Tarnow-Mordi et al, AJOG accepted manuscript 2014 1-s2.0-S000293781400283X-main.pdf

8/10/2019 Tarnow-Mordi et al, AJOG accepted manuscript 2014 1-s2.0-S000293781400283X-main.pdf

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Accepted Manuscript

Timing of cord clamping in very preterm infants: more evidence is needed.

William O. Tarnow-Mordi, BA, MBChB, MRCP (UK), DCH, FRCPCH Lelia Duley,

MBChB, MD, FRCOG, MSc David Field, MBBS, DCH, FRCPCH, FRCP(Ed), DM Neil

Marlow, DM FmedSci Jonathan Morris, MB ChB, MM, FRANZCOG, DDU, CMFM,

PhD John Newnham, AM MBBS MD FRANZCOG DDU CMFM Nigel Paneth, Roger

F. Soll, MD David Sweet, MD FRCPCH

PII: S0002-9378(14)00283-X

DOI: 10.1016/j.ajog.2014.03.055

Reference: YMOB 9755

To appear in: American Journal of Obstetrics and Gynecology

Received Date: 19 March 2014

Accepted Date: 27 March 2014

Please cite this article as: Tarnow-Mordi WO, Duley L, Field D, Marlow N, Morris J, Newnham J, Paneth

N, Soll RF, Sweet D, Timing of cord clamping in very preterm infants: more evidence is needed.,

American Journal of Obstetrics and Gynecology(2014), doi: 10.1016/j.ajog.2014.03.055.

This is a PDF file of an uneditedmanuscript that has been accepted for publication. As a service to

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http://dx.doi.org/10.1016/j.ajog.2014.03.055http://dx.doi.org/10.1016/j.ajog.2014.03.055


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Clinical Opinion

Timing of cord clamping in very preterm infants: more evidence is needed.

Abstract: 199 words

Text: 2,998 words

William O. TARNOW-MORD, !A, M!"#!, MR"$ %&'(, D"), *R"$") (corresponding author)

WNN+R "etre or Newbor Researc#,

N)MR" "liical Trials "etre, &iersit/ o 0/de/

0/de/, New 0ot# Wales, Astralia

$#oe: 12 932 3444

williamtm5med.s/d.ed.a

6elia Dle/ M!"#!, MD, *R"O7, M0c

Notti#am "liical Trials &it, Notti#am )ealt# 0ciece $arters

" *loor, 0ot# !loc, ee;s Medical "etre

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Daid *ield, M!!0, D"), *R"$"), *R"$%+d(, DM

De?artmet o )ealt# 0cieces, &iersit/ o 6eicester

22-28 $ricess Road West, 6+"+0T+R 6+1 T$, &ited 'idom

?#oe: >> 11 2323>8

[email protected].


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Neil Marlow, DM *Med0ci

$roessor o Neoatal Medicie

&"6 +7A stitte or Wome;s )ealt#

)tle/ 0treet, 6odo W"1+ A&, &ited 'idom

$#oe: >> %4( 24 882>

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@

Roer *. 0oll, MD

De?artmet o $ediatrics, &iersit/ o Eermot "ollee o Medicie

!rlito, ET 43>41

842 3-229

Roer.soll5tmedet.or

Daid 0weetMD *R"$")

Ro/al Materit/ )os?ital, 7roseor Road, !elast, Nort#er relad, &'

$#oe 44>> 2894@@>1

Daid.sweet5belasttrst.#sci.et

Drs Tarow-Mordi, Dr Morris , Dr Marlow, Dr New#am ad Dr 0weet are co iestiators i

t#e N)MR" Astralia $lacetal Trassio 0td/, a mlticetre radomised trial o

deerred cord clam?i i iats less t#a @4 wees estatio.

Drs Dle/ ad *ield are co iestiators i t#e &' "ORD Trial o deerred cord clam?i i

er/ ?reterm iats.

T#e at#ors re?ort o ot#er ?otetial colict o iterest.

Re?rits will ot be aailable.

0orces o di: WOTM, &iersit/ o 0/de/F 6D, Notti#am "liical Trials &itF D,

&iersit/ o 6eicesterF NM, &iersit/ "ollee 6odoF N, &iersit/ o Wester AstraliaF

N$, Mic#ia 0tate &iersit/F R*0, &iersit/ o Eermot "ollee o MedicieF D0, Ro/al

Materit/ )os?ital,!elast.


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>

T#is "liical O?iio otlies w#/ more eidece o srial ad c#ild#ood ollow ? is

eeded i trials o deerred cord clam?i i er/ ?reterm iats

Ri title:

"ord clam?i i er/ ?reterm iats


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3

Abstract:

December 2412, t#e America "ollee o Obstetricias ad 7/ecoloists ?blis#ed a

"ommittee O?iio etitled GTimi o mbilical cord clam?i ater birt#H. t stated t#at

evidence exists to support delayed cord clamping in preterm infants, when feasible. The

single most important benefit for preterm infants is the possibility for a nearly 50 reduction

in !"#.$ )oweer, t#e "ommittee O?iio added t#at t#e ideal timi o mbilical cord

clam?i #as /et to be determied ad recommeded t#at lare cliical trials be codcted

i t#e most ?reterm iats. $blis#ed radomised cotrolled trials %R"Ts( iclde ewer

t#a 244 iats o less t#a @4 wees estatio, wit# assessmets o ero-deelo?metal

otcome i less t#a #al. T#is is a maIor a? i t#e eidece. Wit#ot reliable data rom

R"Ts o?timall/ icldi c#ild#ood ollow ?, we will ot ow w#et#er dela/ed cord

clam?i ma/ do more oerall #arm t#a ood. Ooi trials o dela/ed cord clam?i

?la to re?ort c#ild#ood otcomes i oer 2,444 additioal er/ ?reterm iats. "rret

recommedatios ma/ eed to c#ae w#e t#ese reslts become aailable. 7reater

iteratioal collaboratio cold accelerate resoltio o w#et#er t#is ?romisi

iteretio will im?roe disabilit/-ree srial i abot a millio iats bor er/ ?reterm

loball/ eac# /ear.

Key words: Dela/ed clam?i, $lacetal Trassio, &mbilical cord, Eer/ ?reterm iats,


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1. Introduction:

December 2412 t#e America "ollee o Obstetricias ad 7/ecoloists ?blis#ed a

"ommittee o?iio etitled GTimi o mbilical cord clam?i ater birt#H. t stated t#at

Several systematic reviews have suggested that clamping the umbilical cord ... should be

delayed for at least 30 60 seconds ... because of the associated neonatal benefits,

including increased blood volume, reduced need for blood transfusion, (and decreased

incidence of intracranial hemorrhage in preterm infants ... !vidence e"ists to support

delayed cord clamping in preterm infants, when feasible. #he single most important

benefit for preterm infants is the possibility for a nearly $0% reduction in &'.) J1K

"osistet wit# t#is o?iio, dela/ed cord clam?i %D""( is icreasil/ bei adocated

or t#e rotie care o ?reterm iats.J2, @K t #as bee claimed t#at ailre to im?lemet

t#is ?rocedre ma/ re?reset a ecessar/ #arm or lerable eoates. J>K

li#t o t#e eidece reiewed b/ t#e A"O7 "ommittee, smmarised i two s/stematic

reiews, J3, K ca cliicias ad R!s cotie to s??ort trials o D"" i er/ ?reterm

iatsL T#e aswer is clearl/ /esC. T#e A"O7 "ommittee O?iio added t#e disclaimer t#at

it should not be construed as dictating an e"clusive course of treatment or procedure to

be followed.) *rt#er, t#e eects o seere itracraial #emorr#ae ad ero-

deelo?metal otcome i er/ ?reterm iats remai clear. T#e "ommittee O?iio

cotied the ideal timing for umbilical cord clamping has yet to be established) and

large clinical trials are needed to investigate the effect of delayed cord clamping on

infants delivered at less than *+ wees gestation.)J1K


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2 c#ildre at 18 to 2> mot#s,J2@, 23K bt sed dieret

deelo?metal scales ad were icoclsie. 0#ort term beeits i all te trials J14K

iclded im?roed blood ?ressre ad #aemolobi cocetratio, less blood trassio

ad late-oset se?sis, ad a tred %? Q 4.48( to redced E) o all rades. T#e at#ors

coclded t#at, or +6!W iats o less t#a @4 wees estatio, paucity of data on

neurodevelopmental outcomes and safety concerns tempers enthusiasm for these

interventions. ppropriately designed 45#s to assess shortterm and longterm outcomes

are needed....)

%. &eed for ade'uate power and follow up

Adeate sam?le sie ad ?ower are critical i ?eriatal trials.J2, 2


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ado?ted world-wide. *ollow ? stdies did ot s#ow im?roed srial, ad some s#owed

a icrease i cerebral ?als/.J@1, @2K

3.* ntenatal antibiotics and antenatal #4

T#e ORA"6+ trials o atibiotics i wome at ris o ?reterm birt#, sested t#e #/?ot#esis,

i 2,22 siletos bor to wome wit# ?reterm r?tre o membraes, t#at atibiotics

redced maIor cerebral abormalit/ i iats beore disc#are.J@@K Des?ite t#is, t#ere was

o im?roemet i ctioal im?airmet at see /ears old.J@>K *rt#ermore, two

atibiotics ie to wome i ?re-term labor wit# itact membraes icreased t#e ris o

cerebral ?als/ b/ betwee 4 ad 94P.J@3K

+arl/ trials o ateatal t#/rotro?#i releasi #ormoe %TR)( i wome at ris o ?reterm

birt# sested t#at TR) redced eoatal c#roic l disease J@K ad #os?ital mortalit/.

J@4, >1K


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12

Restrictio o ox/e t#era?/ to cocetratios >4P, ra?idl/ became rotie ?ractice,

reardless o t#e ?resece o #/?oxia. 0riors i t#is R"T were eer ollowed ?. J>4K

6ater, wides?read excesses i t#e icidece o s?astic di?leia ad deat# were attribted to

#/?oxic res?irator/ ailre de to arbitrar/, ia??ro?riate ox/e restrictio. t was

estimated t#at every sighted infant gained may have cost some -6 deaths.)J>2K

T#ese exam?les sest t#at, des?ite ?romisi s#ort-term eidece o beeit, wit#ot

stdies ?owered to detect c#aes i mortalit/ ad wit#ot lo term data we caot

exclde t#e ?ossibilit/ t#at dela/ed cord clam?i ma/ do more #arm t#a ood.

%.( &s &' a reliable surrogate for childhood impairment7

t is clear w#et#er isolated, low rade %7rades 1 ad 2( E) wit#ot w#ite matter damae

or etriclar dilatatio icreases t#e ris o aderse deelo?metal otcome i c#ild#ood.

J>@->9K O t#ree recet co#ort stdies, oe coclded t#at, exce?t w#e accom?aied or

ollowed b/ a w#ite matter lesio, isolated E) is associated wit# o more t#a a mild

icrease %ad ?ossibl/ o icrease( i aderse deelo?metal otcome. J>8K

Aot#er od

t#at, at 18 to 22 mot#s, ero-deelo?metal otcomes o er/ low estatioal- ae

iats wit# isolated low-rade E) did ot dier siiicatl/ rom t#ose wit#ot E). J>9K A

t#ird coclded t#at iats wit# isolated 7rade 1 ad 2 E) #ad a 34P icrease i

moderate-seere erosesor/ im?airmet i earl/ c#ild#ood. J34K

!/ cotrast, lesios ote reerred to as seere %7rades @ or >( E), bt w#ic# are more

?ro?erl/ described as eidece o w#ite matter damae,J31-3>K are clearl/ associated wit#


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1@

reater ris o ero-deelo?metal im?airmet ad ?s/c#iatric disorder. J>@->8K W#ite

matter damae is t#s a better srroate o im?ortat brai iIr/ t#a E) o all rades,

bt ealatio o otcomes i c#ild#ood ?roides still more reliable eidece. t#e T$$

trial, idomet#aci ?ro?#/laxis redced t#e odds o seere %7rade @ or >( E) i extremel/

low birt#wei#t iats b/ @4P com?ared wit# ?lacebo, bt t#ere was o dierece i lo

term otcome. J33K

(. Criteria for new standards of care

"liical trials wit# srroate ed?oits do ot ?roide a a??ro?riate basis or lo-term

cliical ?olic/, i a/ s?ecialt/. J3K We sest t#at a ew stadard o ?eriatal care will

reire %a( reliable, releat eidece o et cliical beeit, iormed b/ %b( data o srial

ad c#ild#ood otcome s#owi o a??reciable eidece o #arm ad %c( t#e ?ers?ecties

o ?arets, ?roessioals ad t#e commit/.

8.- 9hat is net clinical benefit7

*or ma/, o ot#er otcome i er/ ?reterm iats is as im?ortat as srial, J3


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W#e t#ere is o a??reciable eidece o #arm i terms o srial or c#ild#ood disabilit/,

reliable eidece o im?roemets i s#ort-term morbidit/ wold idicate et cliical

beeit. T#e mbers o ?atiets eeded to ier o a??reciable #armC is a matter o

Idemet %see sectio 3.@ below(. )oweer, t#e mber o er/ ?reterm iats i w#om

ero-deelo?met i c#ild#ood is crretl/ re?orted %9( J14K is clearl/ iadeate to

mae sc# a Idemet.

8.* 9hat constitutes reliable, relevant evidence7

Mc# de?eds o t#e alit/ o t#e eidece, t#e sie ad setti o t#e ?o?latio i

w#ic# t#e eidece #as bee obtaied ad t#e im?act o t#e iteretio. A riorosl/

codcted radomised cotrolled trial s#owi a treatmet dierece i @44 ?atiets, wit#

a ? ale o 4.43, is less coici t#a a trial o eal rior s#owi a similar treatmet

dierece wit# t#e same ? ale i @,444. 0imilarl/, a iteretio i w#ic# t#e mber

eeded to treat %NNT( to ?reet oe extra deat# is 14 is liel/ to #ae reater im?act t#a

a iteretio or w#ic# NNT Q 144. T#e im?act o D"" i er/ ?reterm iats o srial

or c#ild#ood disabilit/ is crretl/ ow.

). Implications for clinical practice* guidelines and researc#

$.- &mplications for clinical practice

W#at o?tios are o?e to ?ractitioers ad ?arets o er/ ?reterm iatsL 0ome ma/ o?t

or dela/ed cord clam?i %or mili( becase o t#e s#ort-term eidece o beeit.

)oweer, mili disr?ts t#e eto-?lacetal circlatio ad does ot allow time to acilitate


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a smoot# trasitio o t#e cardio-?lmoar/ ad cerebral circlatio or to aoid ?otetiall/

ecessar/ resscitatio S so it ma/ ris dieret aderse eects t#a deerred clam?i.

Ot#ers ma/ o?t or earl/ clam?i becase o t#e ?otetial #arms o dela/ed resscitatio

ad certait/ abot lo term otcome. Ot#ers, i t#e/ #ae t#e o??ortit/, ma/ wis#

to cotribte to R"Ts to resole t#e certaities, as recommeded b/ arios

at#orities.J3, 14K +ac# o t#ese o?tios is reasoable.

$.* &mplications for clinical guidelines

W#e eidece alls s#ort o reliabl/ s#owi et cliical beeit it is im?ortat t#at cliical

idelies do ot iadertetl/ i#ibit tre researc#. J4K Two wa/s to redce t#is ris are

to esre t#at ?blis#ed idelies em?#asise, i t#e text ad t#e abstract, %i( t#e eed or

rt#er researc# ad %ii( t#at adice ma/ c#ae w#e rt#er eidece is aailable.

$.3 &mplications for research and international collaboration

t ma/ reire t#osads, rat#er t#a #dreds, o ?atiets to s#ow et cliical beeit %or

#arm( reliabl/. J2, 2,844 sbIects. To s#ow t#is wit# a two tailed ? ale 4.41, ad similar

?ower, reires abot 8,@44. J2


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+ac# o t#ese aal/ses ma/ #ae reater ?ower t#a a aal/sis o t#e two o??osi

otcomes combied, becase oise i oe will ot obscre sial i t#e ot#er.

Also, as otcomes im?roe, t#e mbers o ?atiets eeded to demostrate additioal

im?roemet will icrease, i all s?ecialties. #i# icome cotries, ?reterm iats o

less t#a @4 wees estatio ma/ mber abot ieold ewer t#a ?atiets wit# serios

trama J1-@K ad teold ewer t#a ?atiets wit# m/ocardial iarctio. J>, 3K As wit#

trials i t#ose s?ecialties, ?eriatal trials will reire icreasi iteratioal collaboratio

ad a cltre o cotios alit/ im?roemet i w#ic# s??orti trials ad acisitio

o ot#er rioros eidece is a iteral ?art o rotie care. JK

$.8 ustralian /lacental #ransfusion Study and :; 54< #rial

T#e Astralia $lacetal Trassio 0td/ %A$T0( is a iteratioal, mlticetre ?ramatic

R"T to test t#e #/?ot#esis t#at, i 144 iats o less t#a @4 wees estatio, com?ared

wit# immediate clam?i o t#e mbilical cord wit#i 14 secods o delier/, deerred cord

clam?i or 4 secods or more will redce mortalit/ or maIor morbidit/ at @ wees

corrected estatio ad mortalit/ or maIor disabilit/ at @ /ears. J8K As o Marc#, 241>, t#e

std/ #as recrited oer 34 iats, mai it t#e larest o its id to date.

T#e &' "ORD Trial is ?laed as a radomised com?ariso i er/ ?reterm iats o earl/

clam?i o t#e cord beore 24 secods erss deerred clam?i or at least two

mites.J22K )oweer i t#ose babies allocated to dela/ed cord clam?i resscitatio or

stabilisatio will commece at oce at t#e mot#ersC bed side ad t#is s#old eerall/


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1(: ?. 889-944.

.

McAdams, R.M., Time to implement delayed cord clamping.Obstet 7/ecol, 241>. 1%%@(: ?.

3>9-32.

5. Rabe, )., et al., /ffect of timing of umbilical cord clamping and other strategies to influence

placental transfusion at preterm birth on maternal and infant outcomes."oc#rae Database

0/st Re, 2412. -: ?. "D44@2>8.

. Rabe, )., 7. Re/olds, ad . Dia-Rossello,1 systematic review and metaanalysis of a brief

delay in clamping the umbilical cord of preterm infants.Neoatolo/, 2448. %%2(: ?. 1@8->>.

2. 0weet, D.7., et al., /uropean consensus guidelines on the management of neonatal

respiratory distress syndrome in preterm infants0%* update.Neoatolo/, 241@. 1!%%>(:

?. @3@-8.

3. Tarow-Mordi, W.,1ustralian -lacental Transfusion 4tudy.

https+www.an6ctr.org.auTrial7egistrationTrial7eview.aspx8id9**525., 2448, &iersit/

o 0/de/: 0/de/.


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:. 7/att, 7.)., et al., ;71


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%.Abalos, +. /ffect of timing of umbilical cord clamping of term infants on maternal and

neonatal outcomes+ 7#> commentary. The D#' 7eproductive #ealth >ibrary website. Ecited

0%


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*0.0teso, !.., et al., 'xygen saturation and outcomes in preterm infants.N +l Med, 241@.

%+-%22(: ?. 249>-14>.

*%.

-ostnatal corticosteroids to treat or prevent chronic lung disease in preterm infants.

$ediatrics, 2442. 1!%2(: ?. @@4-8.

*.)allida/, ).6., R.A. +#rera, ad 6.W. Do/le, /arly (I 3 days) postnatal corticosteroids for

preventing chronic lung disease in preterm infants."oc#rae Database 0/st Re, 2414%1(: ?.

"D4411>.

**.'e/o, 0.6., D.. Ta/lor, ad W. Tarow-Mordi, @roadspectrum antibiotics for preterm,

prelabour rupture of fetal membranes+ the '71&>/ ! randomised trial. '71&>/ &ollaborative

;roup.6acet, 2441. %)/%921(: ?. 9/ ! trial.6acet, 2448.

%/%9>(: ?. 1@14-8.

*5.'e/o, 0., et al., &hildhood outcomes after prescription of antibiotics to pregnant women

with spontaneous preterm labour+ 2year followup of the '71&>/ !! trial.6acet, 2448.

%/%9>(: ?. 1@19-2


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*:.!riet, .M., et al., eurodevelopmental outcome of children treated with antenatal

thyrotropinreleasing hormone.$ediatrics, 2442. 11!%2 $t 1(: ?. 2>9-3@.

0.

0ilerma, W.A.,1 &autionary Tale 1bout 4upplemental 'xygen+ The 1lbatross of eonatal

Jedicine.$ediatrics, 244>. 11%: ?. @9>-9.

%.'ise/, E.+. ad *.M. )em?#ill, /tiology of retrolental fibroplasia and preliminary report of

cooperative study of retrolental fibroplasia.Tras Am Acad O?#t#almol Otolar/ol, 1933.

)%1(: ?. 13-2>F discssio, >4-1.

.!olto, D.$. ad '.W. "ross, Burther observations on cost of preventing retrolental

fibroplasia.6acet, 19. 1%>3-8.

*.

$a?ile, 6.A., 7. Msic-!ro, ad A. 0c#aeer, 7elationship of cerebral intraventricular

hemorrhage and early childhood neurologic handicaps. $ediatr, 198@. 1!%%2(: ?. 2


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2@

:.$a/e, A.)., et al., eurodevelopmental outcomes of extremely lowgestationalage

neonates with lowgrade periventricularintraventricular hemorrhage.AMA $ediatr, 241@.

1+/%3(: ?. >31-9.

50.

!olisett/, 0., et al., !ntraventricular hemorrhage and neurodevelopmental outcomes in

extreme preterm infants.$ediatrics, 241>. 1%%%1(: ?. 33-2.

5%.

6eito, A. ad N. $aet#, Dhite matter damage in preterm newbornsan epidemiologic

perspective.+arl/ )m De, 1994. (%1(: ?. 1-22.

5.$aet#, N., Rdelli, R., 'aam, +., Mote, W. @rain


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%.Roberts, ., et al., /ffect of intravenous corticosteroids on death within % days in %0003

adults with clinically significant head in?ury (J7& &714# trial)+ randomised placebo

controlled trial.6acet, 244>. %+(%9>>2(: ?. 1@21-8.

.

Roberts, ., et al., The importance of early treatment with tranexamic acid in bleeding trauma

patients+ an exploratory analysis of the &714# randomised controlled trial.6acet, 2411.

%//%9

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