tarnow-mordi et al, ajog accepted manuscript 2014 1-s2.0-s000293781400283x-main.pdf
TRANSCRIPT
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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 $arters
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Daid *ield, M!!0, D"), *R"$"), *R"$%+d(, DM
De?artmet o )ealt# 0cieces, &iersit/ o 6eicester
22-28 $ricess Road West, 6+"+0T+R 6+1 T$, &ited 'idom
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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
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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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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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11
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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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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1
+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.
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