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DOI: 10.1542/peds.2009-3506; originally published online April 26, 2010; 2010;125;1020Pediatrics

Shannon E.G. Hamrick and Georg HansmannPatent Ductus Arteriosus of the Preterm Infant

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Patent Ductus Arteriosus of the Preterm Infant

abstractA persistently patent ductus arteriosus (PDA) in preterm infants canhave significant clinical consequences, particularly during the recov-ery period from respiratory distress syndrome. With improvement ofventilation and oxygenation, the pulmonary vascular resistance de-creases early and rapidly, especially in very immature infants withextremely low birth weight (�1000 g). Subsequently, the left-to-rightshunt through the ductus arteriosus (DA) is augmented, thereby in-creasing pulmonary blood flow, which leads to pulmonary edema andoverall worsening of cardiopulmonary status. Prolonged ventilation,with the potential risks of volutrauma, barotrauma, and hyperoxygen-ation, is strongly associatedwith the development and severity of bron-chopulmonary dysplasia/chronic lung disease. Substantial left-to-rightshunting through the ductusmay also increase the risk of intraventric-ular hemorrhage, necrotizing enterocolitis, and death. Postnatal duc-tal closure is regulated by exposure to oxygen and vasodilators; theensuing vascular responses, mediated by potassium channels,voltage-gated calcium channels, mitochondrial-derived reactive oxy-gen species, and endothelin 1, depend on gestational age. Platelets arerecruited to the luminal aspect of the DA during closure and probablypromote thrombotic sealing of the constricted DA. Currently, it is un-clear whether and when a conservative, pharmacologic, or surgicalapproach for PDA closure may be advantageous. Furthermore, it isunknown if prophylactic and/or symptomatic PDA therapy will causesubstantive improvements in outcome. In this article we review themechanisms underlying DA closure, risk factors and comorbidities ofsignificant DA shunting, and current clinical evidence and areas ofuncertainty in the diagnosis and treatment of PDA of the preterm in-fant. Pediatrics 2010;125:1020–1030

AUTHORS: Shannon E. G. Hamrick, MDa and GeorgHansmann, MD, PhDb

aDivisions of Neonatology and Cardiology, Department ofPediatrics, Emory University, Atlanta, Georgia; and bDepartmentof Cardiology, Children’s Hospital Boston, Harvard MedicalSchool, Massachusetts

KEY WORDSductus arteriosus, prematurity, oxygen, ion channels, platelets,cyclooxygenase, diagnosis, treatment, outcome

ABBREVIATIONSDA—ductus arteriosusSMC—smooth muscle cellEC—endothelial cellPDA—patent ductus arteriosusCLD—chronic lung diseaseBW—birth weightVLBW—very low birth weightELBW—extremely low birth weightIVH—intraventricular hemorrhageBPD—bronchopulmonary dysplasiaNEC—necrotizing enterocolitisDASMC—ductus arteriosus smooth muscle cellPGE2—prostaglandin E2PGI2—prostacyclinNO—nitric oxideDOL—day of lifeBNP—B-type natriuretic peptideNT-pro-BNP—N-terminal-pro-BNPCTnT—cardiac troponin TCOX—cyclooxygenaseRCT—randomized, controlled trialVEGF—vascular endothelial growth factorDOL—day of lifehs—hemodynamically significant

www.pediatrics.org/cgi/doi/10.1542/peds.2009-3506

doi:10.1542/peds.2009-3506

Accepted for publication Feb 22, 2010

Address correspondence to Georg Hansmann, MD, PhD,Department of Cardiology, Children’s Hospital Boston, HarvardMedical School, 300 Longwood Ave, Boston, MA 02115. E-mail:[email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2010 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

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The ductus arteriosus (DA) serves todivert ventricular output away fromthe lungs and toward the placenta inutero by connecting the main pulmo-nary artery to the descending aorta. Apatent ductus arteriosus (PDA) in thefirst 3daysof life isaphysiologic shunt inhealthy term and preterm newborn in-fants.1 In contrast, a persistently patentDA in preterm infants can have clinicalconsequences depending on the degreeof left-to-right shunting. The increase inpulmonary blood flow in the setting ofprematurity can lead to pulmonaryedema, loss of lung compliance, and de-terioration of respiratory status, whichultimately leads to chronic lung disease(CLD). The incidence of PDA in term in-fants has been estimated to be 57 per100 000 live births,2 whereas every thirdpreterm infant with a birth weight (BW)of 501 to 1500 g (very low birth weight[VLBW]) can be expected to have a per-sistent PDA.3 Furthermore, 55% of in-fantswhoweigh�1000g (extremely lowbirth weight [ELBW]) have been de-scribed to have a symptomatic PDA thatultimately leads to medical treatment.4,5

Although spontaneous permanent DAclosure occurs in �34% of ELBW neo-nates 2 to 6 days postnatally4 and in themajority of VLBW neonates within thefirst year of life,6 60% to 70% of preterminfants of�28 weeks’ gestation receivemedical or surgical therapy for a PDA,7

usually with the intention to preventrespiratory decompensation, heart fail-ure, intraventricular hemorrhage (IVH)/brain injury, CLD/bronchopulmonarydysplasia (BPD), necrotizing enterocoli-tis (NEC), and death. The natural historyof a PDA in premature infants cared forin today’s NICUs remains unknown.

ADVANCES IN SCIENCE ANDTECHNOLOGY

Mechanisms UnderlyingPhysiologic Closure of the DA

The fetal DA appears grossly similar tothe adjacent descending aorta and

main pulmonary artery; however,there are essential histologic differ-ences. The medial layer of the DA iscomposed of longitudinal and spirallayers of smooth muscle fibers withinconcentric layers of elastic tissue; incontrast, themedial layers of the aortaand pulmonary artery are primarilyconcentric elastic tissue.8 The intimallayer of the DA is irregular and thickwith neointimal “cushions” composedof smooth muscle and endothelialcells.9 The DA smooth muscle cell(DASMC) is the site of oxygen-sensing,whereas the endothelium releases va-soactive substances that are impor-tant in modulating DA tone. Fetal pa-tency is regulated by low oxygentension and prostanoids, predomi-nantly prostaglandin E2 (PGE2) andprostacyclin (PGI2). PGE2 and PGI2 lev-els are high in the fetus because ofboth placental production and dimin-ished clearance by the fetal lungs.8

After birth at term, a postnatal in-crease in PaO2 and a decrease in cir-

culating vasodilators such as PGE2and PGI2 will induce constriction ofDASMCs and, consequently, functionalclosure of the ductus in newborns. Themechanism by which oxygen con-stricts the ductus is the subjectof much investigation.10–12 Oxygen-sensing mechanisms in the DASMCscause cell-membrane depolarization,which allows for calcium influx andcontraction (Fig 1). Developmentallyregulated potassium channels allowfor voltage-gated calcium channels toopen and increase calcium influx.13 Im-maturity of both potassium and cal-cium channels leads to ineffectiveoxygen-mediated constriction in thepreterm rabbit DA.13,14 In addition, Rho/Rho-kinase pathways can induce cal-cium sensitization in which sustainedvasoconstriction occurs as a result ofpersistent myosin light-chain phos-phorylation.15,16 Rho/Rho-Kinase sig-naling depends on mitochondrial-derived reactive oxygen species, thegeneration of which may be decreased

FIGURE 1Mechanism for oxygen-induced DASMC contraction. The underlined items in bold font show develop-mental maturation. Potassium (K�) channels allow for voltage-gated calcium channels to open andincrease calcium influx. Rho/Rho-kinase pathways can induce calcium sensitization in which sus-tained vasoconstriction occurs due to persistent myosin light-chain phosphorylation, dependent onmitochondrial-derived reactive oxygen species (ROS). Oxygen also induces release of the potentvasoconstrictor endothelin-1 by the ductus, which acts to increase intracellular calcium throughG-protein coupling. Kv indicates voltage-gated potassium channel, ROS indicates reactive oxygenspecies

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in the preterm DA.15 Oxygen also inducesrelease of the potent vasoconstrictor en-dothelin 1 by the ductus; endothelin 1acts to increase intracellular calciumthrough G-protein coupling, although itsrole in closure of the DA after birth iscontroversial.15,17–19

The successful contraction results lo-cally in a “hypoxic zone” and triggerscell death and production of hypoxia-inducible growth factors such astransforming growth factor� and vas-cular endothelial growth factor (VEGF),which result in vascular remodelingand anatomic DA closure, as demon-strated in newborn baboons.9 Failureto generate the hypoxic zone in pre-term infants by insufficient constric-tion prevents true anatomic DAclosure, which explains the DA’s pro-pensity to “reopen” after echocardio-graphic confirmation of its closure.20

New Concept of Initial DAConstriction and SubsequentPlatelet-Driven DA Sealing

Recently, Echtler et al21 demonstratedby intravital confocal microscopy thatplatelets are recruited to the luminalaspect of the murine DA immediately

after birth. Induced dysfunction ofplatelet adhesion or transgenic de-fects of platelet biogenesis (Nfe�/�

[nuclear factor (erythroid-derived 2)]mice) led to persistent DA. It is inter-esting to note that nonaspirin nonste-roidal antiinflammatory drugs such asindomethacin or ibuprofen increaserather than decrease platelet-mediatedthrombosis in both mice and hu-mans,22–24 and indomethacin actuallypromotes platelet accumulation afterendothelial injury.21 Lower plateletcounts have been reported to be asso-ciated with a higher failure rate ofindomethacin-induced PDA closure inhuman newborns.25 In a retrospective,multivariate analysis of 123 prematureinfants born at 24 to 30 weeks’ gesta-tion, thrombocytopenia was an inde-pendent predictor of PDAwith hemody-namic significance (odds ratio: 13.1; P� .0001).21 Thus, platelets may be cru-cial for DA closure by promotingthrombotic sealing of the constrictedDA and luminal remodeling (Fig 2).Similarly, infection-associated inflam-matory mediators such as tumor ne-crosis factor� (TNF-�), are associatedwith late patency of the DA; prostaglan-

dins and reactive oxygen intermedi-ates may be inducible by TNF-�.26 Like-wise, a temporally related infectionincreases the odds for failure of DA clo-sure.26 It is possible thatotherproinflam-matory cytokines affect platelet functionand, thus, inhibit thrombotic sealing ofthe constricted DA.21

Understanding themechanism of func-tional closure of the DA is importantnot only for the preterm infant but alsofor patency manipulation in the new-bornwith ductal-dependent congenitalheart disease. The recent data on sep-arate channels and the potentially cru-cial role of platelets in ductal closureintroduce new options for pharmaco-logic intervention. Rare syndromicforms of PDA, such as the TFAP2B mu-tations in Char syndrome, have beendiscussed elsewhere.27

Mechanisms Underlying thePatency of the DA in PretermInfants

In preterm infants, the sensitivity foroxygen is reduced (see the discussionabove), but in addition, the sensitivityto PGE2, nitric oxide (NO), and perhapsendothelin 1 is increased.7 PGE2 acts

FIGURE 2The role of platelets for sealing of the contracted DA. The scheme delineates the proposed sequence of events that contribute to postnatal DA occlusion.Echtler et al propose a model here in which reversible and incomplete DA constriction is the initial step that triggers DA closure. As a result, the luminalaspect of the DA wall adopts a prothrombotic phenotype with endothelial activation, deposition of von Willebrand factor and fibrin(ogen), and eventuallyendothelial cell (EC) detachment from the internal elastic lamina, which lead to collagen exposure. This process triggers the accumulation of plateletscirculating in the residual DA lumen. The platelet plug that forms seals the residual lumen of the contracted DA and, together with other mechanisms, facilitatessubsequent luminal remodeling. (Adapted with permission from Echtler K, Stark K, Lorenz M, et al. Nat Med. 2010;16[1]:75–82; supplementary figure 9.)



through G-protein–coupled receptorsthat activate adenyl cyclase and pro-duce cyclic adenosinemonophosphate(cAMP) to relax the vascular smoothmuscle layers. cAMP concentrationsalso depend on phosphodiesterase-mediated degradation. Likewise, NOactivates guanyl cyclase to producecyclic guanosine monophosphate(cGMP), which is degraded by a differ-ent phosphodiesterase isoform. In fe-tal sheep there is a developmental in-crease in phosphodiesterase activitysuch that the more immature animalhas less ability to degrade cAMP orcGMP and, thus, more sensitivity toPGE2 and NO.28 This developmental reg-ulation of vascular tone is specific tothe ductus; there is no change in phos-phodiesterase expression with ad-vancing gestation in the fetal aorta.28

Administration of cortisol to immaturefetal lambs in utero will result in a duc-tus that responds to oxygen and pros-taglandin inhibition similar to that in amature fetus,29 which explains the de-creased incidence of a PDA in pretermhumans who are born to mothers whoreceived antenatal corticosteroids.7,30

In summary, the mechanisms underly-ing functional DA closure depend ongestational maturity. The term DA willreact to oxygen and decreased concen-tration of circulating vasodilators bycontraction; these sensing mecha-nisms are reduced in the preterm in-fant; thus, anatomic closure may notoccur. The intriguing role of plateletsin the closure of the DA of preterm andterm infants should be explored in fur-ther experimental and prospectiveclinical studies.

CRITICAL ASSESSMENTS

Risk Factors and ComorbiditiesAssociated With Patency of the DA

A ductal left-to-right shunt will causeincreased pulmonary blood flow. In thesetting of preterm respiratory dis-tress with low plasma oncotic pres-

sure and increased capillary perme-ability, a PDA can result in interstitialand alveolar pulmonary edema and de-creased lung compliance, which, inturn, will lead to higher ventilator set-tings, prolonged ventilation with po-tentially high oxygen load,31 and prob-ably to BPD/CLD. In ELBW (BW� 1000 g)and VLBW (BW� 1500 g) infants, lunginjury is often combined with myocar-dial dysfunction due to left-sided vol-ume overload that, together with aductal steal phenomenon, will worsensystemic perfusion. Therefore, pre-term infants born at �1500 g aresusceptible to hypoperfusion of vitalorgans and resultant additional co-morbidities such as IVH, periventricu-lar leukomalacia, NEC, and (pre)renalfailure. However, although a PDA is def-initely associated with these morbidi-ties, its causal role is not clear.32 A per-sistently patent DA was shown to bea risk factor for increased mortalityrate in a single-center, retrospectivestudy.33

Chronic Lung Disease

PDA has been shown to be a risk factorfor CLD after risk adjustment in apopulation-based study34 and a studyperformed through the EuniceKennedy Shriver National Institute ofChild Health and Human DevelopmentNeonatal Network.35 Preterm baboonsexposed to a PDA for 14 days have ar-rested alveolar development, which isa characteristic of the “new” BPD.32,36

However, prophylactic PDA ligationwithin 24 hours of life did not decreaseBPD rates.37

Neurologic Morbidities

Because IVH typically occurs within thefirst few days of life, only trials thatexamine PDA prophylaxis can assessthis relationship.32,38 The prophylacticsurgical-ligation trial did not reveal asignificant difference in IVH (althoughit was not powered to do so). In con-trast, prophylactic indomethacin re-

duces IVH (trial-pooled relative risk:0.66 [95% confidence interval: 0.53–0.82])37,39,40 and might improve long-term neurologic outcome in boys bornat (600–1250 g)41 (see “Neurologic Out-come”). The effect of PDA on periven-tricular leukomalacia is unknown.

Necrotizing Enterocolitis

Preterm infants with PDA have de-creased intestinal and renal bloodflow and blood-flow velocity on ultra-sound compared with gestationalage–matched infants without PDA,42

and these values “normalize” afterductal closure. Results of a systematicreview of PDA treatment trials that de-layed therapy in 1 group for at least 6days suggested that the incidence ofNEC is decreased by early treatment ininfants born at �1000 g.32,43 Likewise,the aforementioned trial of prophylac-tic ligation in the first 24 hours of lifesignificantly reduced NEC.37

TREATMENT OF PDA IN THEPRETERM INFANT

When Is a PDA HemodynamicallySignificant?

Echocardiography and CerebralDoppler Sonography

There have been no stringent clinicalor sonographic criteria on the need forPDA closure to date. Echocardiographi-cally, a left atrium–to–aortic root di-ameter ratio of �1.4 in the paraster-nal long-axis view, a DA diameter of�1.4 mm/kg body weight, left ventric-ular enlargement, and holodiastolicflow reversal in the descending aortaindicate a significant PDA shunt.44

Pulse-wave Doppler interrogation ofthe main pulmonary artery in neo-nates with a hemodynamically signifi-cant (hs) DA demonstrates turbulentsystolic and diastolic flow45 and abnor-mally high antegrade diastolic flow(�0.5 m/second).46 Additional echo-cardiographic markers that indicatea hemodynamically significant PDA




shunt are reviewed elsewhere.45,46 Inaccordance with the holodiastolic aor-tic flow reversal, some neonatologistsconsider a resistance index of�0.9 oncerebral Doppler examination of theanterior cerebral artery a sign of sig-nificant ductal shunting with adversecerebral steal effect. Certainly, if thediameter of the PDA is as large as oreven larger than the main pulmonaryartery on the second day of life (DOL),then early pharmacologic or surgicaltreatment should be strongly consid-ered. However, echocardiography aloneat 48 hours cannot identify infantswith aPDA who go on to develop severe IVHand/or die,47 which thereby underlinesthe need for further clinical and bio-chemical criteria for risk stratification.

B-Type Natriuretic Peptide,N-Terminal-pro-BNP, and CardiacTroponin T: Biomarkers for PDA RiskStratification and Intervention?

A growing body of evidence suggestthat elevated plasma B-type natri-uretic peptide (BNP) or NT-pro-BNP lev-els, now more frequently used asbiomarkers for heart failure48 and con-genital heart disease49 in infants andchildren, may indicate a “symptom-atic” PDA and guide its treatment.50–54

In small series of preterm infants bornat �28 weeks’55 or 25 to 34 weeks’53

gestation, plasma BNP correlated withmagnitudes of the ductal shunt (ie,ductal size,55 left atrium–to–aorticroot ratio,53,55 and diastolic flow veloc-ity of the left pulmonary artery53).

In neonates of�28 weeks’ gestationalage, BNP levels of �550 pg/mL on thesecond DOL were suggested to predictPDA intervention (sensitivity: 83%;specificity: 86%); the indication for in-tervention in this study was based onthe following combined criteria: needfor ventilatory support, narrowestductal diameter of�2 mm, and ductalleft-to-right shunt.55 In neonates bornat 25 to 34 weeks’ gestation, the best

cutoff BNP concentrations on DOL 3 forthe diagnosis of “symptomatic PDA”was determined to be 1110 pg/mL(sensitivity: 100%; specificity: 95.3%)53;the indication for intervention in thisstudy was based on 2 of 5 clinical cri-teria plus evidence of a large PDA withleft-to-right flow according to colorDoppler echocardiography.53 Simi-larly, plasma NT-pro-BNP levels ob-tained from infants born at�33 to 34weeks’ gestation were a good indica-tor of hemodynamically significantPDA at a suggested cutoff NT-pro-BNPconcentration of 10 180 pg/mL on DOL2 (sensitivity: 100%; specificity: 91%)56

and 11 395 pg/mL on DOL 3 (sensitivity:100%; specificity: 95%).57 It is interest-ing to note that BNP concentrationsdecrease not only with age but alsoduring the course of indomethacintherapy for PDA.53,54 BNP-guided ther-apy (ie, no indomethacin administra-tion if the BNP level is �100 pg/mL 12or 24 hours after the first dose) re-duced the number of indomethacindoses during the first course of treat-ment54 and thereby may reduce co-morbidities associated with indometh-acin use. It is also interesting to notethat plasma NT-pro-BNP and cardiactroponin T (cTnT) levels are higher inpreterm infants (VLBW or�32 weeks’gestation) with a PDA who subse-quently develop IVH grade III/IV ordeath compared with those with a PDAand without complications.47 Neverthe-less, in any neonate with suspected orconfirmed significant PDA, it is thecombination of frequent clinical evalu-ations, comprehensive echocardio-graphic studies, and perhaps biomar-kers such as BNP, NT-pro-BNP, or cTNTthat should guide timely and individu-alized decisions on the best treatment.

Pharmacologic Ductus ClosureWith Cyclooxygenase Inhibitors

Nonselective cyclooxygenase (COX) in-hibitors such as indomethacin or ibu-profen inhibit prostaglandin synthesis,

first shown in 1976.58,59 The efficacy ofCOX inhibitors depends on gestationalage. COX inhibitors are less effective inseverely preterm infants,58,59 a fact of-ten attributed to inadequate contrac-tion of the immature DASMC but re-cently suggested to be a result offailure of intimal cushion formation;the latter process involves NO-mediated fibronectin synthesis60,61 andchronic activation of the prostaglandinreceptor EP4 that promotes hyaluronicacid production.62,63 Hyaluronic acid isan extracellular matrix factor that theDASMC use to migrate inward, soblockade of prostaglandinsmay preventintimal cushion formationand, thus, pre-vent effective closure in the most imma-ture infants.62 In fact, COX-1/2 knockoutmice have a persistent PDA,64 andwomen who take indomethacin prena-tally as tocolysis for preterm labor aremore likely tohavean infantwith aPDA.65

Counterintuitively, COX inhibitors aremuch less if at all effective in term (ver-sus preterm) newborns with a PDA.66,67

Most of the randomized, controlled tri-als (RCTs) from the 1980s evaluated 2different treatment strategies for theclosure of the DA68:

● prophylactic treatment, to bestarted in the first 24 hours of life;and

● symptomatic treatment when PDAand its shunt volume have beenfound to be hemodynamically rele-vant according to echocardiogra-phy, typically between 2 and 7 daysafter birth.

However, given the nature of neonatol-ogy as an ever-evolving discipline thatdeals with declining gestational age atbirth, better survival rates, andchangingpractices, the above-listed strategiesmaynotapply to today’smostprematureinfants. Because 100% oxygen is notmore effective than room air69 and mostlikely harmful in near-term newborn re-suscitation (higher mortality rate in 2meta-analyses,70,71 including a small sub-



group analysis in preterm infants),71

more and more centers now use roomair as the initial gas in the deliveryroom.72,73 Oxygen concentrations as lowas 30% (vs 90%) also seem to be benefi-cial in the resuscitation of very prema-ture infants born at 24 to 28 weeks’ ges-tation by reducing oxidative stress andthe riskof BPD.74Moreover, the results ofrecent studies suggest that the oxygenload for VLBW infants in the NICU isunderestimated31 and that long-accepted targets of oxygen satura-tions for preterm infants in their firstweeks of life might be too high.75–77 It isunclear whether “tailored” oxygen re-suscitation and intensive care may in-crease or decrease the incidence ofhsPDA in VLBW infants. Two decadesago, it was demonstrated that reactiveoxygen metabolites relax the lamb DAby stimulating prostaglandin produc-tion,78 whereas the results of more re-cent work suggested that immaturityof mitochondrial reactive oxygenspecies generation is associatedwith reduced and delayed oxygen-mediated ductal constriction.15 Antena-tal steroids are now given to almost 90%of eligible preterm infants. Prophylacticendotracheal surfactant administrationand early extubation to continuous posi-tive airway pressure are frequently per-formed. Today, the minority of VLBW in-fants still remain intubated past DOL 3,and only a subgroup remains with se-vere respiratory distress for which onewould question treating a PDA. Hence,the results of previous trials (discussedbelow) need to be interpreted carefully,and those who perform future studiesneed to take into account thesemanage-ment changes.

CURRENT EVIDENCE AND AREAS OFUNCERTAINTY

Neurologic Outcome

Although indomethacin is known tocause profound reduction in cerebralperfusion, an RCT showed that low-

dose prophylactic indomethacin re-duces the incidence of IVH identified bycranial ultrasound.79 Proposedmecha-nisms include maturation of the cere-bral vascular basement membrane,improvements in cerebral vascular au-toregulation, and anti-inflammatory ef-fects.80,81 Ballabh et al82 (2007) demon-strated that prenatal COX-2 inhibitiondecreased angiopoietin 2 and VEGF lev-els, as well as germinal matrix endo-thelial cell proliferation, and loweredthe incidence of germinal matric hem-orrhage (GMH� IVH grade I) in pups ofpregnant rabbits. The authors specu-lated that by suppressing germinalmatrix angiogenesis, prenatal inhibi-tion of COX-2 (celecoxib) or VEGF recep-tor 2 (ZD6474) may be able to reduceboth the incidence and severity of GMHin susceptible premature infants.82

However, there are currently no hu-man data to support this hypothesis. Alarger RCT, the Trial of IndomethacinProphylaxis in Preterms (TIPP),38 con-firmed a reduction in IVH with indo-methacin therapy but failed to show abenefit in its combined primary out-come of improved survival and neuro-logic functional status (ie, compositeof death, cerebral palsy, cognitivedelay, deafness, and blindness at acorrected age of 18 months). Subse-quently, authors of a Cochrane meta-analysis39 concluded that “there is no ev-idence to suggest either benefit or harmin longer term outcomes including neu-rodevelopment” anddid not recommendprophylactic use of indomethacin. How-ever, others criticized that the pri-mary outcome’s anticipated effect size(�20%) in the TIPP trial was too large; asmaller effect size (�3%) would havebeen more appropriate on the basis ofthe incidence of IVH in that particularpopulation and its association with neu-rodevelopmental outcome.83 Ment et al41

reevaluated their original trial data from1994 and found that indomethacin-treated boys had significantly less hem-orrhage and higher scores in 1 neuro-

cognitive test than girls, which suggeststhat the effect of indomethacin was gen-der specific. In the TIPP study, a negativeeffect of indomethacin in girls was amore prominent observation than a pos-itive effect in boys.84 Longer courses ofindomethacinhavebeenassociatedwithlessmoderate-to-severewhitematter in-jury on brain MRI.85

Pulmonary Outcome

Controversy exists as to whether ibu-profen treatment86 or indomethacinprophylaxis (see TIPP trial results87)may increase the incidence of BPD/CLDin ELBW infants without PDA. So far,treatments for PDA closure have notresulted in a reduction of BPDrates.88,89 The uncertainty about thebenefits and risks of the use of COXinhibitors can only be resolved by per-forming an RCT that includes a placebogroup in which PDA treatment is of-fered to infants in very limited circum-stances only.88 Also unclear is the opti-mal dosing and duration of COXinhibition. Authors of a 2007 Cochranesystematic review noted that a pro-longed indomethacin course did notsignificantly improve the frequency ofPDA treatment failure, CLD, IVH, ormor-tality.90 A reduction in transient renal im-pairment was seen but countered by anincreased risk for NEC: “There is a pau-city of data on optimal dosing and dura-tion of indomethacin therapy for thetreatment of PDA, in particular for ELBWpremature infants. It is likely that a sin-gle standard indomethacin regimen isnot the ideal for every premature infant.Therefore, individual patient responseshould be considered and evaluated,particularly in ELBW infants. . . .”90

ADVERSE EFFECTS OF COXINHIBITORS

Renal failure/oliguria seems to bemore frequent with indomethacin thanibuprofen (19% vs 7%; P � .05), al-though it is reversible.91 Nonetheless,these alterations in fluid status may




affect ventilatormanagement and sup-plemental oxygen use and increase therisk of CLD in treated ELBW infantswithout PDA.87 Indomethacin in con-junction with postnatal corticoste-roids may increase the risk ofintestinal perforation.92,93 It has beenreported that prophylactic ibuprofenis associated with severe pulmonaryhypertension; an RCT was halted earlybecause of this concern (n� 135).94,95

However, the association between pro-phylactic ibuprofen and pulmonary hy-pertension was not noted in a largerclinical case series of 227 pretermnewborns.96

IBUPROFEN VERSUSINDOMETHACIN

The rate of the primary ductal closureis similar for both drugs, that is, 60% to80% in mixed populations of prema-ture infants (eg, 66%–70%, gestationalage 24–32 weeks91), with decreasingefficacy and higher recurrence ratesin extremely premature infants. Afterprimary treatment failure in infantsborn at �1000 g or � 28 weeks’ ges-tation, successful PDA closure after asecond course of either indomethacinor ibuprofen was found in 44%97 and40%,5 respectively. The lowest sponta-neous or drug-induced closure rates(primary and secondary) were foundin themost immature infants (ie, thoseborn at�26 weeks’ gestation).4,20,91

Ibuprofen does not seem to be as po-tent a vasoconstrictor on the mesen-teric, renal, and cerebral vascularbeds when compared with indometha-cin. In the largest prospective head-to-head study to date (N� 74 per group),there were no statistically significantdifferences in the adverse events ofhemorrhage, CLD/BPD, and NEC be-tween the 2 drugs; however, NEC wasdiagnosed twice as often with indo-methacin treatment (8 vs 4; P � .37),whereas BPD occurred more fre-quently with ibuprofen (39 vs 29; P �

.1) (nonsignificant trends).91 As dis-cussed above, prophylactic indometh-acin decreases the rate of IVH,38 al-though the underlying mechanismsare poorly understood. At present, thecosts for treatment doses of ibuprofenare similar to those for indomethacin.Indomethacin and ibuprofen are multi-ple times more expensive in the UnitedStates than in Canada, Europe, andAustralia.98

PROPHYLAXIS VERSUSSYMPTOMATIC TREATMENT

Prophylactic trials with COX inhibitorshave consistently revealed a de-creased need for surgical ligation, de-creased incidence of pulmonary hem-orrhage, and decreased incidence ofserious IVH.32 However, there is a highrate of spontaneous DA closure(60%),99 which suggests that many in-fants are unnecessarily exposed todrugs with potentially serious adverseeffects. Absence of major lung diseasepredicts spontaneous closure,4 whichmay be explained by the higher pulmo-nary vascular resistance seen withmajor lung disease creating a higher-pressure transmission to the DA,which makes the constrictive mecha-nisms less effective.

On the basis of the current data, thereis no role for ibuprofen prophylaxis inVLBW infants who are at risk forPDA.86,99 A reduction in serious IVH withprophylactic use may justify this prac-tice in selected high-risk patients, al-though the criteria are subject to de-bate. A recent pilot study100 examined anew treatment strategy, based on thedegree of ductal constriction by echo-cardiogram after the first dose ofprophylactic indomethacin, that mayallow for less exposure to COXinhibitors.100 At the timewhen a seconddose of indomethacin was due, thepatients were randomly assigned toeither further treatment only if theductus was�1.6 mm (echocardiogram-

directed group) or completion of theusual 3-day course of indomethacin re-gardless of ductal size (standard-therapy group). The authors found thatthe incidence of PDA closure, reopen-ing, and ligation was not different be-tween the 2 groups, but indomethacinexposure was significantly less in theechocardiogram-directed group (forBNP-guided PDA therapy, see ref 54).However, although not powered to as-sess neurologic outcomes, there was atrend toward a higher incidence ofIVH in the echocardiogram-directedgroup.100

On the basis of the current clinicaldata, there are no benefits and possi-bly harm with both early use of ibupro-fen (prophylaxis, treatment) in thefirst 24 hours of life (eg, pulmonary hy-pertension,94,95,99 but see ref96) and pro-longed courses of indomethacin forPDA treatment (eg, NEC).90

SURGICAL LIGATION OF THE DA

Surgical ligation is performed for PDAclosure when treatment with COX in-hibitors is contraindicated or fails. Be-yond the fourth week of life, the suc-cess rate of pharmacologic treatmentdecreases rapidly as the ductal tissuematures and becomes less regulatedby prostaglandins. There are low mor-bidity and mortality rates in experi-enced centers; however, adverseevents are reported: recurrent laryn-geal nerve damage, chylothorax (tho-racic duct injury), pneumothorax, a pe-riod of left ventricular dysfunctionimmediately after ligation, and con-cerns over the development of scolio-sis.101–105 Additional data from the TIPPstudy have indicated that infantswhose DA is ligated may be at greaterrisk for poor developmental outcomecompared with infants treated medi-cally,106 but the current data are incon-clusive as to whether the neonatestreated surgically were particularlysick or whether PDA ligation itself con-



tributed to adverse neurodevelop-ment. A preterm baboon study thatcompared surgical ligation at DOL 6versus no PDA treatment and evalu-ated brain histology at DOL 14 revealedsmall differences in brain weight fa-voring ligation with no evidence ofovert injury in either group.107 A retro-spective study of 446 preterm infantsrevealed that surgical ligation was as-sociated with CLD on regression anal-ysis but not with neurodevelopmentalimpairment.108 As mentioned above, atrial of prophylactic ligation in the first24 hours of life did significantly reducethe incidence of NEC.37 It is unfortunatethat there have been no recent prospec-tive RCTs comparing outcomes after li-gation with outcomes after either placeboor medical treatment.37,102,109,110 There-fore, the risks and benefits of surgicalligation in PDA compared with contem-porary alternatives are unknown.89

Again, the only way to resolve the ben-efits and risks to the use of either COXinhibitors or primary surgical ligationis by performing an RCT that includes aplacebo group in which PDA treat-ment is offered to infants in very lim-ited circumstances (eg, pulmonaryhemorrhage, persistent cardiovas-cular instability, pulmonary edemanecessitating high ventilator set-tings, severe ductal steal in the cere-bral or intestinal circulation).

CONSERVATIVE TREATMENT OF PDA

Vanhaesebrouck et al111 prospectivelystudied 30 neonates �30 weeks’ ges-tational age. All infants with PDA weretreated following a standard protocolas soon as a diagnosis of a hemody-namically important PDA (DA diame-

ter � 1.4 mm according to colorDoppler) was made. Initially, conser-vative treatment was performed andconsisted of fluid restriction (maxi-mum: 130mL/kg per day beyond day 3)and adjustment of ventilation (lower-ing inspiratory time and giving higherpositive end-expiratory pressure). Itwas planned that infants with a PDAwho did not show clinical improve-ment and/or deterioration, with con-tinuing need for ventilatory support,would undergo ductal ligation. Nomedication for prophylactic or thera-peutic treatment of PDA was given. Tenneonates developed a clinically impor-tant PDA. After conservative treatmentthe duct closed in all neonates, andnone of them required ductal ligationor medical treatment. The rates of ma-jor complications were no higher thanthose reported in the literature. Hence,for a selected subgroup of VLBW pre-term infants, conservative treatmentconsisting of fluid restriction and ven-tilator adjustment may be an alterna-tive treatment, although its efficiencyshould be studied in larger trials.

CAN WE DEFINE OBJECTIVE ANDRELIABLE CRITERIA FOR THEPREDICTION OF PDACOMPLICATIONS AND THE NEEDFOR TIMELY INTERVENTION?

Sehgal and McNamara45,112 recentlysuggested a staging system for PDAbased on clinical and echocardio-graphic criteria. The aforementionedechocardiographic criteria and bi-omarkers such as BNP, NT-pro-BNP,and cTNT47 may allow the creation of aclinical algorithm for identifying at-risk infants and determining indica-

tion, timing, and best mode of therapy.A future RCT on ductus interventionshould investigate whether an algo-rithm based on predefined clinical,echocardiographic, and biochemicalcriteria versus an algorithm that ex-cludes biomarkers decreases the rateof “rescue PDA ligation” and adverseoutcomes such as IVH grade III � IV,BPD, NEC, and death.

CONCLUSIONS

In his article on the natural history ofpersistent DA, Campbell astutely pre-dicted in 1968 that “as the years pass,more physicians will be advising oper-ation for a persistent ductus arterio-sus with no personal experience of itsnatural course without operation.”113

This statement seems to likewise betrue for COX inhibition; it is unfortu-nate that today we are in that very sit-uation.89 Closure of the preterm PDAeither by COX inhibition or surgical li-gation is currently justified only by thereduction in severe IVH with prophy-lactic administration of indomethacinand, potentially, the reduction in NECwith prophylactic surgical ligation;however, given the risks of either ther-apy and the high rate of spontaneousclosure, these prophylactic strategiescannot be recommended for all pre-term newborns. Treatment strategiesfor the symptomatic PDA may be justi-fied for select patients.

ACKNOWLEDGMENTWe thank Dr Bernard Thebaud, Univer-sity of Alberta, for critically reading themanuscript.

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DOI: 10.1542/peds.2009-3506; originally published online April 26, 2010; 2010;125;1020Pediatrics

Shannon E.G. Hamrick and Georg HansmannPatent Ductus Arteriosus of the Preterm Infant

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