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Journal of the American Heart Association
J Am Heart Assoc. 2022;11:e025784. DOI: 10.1161/JAHA.122.025784 1
CONTEMPORARY REVIEW
Patent Ductus Arteriosus: A Contemporary
Perspective for the Pediatric and Adult
Cardiac Care Provider
Carl H. Backes , MD; Kevin D. Hill , MD, MSCI; Elaine L. Shelton , PhD;
Jonathan L. Slaughter , MD, MPH; Tamorah R. Lewis , MD, PhD; Dany E. Weisz , MD;
May Ling Mah , MD; Shazia Bhombal , MD; Charles V. Smith , PhD; Patrick J. McNamara , MD;
William E. Benitz , MD; Vidu Garg , MD
ABSTRACT: The burden of patent ductus ar teriosus (PDA) continues to be significant. In view of marked differences in preterm
infants versus more mature, term counterparts (viewed on a continuum with adolescent and adult patients), mechanisms reg-
ulating ductal patency, genetic contributions, clinical consequences, and diagnostic and treatment thresholds are discussed
separately, when appropriate. Among both preterm infants and older children and adults, a range of hemodynamic profiles
highlighting the markedly variable consequences of the PDA are provided. In most contemporary settings, transcatheter
closure is preferable over surgical ligation, but data on longer- term outcomes, particularly among preterm infants, are lack-
ing. The present review provides recommendations to identify gaps in PDA diagnosis, management, and treatment on which
subsequent research can be developed. Ultimately, the combination of refined diagnostic thresholds and expanded treatment
options provides the best opportunities to address the burden of PDA. Although fundamental gaps remain unanswered, the
present review provides pediatric and adult cardiac care providers with a contemporary framework in PDA care to support the
practice of evidence- based medicine.
Key Words: patent ductus arteriosus ■ pediatric cardiology ■ treatment
The ductus arteriosus (DA) is a vascular structure
that bridges the 2 major arteries leading from the
heart, connecting the proximal descending aorta
to the pulmonary artery near the origin of the left branch
pulmonary artery. The DA is an essential component
of fetal circulation, diverting cardiac output away from
the lungs toward the placenta to support systemic ox-
ygenation. At birth, the placental circulation is clamped
and removed, resistance in the pulmonary vascular
bed decreases, and the lungs become the source of
oxygenation and gas exchange; thus, the DA is no lon-
ger necessary. In normal term infants, the DA closes
in >90% by 48 hours and in 100% by 96 hours of age.1
In preterm infants, structural and physiological imma-
turity of the ductus is associated with later closure of
the DA and increasing the probability that the DA will
remain patent at the equivalent of term gestation.2,3 For
example, among infants born at <26 weeks’ gestation,
the median age at spontaneous DA closure is 66 days,
and at term equivalent age the DA remains patent in
>25%,2 referred to as a patent DA (PDA). In a few indi-
viduals, a PDA will remain open into later childhood or
adult life.
The clinical consequences of a PDA are depen-
dent on its size and the cardiopulmonary status of
the patient. Although fundamental questions on best
treatment practices for the PDA remain unanswered,
the present review is intended to provide pediatric
and adult cardiac care providers with a contemporary
framework to support the practice of evidence- based
Corres ponden ce to: Carl H. Bac kes, MD, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, OH 43205.
Email: carl.backes@nationwidechildrens.org
This article was sent to Mark W. Russell, MD, Guest Editor, for review by expert referees, editorial decision, and final disposition.
For Sources of Funding and Disclosures, see page 19.
© 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use
is non-commercial and no modifications or adaptations are made.
JAHA is available at: www.ahajournals.org/journal/jaha
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J Am Heart Assoc. 2022;11:e025784. DOI: 10.1161/JAHA.122.025784 2
Backes et al PDA: A Contemporary Perspective
medicine. In view of marked differences in preterm in-
fants and more mature, term counterparts (viewed on a
continuum with term infants beyond the first months of
life, older children, and adult patients), the mechanisms
regulating ductal patency, genetic contributions, clini-
cal consequences, and diagnostic and treatment ap-
proaches are discussed separately, when appropriate.
NORMAL EMBRYOLOGY, ANATOMY,
AND PHYSIOLOGY
In normal cardiovascular development, the sixth em-
bryonic aortic arches undergo morphological trans-
formations that result in bridges between the main
pulmonary artery and the descending aorta distal to
the left subclavian artery (Figure1).4 The proximal por-
tions of the sixth embryonic arches form the branch
pulmonary arteries, whereas the distal left sixth arch
forms the DA.4 This transformation occurs in the first
8 weeks of fetal development in humans. Although an
essential fetal structure, the DA is abnormal if it remains
patent beyond the neonatal period. The DA may per-
sist in a wide variety of sizes and configurations, with
variable relationships to adjacent structures (Figure2).
These anatomic considerations provide insight into
pathophysiologic consequences (discussed below).
MECHANISMS REGULATING FETAL
DUCTAL PATENCY AND CLOSURE
The fetal DA has intrinsic tone, which requires di-
lating factors to maintain patency in utero (Figure3A).
During early fetal development, endothelially derived
nitric oxide (NO) is the primary relaxing agent and acts
through cyclic guanosine monophosphate (cGMP)/
protein kinase G signaling.5 As the fetus approaches
term gestation, the burden of keeping the DA patent
shifts to prostaglandin E2, originating from the pla-
centa,6 which interacts with the G- protein– coupled
receptor, prostaglandin E2 receptor 4 (EP4), to initiate
the cyclic adenosine monophosphate (cAMP)/protein
kinase A signaling cascade.7 Irrespective of the initiat-
ing signaling molecule, these pathways cooperatively
decrease the concentrations of intracellular calcium,
thereby preventing DA smooth muscle cell contraction
during fetal life.8,9
MECHANISMS REGULATING NORMAL
POSTNATAL DUCTAL CLOSURE
Postnatally, the DA functionally closes and perma-
nently remodels into the fibrous ligamentum arterio-
sum. Several molecular, structural, hemodynamic, and
maternal environmental/infection factors have been
described that contribute to postnatal ductal closure.
Molecular Factors
Postnatal DA closure is facilitated by sharp reductions
in dilating factors and increases in intracellular calcium
levels (Figure3B). The onset of respiration dramatically
Nonstandard Abbreviations and Acronyms
DA ductus arteriosus
HSPDA hemodynamically significant patent
ductus arteriosus
IE infective endocarditis
PAH pulmonary arterial hypertension
RD risk difference
Figure 1. Schematic of embryonic aortic arch system.
The 6 pairs of embryonic aortic arches are shown (left-sided
arches are numbered). Broken-lines represent portions that
involute in normal development. The distal left sixth embryonic
arch normally persists and becomes the PDA, bridging the left
pulmonar y artery to the proximal descending aorta. The right
distal sixth arch normally involutes, as does the eighth segment
of the right dorsal aor ta (*), which results in a leftward aortic
arch. PDA indicates patent ductus arteriosus; LCA, left carotid
arter y; LSCA, left subclavian ar tery; RCA, right carotid ar tery;
and RSCA, right subclavian artery. Reproduced from Schneider
and Moore [4] with permission. Copyright ©2006, American Hear t
Association, Inc.
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J Am Heart Assoc. 2022;11:e025784. DOI: 10.1161/JAHA.122.025784 3
Backes et al PDA: A Contemporary Perspective
increases the alveolar PaO2, which acts as a principal
regulator of DA closure. Emerging evidence suggests
that immature biochemical oxygen- sensing mecha-
nisms contribute to maintenance of ductal patency in
preterm infants.10
Structural Factors
Compared with term infants, rudimentary or absent
intimal cushions, fewer mature contractile smooth
muscle cells, and lack of vasa vasorum are structural
components that contribute to sustained ductal pa-
tency in preterm infants.
Hemodynamic Factors
Recent evidence suggests PDA tone may also be
regulated by biomechanical factors, particularly
among preterm infants. Although data are mixed,11
some investigators have observed an association
between thrombocytopenia and delayed ductal clo-
sure in very preterm infants.12 Interestingly, among
thrombocytopenic premature infants, platelet transfu-
sions fail to accelerate PDA closure. These observa-
tions have led some health care providers to postulate
that platelet function, not platelet number, may be a
regulator of preterm PDA status.13
Maternal Environmental/Infection Factors
Congenital rubella syndrome may contribute to post-
natal ductal patency.14 Zika virus is emerging as an-
other potential infectious cause of PDA.15 In addition to
infectious origins, prenatal teratogens are associated
with increased incidence of PDA. For example, tetrahy-
drocannabinol concentrations secondary to cannabis
use among pregnant women have been associated
with a greater incidence of PDAs.16,17
GENETIC CONTRIBUTORS
PDA has a complex and multifactorial genetic cause.
Evidence suggests that the PDA is likely 2 overlapping
Figure 2. Variations in patent ductus arteriosus (PDA) configuration.
Illustration of multiple configuration of PDAs: type a (“conical”) ductus, with defined aortic ampulla and constriction near the pulmonary
arter y (PA) end; type b (“window”) ductus, with short length and constriction at the aortic end (wide PA end); type c (“tubular”) ductus,
without constrictions at the aor tic or pulmonary ends; type d (“saccular”) ductus, with constricted aortic and pulmonary ends and a
wide center; type e (“elongated”) ductus, which is narrow with a constricted pulmonary end; and type f (“fetal”) ductus, which is found
largely in premature infants and is long, wide, and tortuous. AO indicates aorta.
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Backes et al PDA: A Contemporary Perspective
disorders, wherein preterm PDA arises from structural
and physiological immaturity, and term PDA arises
from genetic alterations.18 PDA is a common finding
in dysmorphic syndromes associated with congenital
heart disease, with an estimated 10% of PDA cases
associated with chromosomal abnormalities (Ta b l e 1).
PDA exists in syndromic and nonsyndromic forms;
syndromic cases of PDA, more common in term in-
fants, are associated with chromosomal aneuploidy
(eg, trisomy 21), chromosomal microdeletion (eg,
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Backes et al PDA: A Contemporary Perspective
22q11.2 deletion), and single- gene defects (eg, Char).
Among term infants, epidemiologic studies report an
increased recurrence risk in siblings of 2% to 4% for
PDA.19 Interestingly, among preterm infants, the inci-
dence of PDA (requiring therapy) in monozygotic twins
is higher than in dizygotic twins.20 However, most cases
of nonsyndromic PDA are attributable to multifactorial
inheritance, wherein underlying genetic predisposi-
tions and environmental triggers at vulnerable times
are likely contributory.21,22 Lack of available human DA
tissues precludes studies on the mechanisms of DA
function, but mouse models have been developed that
provide insight on pathways in DA regulation.23
EPIDEMIOLOGY
PDA represents the most common cardiovascular
condition of preterm infants,24 and the incidence of
PDA is inversely related to gestational age at birth.3
Recent evidence suggests that >50% of infants born
at <26 weeks of gestation have an open ductus be-
yond 2 months postnatal.3 Data among term infants
suggest that PDAs are observed in ≈1 in 2000 births,
accounting for 5% to 10% of all congenital heart dis-
ease.24 Longitudinal cohort studies suggest that the
incidence of “silent” PDA, those cases discovered by
cardiac imaging in the absence of clinical manifesta-
tions, approach 1 in 20 births.25
PATHOPHYSIOLOGY
The hemodynamic consequences of PDA are mark-
edly variable. In infants whose pulmonary vascular re-
sistance decreases at birth and PDA remains patent,
a continuous left- to- right shunt develops. Shunt flow,
according to the Poiseuille Law, is proportional to the
pressure gradient between the aorta and pulmonary
artery and inversely related to the resistance to flow.
The impact of changes in pulmonary and systemic re-
sistances is greater among patients with a larger ductus
and less resistance to flow than in those with a smaller
ductus and greater resistance to flow. Modifiable de-
terminants of pulmonary vascular resistance (eg, PaO2
and pH) also modulate transductal flow.26
A left- to- right ductal shunt results in excessive pul-
monary blood flow. The magnitude of the PDA shunt
and its associated cardiopulmonary interactions dic-
tate the pathophysiologic features of this lesion in
clinical care. Specific features of cardiovascular me-
chanics associated with prematurity predispose
neonates, in particular, to greater PDA- associated
cardiorespiratory compromise. A left- to- right ductal
shunt results in increased pulmonary blood flow and
left heart dilatation, culminating in higher left ventricular
end- diastolic pressures, upstream pulmonary venous
pressure, and pulmonary congestion, a pathophysiol-
ogy exacerbated among preterm neonates because
of greater elastance of immature ventricles.27 Unlike
in adults, in whom pulmonary vascular distention and
capillary bed recruitment assist in managing increased
pulmonary blood flow without associated changes in
capillary hydrostatic pressure, the pulmonary vascular
bed in neonates is already nearly fully recruited and
poorly compliant.28 PDA- associated increases in pul-
monary blood flow therefore result in increased pul-
monary arterial pressure and a shift in the pulmonary
pressure head to downstream capillary filtration sites,
leading to pulmonary interstitial edema, reduced lung
compliance, and impaired oxygenation.29,30 Additional
increases in left atrial and volume and pressure over-
load associated with larger ductal shunts may further
worsen pulmonary venous pressure and culminate in
Figure 3. Molecular pathways involved in int rauterine ductus arteriosus (DA) relaxation (A) and molecular pat hways involved
in postnatal DA constriction (B).
A, Endothelial NO synthase (eNOS)– derived NO, CO, and atrial natriuretic peptide (ANP) initiate the cGMP signaling cascade by
activating membrane - b ound or soluble guanylate cyclase (sGC). cGMP subsequently activates protein kinase G (PKG), which decreases
the intracellular calcium concentration by inhibiting voltage- dependent calcium channels ( VDCCs) and promoting calcium uptake into
the sarcoplasmic reticulum. PKG also activates voltage- gated potassium channel (Kv), ATP- gated potassium channel (KAT P), and large
conductance calcium- activated potassium channel (BKCa), which trigger potassium efflux and membrane hyperpolarization, resulting in
VDCC inhibition. In addition, prostaglandin E2 (PGE2), working through the prostaglandin E2 receptor 4 (EP4), activates adenylyl cyclase.
Adenosine also activates adenylyl cyclase, which, in turn, activates the cAMP/protein kinase A (PKA) signaling cascade. PKA activates
Kv, KATP, and BKCa and inhibits myosin light chain kinase (MLCK), which subsequently reduces phosphor ylation of myosin light chains
(MLCs), thereby preventing vasoconstriction. B, Increased O2 tension increases the concentration of intracellular calcium via several
pathways. First, O2 stimulates mitochondrial production of ATP and H2O2, which inhibit vasodilating KAT P and Kv. H2O2 also activates
the ras homologous protein (Rho)/rho- associated protein kinase (ROCK) cascade, which promotes constriction by inhibiting MLC
phosphatase (MLCP)– mediated MLC dephosphorylation. In addition, O2 upregulates the production of 8- iso- prostaglandin F2α (8- iso-
PGF2α), which signals through thromboxane receptor (TR) to activate Rho/ROCK and inositol trisphosphate (IP3) signaling cascades.
Furthermore, O2 promotes constriction by cytochrome P450 (CYP450)– mediated binding of endothelin- 1 (ET- 1) to endothelin receptor
A (ETA), which subsequently activates the IP3 pathway. Similarly, glutamate activates IP3 signaling via noradrenaline (NA) production.
Once activated, IP3 then binds to IP3 receptor (IP3R) on the sarcoplasmic reticulum, causing movement of calcium into the cytoplasm.
Intracellular calcium concentrations are also regulated by transient receptor potential melastatin- 3 channel (TRPM3), which becomes
activated under hypo- osmotic conditions. Accumulation of intracellular calcium facilitates activation of MLCK, which phosphorylates
MLC, allowing for myosin and actin interaction and subsequent muscle contraction. [Ca2+]i indicates concentration of intracellular
calcium; and [Ca2+]SR, concentration of calcium in the sarcoplasmic reticulum.
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Backes et al PDA: A Contemporary Perspective
alveolar edema and further deterioration in respira-
tory mechanics and function. Preterm neonates with
respiratory distress syndrome are more sensitive to
increases in microvascular perfusion pressure and
demonstrate exaggerated increases in interstitial and
alveolar lung fluid accumulation, resulting in second-
ary surfactant dysfunction.31,3 2 Diastolic flow reversal in
the descending aorta attributable to ductal shunting to
the pulmonary artery can occur and is associated with
reduced abdominal organ blood flow.33 Absent or re-
verse end- diastolic flow may occur in the celiac, supe-
rior mesenteric, and middle cerebral arteries, although
only middle cerebral artery flow aberrations have been
associated with neonatal morbidity.34
Table 1. PDA Associated With Genetic Syndromes (Selected)
Syndrome Gene(s) Location Additional cardiac lesions
Tri s om y 2 113 Copies of chromosome 21 Atrioventricular septal defect; atria l
septal de fects; ventr icular septal
defect; tetralogy of Fallot
Tri s om y 1823 Copies of chromosome 18 Atrial and ventr icular s eptal
defects; nonspecific cardiovascular
morphologic abnormalities
Tri s om y 1333 Copies of chromosome 13
22q11.2 deletion4TBX1, CRKL 22q 11. 2 Inter rupted aor tic arch (type
B); tetralogy of Fallot; trun cus
arteriosus; ventricular septal
defects; aortic arch abnormalities
Wolf- Hirschhorn5NSD2, WHSC1, LETM1, CTBP1,
CPL X1, FGFRL1
4p Deletion Atrial and ventricular septal
defects; nonspecific cardiovascular
morphologic abnormalities
Char6TFAP 2B 6 p12. 3 Ventricular septal defect
Cantu7ABCC9, KCNJ8 12p12.1 Bicuspid aortic valve; hypertrophic
cardiomyopathy
Carpenter8RAB23, MEGF8 6p12.1- p11.2, 19q13.2 Nonspecific cardiovascular
morphologic abnormalities
CHARGE9SEMA3E, CHD7 7q 21.11, 8 q1 2. 2 Tetralogy of Fall ot; ventricular
septal defect; atrioventricular septal
defect; aortic arch abnormalities
Holt- Oram10 TBX5 12q 24 .1 Atria l and ventricular septal
defects; hypoplastic left heart
syndrome
Loeys- Dietz (forms 1– 5)11 TGFB R1 (1), TGFBR2 (2), SMAD3
(3), TGFB2 (4), TGFB3 (5)
9q22.33 (1), 3p24.1 (2), 15q22.33 (3),
1q41 (4), 14q24.3 (5)
Aortic aneurysm; aortic dissection;
arterial dissection
Mowa t- Wi lso n12 SMA D1P1, ZEB2 2q22.3 Tetralo gy of Fallot; ve ntricul ar
septal defect
Noonan13 PT P N11 (1), LZ TR1 (2, 10), KRAS
(3), SOS1 (4), RAF1 (5), NRAS
(6), BRAF (7), R IT1 (8 ), SOS2 (9),
MRAS ( 11) , R RAS2 (12 ), M A PK1
(13)
12q24.13 (1), 22q11.21 (2, 10),
12p12.1 (3), 2p22.1 (4), 3p25.2
(5), 1p13.2 (6), 7q34 (7), 1q22 (8),
14q21.3 (9), 3q22.3 (11), 11p15.2
(12), 22q11.22
Dysplastic/stenotic pulmonary
valve; pulm onary arter y stenosis,
atrial septal defect; cardiomyopathy
Periventricular heterotopia (X
linked)14
FLNA Xq28 Bicuspid aortic valve
Rubinste in- Taybi (forms 1 and 2)15 CREBBP (1), EP300 (2) 16p13.3 (1); 22q13.2 (2) Nonspecific cardiovascular
morphologic abnormalities
ABCC9 indicate s ATP- bi nding ca ssette, su bfamily C m ember 9 (ak a, sulfonylurea re ceptor 2) enc oding ge ne; BRAF, B- Raf encoding gene; CH ARGE,
coloboma of the eye, heart defe cts, atres ia of the choanae, retardation of growth and /or developm ent, geni tal hypoplasia, a nd ear abnormalities (eg, de afness);
CHD7, chromodomain– helicase– DNA- binding protein 7 (aka, ATP- dependent helicase CHD7) encoding gene; CPL X1, complex in- 1 enc oding ge ne; CREBBP,
CREB- binding protein encoding gene; CRKL, Crk- like protein enc oding ge ne; CTBP1, C- terminal– binding prote in 1 (aka, CtB P1) encoding ge ne; EP300, histone
acetyltransfe rase p30 0 (aka, p30 0 HAT, adenovirus early regio n 1A– associated p rotein p30 0) encod ing gene; FGFRL1, fibroblast growth factor receptor- like
1 encodi ng gene; FLNA, fi lamin A, α encoding gene; KCNJ8, potassium inwardly rectif ying channel, subfamily J, member 8; K RAS, K- Ras encoding gene;
LETM1, leucine zipper- EF- hand co ntaining transmembrane protein 1 encoding ge ne; LZ TR1, leucine– zipper- like transcriptional regulator 1 encoding gene;
MA PK1, mito gen- activated protein kinase 1 (aka , MAPK1, p42MAPK, ERK2) encoding gene; MEGF8, multiple epidermal growth factor- like domains 8; MRAS,
Ras- re lated protein M- Ra s (aka, mu scle RAS oncoge ne homolog, R- Ras3) encoding gene; NRAS, neuroblastoma RAS viral oncogene homolog encoding gene;
NSD2, nuclear re ceptor binding SE T domain p rotein 2 encoding gene; PDA, patent ductus ar teriosus; PT P N 11, tyrosine- protein phosphatase nonreceptor
type 11 (aka, protein- tyrosine phosphatase 1D, Src homology region 2 domain- containing phosphatase- 2, protein- tyrosine phosphatase 2C) encoding gene;
RAB23, Ras - related protein Rab- 23 encoding ge ne; RA F1, RAF proto- oncogen e serine /threonine- protein kina se (aka, proto- onc ogene c- RAF, c- R af, Raf- 1)
encoding gene; RIT1, GTP- binding prote in Rit1 encoding gene; RRAS2, Ras- related protein R- Ras2 encoding gene; SEMA3E, semaphorin 3E encoding gene;
SMAD, mothers agai nst deca pentap legic ho molog (ak a, SMAD family member) encoding genes; SOS, son of sevenless homolog encoding genes; TBX, T-
box transc ription factor enco ding gen es; TFAP2B, tra nscription factor A P- 2 β (aka, AP2- β) encoding g ene; TGFB, tran sforming growth factor enco ding gen es;
TGFBR, transforming growth factor- β receptor enco ding gen es; WHS C1, probable histone- lysine N- methyltransferase nuclear receptor binding SET domain
protein 2 encoding gene; and ZEB2, zinc finger E- box– binding homeobox 2 encoding gene.
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DEFINING THE HEMODYNAMICALLY
SIGNIFICANT PDA
Among preterm infants, health care providers are
often unable to clearly discern if the PDA is causal of,
or merely associated with, adverse outcomes. Thus,
contemporary definitions of a hemodynamically signifi-
cant PDA (HSPDA) are not simply echocardiographic-
derived markers of atrial or ventricular chamber
enlargement, but rather various clinical and echocar-
diographic parameters aimed at identifying preterm
infants in whom ductal shunt volumes are estimated
to be primary pathological contributors to physiologic
instability (Ta ble2).35 In contrast, among term infants,
older children, and adults, general consensus is that
echocardiographic evidence of left atrial or left ventric-
ular enlargement attributable to the ductus constitutes
an HSPDA (Tab l e 3).36
CLINICAL CONSEQUENCES IN
PRETERM INFANTS
In the setting of unique developmental vulnerabilities,
PDA among preterm infants is associated with sev-
eral adverse outcomes, including death, that are not
typically observed in older, more mature patients.37- 3 9
Despite decades of investigation, clarity on the relative
contributions to short- and longer- term sequelae of a
persistent ductus, including treatments used to close
the ductus, have not been resolved.40- 43
Respiratory
The potential pathological effects of left- to- right ductal
shunting include an association with increased respiratory
support, mechanical ventilation, and chronic lung disease
(notably, bronchopulmonary dysplasia [BPD]). PDA expo-
sure has been associated with pulmonary hemorrhage,
with estimates suggesting an incidence of 3% to 23%,
depending on the gestational age, ductal size, and as-
sociated PDA treatments.44,45 However, a recent meta-
analysis of early treatment (defined as treatment initiated
by postnatal day 7) compared with expectant manage-
ment for an HSPDA among infants at <37 weeks of ges-
tation observed no differences between the 2 groups in
rates of pulmonary hemorrhage (relative risk [RR], 0.58
[95% CI, 0.30– 1.11]; 5 studies; N=332).46
Emerging data suggest that duration of exposure,
rather than simply the presence or absence of a duc-
tal shunt, may contribute more to observed outcomes.
Among infants born at <28 weeks of gestation, the risks of
the composite outcome of BPD or death were greater after
7 to 13 days of exposure to moderate- to- large PDAs than
in infants who closed their ductus in their first postnatal
week (odds ratio [OR], 2.12 [95% CI, 1.04– 4.32]).47 For the
outcome of increased BPD alone, PDA exposure ≥14 days
was associated with increased BPD (OR, 4.08 [95% CI,
Table 2. Comprehensive Grading Schema for HSPDA Among Preterm Infants
Clinical Echocardiography
Asymptomatic No
PDA
No evidence of ductal flow on 2D or Doppler interrog ation
Mild symptoms
• MAP <8 mmHg (on respiratory support of
NCPAP or mechanical ventilation)
• Feeding intolerance
Small,
non- HSPDA
• Transductal d iameter <1.5 mm
• Restrictive continuous tra nsduct al flow (DA Vmax >2.0 m/s)
• No signs of l eft hea rt volu me loadin g (eg, mitral
regurgi tant jet >2.0 m/s or LA:Ao >1.5:1)
• No signs of l eft hea rt pressure loading (eg, E/A ratio
<1.0or IVRT <50)
Moderate symptoms
• MAP 9– 12 mmHg (ventilation requireme nt)
• Evidence of abdom inal distention and/or
persistent emesis
Moderate, HSPDA • Transductal d iameter 1.5– 3.0 m m
• Unrestr ictive pulsatile transductal flow (DA Vmax <2.0 m/s)
• Mild- mod erate lef t hear t volume lo ading (eg, L A:Ao
1. 5 – 2.1 )
• Mild- mod erate lef t hear t pressu re loadin g (eg, E/A ratio
≥1.0 or IVRT 50 – 60)
• Decrea sed or abs ent diastolic flow in the superior
mesenteric, middle cerebral, and/or renal arteries
Severe symptoms
• MAP >12 mmHg (high ventil ation requirements
or HFOV)
• Marked abdominal distention and/or erythema
Large HSPDA • Transductal d iameter >3.0 m m
• Unrestrictive pulsatile transductal flow
• Severe lef t hear t volume loading (eg, LA:Ao >2.1,
mitralregurgitant jet >2.0 m/s)
• Severe lef t hear t press ure loadi ng (eg, E/A ratio >1.5 or
IVRT >60)
• Reversal of end- diastolic flow in superior mesenteric,
middle cerebral, and/or renal arteries
2D indicate s 2 dimens ional; DA Vmax, transducta l maximal flui d velocit y; E/A (ratio), peak velocit y blood f low from the l eft ventricula r relaxation in ea rly dias tole
(E- wave) to peak veloci ty flow in late diastol e caused by atrial co ntractio n (A- wave); HFOV, high- frequency oscillatory ventilation; HSPDA, hemo dynamically
signif icant PDA; IVRT, isovolumic relaxati on time; LA:Ao, left atrial dia meter to aor tic root diameter rati o; MAP, mean airway pressure; NC PAP, nasal c ontinuous
positive airway pressure; and PDA, patent ductus arteriosus.
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Backes et al PDA: A Contemporary Perspective
2.32– 7.22]) compared with infants whose ductus closed
in the first postnatal week.47 However, duration of ductal
patency may be a biomarker of increased pulmonary or
systemic illness, rather than causal, for development or
progression of observed outcomes (BPD or death).48
Neurologic
Independent of the presence of PDA, prematurity is
associated with intraventricular hemorrhage, periven-
tricular leukomalacia, and compromised school- aged
performance.4 9- 51 Most intraventricular hemorrhage oc-
curs in the first postnatal week, coincident with decrease
of pulmonary vascular resistance and emergence of a left-
to- right PDA shunt in some preterm infants. Prophylactic
indomethacin is provided in the first postnatal days and
often before a diagnosis of a PDA. Compared with pla-
cebo, administration of prophylactic indomethacin after
preterm birth reduces the incidence of symptomatic PDA
(risk difference [RD], −0.24 [95% CI, −0.28 to −0.21]; RR,
0.44 [95% CI, 0.38– 0.50]) and surgical PDA ligation (RD,
−0.05 [95% CI, −0.08 to −0.03]; RR, 0.51 [95% CI, 0.37–
0.71] ).52 In addition, prophylactic indomethacin reduces
the incidence of severe periventricular and intraventricu-
lar hemorrhage more effectively than does placebo (RD,
−0.05 [95% CI, −0.07 to −0.02]; RR, 0.66 [95% CI, 0.53–
0.82])52; however, these early neurological benefits may
be unrelated to closure of the ductus.53 However, pro-
phylactic indomethacin is not associated with reduced
mortality or improved neurodevelopment at 18 months of
age (RD, 0.01 [95% CI, −0.04 to 0.06]; RR, 1.02 [95%
CI, 0.90– 1.15]).52,54 In view of these observations, rates of
indomethacin use in the first 24 hours postnatal is ≈7%
across US hospitals.55 In the absence of clear evidence,
controversies persist on the benefits (or lack thereof) and
optimal use of indomethacin prophylaxis for preterm in-
fants.42,56,57,58,59,60 Some investigators have called for the
abandonment of routine prophylactic indomethacin to
all preterm infants,42 whereas others have suggested a
nuanced approach that takes into consideration an in-
dividual center’s baseline risk of intraventricular hemor-
rhage.56 Surgical ductal ligation has been associated with
neurodevelopmental impairment in early childhood,61 but
failure to account for confounding effects because of pa-
tient illness limits data interpretation.62
Intestinal Injury
Diastolic flow reversal in the abdominal aorta and sys-
temic arteries (renal, celiac, and superior mesenteric) is
common among preterm infants with PDA.63 Although
data are mixed, contemporary randomized clinical tri-
als have not observed differences in rates of necrotiz-
ing enterocolitis following ductal closure compared
with nonclosure.64,65 More important, simultaneous
administration of early systemic hydrocortisone and
indomethacin for intraventricular hemorrhage prophy-
laxis increases the risk of spontaneous intestinal per-
foration and is contraindicated.66
CLINICAL CONSEQUENCES AMONG
OLDER PATIENTS (TERM INFANT
THROUGH ADULTHOOD)
Pulmonary Arterial Hypertension and
Eisenmenger Syndrome
Although the precise pathophysiological mechanisms
are not completely understood, long- standing left- to-
right shunting exposes the pulmonary arterial system
Table 3. Comprehensive Grading Schema for HSPDA Among Ol der Children and Adults
PDA size Physiological symptoms
Silent or trivial • “Silent” (inaudible) PDAs are asymptomatic*
• No hemodynamic or anatomic sequelae
• Normal exercise capacity
• Normal renal, hepatic, and pulmonary function
Small • Small left- to- right shunt, not HSPDA
• No restri ctions of exe rcise capacity
Mild/moderate • Mild- moderate left- to- right or bidirectional shunt, HSPDA
• Mild- moderate hemodynamic or anatomic sequelae (mild/moderate LAE and/or LVE, mild-
moderate left ventricular dysfunction)
• Mild or moderate hypoxemia/cyanosis
• Mild or moderate PH
• Potential for mild rena l, hepatic, a nd pulmonary dysfunction
Large • Larg e left- to- right, bidirec tional, or right- to- left shunt
• Severe hemodyna mic or anatomic sequ elae (severe LAE and/or LVE, moderate to severe lef t
ventricular dysfunction)
• Moderate or severe hypoxemia/cyanosis
• Severe PH
• Risk of Eisenmeng er syndro me with PH an d right- to- lef t shunting
HSPDA indicates hemodynamically significant PDA, defined as left atrial/ventricular enlargement and/or sustained pulmonary blood flow to systemic blood
flow ratio (Qp/Qs) ≥1.5; LAE, l eft atri al enlargement; LVE, left ventri cular en largem ent; PDA, paten t ductus arterio sus; and PH, pu lmonar y hyper tension.
*Not all asymptomatic PDAs are silent.
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Backes et al PDA: A Contemporary Perspective
to higher pressures and greater blood flows. Over time,
this leads to progressive morphological changes in the
pulmonary vasculature, including arteriolar medial hy-
pertrophy, intimal proliferation and fibrosis, and even-
tual obliteration of pulmonary arterioles and capillaries,
characterized by increased pulmonary vascular resist-
ance with development of pulmonary arterial hyper-
tension (PAH).67 When pulmonary vascular resistance
approaches and exceeds systemic vascular resistance,
ductal shunting reverses and becomes right to left, clas-
sically described as Eisenmenger syndrome. Clubbing
of toenails and spared (or mild) clubbing in the fingers is
pathognomonic for Eisenmenger syndrome in the set-
ting of a PDA.68 In this setting, patients may develop right
ventricular systolic failure, the most common cause of
death among patients with Eisenmenger syndrome.69
Infective Endocarditis
Historical estimates suggest an incidence of infective
endocarditis (IE) of ≈1% among patients with a PDA.70,71
Sadiq et al observed that, among 2908 children aged
<16 years admitted to a single pediatric cardiology
center over a 6- year time frame, 96 (3.3%) fulfilled di-
agnostic criteria for IE; PDA was the cardiac lesion in 14
children with IE (14.6%).72 Alternatively, of nearly 3 mil-
lion deaths in Sweden (1960– 1993), Thilen and Astrom-
Olsson reported 2 cases of IE as a complication of
PDA.73 Historically, risk of IE was commonly cited as an
indication for ductal closure beyond infancy74; however,
recent guidelines from the American Heart Association
no longer support use of antibiotic prophylaxis (outside
the first 6 months following definitive ductal closure)
among patients with PDA to prevent IE.75
DIAGNOSTIC ASSESSMENT OF THE
PDA
Diagnostic assessments vary according to the hemo-
dynamic significance of the ductus.
Unique Considerations in the Diagnosis of
PDA Among Preterm Infants
In contemporary medical settings, transthoracic echo-
cardiography is the preferred noninvasive modality to
assess ductal significance in preterm infants (Ta b l e 4).
Interrogation of ductal flow using 2- dimensional and color
flow Doppler can determine ductal size and shunt direc-
tion (Figure4A), as well as shunt volume (Figure4B).76,77
ASCERTAINMENT OF HEMODYNAMIC
SIGNIFICANCE
To target infants with the highest probability of de-
riving benefits following ductal treatment (described
below), health care providers have attempted to define
subgroups of preterm infants, based on clinical or so-
nographic criteria, with HSPDAs. However, lack of a
standardized or validated definition of HSPDA has led
to medical uncertainty about which infants with a diag-
nosis of PDA should receive treatment. This may relate,
at least in part, to the lack of consistency in the defini-
tions of HSPDA used to date in published randomized
clinical trials. A systematic review of the definition of
HSPDA used in published trials highlighted marked
variance with the use of arbitrary echocardiographic
thresholds, which were not validated against relevant
clinical outcomes.78
Historical Determinants of Ductal
Significance: An Oversimplification
The measurable physiological impacts of PDAs in
preterm infants are related to shunt volumes, intrin-
sic cardiopulmonary adaptive mechanisms, and du-
ration of exposure; therefore, arbitrary subjective or
single- point estimates of PDA sizes are unlikely to de-
fine hemodynamic significance accurately. However,
many trials relied solely on PDA diameters to adju-
dicate hemodynamic significance, which represents
an evaluative and physiological oversimplification.
This is attributable to the high likelihood of measure-
ment error related to geometric assumptions (circu-
lar in cross- section) or operator- dependent factors in
echocardiographic- based measurements of ductal
size.45,79,80,81 A PDA diameter of ≥1.5 mm is often used
to define hemodynamic significance, but the data
to support this practice are not evidence based.82
Moreover, several studies have demonstrated the
poor reliability of individual imaging measures and
the weak relationship of ductal diameter to echocar-
diographic indices of pulmonary or systemic blood
fl ow.83- 85 Although left atrial/aortic ratios are also
commonly used to determine ductal significance,
the metric is prone to significant operator- dependent
error and may be falsely normal in the context of a
large interatrial left- to- right shunt decompressing the
left atrium.84 In a comparative evaluation using mag-
netic resonance imaging, holodiastolic flow reversal
in the postductal arch was the most accurate and
reliable echocardiographic estimate of PDA shunt
volume.86
A Comprehensive Approach to Defining
HSPDAs
Rather than a unidimensional approach (eg, ductal
diameter), contemporary definitions of HSPDA in-
tegrate a comprehensive echocardiographic as-
sessment (Table5). The evaluative goal is to identify
preterm infants in whom ductal shunt volumes are
estimated to be primary pathological contributors
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Backes et al PDA: A Contemporary Perspective
to current physiologic instability, considering other
concurrent pathologies (eg, lung immaturity and/
or ventilator- associated injury). The process of ad-
judication of hemodynamic significance should
incorporate clinical and echocardiographic param-
eters in a manner that helps health care provid-
ers recognize a hierarchal model of shunt volume
(small or large), rather than mere ductal patency.
The McNamara PDA staging system proposed
adjudicating hemodynamic significance based on a
composite of clinical and echocardiographic crite-
ria (see Table2, above).35 Prolonged exposures to
higher- volume shunts are associated with greater
risks of prolonged oxygen dependency87 or the
composite outcome of death or BPD.88 The PDA
scoring system recently proposed by El- Khuffash
et al, derived from a prospective evaluation of an
untreated cohort, combined gestational age with 4
Table 4. Diagnostic Assessments
Preterm infant*Diagnostic modalities*Term infant/adult†
Continuous, “machinery” murmur diastolic rumble;
prominent LV impulse; tachycardia, tachypnea,
abdominal distention; prediastolic and postdiastolic
hypotension;
postductal systolic hypotension
Physical examination‡Dif ferential cyanosis (clubbing of the toe s, not the
fingers)§; high- frequency, diastolic decrescendo
murmur; holosystolic; peripheral edema
Cardiom egaly with LA an d LV enlargeme nt,
pulmonary artery dilation, and increased pulmonary
vascular markings
Chest radiograph‡Calcif ications on the ductus; clear l ung fields; dilated
pulmonary arteries without significant cardiomegaly
Findings are highly variable and lack sensitivity/
specificity
ECG‡Ventricular hyper trophy, and ST- segme nt or T- wave
depression
Diastolic flow reversal in postductal a rch; LA dilation
(LA:Ao); ductal diameter indexe d to LPA diameter;
PDA Vmax (CW); ductal left- to - right dia stolic fl ow; LVO;
pulmonary vein diastolic (PVD) Vmax; IVRT
Echocardiogram Right- to- left ductal shunting in systole can b e diff icult
to separate f rom adjac ent LPA; transe sophag eal
echocardiogram may be useful
…CT Faster imaging and breath holding to identify
thromboembolic disease; cardiac gated CT can
identif y calc ifications; may reveal PDA not seen o n
echocardiogram
…Magnetic resonance imaging Gold standard for noninvasive flow, function,
quantification, and anatomic evaluation without
ionizin g radiation for adults; may reveal PDA not seen
on echocardiogram
Safety and feasib ility of d evice closure dem onstrated
in infants weighing 700 g; venous- on ly approach
increasingly adopted
Cardiac catheterization Test occlusion to asse ss tolerance to clos ure (chang e
in PAP, systemic BP); pulmonary vascular reactivity
testing ca n identify resp onse to vasodilators
Lower values (cerebral, renal ) may be markers of
ductal significance; may be beneficial for longitudinal
assessment
Near- infrared spectroscopy Unclea r diagnostic value i n PDA assessment, but u sed
in other cardiovascular conditions and perioperative
settings
Unclear diagnostic value; insufficient evidence to
support universal monitoring
Biomarkers Unclear diagnostic value in PDA assessm ent, but used
in other cardiovascular conditions and perioperative
settings
… indicate s gold sta ndard for diagnosing PDA in preter m infants is transtho racic ec hocardiography; BP, blood pressure; CT, computed tomography; CW,
continuous wave; IVRT, isovolumetric relaxation time; LA, left atrial; LA:Ao, left atrial dia meter to aor tic root diameter rati o; LPA, left pulmonar y artery; LV, left
ventricular; LVO, LV output; PAP, pulmonary ar teria l pressure; PDA, patent du ctus ar teriosu s; and Vmax, maximum velocity.
*Findings described for preterm infants with hemodynamically significant PDA.
†Findings described for adult patients with PDA and associated pulmonary arterial hypertension.
‡Findings are highly variable and lack sensitivity/specificity.
§Recomm end measurement of oxygen s aturatio n in upper a nd lower ex tremiti es in adults to assess for the pres ence of right- to- left shunting (dif ferenti al
cyanosis).
Figure 4. Ductal size and shunt direc tion evaluation (A ) and ductal shunt volume evaluation (B).
A, Echocardiographic verification of patent ductus ar teriosus (PDA) presence, with PDA size and shunt direction assessment. a,
Color flow of PDA . b, Pulsatile pattern with left- to- right low- velocity flow with wide differential between systole and diastole.
c, Restrictive pattern with higher velocity in both systole and diastole. d, Bidirectional pattern with right- to- lef t ductal flow during
systole. B, Echocardiographic examination of left atrial and left ventricular enlargement and quantification of ductal impact on cardiac
performance. a, Dilated left atrium (A) and ventricle (V). b, M- mode measurement, demonstrating a dilated left atrium indexed to the
aortic diameter. c, Elevated and pulsatile pulmonary venous flow, demonstrating high pulmonary venous diastolic flow. d, Shortened
isovolumetric relaxation time. e, Transmitral flow, demonstrating an early/atrial flow ratio of 1. f, Reversal of diastolic flow in the
postductal descending thoracic aorta. IVRT indicates isovolumetric relaxation time; LA:Ao, left atrial diameter to aortic root diameter
ratio; MPA, main pulmonar y artery; MV E/A, mitral valve early/atrial flow ratio; and PV D, pulmonary vein diastolic velocity.
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Backes et al PDA: A Contemporary Perspective
echocardiographic characteristics derived on post-
natal day 2, which provided accurate predictions of
the composite outcome of death or BPD (area under
the curve, 0.92 [95% CI, 0.86– 0.97]).89 However,
benefit from ductal closure based on these criteria
has not yet been demonstrated.
A
B
ac e
bd f
ab
cd
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Backes et al PDA: A Contemporary Perspective
UNIQUE CONSIDERATIONS IN THE
DIAGNOSIS OF PDA AMONG OLDER
PATIENTS (TERM INFANT THROUGH
ADULTHOOD)
Transthoracic echocardiography provides adequate
imaging in term infants, but poor acoustic win-
dows in older patient populations may limit utility.
Transesophageal echocardiography can be used
with views in the upper esophagus using a clockwise
rotation from the aortic views.90 However, color flow
Doppler assessment can be misleading, particularly
in the presence of elevated pulmonary vascular resist-
ance, wherein right- to- left shunting in systole at the
ductus can be difficult to separate from adjacent struc-
tures, including the left pulmonary artery. These obser-
vations have led health care professionals to consider
diagnostic modalities for PDA in older patients beyond
echocardiography, including magnetic resonance im-
aging or computed tomography.
Among adolescent and adult patients with PAH,
cardiac magnetic resonance imaging or computed to-
mographic imaging may illuminate a PDA that was not
revealed during echocardiography. Cardiac magnetic
resonance imaging has long been considered the gold
standard for noninvasive flow assessments, function
quantification, and anatomic evaluation, providing useful
information on ductal morphology and characteristics,
without ionizing radiation. Alternatively, computed tomog-
raphy provides faster imaging and allows breath holding,
preferable for identifying in situ thromboembolic disease
that is prevalent in older patients with long- standing PDA
and associated PAH.91 In addition, cardiac- gated multi-
detector computed tomography scans can identify and
track the extent of calcifications found in subsets of adults
with PDA. This is particularly important to identify when
considering definitive closure (discussed below).92
Table 5. Comprehensive Echocardiographic Assessment of Ductal Significance in Preterm Infants
Echocardiographic
measures Significant PDA Limitations Measurement technique Normal range
Size of ductus
Indexed to LPA diameter PD A/ L PA >1.0 LPA dilation, high- volume
shunt
High- PS vi ew in 2D …
Systemic blood flow (postductal aorta, celiac, MCA)
Flow pat terns: an tegrade,
absent, retrograde
diastolic flow
Flow reversal for dia stolic
steal; abnormal end organ
flow pattern
Accuracy determined by
measurement location angle
of insonation
Aorta: high- PS, PW Doppler
parallel to angle of f low
(diaphragm)
Celiac: sagittal view,
midabdominal
MCA: axi al view, tempo ral
fossa
Forward diastolic flow
Markers of pulmonary overcirculation
1. LVO LVO ↑ [>300] sec ondar y to
increased preload
Dependent on LVOT
morphology; minimize angle
correction
LV- VTI and Aorta: PW at
hinge points of aor tic valve
150– 300 mL/min per kg
2. Mitral valve E/A ratio E/A ≥1 indicates ↑ LA
pressure
Both unrel iable in the
setting of severe mitral valve
regurgitation
Apical 4Ch; PW Doppler
perpendicula r to the MV; at
tips of the le aflets
<1
3. IVRT IVR T <40 Apical 5Ch; PW at
intersection of inf low and
outflow on color Doppler
40– 60 ms
Left he art volume loadi ng
1. L A:Ao ≥1.6 Abnormality could be
secondary to LV dysfunction
PS, long- ax is M- mode
through aortic valve annulus
(LA:Ao)
LA: Ao <1.6
2. PV D- wave velocity ↑ PV diastol ic wave
velocit y [>0.5 m/s]
indicates ↑ PV return
Peak velo city de crease s as
PV dilates w ith larger shunts
Apical 4Ch PW Doppler
parallel to the RUPV inflow
0.2– 0.50 m/s
3. LPA end- diastolic
velocity
↑ PBF leads to ↑ mean
and end- diastolic flow
velocity
LPA dilation commonly
occurs concurrently with ↑
volume shunt
High- PS pa rallel to f low in
the LPA, dista l to the ducta l
insertion
<0.2 m/s
2D indicate s 2 dimens ions; 4Ch, 4 ch amber; 5C h, 5 chambe r; E/A, ratio of peak velocity bl ood flow f rom left ventricu lar rela xation in early di astole (E ) to peak
velocit y flow in late diastole caused by atrial contraction ( A); IVRT, isovolumetric rela xation time; LA, left atri al; LA:Ao, left atrial diameter to aortic root diameter
ratio; LPA, lef t pulmon ary ar tery; LV, left ventricular; LVO, LV outflow; LVOT, LVO tr act; MCA, middle cerebral ar tery; MV, mitral valve; PBF, pulmonary blo od flow;
PDA, patent du ctus ar teriosu s; PS, parasternal (vi ew); PV, pulmonar y vein; PW, pulse wave; and RUPV, right u pper PV; V TI, velocity time integral.
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Backes et al PDA: A Contemporary Perspective
In the setting of long- term ductal exposure, he-
modynamic assessment by cardiac catheterization
provides critical information on the risk/benefit profile
of ductal closure (Figure5). A 2018 joint statement
from the American Heart Association and American
College of Cardiology recommended, on the basis
of consensus expert opinion, that cardiac catheter-
ization can be useful in adult patients with PDA and
suspected PAH.36 In the setting of elevated pulmo-
nary vascular resistance, the PDA may serve as a
physiologic “pop- off” for the right ventricle, allowing
for egress of blood, albeit deoxygenated blood, from
the right ventricle to the systemic circulation. In this
setting, closure of the PDA may precipitate right ven-
tricular failure. Test occlusion of the ductus during
the catheterization can evaluate physiologic tolerance
of the right ventricle to shunt closure.93 In addition,
in the setting of concerns for PAH, performance of
pulmonary vascular reactivity testing during cardiac
catheterization can identify responsiveness to pulmo-
nary vasodilators.94
PDA TREATMENTS IN PRETERM
INFANTS
Indomethacin
Indomethacin, a cyclooxygenase inhibitor (see above)
targeting prostaglandin synthesis, is the prototypical
NSAID and is the most extensively studied medical
treatment for ductal closure among preterm infants.
Thirty- nine randomized trials (23 as prophylaxis,52 4 for
early treatment of an asymptomatic PDA,95 and 12 for
treatment of a symptomatic PDA96) demonstrate con-
sistent efficacy for achievement of ductal closure (RR
for persistent patency, 0.39 [95% CI, 0.35– 0.44], 0.41
[95% CI, 0.26– 0.65], and 0.40 [95% CI, 0.32– 0.50]),
at mean ages at treatment of <1, 2.5, and 6 days, re-
spectively. Despite efficacy in closing the ductus, ran-
domized trials have not identified benefits with respect
to most other outcomes (including mortality, BPD,
necrotizing enterocolitis, and neurodevelopment).40- 42
Indomethacin treatment is often followed by oliguria
and increases in serum creatinine levels, which have
Figure 5. American Heart Association guideline for management of noninfant patients with hemodynamically significant
patent ductus arteriosus (HSPDA).
Flowchart and guideline for the management of older patients and adults with HSPDA. Adapted from and based on recommendations
in Stout et al36. ECHO indicates echocardiography; IE, infective endocarditis; PASP, pulmonary arterial systolic pressure; PH,
pulmonary hypertension; and PVR, pulmonary vascular resistance.
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Backes et al PDA: A Contemporary Perspective
been linked to increased risks of spontaneous intesti-
nal perforation, particularly in infants also exposed to
postnatal corticosteroids.97,9 8
Ibuprofen
Ibuprofen has been compared with placebo or non-
treatment in 15 randomized controlled trials (6 as
prophylaxis99 and 9 as treatment64). Collectively, these
trials demonstrated efficacy for PDA closure compara-
ble to that of indomethacin (RR, 0.45 [95% CI, 0.40–
0.51]). Oral dosing appears to be more effective than
intravenous dosing (RR, 0.38 [95% CI, 0.26– 0.56]).64
Direct comparisons to indomethacin also support
comparable efficacy64,99 and suggest that oliguria and
necrotizing enterocolitis are less likely in infants treated
with ibuprofen.64 Other outcomes, with the exception
of ductal patency (and “rescue” NSAID treatment or
ligation), are not changed by ibuprofen prophylaxis99
or treatment.64 Comparable efficacy for ductal closure
and the lower risk of adverse effects have led some re-
viewers to designate ibuprofen as the NSAID of choice
for medical PDA closure.64
Acetaminophen
Recent reports have suggested that acetaminophen
(paracetamol) might be a less toxic, but similarly effec-
tive, alternative to indomethacin or ibuprofen for induc-
ing ductal closure. Most reports are anecdotal, without
controls, and there are few randomized trials.100 The 2
randomized trials comparing acetaminophen with pla-
cebo101 or no treatment102 enrolled a combined total
of 80 subjects and found that treatment reduced the
RR of ductal patency after 4 to 5 days of treatment
by 51% (RD, −0.21; RR, 0.49 [95% CI, 0.24– 1.00]).10 0
No differences in mortality, oxygen use at 36 weeks’
postmenstrual age, or other outcomes were observed.
Several small trials comparing acetaminophen with
ibuprofen or indomethacin found no differences in
rates of ductal closure between the treatments,100 sug-
gesting therapeutic equivalence. However, prospec-
tive nonrandomized data from the Early Treatment
Versus Delayed Conservative Treatment of the Patent
Ductus Arteriosus (PDA- TOLERATE) trial indicate that
acetaminophen is no more effective than conservative
treatment and is less effective than indomethacin in in-
ducing ductal closure.
103
Pharmacogenetics of Drug Treatment for
PDA
Recent evidence has shown that unpredictable re-
sponses to pharmacological PDA treatments (eg, in-
domethacin and ibuprofen) may reflect differences in
developmental trajectory (ontogeny), genetic variability
of drug- metabolizing enzymes, and drug targets.22 For
example, current weight- based dosing of indometha-
cin leads to variable drug exposures, with up to 14- fold
variation in drug concentrations 24 hours after identi-
cal intravenous drug dosing.104 To that end, genetic
variability in indomethacin metabolism may explain the
variability observed in drug exposures. Indomethacin
is metabolized by the cytochrome P450 enzymes, pri-
marily CYP2C9,105 and uridine 5’- diphospho- glucuron
osyltransferase (UGT) enzymes.10 6 Infants have low ex-
pression levels of CYP2C9 in fetal and early neonatal
life, and UGT enzymes are also expressed at relatively
low levels.107,108 For both enzymes, expression matures
rapidly during infancy.
In addition, CYP2C9 genotype has been associ-
ated with response to indomethacin in preterm infants
with PDA.109 The G allele of rs2153 6 28 was associated
with increased odds of response to indomethacin in
the case- control analysis (OR, 1.918 [95% CI, 1.056–
3.483]). Moreover, the polymorphism CYP2C92 was
associated with drug failure in a multicenter cohort
study of preterm infants receiving indomethacin for
PDA.110 The mechanisms by which variants in these
and other genes alter NSAID responses have not been
established, but may relate to the complex molecular
network regulating ductal patency before and after
birth.
Surgical Closure
Surgical ligation of the ductus, usually performed by
application of a surgical clip via a left posterolateral
thoracotomy,111 has the advantage of virtually univer-
sal achievement of ductal closure (although rare cases
of ligation of the left pulmonary artery or mainstem
bronchus have been reported). Only 4 procedural
PDA- closure trials have been conducted in preterm
infants.65 ,112 ,113 ,114 ,115 ,116 All trials evaluated open surgi-
cal ligation, rather than minimally invasive transcatheter
closure (discussed below), and were conducted before
the 1980s, before modern intensive neonatal care ad-
vances (eg, antenatal corticosteroids and surfactant)
that have allowed many preterm infants with PDAs to
survive.117 Prophylactic ligation of the ductus on the
day of birth for infants <1000 g in weight was associ-
ated with lower rates of necrotizing enterocolitis, more
frequent oxygen use and mechanical ventilation at
36 weeks, and no difference in mortality.65 Despite the
clear differences in ductal patency, ligation for symp-
tomatic PDA did not demonstrably decrease any ad-
verse outcome.40 The landmark National Collaborative
Study, comparing ligation with indomethacin for treat-
ment of persistent PDA, found that ligation was more
likely to produce ductal closure (RR, 0.04 [95% CI,
0.01– 0.27]), but was associated with higher rates of
pneumothorax and retinopathy of prematurity, with-
out affecting mortality, chronic lung disease, or other
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Backes et al PDA: A Contemporary Perspective
outcomes (by study design, the ductus was closed in
all subjects before study completion).
113
Ductal ligation is often followed within hours by car-
diorespiratory deterioration (postligation syndrome),
apparently attributable to altered afterload, leading to
impaired left ventricular systolic performance118; this
complication is more likely in infants who undergo liga-
tion at <30 postnatal days.119 Surgical ligation has also
been associated with increased risks of BPD114 ,12 0 and
neurodevelopmental impairment.
121 Long- term compli-
cations of surgical ligation include left vocal cord pa-
resis122 and scoliosis.123 In view of these observations,
rates of surgical ligation across US hospitals have de-
creased markedly over the past decade (8.4% in 2006
to 1.9% in 2015).55
Transcatheter Closure
Transcatheter closure is the procedure of choice for
definitive PDA occlusion in adults, children, and infants
≥6 kg, but application in smaller, preterm infants is a
more recent development.124 Availability of devices
specifically designed to address the unique ductal
morphology of preterm infants, including several with
the type F (fetal) PDA (see Figure2), coupled with in-
creasing experience among interventional teams,
has led to growing interest and use of this approach
(Figure6A). A multicenter, nonrandomized, single- arm
trial performed under the auspices of a US Food and
Drug Administration investigational device exemption
protocol and continued access program evaluated
safety and effectiveness of the Amplatzer Piccolo
Occluder device in 200 patients, including 100 weigh-
ing ≤2 kg and 33 weighing ≤1 kg. The trial demon-
strated high implant success rates (191/200 [95.5%]
and 99/100 [99%] at ≤2 kg) and low major complica-
tion rates (4/194 [2.1%]), with effective ductal closure
documented in 172 of 173 (99.4%) at 6 months. Five
infants were observed to have new evidence of mod-
erate tricuspid regurgitation on echocardiography fol-
lowing transcatheter closure, likely related to catheter
manipulation across the tricuspid valve.
126 Following
review of these results, the device was approved by
the US Food and Drug Administration for transcatheter
PDA closure in infants who weighed ≥700 g and were
aged ≥3 postnatal days.127
Evidence that the risk of an adverse event following
transcatheter PDA closure is inversely related to post-
natal age or procedural weight remains unclear.124,128
However, heterogeneity across studies in definitions
for complications, timing (intraprocedural or post-
procedural) of event reporting, and adjudication of
procedural- related adverse events limits the interpreta-
tion of available data on the risks of complications fol-
lowing transcatheter PDA closure. Recent procedural
modifications, including adoption of vascular access
using femoral venous, rather than femoral arterial, ap-
proaches, have led to marked reductions in the inci-
dence of postprocedure limb ischemia (Figure6B).129
Moreover, consensus- based guidelines outlining con-
temporary strategies to prevent and manage compli-
cations associated with transcatheter closure will likely
contribute to improved safety profiles.130
In the absence of direct comparisons, the optimal
treatment to achieve definitive ductal closure among
preterm infants remains unknown. Despite promising
short- term data, longer- term outcomes following tran-
scatheter PDA closure are lacking. Whether the greater
certainty of achieving ductal closure with this approach
will be associated with increased benefits to treated
infants (compared with NSAID treatment or conserva-
tive management, described below) also remains to be
determined.
124,129
Conservative Management
Despite evidence that a persistent ductus is associated
with worse outcomes, including death, randomized
trials of both pharmacological and surgical ligation
treatments to close persistent PDAs in preterm infants
have not demonstrated long- term benefits.40,41,43 To
that end, trials of treatment to close the ductus have
provided evidence that those measures, at least when
applied nonselectively, do not improve outcomes.40
These observations have led to increasing adoption
of conservative approaches to PDA management.
In conservative management, health care providers
avoid definitive (transcatheter or surgical) closure, while
awaiting the possibility of spontaneous closure.
131
With conservative management, several strategies
to manage consequences of the ductus are often used,
including fluid restriction, diuretics, systemic afterload
reduction, increases in positive airway pressures, or
maintenance of higher hematocrits; however, these
approaches have not been evaluated in systematic
randomized trials.41,131 Although data are mixed,
132,133
adoption of conservative management has not been
found to be associated with differences in outcomes.131
However, among “high- risk” subgroups, such as in-
fants born at <26 weeks’ gestation, with evidence of
HSPDAs producing demonstrable circulatory compro-
mise, or with persistent patency well beyond the ex-
pected age of spontaneous closure, questions on the
safety and effectiveness of conservative management
versus alternative treatments (definitive closure) remain
unanswered.3 ,13 2 ,13 3
Timing of Therapy
Because a speculative analysis of experiences with oral
or rectal indomethacin from the 1970s suggested that
treatment after 12.5 days of age may be less effective
than treatment at an earlier age,134 considerations of
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Backes et al PDA: A Contemporary Perspective
treatment approaches for PDA have been influenced
by concerns that deferral of early treatment might result
in missed opportunities for effective NSAID treatment.
However, that analysis did not account for the expected
frequency of early spontaneous closure, which is com-
mon.3 Data from randomized clinical trials, including
those of indomethacin, do not support declining efficacy
with advancing postnatal age; trials that randomized
A
B
a
b
c
d
e
f
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Backes et al PDA: A Contemporary Perspective
subjects at a mean postnatal age >7 days (range, 7.4–
20.1 days) demonstrated PDA- closure efficacy (RR, 0.35
[95% CI, 0.25– 0.48]) equivalent to trials of treatment at
earlier ages. In the PDA- TOLERATE trial, NSAID treat-
ment was followed by PDA closure in 46% of subjects
in the early (8±2 days) treatment group and in 44% of
those in the conservative treatment group who received
rescue treatment (at 21±8 days of age).80 ,10 3 The age at
which medical therapy becomes ineffective therefore re-
mains uncertain, but deferral of treatment into the fourth
postnatal week does not appear to compromise its utility
for achievement of ductal closure.
Postdischarge Treatment
At present, data on the posthospital outcomes of pre-
term infants who are discharged home with a persistent
PDA are lacking. Herrman et al reported that, among
21 infants discharged with an open ductus, 86% (18/21)
underwent spontaneous closure.135 This is consistent
with a recent report of spontaneous closure in 52 of 68
(76%) infants discharged with an open PDA, with contin-
ued evidence of closure beyond 2 years postnatal.136 In
a recent prospective multicenter study of 201 premature
infants discharged home with a PDA and followed up at
6- month intervals through 18 months of age, the authors
observed spontaneous ductal closure occurred in 47%
and 58% of infants at 12 and 18 months, respectively.13 7
In the absence of data, optimal outpatient surveillance
among preterm infants discharged with a persistent PDA
remains unknown.13 5,136
PDA TREATMENTS IN OLDER
PATIENTS (TERM INFANT THROUGH
ADULTHOOD)
Beyond the first postnatal months, term infants are
outside the window when pharmacological therapy
(indomethacin and ibuprofen) to close the ductus is
effective. Although diuretics may be used to treat pul-
monary overcirculation among term infants with a PDA
in the first months of life, decisions about the need for
ductal closure are largely driven by presence (or ab-
sence) of HSPDA, with consideration to the direction of
ductal shunting and pulmonary artery systemic pres-
sure and/or pulmonary vascular resistance indexed to
systemic pressure (see Figure5). The frequency and
timing of outpatient follow- up are determined on the
basis of PDA classification (Ta b l e 6).
Management of HSPDA
Transcatheter PDA closure remains the mainstay for
definitive ductal closure in older patients.
138 In patients
weighing >6 kg, most PDAs are amenable to tran-
scatheter occlusion, with the notable exception of the
type B ductus (see Figure2). According to 2011 guide-
lines from the American Heart Association on cardiac
catheterization in pediatric heart disease, based on
consensus expert opinion, transcatheter PDA occlu-
sion is indicated in older patients for the treatment of
an HSPDA with “left- to- right shunt that results in any of
the following: congestive heart failure, failure to thrive,
pulmonary overcirculation, or an enlarged left atrium or
left ventricle, provided the anatomy and patient size are
suitable” (class I recommendation, level of evidence
B).139
Management of PDA With Associated
PAH in Term Infants and Older Children
Among term infants and older children, high levels of
pulmonary artery pressure associated with unrestric-
tive ductal shunting may relate to excessive flow, and
not high pulmonary vascular resistance indicative of
pulmonary vascular disease. In this context, health
care providers may consider transcatheter closure fol-
lowing short- term pulmonary vasodilator testing (eg,
decrease of ≥20% in mean pulmonary artery pressure
Figure 6. Percuta neous patent ductus arteriosus (PDA) closur e (A) and intraprocedural imaging of percutaneous PDA
closure (B).
A, Illustration of percutaneous device release for closure of a PDA. An end hole catheter is used to cross the tricuspid valve into the right
ventricle (RV), then a soft, floppy- tipped wire is advanced across the PDA and into the descending aor ta (DAO) (data not shown). At this
point, the catheter in the right ventricle is removed over the wire, and a delivery catheter is advanced over the wire through the venous
sheath into the PDA and descending aor ta (data not shown). The device is advanced to the tip of the catheter (a). The device is deployed
under fluoroscopic and transthoracic echocardiography guidance within the PDA with careful attention to avoid device protrusion
into the aorta or pulmonary artery (b). When position is satisfactory, the device is released from the delivery cable (c). B, Radiographs
illustrating steps and final result of a percutaneous PDA closure procedure. a, Following femoral vein access, a 4F catheter is introduced
and advanced to the RV under fluoroscopic guidance, wherein a floppy- tipped wire is guided via this catheter through the PDA and into
the descending aor ta, after which a 4F delivery catheter is exchanged. b, An angiogram is obtained for configuration and dimensional
data of the PDA, which permits selection of the most appropriate device for closure. c, The device is then advanced through the deliver y
catheter and deployed, but not fully released. d, Additional echocardiographic imaging is obtained to confirm placement of the device.
e, Additional angiographic imaging to evaluate for aortic or left pulmonary obstruction attributable to the device. f, Device is released;
additional imaging to evaluate postrelease positioning and stability, residual shunting, and other clinical parameters (eg, presence of
new or increased tricuspid valve regurgitation) may be warranted. Reproduced from Barcroft etal125 with permission. Copyright ©2022
Elsevier. LPA indicates left pulmonary artery; and MPA, main pulmonar y artery.
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J Am Heart Assoc. 2022;11:e025784. DOI: 10.1161/JAHA.122.025784 18
Backes et al PDA: A Contemporary Perspective
after administration of 100% oxygen and/or 80 parts
per million of inhaled NO) and a favorable hemody-
namic response to test occlusion.140 In a study by Niu
et al, the authors describe that younger patients with
pulmonary artery/systolic blood pressure ratios (car-
diac index) <0.8 during test occlusion were considered
to have favorable hemodynamics and underwent suc-
cessful PDA closure, despite many in the cohort hav-
ing met historical thresholds for being poor candidates
for intervention (pulmonary vascular resistance index,
>6 Wood units m2).94
Management of PDA With Associated
PAH in Older Patients and Adults
Recent American Heart Association/American
College of Cardiology guidelines emphasize that con-
siderations for ductal closure among older patients
be made in the context of evaluation of left- to- right
shunting and hemodynamic assessment for PAH (see
Figure5).36 Correspondingly, European guidelines
suggest pulmonary/systemic shunt ratios of <1.5 and
pulmonary vascular resistances of >5 Wood units as
prohibitive for ductal closure in adults.69 Supportive
pharmacologic treatments (eg, endothelin recep-
tor antagonists and phosphodiesterase- 5 inhibitors)
have been shown to improve functional capacities in
adult patients with Eisenmenger syndrome, includ-
ing marked increases in survival advantage for those
on PAH therapies versus not on PAH therapies (97%
versus 69%; P<0.01).141 Before transcatheter closure,
balloon test occlusion provides insight on risk/benefit
profiles, which are particularly valuable for patients
with evidence of PAH.
Definitive Closure (Transcatheter or
Surgical Ligation)
Transcatheter PDA closure in older patients remains
the mainstay for definitive ductal closure.
138 Following
hemodynamic assessment, for patients with unfa-
vorable ductal morphology for transcatheter closure,
surgical intervention remains feasible via both video-
assisted thoracoscopic or open thoracotomy, with high
degrees of success and low complication rates.14 2,143
Management of “Silent” or Small PDAs
Since the first surgical PDA ligation by Gross in 1939,
thresholds for intervention on the basis of IE risk have
been appropriately recalibrated as a function of the
advent of antibiotic treatment and the ability to offer
transcatheter PDA occlusion.
144 ,145 In other words, pre-
vious indications to close were based on prevention
of endarteritis, wherein closing the PDA would curtail
the need for long- term antibiotic prophylaxis. Because
“silent” or small PDAs are not considered HSPDA (see
Table2, above), societal guidelines no longer recom-
mend antibiotic prophylaxis; thus, the rationale for
closing “silent” or small PDAs no longer exists.36 ,75
CONCLUSIONS
PDA is a complex pathophysiology, resulting in mark-
edly variable clinical consequences. To provide more
targeted, individualized treatments, a better under-
standing of the molecular mechanisms of ductal
closure, the effect of each patient’s clinical and echo-
cardiographic biomarkers on both treatment success
and improved outcomes, as well as genetic variants
Table 6. Recommended Frequency of Outpatient Follow- Up and Treatment Among Term Infants, Older Children, and
Adults With PDA
Classification
Assessment intervals and treatment options
Pediatric/ACHD
cardiologist ECG TTE
Pulse
oximetry
Exercise
test*Treatment
“Silent ” or trivial PDA†36– 60 months 36– 60
months
36– 60
months
As needed As needed None
Small PDA‡24 mon th s 24 mo nths 24 mo nths As needed As needed None
HSPDA§ or PDA with mild
or moderate PH
6– 12 mo nt h s 12 mo nt hs 12 mo nt h s Each visit 12– 24 mont hs Closure is recommended if PDA
causing LAE /LVE with net lef t-
to- right sh unt, PASP <50% of
systemic, a nd PVR <1/3 systemic‖
PDA with severe PH and/or
Eisenmenger syndrome
3– 6 months 12 m on th s 12 m o nt hs Each visit 6– 12 mo nt h s Closure is NOT reco mmende d with
net left- to- right shu nt and PASP or
PVR ≥2/3 sys temic
ACHD indic ates adult congenital hea rt dise ase; HSPDA, h emodynamically significant PDA; LAE, left atria l enlarg ement; LVE, lef t ventricular enl argeme nt;
PASP, pulmonary ar tery systolic pre ssure; PDA, p atent ductus arter iosus; PH, pu lmonar y hypertension; PVR, pulmonar y vascular resistance; and T TE,
transthoracic echocardiography.
*Six- minute walk test or cardiopulmonary exercise test.
†No hemodynamic or anatomic consequences of the PDA.
‡Small shunt that is not HSPDA and is asymptomatic.
§HSPDA=LAE/LVE and/or su stained pulmona ry blo od flow to syste mic bloo d flow ratio (Qp/Qs) ≥1.5.
‖PDA closure c onside red: net lef t- to- right shu nt if PASP ≥50% systemic and/or PVR is ≥1/3 systemi c.
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J Am Heart Assoc. 2022;11:e025784. DOI: 10.1161/JAHA.122.025784 19
Backes et al PDA: A Contemporary Perspective
in drug metabolism and drug targets should be pri-
oritized.
146 Irrespective of patient age, incorporating
clinical and cardiac imaging parameters that recog-
nize a hierarchal model of adverse ductal sequalae is
recommended. The critical need for contemporary,
pragmatic clinical trials that evaluate the impact of ex-
isting PDA treatments on important patient outcomes
is acknowledged.
Affiliations
Center for Perinata l Research, The Abigail Wexn er Research Insti tute at
Nationwi de Children’s Hospital, Columbu s, OH (C.H.B., J.L.S.); Division
of Neonatology, Nationwide Child ren’s Hospita l, Columbus, OH (C.H.B.,
J.L.S.); Department of Pedi atrics, T he Ohio St ate Univer sity Co llege of
Medici ne, Columbus, OH (C.H.B., J.L.S., M.L.M., V.G.); The Heart Center,
Nationwi de Children’s Hospital, Columbu s, OH (C.H.B., M.L.M., V.G.); Duke
University Pediatric and Congen ital Hea rt Disease Center, Durham, NC
(K.D.H.); Duke Clini cal Research Institute, Durham, NC (K.D.H.); Department
of Pediatrics (E.L.S.), and Dep artme nt of Pharm acolog y (E.L.S.), Vanderbilt
University Medical Ce nter, Nashvill e, TN; ; Divis ion of Epid emiolo gy, College
of Public Health, The Ohio State U niversity, Columbus, OH (J.L.S.); Divisi on
of Neonatology (T.R.L.), and Division of Cl inical Pharmacology, Toxicology
and Therapeuti c Innovatio n (T.R.L.), Children’s Mercy – Kansas Cit y, Kansas
City, MO; Depa rtmen t of Pediatrics, University of Missouri– Kansas Ci ty
School of M edicin e, Kansas C ity, MO (T.R.L.); Depar tment of Pae diatric s,
University of Toronto, Onta rio, Canada (D.E.W.); Depar tment of Newborn a nd
Developmental Paediatrics, Sunnybrook Health Science Center, Toronto,
Ontari o, Canada (D.E.W.) Division of Neonata l and Development al Medicine,
Depar tment of Pediatric s, Stanford Univers ity Sch ool of Medicine, Luc ille
Packard C hildren’s Hospita l, Stanford, CA (S.B., W.E.B.); Center for Integ rated
Brain Re search, University of Washington School of Medicine, Sea ttle,
WA (C.V.S.); Department of Pediatrics (P.J.M.), and Depar tment of Inte rnal
Medici ne (P.J.M.), University of Iowa, Iowa City, IA; Center for Cardiovascular
Research, The Abigail Wexner Resea rch Institute at Nationwide Children’s
Hospital, Columbus, OH (V.G.); and Department of Molecular Gene tics, The
Ohio State Univers ity, Columb us, OH (V.G.).
Sources of Funding
None.
Disclosures
Drs Backe s, Slaughter, and McNama ra are investigators o n the upcoming
“PIVOTAL” (Percuta neous Intervention Versus O bser vational Trial of Arterial
Ductus in Low- We ight Infa nts; UG3HL161338- 01), funded by the National
Heart, Lung, and Blood Insti tute. For the conduct of th is study, the
investigators received additional funding from Abbott to support the trial;
however, Abbott has no influence in the desig n, conduc t, or execution
thereof of the study. The remaining authors have no disclosures to report.
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