Worse outcomes of early targeted ibuprofen treatment compared to expectant management of patent ductus arteriosus in extremely premature infants

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© 2021 Journal of Clinical Neonatology | Published by Wolters Kluwer - Medknow
Aims: The aim of the study is to evaluate two dierent patent ductus
arteriosus (PDA) management approaches and their impact on neonatal
mortality and/or bronchopulmonary dysplasia (BPD) and 2‑year outcomes.
Subjects and Methods: For two consecutive periods, data on early mortality
and morbidity were obtained retrospectively, while long‑term morbidity data in
children born before 28 weeks of gestation were collected prospectively. In the
early targeted treatment period (TTP), ibuprofen was early indicated on patients
withhighclinicalriskandPDAdiameterofmorethantwomillimetersintherst
3days.Intheexpectanttreatmentperiod (EXP),theexpectantapproachwasused.
Results: A totalof201eligibleinfantswerescreened.Of these,99weremanaged
intheTTPand102intheEXP.From99infantsintheTTP,24patientsweretreated
early and 17 later. From 102 infants in the EXP, 17 infants with symptomatic
PDA were treated. Severe BPD and/or death were more frequent in theTTP as
comparedto EXP(28 and 16 infants, respectively; P = 0.007; odds ratio = 2.12;
condence interval = 1.06–4.23; c = 0.216). Moreover, infants who underwent
the expectant approach did not need further cardiological interventions after
discharge. Conclusions: Early targeted treatment of large PDAs was associated
withan increasedrisk ofsevere BPDand/or death. Wemust payattention tothe
sideeects ofearlyibuprofen treatmentbecause these mayoutweigh thebenets
of ductus closure, especially in the vulnerable population of extremely preterm
infants.
 Bronchopulmonary dysplasia, echocardiography, extremely preterm
infant, ibuprofen, patent ductus arteriosus
Worse Outcomes of Early Targeted Ibuprofen Treatment Compared
to Expectant Management of Patent Ductus Arteriosus in Extremely
Premature Infants
Jana Termerová, Aleš Antonín Kuběna1, Ráchel Paslerová, Karel Liška
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Website:
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DOI:
10.4103/jcn.jcn_73_21
Address for correspondence: Dr. Jana Termerová,
Department of Obstretics and Gynecology, Division of
Neonatology, First Faculty of Medicine, Charles University and
General Faculty Hospital in Prague, 18 Apolinarska Street, 128 00
Prague 2, Czech Republic.
E‑mail: jana.termerova@vfn.cz
assignment not independent of baseline prognostic
factors.[5]Theriskappearstodependnotonthepresence
of a PDA but on the magnitude of the PDA shunt and
PDA exposure duration.[6] Moreover, the availability of
precision ultrasound for infants <28 weeks of gestation
wasinsucientin olderstudies.[7]
Original Article

Prolonged high pulmonary blood ow through an
immature pulmonary vascular bed may increase
the risk of chronic lung damage. However, there is
no clear evidence that prophylactic or early closure of
patent ductus arteriosus (PDA) reduces the incidence
of bronchopulmonary dysplasia (BPD).[1‑3] Reasons
for possible bias in past studies may include early
backup treatment and a generally high percentage of
treatment in control groups, inconsistent denition of
hemodynamically signicant PDA (hsPDA),[4] high rate
of spontaneous closure in the placebo arm, low rate of
treatment‑inducedclosureintreatedarms, and treatment
Divisionof Neonatology,
Departmentof Obstetrics
andGynecology,Charles
University,FirstFaculty
ofMedicine andGeneral
UniversityHospital in
Prague,1Institute ofMedical
Biochemistryand Laboratory
Diagnostics,Charles
University,FirstFaculty
ofMedicine andGeneral
UniversityHospital in
Prague,Czech Republic

How to cite this article: Termerová J, Kuběna AA, Paslerová R, Liška K.
Worse outcomes of early targeted ibuprofen treatment compared to
expectant management of patent ductus arteriosus in extremely premature
infants. J Clin Neonatol 2021;10:209-15.
Submitted:07‑Jun‑2021
Accepted:29‑Jun‑2021
Published:24‑Sep‑2021
This is an open access arcle distributed under the terms of the Creave Commons
Aribuon‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak,
and build upon the work non‑commercially, as long as the author is credited and the new
creaons are licensed under the idencal terms.
For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com
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Termerová, et al.: Early targeted treatment of patent ductus arteriosus
210 Journal of Clinical Neonatology ¦ Volume 10 ¦ Issue 4 ¦ October-December 2021
Early cardiac ultrasound‑targeted treatment is only
indicated for patients with large shunts; thus, the number
of infants who receive unnecessary treatment is reduced.
This approach was used in the ductal echocardiographic
targetingandearlyclosuretrial,whichshoweda reduction
in pulmonary hemorrhage. However, the targeted
indomethacin treatment had no eect on the primary
outcomeof death orabnormal cranial ultrasoundand also
had no eect on the incidence of BPD.[8] Furthermore,
prophylactic indomethacin was not associated with either
reduced or increased risk of BPD or death.[9] To our
knowledge,onlyonedouble‑blind,multicenter,randomized
controlled trial of early echocardiography‑targeted
ibuprofentreatment hasbeen publishedto date.Despite a
proven reduction in the incidence of PDA, there was no
reported dierence in survival without cerebral palsy and
respiratory outcome.[10] Owing to the good results of the
conservative treatment,[11,12] we changed our approach to
PDAfromearlyultrasound‑targetedtreatment toexpectant
management.
Objectives
We aim to evaluate two dierent PDA management
approaches: the early ultrasound‑targeted and the
expectantandtheirimpactonneonatalmortalityorBPD
and2‑yearoutcomes. Wehypothesizedthatthere would
benodierence in theincidenceof BPD betweenthese
two time periods. To increase sensitivity, we used three
levelsofBPD toassesstheimpactonqualityoflife.

Patients
Ourstudywasasingle‑centerstudyconductedinatertiary
levelneonatalintensivecare unit.Allviable infants born
between 23 0/7 and 27 6/7 weeks of gestational age
were included in the study.We retrospectively analyzed
earlymortalityandmorbiditiesintwotime‑seriescohorts
of two groups comprising neonates born between July
2011 and June 2015. In addition, follow‑up data up to
2 years of corrected age were prospectively collected.
Institutional ethical approval and parenteral consents
wereobtainedfor publicationofdata.
Echocardiography examination and patent ductus
arteriosus management
All echocardiography studies were performed using
the GE Vivid e Ultrasound Machine (GE Healthcare,
Chicago, USA) with a 10 MHz transducer. Complete
diagnostic echocardiography was performed to exclude
patientswithcongenital heartdisease.
In both periods, all infants were screened during the
rst 3 days of their lives for hsPDA. Our denition of
hsPDA was based on the diameter of PDA of at least
2 mm and pulsatile ow pattern measured in the high
left parasternal view, the site of maximal constriction
withcolorimages.
In the early targeted treatment period (TTP:
7/2011‑6/2013,n= 99),infants witha left‑to‑rightow
fromhsPDAandhigh‑riskfactors(noantenatalsteroids,
dicult adaptation after delivery, or high ventilation
supportinthe1stdaysoflife)weretreatedduringtherst
3daysoflifewithibuprofenlysine(15minintravenous
infusion: 10 mg/kg, followed by 5 mg/kg after 24 and
48 h [Arfen injection, 400 mg/3 ml, Lisapharma, Erba,
Italy]). During the expectant treatment period (EXP:
7/2013‑6/2015, n = 102), infants with hsPDA were
observed and not treated in the rst 3 days of life. In
both periods, the neonates were monitored for the
development of severe clinical signs of hsPDA, which
include pulmonary hemorrhage, severe respiratory
failure requiring mechanical ventilation, cardiac
decompensation, and renal insuciency. Patients with
these clinical signs and echocardiography‑conrmed
hsPDA were treated later, using an ibuprofen dosing
schemereectedon thepostnatalage.[13]
Surgical ligation was performed in both periods only
after the failure of pharmacological treatment in infants
with high mechanical ventilation parameters (mean
airway pressure >15 cm H2O, requiring high‑frequency
oscillatory ventilation) that could not be disconnected.
We are not aware of any fundamental changes in our
therapeutic approach to intensive care management of
extremelypremature infantsbetween thesetwo periods,
includingtheuse ofpostnatalsteroids.
Study endpoints
The primary outcome of this study was the composite
outcome of BPD and/or death before 36‑week
postmenstrual age (PMA). Since we used a high‑ow
nasal cannula (HFNC), we slightly modied the
consensus denition (2002).[14,15] Mild BPD was dened
astheneed forsupplementaloxygen(O2)ortheneedfor
pressure support (including HFNC) for at least 28 days
old.Moderate BPDwas thetreatment needof <30%O2
or HFNC with low oxygen therapy at 36‑week PMA,
which we changed to low‑ow nasal cannula (LFNC)
in children with HFNC and determined the need for
O2 <30%. Furthermore, severe BPD requires O2 ≥30%
and/orpositive pressure supportat36‑week PMA(every
infant with nCPAP at 36‑week PMA; HFNC was
changedto LFNCanddeterminedtheneedofO2≥30%).
OurtargetedSpO2was93%–96%at36‑weekPMA.
Secondary outcomes included duration of invasive
and noninvasive ventilation support and pulmonary
hemorrhage (those with respiratory deterioration
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Termerová, et al.: Early targeted treatment of patent ductus arteriosus
211
Journal of Clinical Neonatology ¦ Volume 10 ¦ Issue 4 ¦ October-December 2021
and massive bleeding). Additional outcomes are as
follows: composite outcomes of death before 36‑week
PMA and prevalence of necrotizing enterocolitis, Bell
Stages 2 and 3,[16] spontaneous intestinal perforation,
intraventricular hemorrhage Grades 3 and 4, modied
Papile nomenclature,[17] and retinopathy of prematurity
requiring treatment. Moreover, we recorded the age at
PDAclosureandthenumberof necessaryligations.
In the follow‑up examination at 2 years of age, major
neurodevelopmental disability was determined provided
at least one of the following conditions was present:
cerebralpalsyaectingindependentlocomotion(walking
with support or inability to walk), cognitive delay (a
BayleyIIMentalDevelopmentIndexscoreof<70,more
than 2 standard deviation below the mean of 100),[18]
visual impairment (light perception only or blindness),
and hearing impairment (uncorrectable deafness or use
ofhearingaids).Wealsoobservedthedurationofsteroid
inhalation therapy and cardiological follow‑up, where
thereis aneed forligation, treatment by catheterization
following discharge, or severe pulmonary hypertension
requiringtreatment.
Statistical analysis
Data were analyzed using Wolfram, Mathematica,
version11.3(WolframResearchofChampaign,Illinois).
Statistical dierences between the study periods were
calculated using Chi‑square tests (including Yates
correction)for categoricalvariables andMann–Whitney
U‑test for quantitative variables. The cumulative
incidence of ductal patency rates and length of
respiratory support were analyzed using Kaplan–Meier
estimation.Thedierencesbetweenthetwoperiodswere
analyzed using Cox proportional hazards regression.
Statistical signicance was set at P < 0.05. In addition,
the corresponding eect size was calculated. According
toCohen’sconvention, theeectsize was verysmallat
d<0.2,smallat0.2≤ d<0.5,mediumat0.5≤ d<0.8,
andlargeatd≥0.8.

We analyzed the medical records of 201 infants: 99
from the TTP and 102 from the EXP. Table 1 shows
no signicant dierences in baseline characteristics
between the periods studied. Of the 99 infants from
the TTP, 44 patients had hsPDA and 24 of those were
treatedearly(during therst3days).Later,treatmentin
the TTP was administered to 17 infants based on their
severe clinical symptoms (to 11 infants with hsPDA,
but without clinical risk at the beginning of their life,
and to six infants without hsPDA in the rst 3 days).
Sevenotherinfants, who receivedearlytreatment,got a
second‑coursetreatment.
Ofthe102infantsfrom the EXP,39infants had hsPDA
duringtherst3days.Uponobservationofclinicalsigns
of hsPDA, 17 infants were treated. Figures 1 and 2 are
graphical representations of the dierences in treatment
betweenthetwo groups.
There was a similar percentage of hsPDA incidence in
therst3daysoflifeinbothperiods(TTP44,EXP39).
PDA closure in the 1st week of life was more frequent
intheTTPthan in theEXP(TTP18,EXP9), inwhich
more children underwent closure of PDA after the
2ndmonthoflife(TTP10,EXP15)withtheCoxmodel:
P =0.036. The number of children who underwent
ligation was low in both periods (TTP 3, EXP 4).
PDA at the time of discharge was more frequent in
the EXP group compared to TTP group (TTP 13, EXP
22)[Figure3].
Adverse outcomes
The total of 21 and 13 patients died in the TTP and
EXP, respectively (P = 0.133; c = 0.112, small eect
size). However, severe BPD and/or death were more
frequent in the TTP than in the EXP (7 and 21 vs. 3
and 13, respectively) [P = 0.007; c = 0.216 medium
eect size, Table 2]. There were no signicant
dierences in other early morbidities observed between
the periods [Table 3]. Pulmonary hemorrhage occurred
more frequently in the EXP than in the TTP (TTP 15,
EXP 22); however, the dierence was not statistically
signicant (P = 0.277, c = 0.082). We observed a mild
tendency toward prolonged noninvasive respiratory
support in the EXP. The mean duration of noninvasive
respiratory support in the TTP was 61 days (until the
34 + 4/7 postnatal week), while that in the EXP was
68 days (until the 35 + 5/7 postnatal week). The time
ofnoninvasiverespiratorysupport, according totheCox
model, depends on a continuous variable which is the
gestationalweek(P<0.001),andontwobinaryvariables,
which are the two consecutive periods (P = 0.007).
Everyweekofimmaturity represented 1.72timeshigher
riskforlong‑term noninvasive respiratorysupport.Early
treatment reduces the risk for noninvasive respiratory
support0.64times(relativerisk=0.64,95%condence
interval:0.47–0.89).
Long‑term outcomes
Of the 201 children observed, 2‑year follow‑up results
were available for 145 children (87%); however, 9
children from the TTP and 13 children from the EXP
were lost. From the TTP, two children underwent PDA
catheter closure, and three children were treated by
ligation within 2 years following discharge from our
clinic; two more children were observed for PDAs at
2years ofcorrected age. Fromthe EXP,onlyone child
underwent ligation for PDA after discharge.An infant
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212 Journal of Clinical Neonatology ¦ Volume 10 ¦ Issue 4 ¦ October-December 2021
with severe pulmonary hypoplasia from the EXP died
after discharge due to severe pulmonary hypertension
secondarytoseverepulmonaryhypoplasia;anotherchild
fromtheEXPwassurveyedforpulmonaryhypertension.
A partial anomalous pulmonary venous connection was
detected in one child after release. We did not observe
any dierences between the two periods in terms of
fundamentalendpoints. Cerebral palsy (TTP4, EXP4),
severe hearing disorders (TTP 0, EXP 2 [twins with a
family history of the hearing disorder]), severe visual
impairment (TTP 1, EXP 1), and severe psychological
or mental developmental delay (TTP 7, EXP 8)
were reported. The duration of therapy with inhaled
corticosteroids did not dier between the two periods
afterdischarge.

Thisstudy showedanassociationbetweenearlytargeted
ibuprofen treatment and the composite outcome of
severeBPDand/ordeath.Weobservedmoreinfantswith
severeformsofBPDand/ordeathintheTTPthaninthe
EXP;onthecontrary,lowermortalityandmorefrequent
butmildtomoderateformsofBPDwerereportedinthe
EXP. This suggests that early ibuprofen exposure may
have a negative impact on the composite outcome of
BPDand/ordeath inextremelypretermchildren.
We hypothesize that early ibuprofen therapy can
negatively aect immature renal function and cause
pulmonaryedema,resultinginmoreaggressiveventilation
modes injuring preterm lungs. Although ibuprofen is
less likely to induce oliguria than indomethacin,[2] the
early treatment of the most vulnerable preterm infants
can have serious side eects. In agreement with our
assumption, the trial of indomethacin prophylaxis in
pretermrevealeddecreasedurineoutputandanincreased
needforsupplementaloxygenat the beginningoflife.[19]
Similarly,Chenetal.reportedatwo‑foldrisk of BPD in
infants exposed to oral ibuprofen during the 1st day of
life.[20] Possible mechanisms by which ibuprofen could
adversely aect immature lungs include the reduction
in pulmonary prostacyclin levels,[21] the development of
pulmonary hypertension,[22] and the negative eect on
angiogenesis.[20]
In contrast to the present study, a retrospective cohort
study by Jensen etal. in preterm infants found no
association between prophylactic indomethacin
Figure 1:Diagramshowingthetwo‑stagedperiods
Figure 3:Kaplan–Meiercurvesforthepersistenceofductusarteriosus
forthe twoperiods:targetedtreatmentperiod(red line)andexpectant
treatmentperiod (blue line); the tablesummarizesthe closing of
hemodynamicallysignicantpatentductusarteriosusinthetwoperiods
Figure 2:Comparisonofthetimingoftreatmentinthetwoperiods
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Journal of Clinical Neonatology ¦ Volume 10 ¦ Issue 4 ¦ October-December 2021
and risks for BPD/death before 36‑week PMA. In
addition, a meta‑analysis reported a slight reduction
in the risk‑adjusted odds of mortality associated with
indomethacin prophylaxis.[23] Moreover, Chock etal.
reported no association between treatment and BPD/
death in a retrospective study, where 75% of infants
weretreatedwith indomethacin.[24]
The benets of our study include the use of the entire
three‑level Jobe and Bancalari classication.[15] The
mere denition of BPD as oxygen therapy after
36 weeks of PMA used in the previously mentioned
studies may not sensitively predict the impact on
quality of life. A large proportion of such infants
has only mild or minimal problems with long‑term
respiratory health, while the diagnosis of severe BPD
is more consistently associated with worse long‑term
respiratory outcomes.[25] The updated denition based
onaworkshophosted by theNationalInstituteof Child
HealthandHumanDevelopment (published 2018)takes
into account the use of the HFNC and its association
withlong‑termeects.[26]
This study does not question the possible negative
impact of PDA on developing lungs but whether early
ibuprofentreatment willfavorably aectoutcomes. The
higher rate of moderate BPD and longer duration of
noninvasiveventilationcanbeexplainedbythesurvival
Table 1: Basic characteristics between the two consecutive periods
TTP EXP P values 
#
##
n99 102
Birthweight,gmean±SD 774±185 774±203 0.88 0.00024#
Gestationalage,weeks,mean±SD 25.6±1,4 25.8±1,43 0.316 0.125#
Males,n(%) 39(39) 53(52) 0.097 0.125##
Fullcourseofantenatalsteroids,n(%) 29(29) 31(30) 0.865 0.012#
Twins,n(%) 38(38) 29(28) 0.178 0.106##
IUGR,n(%) 17(17) 22(22) 0.478 0.056#
Intubationinthedeliveryroom,n(%) 32(32) 33(32) 0.559 0.042#
Chorioamnionitis‑histology,n(%fromexaminated) 54(61) 72(76) 0.054 0.147##
Caesareansection,n(%) 62(63) 69(68) 0.464 0.053#
TTP–Targetedtreatmentperiod;EXP–Expectanttreatmentperiod;IUGR–Intrauterinegrowthretardation
Table 2: Degrees of bronchopulmonary dysplasia in the two periods
BPD mild or
without, n
BPD moderate, nBPD severe and/or death, n
(severe BPD+death)
TTPn,(%) 61(62) 8(8) 28(28)
EXPn,(%) 64(63) 22(22) 16(16)
P=0.007,OR=2.12(1.06,4.23),mediumeectsize
0.216forBPDsevereand/ormortality

TTP EXP P values


interval 95 %)

#
##Small
###
Death,n(%) 21(21) 13(13) 0.133 1.84(0.87,3.92) 0.112##
BPD severe and/or death, n (%) 28(28) 16(16) 0.007* 2.12(1.06,4.23) 0.216###
Severemorbidityand/
ordeath,n(%)
45(45) 52(51) 0.481 0.8(0.46,1.39) 0.055##
IVHgradeIII+IVand/
ordeath,n(%)
32(32) 25(25) 0.273 1.47(0.79,2.73) 0.086##
NEC/SIPand/ordeath,n(%) 32(32) 27(26) 0.411 1.33(0.72,2.44) 0.061##
ROPwiththerapyand/
ordeath,n(%)
24(24) 14(14) 0.102 2.01(0.97,4.16) 0.122##
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214 Journal of Clinical Neonatology ¦ Volume 10 ¦ Issue 4 ¦ October-December 2021
of more children in EXP and the known negative
impactof long‑term PDA.Infantswho wereexposedto
moderate‑to‑largePDAs for 7‑13 days had a double risk
of BPD/death. The exposure time and the large PDAs
(signicanceof theshunt) are importantrisk factorsfor
developingBPD/death.[6]
Althoughtherewasnostatisticallysignicantdierence,
a higher incidence of pulmonary hemorrhage was
observed in the EXP. This nding is consistent with
previous studies[8,10] and was not associated with a
higher incidence of intraventricular hemorrhage. There
werenoreductionsinthetendencyforlatesymptomatic
treatment despite more early PDA closures in theTTP.
It is possible that we were not able to select infants
that would benet from early treatment. In addition,
the PDA diameter and clinical risks as indicators of
hemodynamicsignicancemaynotbesucient.Astudy
by El‑Khuash etal. oered more precise predictive
factors,including diastolicfunctions of the left heart,[27]
butthispredictive approachhasnotyetbeenveried.
Themainlimitationsofourstudy,besidesitsretrospective
nature,werethe limitedsamplesize and arbitrarycriteria
forearlyPDAtreatmentdenedonlybythePDAdiameter
and clinical risks. This precluded us from adjusting for
potential confounding variables. In the two consecutive
periods, the better outcome of the early period may be
inuenced by the overall improvement in neonatal care
overtheyearsandnotby the change in approach toPDA
treatment.Theresultsof ongoingmulticenterrandomized
prospective trials, such as the Baby‑OSCAR[28] and
BeNeDuctusTrial,[29]will providemore reliable evidence
ofthelink betweenearlyPDAtreatmentandBPD.

Thisstudydemonstrated thatearlytargetedtreatment of
hsPDA was associated with an increased risk of severe
BPDand/ordeath.PDAsmayindeedcontributetoBPD
development, but the harmful side eects of ibuprofen
may outweigh its benets in extremely premature
children. Fluid adjustment should take into account the
possible side eects of early pharmacological treatment
inthispopulation. Using adrugwith fewer sideeects,
such as acetaminophen, may be a suitable alternative
for extremely premature infants. Further goals include
nding a better group of predictive factors that identify
asubgroupofprematurenewbornsthatwillbenetfrom
PDA pharmacological treatment. In future trials, we
must assess the risk‑benet analysis of treatments and
well‑categorizedrespiratoryoutcomes.
Acknowledgment
We acknowledge the support of Monika Costa and
Dr. James I. Hagadorn, Hartford, Connecticut, for the
proofreader and wider professional support. Thanks to
Dr. Blanka Zlatohlavkova and Prof. Richard Plavka,
CharlesUniversity,Prague,fortheir valuable comments
andcriticismof thiswork.
Financial support and sponsorship
Nil.
Conicts of interest
Thereareno conictsofinterest.

1. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous
indomethacin for preventing mortality and morbidity in preterm
infants.Cochrane DatabaseSystRev2010;(7):CD000174.
2. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of
patentductusarteriosusinpretermorlowbirthweight(orboth)
infants.Cochrane DatabaseSystRev2020;2:CD003481.
3. Schmidt B, Roberts RS, Fanaro A, Davis P, Kirpalani HM,
Nwaesei C, et al. Indomethacin prophylaxis, patent ductus
arteriosus, and the risk of bronchopulmonary dysplasia:
Further analyses from the Trial of Indomethacin Prophylaxis in
Preterms(TIPP). JPediatr2006;148:730‑4.
4. McNamara PJ, Sehgal A. Towards rational management of the
patentductus arteriosus: The needfordisease staging.Arch Dis
ChildFetal NeonatalEd2007;92:F424‑7.
5. Weisz DE, McNamara PJ. Patent ductus arteriosus ligation
and adverse outcomes: Causality or bias? J Clin Neonatol
2014;3:67‑75.
6. Clyman RI, Hills NK, Liebowitz M, Johng S. Relationship
between duration of infant exposure to a moderate‑to‑large
patent ductus arteriosus shunt and the risk of developing
bronchopulmonary dysplasia or death before 36 weeks. Am J
Perinatol2020;37:216‑23.
7. Benitz WE, Bhombal S. The use of non‑steroidal
anti‑inammatory drugs for patent ductus arteriosus closure in
preterminfants. SeminFetalNeonatalMed 2017;22:302‑7.
8. Kluckow M, Jeery M, Gill A, Evans N. A randomised
placebo‑controlled trial of early treatment of the patent ductus
arteriosus.ArchDisChild FetalNeonatalEd 2014;99:F99‑104.
9. Jensen EA, Dysart KC, Gantz MG, Carper B, Higgins RD,
Keszler M, et al. Association between use of prophylactic
indomethacin and the risk for bronchopulmonary dysplasia in
extremelypreterm infants.JPediatr2017;186:34‑40.e2.
10. Rozé JC, Cambonie G, Le Thuaut A, Debillon T, Ligi I,
Gascoin G, et al. Eect of early targeted treatment of ductus
arteriosus with ibuprofen on survival without cerebral palsy
at 2 years in infants with extreme prematurity: A randomized
clinicaltrial. JPediatr2021;233:33‑42.e2.
11. Benitz WE. Treatment of persistent patent ductus arteriosus in
preterm infants: Time to accept the null hypothesis? J Perinatol
2010;30:241‑52.
12. RollandA,Shankar‑AguileraS,Diomandé D,Zupan‑SimunekV,
Boileau P. Natural evolution of patent ductus arteriosus in the
extremely preterm infant. Arch Dis Child Fetal Neonatal Ed
2015;100:F55‑8.
13. Hirt D, Van Overmeire B, Treluyer JM, Langhendries JP,
MarguglioA,EisingerMJ, et al.An optimized ibuprofen dosing
schemefor pretermneonateswith patentductusarteriosus,based
on a population pharmacokinetic and pharmacodynamic study.
BrJ ClinPharmacol2008;65:629‑36.
14. WalshMC,Wilson‑CostelloD,ZadellA,NewmanN,FanaroA.
[Downloaded free from http://www.jcnonweb.com on Friday, September 24, 2021, IP: 83.28.226.85]

Termerová, et al.: Early targeted treatment of patent ductus arteriosus
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Journal of Clinical Neonatology ¦ Volume 10 ¦ Issue 4 ¦ October-December 2021
Safety, reliability, and validity of a physiologic denition of
bronchopulmo‑nary dysplasia.JPerinatol2003;23:451‑6.
15. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J
RespirCrit CareMed2001;163:1723‑9.
16. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R,
Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic
decisionsbased uponclinicalstaging.AnnSurg 1978;187:1‑7.
17. Benson JE, Bishop MR, Cohen HL. Intracranial neonatal
neurosonography:Anupdate.Ultrasound Q2002;18:89‑114.
18. Bayley N. Bayley Scales of Infant Development. 2nd ed. San
Antonio:ThePsychologicalCorporation;1993.
19. Schmidt B, Roberts RS, Fanaro A, Davis P, Kirpalani HM,
Nwaesei C, et al. Indomethacin prophylaxis, patent ductus
arteriosus, and the risk of bronchopulmonary dysplasia:
Further analyses from the Trial of Indomethacin Prophylaxis in
Preterms(TIPP). JPediatr2006;148:730‑4.
20. ChenX,Qiu X, Sun P,LinY,HuangZ,YangC, et al. Neonatal
ibuprofen exposure and bronchopulmonary dysplasia in
extremelypremature infants.JPerinatol2020;40:124‑9.
21. Bravo MC, Cordeiro M, Deiros L, Pérez‑Rodríguez J. Lethal
pulmonary hypertension associated with ibuprofen treatment
in a very low birth weight infant. J Paediatr Child Health
2014;50:85‑6.
22. Rodriguez‑Castano MJ, Aleo E, Arruza L. Oral sildenal for
severepulmonary hypertensiondevelopingafteribuprofen usein
aneonate. IndianPediatr2016;53:349‑50.
23. Jensen EA, Foglia EE, Schmidt B. Association between
prophylactic indomethacin and death or bronchopulmonary
dysplasia:Asystematicreviewandmeta‑analysisofobservational
studies.Semin Perinatol2018;42:228‑34.
24. Chock VY, Punn R, Oza A, Benitz WE, Van Meurs KP,
WhittemoreAS, et al.Predictorsofbronchopulmonarydysplasia
or death in premature infants with a patent ductus arteriosus.
PediatrRes 2014;75:570‑5.
25. BancalariE, JainD.Bronchopulmonarydysplasia: Canweagree
ona denition?Am JPerinatol2018;35:537‑40.
26. Higgins RD, Jobe AH, Koso‑Thomas M, Bancalari E,
Viscardi RM, Hartert TV, et al. Bronchopulmonary dysplasia:
Executivesummary ofaworkshop.J Pediatr2018;197:300‑8.
27. El‑KhuashA, James AT, Corcoran JD, Dicker P, Franklin O,
Elsayed YN, et al. A patent ductus arteriosus severity score
predictschronic lungdiseaseordeath beforedischarge.J Pediatr
2015;167:1354‑61.e2.
28. GuptaS,Juszczak E, Hardy P,Subhedar N,WyllieJ, KelsallW,
et al.Studyprotocol:Baby‑OSCARtrial:Outcomeafterselective
earlytreatmentforclosureofpatentductusARteriosusinpreterm
babies, a multicentre, masked, randomised placebo‑controlled
parallelgroup trial.BMCPediatr2021;21:100.
29. Hundscheid T, Onland W, van Overmeire B, Dijk P,
van Kaam AH, Dijkman KP, et al. Early treatment versus
expectative management of patent ductus arteriosus in preterm
infants: A multicentre, randomised, non‑inferiority trial in
Europe(BeNeDuctus trial).BMCPediatr2018;18:262.
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