinrcnt alld R$('.1r(h Tr.r: 1ilrc ilr liunr,li: IiciiloluciiL)11 nnd

tii,.. \\'!lC Divrsi(n o; Reorrro'.rcrir-c Hd,rith (Tu(hllical S'-ii't'(rrtl

.{,lditional support rias pror-ided tor the imPlemenlatron oi thc srudY bl-: i\lunicipal

Govemment, Citi of Rosario, Argentina; Ministry of Health, Cuba; National Institute of

Public Health, Mexico; The Poputation Council - Regional Of6ce for Latin America and the

Caribbean; Ministry of Health, Saudi Arabia; Swedish Agencv ior Research Cooperation-

sith Developing iountries 6[DA/5AREC); Ministrv of Public Health and Faorlt-v of

lvledicine, Khon Kaen Universiqv, Thailand; DePartment for International DeveloPment(DflD) of the United Kingdom; Mother Care - Iohn Snow lnc.; National Institute for Child

Health & Human Development (NICHD), National Institutes of Health (NIH), USA; the

l{orld BankFor the preparatory phase: University o[ western Ontario, DePartment of EPidemiology

& Biostatistics, Canadi; National lnstitute of Public Health, Noruay; United Nations

Development Programme; University of Uppsala, DePartment of Obstetrics & Gynaecol'

ogy, Sweden.' We would like to thank esPecially the r'romen and their babies who participated in this

trial and the many doctors, nurses and other staff of the clinics and hosPitals that made the

implementation of this Proiect Possible.Special thanks are given to Dr M. Koblinskv lor her personal interest and suPPort for

this project, to Dr O. Meirik for his permanent encouragement and suPPort, to Dr D Khan

Neeiorui. for het eiforts in editing the trial's Ne\{sletter and to \4rs Christine Crav for her

help in the preparation of the manuscriPt.

r 1996 Blaclscll Science Ltd Pnnlintri. n .l P{ nhl El'itt ,iolosy 72, SUFPI 1 27-53


Manbers of the WHO Antctlatll Care Trial R*eorch Grortp

Trial coordinating unit

Data coordinating unit

tisticianms Analyst, Statistiial Assistant (until July 1997)

en (from JulY 1997)

Steering committee

Health economics SrouP

Miranda Mugford, Health Economist' UK

iri" ii*,..,"nt"rtit Economics Researcher' uK

ffi fox-tusnbY, Health Economist' UK

QualitY of care grouP

Ana Lans.er, Reproductive Health Specialist' ltlerico

c"i,*o "ui*"n.iu, Public Ht"rlth Spccirlist' Nlexico

\lariana Ro-mero, Public Health EPidemiolotist' Argentrna

Georgina Roias, PsYchologist' Cuba

iirt? f".n"iti,, Public llealth Nurse' Thlilnnd

iUuneera AIOsmi, Nurse' Sau'li ArabLr

r.lg96BlackwdllSdcnrcLrd,nr.lri,lr(fln/Ari,rdlxlEi'i.lc,,xd'rtiYflSuPFl:':7-iS

Tllc ltIHO at ctntal care RCT:;nlilrttilk' n'lrl stl/dy dfsiq'I

Data and s.rfetl' monitoring committee

Countn data coordinators

Eciuardo Bcrgcl, Argentina

Liana CamPodonico, ArgentmiEIva Diaz, CubaMohammed Gandeh, Saudi tuabia

Yaortaret Sirguakool' Thailand

Field coorditrators

.ilicia del Pino, ArBentinaIuan Vdzqucz, Cuba

iuaUi "*e"a

Helal' Srudi Arabia

Kamron Chaisiri, Tlniland

-D,r"i;.-ir)riir;.1 : rtsiil ltiiLrrts nti'1 si!i(

Centro Rosarino de Estudios Perinatales (CREP)' Rosario' Argentina

Countrv coordinators

los6 M. Beliziin and Guillermo Carroli

Clinic suPen'isors

Susana Difulvio; Madela Ferronato; Sil\ia Galliano

Clinic directors / Physicians

( l99B Blnckr{'ell Sciencc Ltd. Pndlrn,'i( nnJ Pnnnt//l EPidc'niotog! 72' SuPPl 2' 27-53

5l

i

I

I

54 l. Villor et al'

lleco; G.U. Paz; R.A. Gorina; G' Lombarte;

; S. Carbognani; E.F. Guzmac D' Crmta;

ini; S. Parfait; A. Cartizo; l Alcacer;

D. \'lovano; A. Treidel; !l Alesandrelli;

; I. Blanco

Trial focal Persons in clinics

M. Baneiro; S. Vera; I C6rdoba; A Martinez; N Sosa; E Rol6n; S Pirani; B' Moreto;

ii. i"tri.^l, n. ;g-l,izam6,t; N Band; G' Deft€s; N' Arin€; F' Burgueio; S' clemente; A'

Piekella; .q.. Mdrquez; S Aguilar

Chiel nridu'ife or ntrrse

S. Abarno; T.R Paz; R.A. Raitrome; C- '\meriso; \l Carr6; V' LrlPez; !l E Galiano; L'

Ba,lin; O. SamPieri; C Llompart; S' Seco

Hospital Gineo-Obst6trico 'America Arias" Havana' Cuba

Counrrv coordinators

L'baltlo Farnr.rt .rrrd Juan V'izqr'rez

Field coordinator

tuan Carlos Vdzquez

Clinic suPen'isors

Isabel Rivero; Guillermina Curra; Juan Quintero

Clinic coordinators

Alfrctlo Abeleltla: Elise.r r-le Annas; Jorge L. Grrcia YY, M.". De los Angclx Golpe; Luz

it.riJ* v-iG, fsrrcl C.rLrrer'r; Rot'citt' l''icz; Zeiln Riter6n; Dolores Mustelicr; Lisette

f .'it.-"n,ti"; llarhl Aquin(); CLr ra Hern'in.lcz B'tngo

Trial foc.rl Pcn;ons irr clinics

Nrrrma Trianr; Piblo Ven('re(r; Crrcit'lo Espirosa;SiN'ia Niela; D'rimi Mrso; Olga

i;l;'ig.i;il i'1"; i.ra P('rez !lt'm':incz: \l'ridi l. Roso; lllirn'r '\* artr Diaz; Raisa Calvo;

Anrarilvs lllartin

r loos Rl.r.h..ll Sl:rctrt:r Lrd. lir,lli'ririr r 'l .1'/i nh E/'i''')"ir'/"."iv 12' SuPFI :' l7-i8

Tfic l4/H() inlc tttttl cflrc IiCf; ,tllionnh' n'rl slrr'h7 rltsiqrr 55

I-losPital tocal t*rsonsk'rsuDcls.rclo;Odr)ri(('Sttrk)Donurrso;Rnf cl\';rrrcsas;Carlrrsl('rtric;BirtraraTrilkr;D.rvi.lc Casrgrandi; L()urJ$ Marcr(r

Ir{inistry of Health, Riyadh and National Cuard King Khalid Hospital'

Jeddah, Saudi Arabia

Countrv coordinators

) agob Al'\4azrou and Hassan Ba'arletl

Local investiSation team

\1<.hanrltrctl BllLlo; T.rrtfik Khol'r; Talal lkranr; Kh'rli'l '\['[r'.rs

Trial focal Persons in clildcs

Zainat, Emam; Kh.rdija \'larzoc; Antulmma Salicr; Omvm'r Salcm; Kalthoour i\'[ostafa;

Sh;k; B"t;;; Firida Akbar; Kha*ria ElAhm'rd1'; Buthai'rra lvl.shlrour; Glrava EI'Ta1'eb;

Sobiria El-Sod.rnr'; Sohta Al-Sheikh

Ciilti. (iirectors,''pitvsicians

S.1iliaBan..lD:.Amir.rHem:r.i:\uzira\{aIri1,ar;RiiatEI-Bilmarr'i;HctlcllHnssa|l;\^.,cdad;il; i* ;;Ja; Farida Sar'rrtak; Mol'nmtned Haicz; Anal Kamal: Sa(a Hatata;

Favka Ashkan

Faculty of Medicine, Khon Kaen University Provincial Health Office

"iJ i'""ftft Promotion Centre, Region Khon Kaen' Thailand

Countq' coordinators

Pisake Lumbiganon; r.'arong Winiyakul; Kamron Chaisiri; Chompilas Chongsomdui

Clinic suPervisors

PongsriSarrduisrriya;PannapaMadst}un;JitlaPratniwauPanavadeesutthiwong

HosPital directors/PhYsicians

Uthni Uklrotsnnakarn; I'ra1'<xrn Kortit: Suri)a RattanaParilr'\'a; Sus'annachai Watta)'in8-

charoenchai; Xarrcrrit nfte#ciitrpht'ng: Kaicm Phathiritlri6ul; ChomPot Woratharakul;

Cha\\'alit r.\iharargkul; Tuem SaYbuathors; \Vichai UssavaPhark; IIPoP StnPaoPradrsr;

\ViPat Saliddeechaikool

a lqgs lJlrckNcll Sci{rntto Ltd Pn('drnlrii n'rJ P''j'/ah' El)i'h,,r;",,lotu 13' SuPPl l :7-58

56 l. Villar el al.

Trial focal Persons in clinics

.\nchana Puchoksiri; Jirnwan KitlerdPomPatoi; Arunvanhupan; Sukalya SrialnaraU t{imon R'rtanlchoilt; Such'rda

i Changthom; Khannistha :llaheor; Suntosapom Ciuipromm'r

Chief midwife or nttrse

Iarunvanee Pulvasunti; Jintana Suvannatat; PrakaytiP boPrasert; Naveeya Chuaksuchinda;

i*.'r^,rn Xr.n "neejan;

PomthiP Kon8nSaea Khanittha Chansafiuan; Supawadee Asada-

,rio.rgtot; p"t.tt"t* Silee; noon$hiP fongsap; Boonlerd Chanchurnni; Supunya Sonhai

Administrative and secretarial suPPort

loyce Sta:ks (uP to Se PtemL'er '1996)

Christine Crav (trom Octobcr l996)

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olled Trial' Pneditlric atll.d Pctinotal

ttn.lc.l Theory ' Sfroleties lor Q aliloli-oc rleseatch'

anoli G, Farnot U, Lumbiganon P' ef al The practice

]ri,J il iiri"t"" p"rts ofihe world particiPating in

c"î"riJ iiii. ra o*ic attd Pctittotol E1idmtiology

A randomized comParison of routhe vs selective iron

:';':,;;;;li";;)iutt cottcse olNutritior 1e1; 10: 3-10'

;l;fi#i ;ril;it'i"rs. rvJ Eigtand lournot olMedicine

Sondergaard O Randomized studY of

tood toi ['"cet 196;348:7467-7471' -

i"t"g"*"nt fo' l"tge cornmunity trials

C, HoPkins M' Kennedy J Simulated'

irial br ish lournql ol Obslettics otd

S, FaYers P' Machin D Randomised

nal oiCancl1995; 31A: 1934-7944'

i 1996 Black}rell Science Ltd I'ncrirnlrr' n"ri P 'tit,I]tdl

Epidcniol8 1z' Suppl 2' 27-55

58 l. Villnt et al.

Q[ the results of a trial on medical Practicc:o,rtroll.r'l Cli,ri.nl T rids 1996; 77l. 535'

actice. lrrcet 1993i 312; 8n-g/-g'man sPirit: The chatlenges of randomizedwnal 1995; 153: 753-786'6;34S:1172'

39 Vitlar l, controlled trials for the

evaluahon o ne 7996:2* 365-375'

40 Begg C, (l'l lmProvin8 the quality

of reportrng tement ,|,4rVtA 1996;276:

637-539.ai' S.i"f, KF. Subverting randomization in controllerl trials lA'vl'4 195; 274:1{5G1'158'

ii COar".fr" P. Blindini during data analvsis and writing of manuscriPts' Controllcd

Cliticnl Trials l 6:77:2' :t-293

ii i.n"r, ii. nnnao-;"a trials. human nahrre and reporrint liuidelines. l.Ancct 7996:

3{8:596_598+l- i.h.ll, KF, Chalnrers l, Ha)-es RJ, Altman DG Empirical evidence oi bias: dimensions

"i-"ii.J"r"gi."l quality assciated rvirh esrimarE of treatment eftect in controlled trials.

of clinical triaIaborntive Crthe coilaborirt

17 Arqentine Episiotonrv Tiiii C"iiacorat

control,.'d trial. Ii,rccl 199i; 3-12: 15:i-l51Sli"'\;iiir i, ri*", U, Barros F, i/ictora C, Lanser '\, Betizi'n J\I A ran'{onized trial oi

pty.f,"l*Of t"pp"rt during high risk preg rancies \ko Errglnrr'i /orirrrnl of Mrdicitrc 1992;

327:12(fi-1271ig Sî,f, A, Hatcher J, Nlackenzie I, Thompson S, Bal t' M'rcturria I' cl 'rl Randomize''i

i""-iiJ,.irr of heatmenr oi clrronic suppurative oritrs medll in Kenlran school clrildren.

Lrx,!?t 1996; 3'lS: 1123-1131

SO A"ti.;n;Vt, Villar l, Corrz.rlcz L Compodonico L' Bergel E Cllcium suPPlementatio!'r

io pr".=nt t vp"rt"*ive tlisorders oi pregnancv. -\-.:t, Errgl,rrrrl /orrra,rl ,r[,lIdicirre I991; 32-l:

1399-r {05-ii Vtacuettt F, StePhens R. Marketing clinical trials Larrcet 1996; 3'18: 111-l 12'

ii ii"aa" p.,'i, viitnt J, Carroli G Randomized clinical trials in Perin'ltoloty in Latin

America. Enrly Hrr.arott D&'cloPnlc l 1992;29: i2i-127 '

, l,r,)S lit.r(l\.(.ll c(rc'riL I...1. i'.r,,lir ,r.,r,trl I',,r,,r,r:,'l E-r.l,rii,i,\u rl, SuPPI l. l:-i5

Origirrul Arti<:lc"'

PATTERN AND FACTORS ASSOCIATED WITH GLYCEMICCONTROL OF SAUDI DIABETIC PATIENTS

Ahdul Rrhrrau r\l-Nuaiur. rrB. mcpc r.rcp. Solcmrn N,lirdad. lrssc. iusc. prrD:

Khalid Al-Rube ran. MIr FRcrci Yacob Al-Mazrou. rtu. phD. Frr('Cp:

Omcr Al-Attas. phD: Nasscr Al-Daghari. [,tsc

Background: Thc pattcrn and factors which can bc assciated with the glyccmic control of Saudi adult diabeticpaLients were exanrincd in this study.Patienls alld llelhods: Confirmcd diabetic patrenls lionl all regions of Sardi Arahia conslituted thc stud]popularion. Random blood glucosc <10 mnrol/L and >l0lnnrol/L Nas used to catcgonze patieuts into Sood andpoor SI),cemic control paticnts. respectivel).Results: Thcre werc 613 confirnrcd non-insulin dependent diabelic patients (NIDDM).50% \['ith Sood gl!'ccmicconlrol. Patienls with poor gllcemic conrrol *ere sig ificanrly older than patients with good glycemic control(51 5 rs. .17 \ears. Pd) 0001). The insulin-rreared diabetic populrtion amountcd to l3ft. comp.tled rvith J3%and -l-1% for oral agenl and dier. respeclivel) The rite ol insulin users among poor gllcenric conlrol diab€ticpopulation uas Istt. compared with 509r for oral xErenls. There \\as:r significant relalionship bet$'een

Sl\cefiic conuol and age. and lrealmenl nloduljties ol Dl\'l Subjects who had good glycemic control of DMrvere yoonger and tbllowing J dicl regimen. 'rhilc lhose \rho had poor glFenlic control werc older and on

insulin trcatment- Multivariale analysis cornprising.lI5 indiYiduals $as conducted to fin(l out thc faclors that

can potentially influence. or ma)' be associaled \\ilh. lhe control of DM.Conclusion: The association ol insulin therap) with po()r glycemic control is not a cluse+ffect relationship-

lnsulin therapy in our study populat,on is underutilizfd. given the high rate of poor glycemic conrrol and high

rare of relauve occurrence of complication amon€l th. Scudi diabetic population. There is a nced to addrcss thc

imponrnce ol maintaining go<xl glyccmic conlrol. and the relson for the low rate of insulin users. Closeperiodic monitoring of g)ycemrc control. urilizins laboralories and homc glucose moniloring deviccs. is

required. Eflbctive impletncntation of rhese D)easures. in addirron ro diabetes education. will have an irnpJct on

rhe turure outcome of the Srudi dirbetic populalion.Ann Soutli ltled l99E: l8(2 t.109'l 12.

Ke1 Words: Dirl)eres mellltus. gl)-cemic control.

Drrhetes urellitus (DM) is a diseasi rvith a high prevalence

rvorldrvide. and in rhe last feu, lears ils prevalence has

become nrore widespread in the third \r'orld or developingcounrries.r This is especially the case in the MiddleEastern courrtrics. uhich havc expericnccd an upward

surge in the prevllcrrce of DI\1 over rhc lasl l0 yelrs.- -fhis

is rhe likclv result of economical dcvelopment and changcs

rn lifestyle. especially in nutritionul habits.r The long-ternr

nicrorasculur and nracrovascular coutplications of.liltere:' are rcsponsrblc for sigrific nt morbidity and

rntrrtalirl' Diabctcs is thc leading catlsc of

I-r()n rhJ DcpJnnrtrr r)f N'lcdi.itrc (Drs Al'Nurnn \lrtd."l xnd Ai'R!ltr'rrnr. Kin! lih.rtid Linitcr\iry Horprtul. rhc DepJnn]e r ol ItrGrhernisr^(Dr\ .\l lrrrs rnd Al'Drlhuri) I'i'rS Sru{l U r\crvt\. !rrd Ihc D.Prrurl.rnlof Prc\.trr'\e Nlcdrcitr.lDr Al-iUr,'rou) Ilrnr\rn'ot Hc]lrh R,\rdh. Sruil,

\Jdr.ss rcp r rcqucsrs Jnd corrcsB)ndcn.. rr' DI ^l-Nuairrr:DcprnnEnr ol Medrcinc (MBC-.16). KrnS Fri$l st-..eirh\r llosprrrl I

Rc!('rrch C.nrrc. P.O. Br)\ -1151. Rivrdh I ll I l. SJrdr ArrbirAcccpred lbr publicrlirnr l5 No\cmbcr l19? Rc.ttvcd l0 APril l9{)7

blindness in adulrs. the nrost common cause of end-stagte

renal disease, accounting for 3Ola-40% of lhis population.is responsible for.10c,/c of all non-traumatic ampulations ofthe lower exlremities in adults. and is a major risk factorfor cardiac and cerebrovascular diseases."

Saudi Arabia has an estinatcd population of 13.2

million. 70% of rvhom are under 30 years of age.6 DM'rclated complications arc a fiequent (rcurrence among

Suudi diabctic patients. A review of 1000 consecutive

Saudi diabetic patrents in a gencral hospital showed an

incidence rate ol 329i for rctinoPathy. 26% lorlrl,pertension. il.l9. fol ischenrrc hcart disease. and 6.9'lilu ren l insufticiencl'.' Diaberes-related hospituladmissions arc liequenl and tcnd to occupy hospital beds

[or a longer time. as comprred to orl]er di:,cases.s

Eprdenriological studies hrve establishcd a relalionshiptrcrween hyperglyccmi nd the de!elopment ol lhe long-rcrnr complications of diabcres.'' rr The importancc of tightglycenric control with respect to dl]lay or In the prevcntion

,turtlr o! Suth tlt,li itt lil lN. ,\r 1. lt)t)lt I09

.\l--\l il'.'

of compir.ation. \\a\ nol cslirhlrshed unril lecentlr'. 'flrc

Diaherei Compii,-ation Contr<tl Tri:rl (DCCT) has provcrl

lhe imponan:. o: tight glyccmic cotttrol lirr thc prcvcntiulof conrrol complicalion antong insulin-tlcpel]dcnr Dl\'lpatienrs. - The conclusions ol Ihe I)CCT stu(l)' rcprobabil apolicable to the non'insulin dcpcndent dilhctcsrnellitu< r\lDD\Ir pitricnts as u'cll. Scvcral faclors uercrccognize6 a. plly'ing a tole in glyccmic control. iulons*'hiCh ar: duration ol- DIll. obesilr and hr pcncnsion.r-' r'

This oap3: is part ol a populution-b sctl

cpirlemio)ogical studl of chronic ntctabolic dtstrrdcr untonlSludi aciul: subje:ts liotn all rcgions ol Sludi Arabil. Itlrruses o: lhe pattern and factors afl'ectin! glvccntic

control oi non-insulin dependent diabetic patients.

Patients and Methods

The \ational Epidemiological Household Survey forChronic \'letabolic Diseases, which included DM, was

conducted among Saudi subjects over the age of l-5 years

in different regions of Saudi Arabia between 1990 and

1993. This \ras a nal.ional study wiih several objectives,

among them to measurc the Prevalence of Dlvl,

h ypercholesterolem ia and obcsity at national. regional and

rrrbal lerels Based on this, a sample srze of 37.000 u'as

calculated in order to sludy the pattern o[ glycemic controlof Saudi diabetic p3trents- A multistage slratified cluster

r3r':dom sampling technique was used for the selection ofthc studi population. The assigned population sample oIrhc srudS *as distribured between the different regions in

accordanc,: rlrth the regional population distribution as

provided h1 the National Population Council (NPC). There

u'as an initial adjustment for t1'pe of area (urban or rural),and populatron distribution in each region. as per the NPC.

Ciries and rillages ofeach region were ltsted and a random

sclcction of .r certain number of cities and villages

conducled in accordance u'ith the allocated share of each

region rn the national sample. The administrarive nraps oiIhc selccted ctttes and villales wcre revieq'ed lnd a

random selection of a number oi dlstricls in these cities

and villasc\ !\ as made

Primarl' care physicians \\'ho worl in these localitiesu,crc assenrbled and givert tlrientation lecturcs and

rvorkshops on difl-erent aspecls of the studi'. such as fillingout thc forms that include pcrsonal. dtmographic. social

irnd medical historl'. spccificalll dara rclaling to DM. such

il\ prcsent historl oi scll--reportins. Thc nlcdicll rccords ol

llrc\c plucntr '...crc rcYic\r,cd tt, conlirnr the diagnosii ol'

DIr4. Thc primari cirrc nh-vsiciilns uere itlso lrarucd ttn the

propcr mcthod rrl blrrxl hirrdlinS. ilnd nleusurcmcDt ol

hui:hl and rrcighl. lvhich is done al thc Prrnrarv Carc

Clinic (l'CCr. usurlly t\\,o or thrcc drvs alicr the prttcnl'sittrtrul "isltEvcn'third purirllel strect in anv of thcsc ltrulitics u'as

sclccred- und thctr cvcl\ third llouse u'lrs includccl in thissrud) All subjccti ovct thc agc ol l5 1'curs in tlre\c lrouses

rvcrc askcrl to plrticilirlc in lhis slu(l!- All thc intcr\ icu,e(l

sul'riccls rvcre rcqucstcd t() xttcrd llrc PCC lirr rvciglrt.Ircilht and bltxxl rncnsurcrncnts. Rantkrn blcxxl samplcswerc dnrwn in nn IIDTA tutrc. ccntrilirgcd. and lhc scrunrstored liozcn unlrl conrpletion ol lhc t rget s mplc. 1'hcsumplc's u'clc senl li()zcn to the Cenlrul Laktratory. KingSaud Univclsity. Riyildh. from all ()vcr thc countr\,.

Slmples u,ere stu-cd ll -10'C until assayctl. Upolrcuchirs thc targct nurrber of 100 subiccts pcr physiciiln incach district or city. or 50 subiccts pcr physiciun in caclrvillase-. rhc records wcrc scnt ro thc ccntrll oflicc inRiyadh lirr data entry. A computer program was dcsigncd.usin!: DBasc IV soliware package for data enlry. Alicr lhccomplctron of data entry. thcre was a final adjuslmcnt lorgender. age. region, urban or rural population distributron.in accordance with the NPC. using Statpack Gold soltwarcpackage, of a number of records fronr different regions and

age groups.Serum samplcs were used for glucose analysis on a

glucose analyzer (Beckman Paragon, Fullcrton. CA. USA)The method depends on the rate of oxygen consunrption b]the enzymc glucose oxidase. The instrument rvas calibratetlprior to glucosc determination. using qualitl controlsamples provided with thc solutions. The mcan valucsobuined on the controls were within thc values quoted h1

the manufacturer. The results were expressed by SI units(mmol/L). The intra- and inlerassay coefficicnts ol'variation were 1.'7 7o and, 2.69o, respectivclv.

A cutoff of random blo<d glucose (RBS) of l0 mmol/l-was uscd to categorize patients rnro goo<J (RBS<10

mmol/L) and poor glycemic control ([tBS>10 mmol/L).The WHO criteria for defilition of obesity (BMI>30) v.as

adopred.r6There are many variables which are belicved to

rnfluence the glycemic control of diabetic paticnr!i. Thesernclude age, gender. body mass indcx, region. plirce r;lresidencc (urbau or rural), duration oi DM. and treatmcnLmodalities of DM (dret, oral agents and insulin).

Vanous types ol-univariate analyses rvere emploled t(lassess the distribution o[ observations. to providc' an

understanding of thc relationships between variables. unC

lo selecl rhe variables surtable for inclusion in multivarrareanallses. Chi-squared test. Student's l-test, and Fisher'sexact lesl wcre performed to assess the significance of thcrelationships bet,a'cen variables. The 57c lcvel was set s

thc ler cl ol significancc.\{ultiple logistic analysis was uscd lo cxanriDe thc

assoc'iation bctrvccn the odds ol gll'cenric control and anrpretlictrrr.belielc'd to inlluence rt. ildjusling il lbr thc othcrpretlicrors incluclcd in rhc Sclrlcssemln nrodel. I98?.r;

Lolit tp) = 115,*, + b.\, + .... + bt\l

A back\v rd elirnination rv s crnploycd to sclcct lhc bcst,tiuing rrrtrlcl. Thc initi l nrodel inclucled all uain cflcctsThc cll'ccl with thc srn llcst Z-ralro u,as rsnrolcd urrd thcmtxl,.,l rclitted witll rhe renlaiDing cfl'ccts. Thc- unal!sis hld

It0 Aa at..,l \ t.tt ihln ,,.l;'/ /ri. M,:. /q'Jl

proceeded by deleting effects onc at a time until the b€sl-firtin8 model was reached. The adequacl'of fit of a givenmcdel was assessed by both the likelihood ralio resr andthe goodness o[ fit chi-squarc. ln multivariatc analysis.only the obscrvalion that has information on all variablcsincluded in the multivariate equation would bc accountedlbr in the analysis. Hcncc. out of6l3 individuals. only 415$crc includcd in the multivariate analysis.

Srarisrical analyscs were performed bv using StatpackC<,1d.'' and subroutine of the BMDP LR softwareconrputcr package.re

Results

There were 613 sampled subjecrs who were confirmedas diabetic patients. 507c of whom had good glycemiccontrol (Table l). The mean (and standard deviarion) ofage for subjects who had good control of DM were 47.0(1,1.8) years. compared wirh 51.5 (13.8) years for those\{ i'ro had poor conuol (T=3.88. DF=61 l. P=0.0001 ).

There u'as normal age distriburion, hence there was no:l:ri ibr transformation or categorizarion. and the variablerr< u'as used as a continuous one. The dlsrribution of aeerras as follows: median, mean (SD) 49.48.92 (12.8) ),ears.nrode 45 years. standard error 0.48 years. variance 163.E9\ears squares. skewness and kunosis 0.06 and 0.2.

There was no specific difference of means of BMIbettreen good and poor glycemic control patienrs, 28.7(5.4) and 28.3 (5-5), respectively. The prevalence ofol)esrty sas high among the parients of the two groups.39c,t and 349a for good and poor glycemic control patients.respectively. There was. however. no significantdifTerence.

There rvas no specific pattern for mcans of RBS forcach aee eroup of male and female patients rvith gccd andpoor glycemic control There was no significant differencebet\\een means of RBS of male and female parients of eachage group. whether among good or poor glycemic groups.

There was a signiftcant relationship between glycemiccontrol and age (Table l.). and treatmenr modaliries of DM(Table 2). Subjects who had good glycemic control of DMwere younger and following a diet regimen, while thosewho had poor glycemic control were older and on insulintrcatment.

IUultiYariate analysis comprising 415 individuals wasconducted to find out the factors that can potentiallvinfluence or are associated wirh the control of DM. and-15 SrZ rvcrc found to have good glycemic control. Thcinl:ial model ircluded the follou'ing factors; agc. gender.BMl. region. placc ol rcsidence. urban vs rural. durationof DN'I. and trcatment modalities of DM. Thc treatmentmodality of DM was the only lcctor which had srgnificanrassociation with glycemic control. Compared to patients onthe diet rcgimen, those on insulin and oral agent treatmentwerc at 1647r and 657. more nsk o[ having poor glycemrccontrol. respectively (Table 3).

CLYCEMIC CONTROL OII DIAIJETIC PATIENTS

T^Br-r I Co,'tftri$ ttlo,,ornt hn..u,t t hlsi.tt dah t,l snot anttpoo. sl,'.n <o ftnldiul'uit l,otit, s

G(xi currrol -lrnrup Poor conlft,l gn,up{mcan1sDr (nrcanlsD) P-vahc

AEc ()'c.rxi)BMIPre!alencc otobcsir]

-'t(N51.5 ( l:1.8) <o.(firlItt I (5 -5) 0.:r.r

71.* 0_ 19

:ltI).17 0 t t-l s,26.7 (5 J)

79.n

'Numbi-.r of recordr u ith availablc dfll

T^Btt- 2. Conpa.ison oI lifi}rc t luctot' \'hich c a[fcct sbc?Dti.

Clyc.mic conuol

Good control group Poor conlrol groupno ( ) no. (+) I. dF*

Rcgion

NonhSoudrCcnrralEast

Resid€nc)UrbanRural

Sex

MaleFcmal.

Treatmcntmodaliircs

lnsulinOral agcnrDicr

90 (52.3)21 110.',l)1-7 6l.O)55 (46.6)

93 (56.1t

lll (50.6)96 i50 0)

158 (49,1)l5t5l5)

23 (29.r)I l3 (42.8)112 (61.7)

6.2482 (47.?)35 (59,3)5l (53.0)63 (53 4)7l (43.31

0.0220E (49.a,

(50 0)

0.29r62 (50.6)I42 (48.5)

10.77

56 (70.9)r5l (57.2)% (35.8)

2 0.0(x)

018

*Chi-squared: "degree of frcedom

Discussion

This is an epidemiological population-based studyrvhich reflects the partern and factors which can potentially-affect glycemic control of Saudi diabetic patients at thenational leve!. Several obsen'ations can be made withrespect to the glycernic control: the high rate of parientswith poor glycenlic control. which amounts to 507c of thestudy diabetic population. is rather an alarnring rate whichprobably reflects the inadeguacy of services provided.including education. and lack of insight into theimportance of eood glvcemic control. whether from thephysicians. patients or both. lnsulin-rreared diabeticpirticnrs amounl ro l3?. comparcd rvith 43% ar,d 44cl tororal agents and diel. respectivell, ln spite of having a

significantly higlrcr ratc o[ insulin users among the poorglycenlic control group whcn compared rvith soodglycemic control diabetic patients (719i vs. 29clo). the rateof insulin users u'as lower than that of oral agents arnongpaticnls \.\,ith poor glycerric conrrol (187. vs. 507r). Poorglycemic diabcrrc patients were significantly oldcr thangood glycemic control diabetic patients.

Mukiple logistic regression analysis has shown thaitreatment modalities arc the only significanl factors whrchcan be associared with <legree of glycemic control. wherc

,\nnuk t'[ Soudi Lr.licttt. l'ol 13. No 2, l94t lll

't\r'lI. :l /r,!n,i(,1sr(rln'ri'xdl\ritl'rIl( ttrkt\\'lt h tt trtt

r\t.-Nt iAlM I I \i

D\l rrcurnrcnr I .l t--r.96 {r (x)5 hypcncnston.ln\ulin (l.t)7' l'(iil';1.", 0 soj r'(ri I oli-l'-ss

Acknowledgcnrents0-79 (l-57 l.ll 0 lr

(,'n\lx'rl

E-i =r',,rr fi acucc ; n rcn I tci=confidcncc;nrcn'rl' The authQrs acknowledge thc Ptolessional erccllencc ol

insurin the*,p) $xr, sisnirrcuntr\ nssocirted *ith p*rt ll-Xllll"*llill tlt}lll''"'i5'iLJ'n'li""HH':thc mirnuscrlPt

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"i";li"

Itn"i;;'*t'i'" ai^.. pitrenrs wirh h-lDD:u Di'rhcre\

CrrL I9' I I?: I

't 'lli 3i ij"i nr crirs{ncation or lhe tdronlc

or oe..'rrr ' lnt I,r. t'.i'iL*",i"', d'{!n conducr' rnrr}\ o\rord

'' ol s' lili: ror rhc lrl\l'ii, ",

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ll'It' Al'Nlurou \" cr al' llith prcY'rlcnct of

i Aahix' lnr 'l Obcs lt,l96r20 irl_52

l A,t,tlll! 4 Soutli tttdt.i'k" li]/ /s Nr) : /t)r/r

The WHO Antenatal Care Randomised Controlled Trial: rationale and study design

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