Percutaneous Closure of the Patent Ductus
Arteriosus in Very-Low-Weight Infants
Danielle Scerbo, MS,*† Clifford L. Cua, MD,‡x Brian K. Rivera, MS,† Laura C. Marzec, IMG,† Charles V. Smith, PhD,{
Jonathan L. Slaughter, MD, MPH,†‡‖** Darren P. Berman, MD,‡x Carl H. Backes, MD†‡x‖
†
Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH
AUTHOR DISCLOSURE Dr Backes is a
consultant for Abbott. Dr Berman is a
consultant for Abbott, Edwards Lifesciences,
and Medtronic. Drs Backes and Slaughter
work under National Institutes of Health grant
R01 HL145032. Drs Scerbo, Cua, Rivera,
Marzec, and Smith have disclosed no financial
relationships relevant to this article. This
commentary does not contain a discussion of
an unapproved/investigative use of a
commercial product/device.
ABBREVIATIONS
PDA patent ductus arteriosus
TTE transthoracic echocardiography
Downloaded from http://neoreviews.aappublications.org/ at Ukraine:AAP Sponsored on July 1, 2020
*The Ohio University Heritage College of Osteopathic Medicine, Athens, OH
‡
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH
x
The Heart Center, Nationwide Children’s Hospital, Columbus, OH
{
Center for Integrated Brain Research, Seattle Children’s Hospital, Seattle, WA
‖
Division of Neonatology, Nationwide Children’s Hospital, Columbus, OH
**Division of Epidemiology, The Ohio State University College of Public Health, Columbus, OH
Practice Gaps
1. Treatment strategies for very-low-weight infants with a patent ductus
arteriosus (PDA) vary markedly among institutions and individual
providers.
2. Percutaneous closure of the PDA is among the safest of interventional
cardiac procedures and is considered the procedure of choice for PDA
closure outside the neonatal period; however, risk-benefit profiles of
percutaneous PDA closure among very-low-weight infants have not
been well-characterized.
3. Given the growing interest in percutaneous PDA closure among very-low-
weight and preterm infants, scrutiny of the available data is necessary to
inform the practice of evidence-based medicine.
Abstract
In view of the known complications of drug therapy and open surgical
ligation, and the potential for prolonged patent ductus arteriosus (PDA)
exposure to be harmful, health care practitioners have sought new
approaches to achieve definitive ductal closure. Interest in percutaneous
(catheter-based) PDA closure has emerged within the neonatal community
as a viable treatment option, because it has been fueled by recent procedural
and device modifications, as well as mounting feasibility and safety data.
Herein, we provide a contemporary review of percutaneous PDA closure
among infants at the crux of the medical debate—very-low-weight infants
(£1,500 g), including: 1) characterization of traditional PDA treatments
(drug therapy, open surgical ligation) and conservative (nonintervention)
management options; 2) a general overview of the major procedural steps
of percutaneous ductal closure, including efforts to reduce thrombotic
complications and the emergence of a novel US Food and Drug
Administration–approved device; 3) a systematic review and meta-analysis to
better understand risk profiles of percutaneous PDA closure in this
Vol. 21 No. 7 J U L Y 2 0 2 0 e469
 population; and 4) discussion of current gaps in our understanding of optimal
PDA care, including the critical need for well-designed, randomized,
controlled clinical trials.

Objectives After completing this article, readers should be able to:

1. Summarize the limitations of traditional treatments for patent ductus
arteriosus (PDA, eg, drug therapy, surgical ligation) that led to growing
interest and use of percutaneous closure in this population.
2. Describe the basic procedural steps of percutaneous PDA closure.
3. Identify the risks associated with percutaneous PDA closure among very-
low-weight infants.
4. Characterize current gaps in our understanding of optimal PDA care.

INTRODUCTION associated with adverse sequalae, and that closure of the

In utero, the ductus arteriosus shunts blood away from the
high-resistance pulmonary vascular bed and toward the
descending aorta and low-resistance placental circulation.
At birth, the placental circulation is clamped and removed,
resistance in the pulmonary vascular bed decreases, and the
lung becomes the source of oxygenation and gas exchange;
thus, the ductus arteriosus is no longer essential. (1) Over
the first few days after birth, the ductus normally undergoes
active constriction and closure. The patent ductus arteriosus
(PDA) closes in 56% and 96% of term infants on postnatal
days 1 and 2, respectively. (2) In contrast, the ductus remains
patent among approximately 70% of infants born before 28
weeks of gestation, with an incidence that is inversely pro-
portional to gestational age at birth. (3)(4)
The presence of a PDA results in persistent blood flow
between the aorta and pulmonary artery. (1) Although the
pathophysiologic consequences of a PDA are widely variable,
ductal patency is associated with pulmonary edema because of
sustained high levels of pulmonary circulation as well as con-
sequent mesenteric and renal hypoperfusion. (5)(6) In addition,
PDAs have been linked to a 7-fold greater risk for mortality (7)
and other adverse clinical sequalae, including chronic lung
disease, (8) intestinal injury, (6) cerebral volume loss, (9) and
congestive heart failure. (10) Although associated with higher
mortality and morbidity, a PDA may not be causative. (11)
In the absence of robust evidence, treatment of a PDA
remains a subject of great debate in the neonatal commu-
nity. (5)(11)(12) Most health care practitioners would agree
that a PDA should be closed before age 1 to 2 years if
asymptomatic but audible PDA can be deferred until age 2
to 3 years to avoid the lifelong risk of bacterial endarteritis.
(13) Yet optimal thresholds and strategies for PDA closure in
very-low-weight infants remain unknown.
TRADITIONAL THERAPIES TO CLOSE PDAs
Early drug treatments (during the first weeks after birth)
with nonsteroidal anti-inflammatory drugs or acetamino-
phen are efficacious in closing PDAs, with closure rates
approaching 50% to 75%. (14)(15)(16) However, harmful
renal and gastrointestinal complications, no demonstrated
long-term neurodevelopmental benefit, and high medical
costs have led to mounting concerns about the use of drug
therapy. (17) Over the past decade, these concerns have led to
a more than 50% reduction in drug therapy use. (18)
Open surgical PDA ligation via thoracotomy is the
method traditionally used to achieve definitive ductal clo-
sure. (19) Although commonly regarded as a simple and
straightforward surgery, associations between PDA ligation
and vocal cord paralysis, chylothorax, and postligation syn-
drome have decreased enthusiasm for the procedure among
clinicians. (18)(20)(21) Although the data are mixed, some
evidence suggests that the surgical and anesthesia effects of
PDA ligation contribute to adverse postoperative cardiopul-
monary sequalae. (22) In fact, surgical ligation of the PDA
may be an independent risk factor for motor impairment,
developmental delay, and moderate-to-severe functional
disability. (22)(23) These observations have led to declining
rates of surgical PDA ligations across US centers. (18)

e470 NeoReviews
Downloaded from http://neoreviews.aappublications.org/ at Ukraine:AAP Sponsored on July 1, 2020
 Risks of traditional therapies (drug therapy, surgical liga-
tion) have led to interest in conservative (nonintervention)
approaches in the management of PDAs. (24) Although
conservative management remains poorly defined, including
evidence regarding the effectiveness of fluid restriction,
diuretic therapy, and positive pressure ventilation, these treat-
ments are often used to reduce symptoms from PDAs and to
provide time for a ductus to close spontaneously. (4) Using
conservative treatment, approximately one-third of premature
infants undergo spontaneous PDA closure by 8 days after birth.
(4) Moreover, longer-term use of conservative therapy over the
first 165 days of age results in PDA closure in 73% of pre-
mature infants. (25) The potential for spontaneous closure,
coupled with a paucity of data on improved outcomes after
ductal treatment, have led to growing acceptance of conser-
vative treatment among health care practitioners. (18)(26)
However, evidence on rates and timing of spontaneous
closure of PDAs are largely derived from single-center studies
without longer-term follow-up, wherein the risks associated
with prolonged exposure to PDAs remain poorly character-
ized. (27) In fact, some evidence suggests that the duration of
PDA exposure is an important predictor of chronic lung
disease and/or death. (28) Thus, conservative treatment
may be a useful adjunct to avoid a potentially unnecessary
intervention in an appreciable number of infants, but the
question remains as to what clinicians should do when a
PDA fails to close after a period of conservative treatment.
PERCUTANEOUS CLOSURE: A NONSURGICAL
ALTERNATIVE TO PROVIDE DEFINITIVE CLOSURE
Advances in interventional pediatric cardiology have led to the
development of an alternative, nonsurgical technique to close
PDAs definitively. (29) Percutaneous closure of the ductus is
among the safest of interventional cardiac procedures and is
considered the procedure of choice for PDA closure outside the
neonatal period. (30) Over the past decade, evidence on the
feasibility, safety, and efficacy of the procedure in older and
more mature neonates has emerged. (31) Not surprisingly, this
has led to growing interest on applicability of the procedure
among smaller infants and more premature infants. (32)(33) In
some centers, percutaneous PDA closure has replaced open
surgical ligation as the treatment of choice for definitive ductal
closure. (29)(34)
EFFORTS TO MINIMIZE COMPLICATION RATES
Before recent device and procedural modifications were
made, rates of procedural complications, including vascular
compromise (arterial thrombosis) and device-related
Downloaded from http://neoreviews.aappublications.org/ at Ukraine:AAP Sponsored on July 1, 2020
stenosis of the left pulmonary artery and/or descending
aorta were higher among very-low-weight infants than in
their more mature counterparts. (35) To mitigate these
complications, a multidisciplinary panel of pediatric inter-
ventional cardiologists, pediatric cardiologists, and neona-
tologists convened at an international symposium multiple
times over 2 years with a goal of reducing risk profiles
among very preterm infants. (36)(37) Based on consensus,
these experts called on the need for 1) the development of
and access to novel devices designed to address the unique
ductal morphologies of very-low-weight infants; and 2) pro-
cedural modifications to mitigate procedural risks, with an
emphasis on limiting vascular compromise.
Novel Devices
On January 11, 2019, the US Food and Drug Administration
approved the Amplatzer PiccoloTM Occluder (Abbott Diag-
nostics, North Chicago, IL) for percutaneous PDA closure in
preterm infants weighing 700 g or more. The Amplatzer
PiccoloTM Occluder was designed to address the unique
ductal morphologies of very premature infants, which are
commonly described as long and tubular without significant
stenosis and similar to the ductus arteriosus seen during fetal
life (type F). (38) Recent completion of a US multicenter,
single-arm study (ADO-II AS TRIAL; NCT03055858) using
the Amplatzer PiccoloTM Occluder showed that among 100
infants of less than 2 kg weight at the time of the procedure,
procedural success (defined as successful placement of the
device within the PDA) was 99% (99/100); rates of clinically
significant adverse events were 2% (2/100), including no
evidence of vascular compromise or device-related stenosis.
(39)(40) Although a comparative study of the benefits and
risks of various PDA closure devices has not been performed,
most clinicians are now using the Amplatzer PiccoloTM
Occluder for percutaneous PDA closure among very-low-
weight infants (Fig 1A). In fact, over the past 2 years, among
233 very-low-weight infants undergoing percutaneous device
closure, the Amplatzer PiccoloTM Occluder was used in
slightly less than two-thirds (142, 61%) of cases (Fig 1B).
Procedural Modifications
Traditionally, vascular access was obtained via both arterial and
venous routes to collect images of the PDA. (34) Risk of
vascular compromise (arterial thrombus, need for systemic
anticoagulation), particularly among very-low-weight infants,
led clinicians to encourage the following procedural modifica-
tions to improve the safety profile of the procedure: 1) avoid-
ance of arterial catheters and retrograde device delivery; and 2)
reliance on transthoracic echocardiography (TTE) guidance for
device placement, rather than traditional aortograms. (41)
Vol. 21 No. 7 JULY 2020 e471

Figure 1. Pie charts showing implant use reported in infants less than or
equal to 1.5 kg at the time of procedure from 2009 to 2019 (A) and 2017
to 2019 (B). AVP II¼AmplatzerTM Vascular Plug 2; AVP IV¼AmplatzerTM
Vascular Plug 4; MVP¼Medtronic Micro Vascular Plug;
Piccolo¼Amplatzer PiccoloTM Occluder.
PROCEDURAL STEPS FOR PERCUTANEOUS PDA
CLOSURE
Preprocedure
In most cases, the infant is transported from the NICU to
the catheterization laboratory. Before the infant’s arrival, the
ambient temperature in the catheterization laboratory is
raised to 24°C to 25°C. In optimal circumstances, a dedi-
cated pediatric cardiac anesthesia team provides sedation
and airway management. Consensus on best anesthesia
practices is lacking, but options for anesthesia are provided
in Table 1. Once anesthesia is optimized, a fluoroscopic
assessment of the chest is performed to ensure appropriate
positioning of the endotracheal tube and evaluate lung
e472 NeoReviews
Downloaded from http://neoreviews.aappublications.org/ at Ukraine:AAP Sponsored on July 1, 2020
expansion. Using the modified Seldinger technique, a 4
French short sheath is placed in the femoral vein; the
femoral artery is not accessed. While flushing the sheath,
baseline laboratory parameters (hemoglobin, venous blood
gas, and activated clotting time) are obtained. Preprocedural
imaging includes TTE with 2-dimensional imaging and
color and spectral Doppler, with an emphasis on defining
ductal morphology and characterizing the relationship of
the PDA to the left pulmonary artery and descending aorta.
Unless contraindicated, infants are administered 1 prepro-
cedural dose of an antibiotic (cefazolin 25 mg/kg).
Procedure
A catheter is advanced under fluoroscopic guidance through
the sheath, up the inferior vena cava, and into the right
atrium and right ventricle. Use of a balloon-tipped end hole
catheter to ensure that the catheter crosses through the
center of the tricuspid valve, and not through its chordae, is
recommended to avoid potential injury to the tricuspid
value. Once in the right ventricle, a soft, floppy-tipped wire
is advanced through the catheter and across the pulmonary
valve into the main pulmonary artery, across the PDA, and
into the descending aorta. 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 aorta (Fig 2A).(42)
A small hand injection of diluted contrast can be performed
under fluoroscopy, to get an image of the PDA, descending
aorta, and pulmonary arteries. Specific measurements of the
PDA, with attention to maximal diameter, narrowest diam-
eter, and length, inform decisions on device selection.
The device is flushed and back-loaded into the delivery
catheter that is across the PDA. The device is advanced to the
tip of the catheter and deployed under fluoroscopic and TTE
guidance within the PDA (Fig 2B), with careful attention to
avoid device protrusion into the aorta or pulmonary artery
(Fig 2C). Before release from the delivery cable, the descend-
ing aorta and left pulmonary artery are carefully evaluated
with TTE and compared with the preprocedural images. If
vascular stenosis related to the device is observed, the device
is recaptured and either repositioned or removed and
exchanged for another device of a different size. If the
device-related stenosis persists after repeated attempt(s),
the procedure is aborted and, based on preprocedural
discussions, the medical team and family may decide to
pursue surgical ligation. In our experience, and consistent
with national-level data, percutaneous closure is feasible in
more than 98% of cases. (39) When satisfied with device
position, device stability, and descending aorta and left
pulmonary artery flow, the device is released from the
TABLE 1. Anesthesia for Percutaneous Patent Ductus Arteriosus Closure
Among Very-Low-Weight Infants

Preprocedure Anesthesia Induction

Intravenous Propofol (1–2 mg/kg) OR
Midazolam (0.1–0.2 mg/kg) OR
Ketamine (1–2 mg/kg)
þ/- Fentanyl (2–4 mg/kg)
Neuromuscular blockade. (optional) Rocuronium (0.6–1.0 mg/kg)
Vecuronium (0.1–0.2 mg/kg)
Succinylcholine (1–2 mg/kg)
Maintenance Anesthesia (Intraprocedure)
Inhalation Isoflurane (volatile agent) titrated to clinical
need and hemodynamic stability
þ/- Fentanyl (2–10 mg/kg)
Neuromuscular blockade Rocuronium (0.6–1.0 mg/kg)
Vecuronium (0.1–0.2 mg/kg)
Postprocedure Recovery
Neuromuscular blockade reversal Neostigmine (0.04–0.08 mg/kg)
Sugammadex (0.4–0.6 mg/kg

delivery cable (Fig 2D). At this point, TTE assessment is prophylaxis is recommended for 6 months after the pro-
repeated. The delivery catheter and sheath within the fem- cedure. (45)
oral vein are removed, and hemostasis is achieved with
gentle manual pressure over the access site.

Immediate Postprocedure
Following hemostasis, the patient is transported back to the
NICU. In the NICU, regular assessment (every 4–6 hours) of
the vascular access site is performed after the procedure, with
the infant supine. Unless contraindicated, infants are admin-
istered 2 postprocedural doses of antibiotics (cefazolin 25
mg/kg). Within 24 hours of the procedure, chest radiography
and TTE are performed, with attention to: 1) device position,
residual shunting (if any), left pulmonary artery, and descend-
ing aorta flow patterns; 2) ventricular function, to assess for
evidence of post–PDA closure cardiac syndrome; and 3)
tricuspid valve function, to evaluate for evidence of tricuspid
regurgitation not observed on preprocedural imaging.

Long-term Considerations
Optimal timing for device surveillance remains unknown. If
not observed on the initial postprocedure TTE, the risk of
device-related stenosis is low. (43) Routine follow-up (phys-
ical examination, TTE) during the first 2 to 3 years after
the procedure is prudent. Over time, consistent with late
Figure 2. Procedural steps for percutaneous delivery of occlusive
endothelization, the device becomes embedded with ma- devices for patent ductus arteriosus closure. (33)(42) Originally
published in Backes, Giesinger, Rivera et al. Percutaneous Closure of the
ture, fibrous connective tissue. (44) In addition, based Patent Ductus Arteriosus in Very Low Weight Infants. Journal of
on American Heart Association guidelines, endocarditis Pediatrics. 2019;213:219. Mandy Root-Thompson, Medical Illustrator.

Vol. 21 No. 7 JULY 2020 e473

Downloaded from http://neoreviews.aappublications.org/ at Ukraine:AAP Sponsored on July 1, 2020

TABLE 2. PubMed/Medline Search Strategy
Terms and Combinations (1/2009–
12/2019)
Patent ductus arteriosus AND congenital AND catheter
OR PDA infant
newborn percutaneous
preterm
premature transcatheter
RISKS OF PERCUTANEOUS CLOSURE AMONG VERY-
LOW-WEIGHT INFANTS
To examine the risk profile of the procedure among very
preterm infants, we conducted a literature search using
PubMed/Medline databases. Combinations of the relevant
medical subject heading terms, key words, and word vari-
ants are shown in Table 2. PubMed/Medline was searched
electronically on October 1, 2019, and then updated on
December 1, 2019. To provide a contemporary risk assess-
ment, the search was limited to reports published from
January 2009 to February 2019. The reference lists of
relevant articles and reviews were searched by hand for
additional studies. Studies were included if infants had
mean or median weights at the time of procedure of less
than or equal to 1.5 kg. In studies reporting infant mean/
median weights greater than or equal to 1.5 kg, individual
patient-level data on infants less than or equal to 1.5 kg at the
time of procedure were included, when possible. Exclusion
criteria were single case reports or multiple case reports in
which only a single case would qualify. Data collected from
selected articles included numbers of infants meeting in-
clusion criteria; age at the time of procedure (days, weeks);
weight at the time of procedure (in kilograms); type of
implant used for PDA closure; number and severity of
adverse events; duration of procedure; duration of fluoro-
scopic imaging; type of anesthesia used; and duration of
anesthesia exposure.
Clinically significant adverse events (eg, embolization,
arterial thrombosis, requirements for unplanned surgery,
death) (46) were recorded and assessed independently by 2
authors (B.K.R., C.H.B.); disagreements on the assignment
of adverse events were resolved by consultation with a
different author (C.L.C.). Only adverse events adjudicated
as probable, probable/likely, or certain were included (Fig 3).
Characteristics of the studies included are summarized
in Table 3. (29)(33)(37)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)
(58)(59)(60) The available evidence suggests that the low rates of
clinically significant adverse events among very preterm infants
undergoing percutaneous closure are encouraging. However,
the studies included are largely limited to retrospective and
single-center experiences, lack comparator groups, and are
devoid of longer-term follow-up beyond initial hospitalization.
Thus, although the present data point to percutaneous closure
among lower-weight infants being safe, questions on clinical
effectiveness remain unanswered.

Figure 3. Forest plot showing pooled incidence of reported clinically significant adverse events in percutaneous patent ductus arteriosus closure
among infants of less than or equal to 1.5 kg weight at the time of the procedure. * Studies report overlapping cohorts; for the purposes of meta-
analysis, the overlapping cases were counted only once to avoid bias and skewing of the results. HCI¼high level of 95% confidence interval; LCI¼low
level of 95% confidence interval; Prev¼prevalence.

e474 NeoReviews
Downloaded from http://neoreviews.aappublications.org/ at Ukraine:AAP Sponsored on July 1, 2020
TABLE 3. Articles Included in the Meta-analysis (1/2009–12/2019)
WEIGHT AT DEVICE(S) USED FOR
REFERENCE # OF CASES AGE AT PROCEDURE PROCEDURE (KG) ANESTHESIA USED PDA CLOSURE

Malekzadeh-Milani et al (47) 80 22–8 daysa 0.9–0.1a GA Piccolo, MVP

Serrano et al (48) 10 42–11 days 1.2–0.2 -- MVP
Sathanandam et al (29) 65 — (0.6–1.5)b GA Piccolo, MVP
Morville et al (49), Morville and 24 21–10 days 1.1 – 0.2 Midazolam, ketamine Piccolo, MVP
Akhavi (50)c
Rodriguez Ogando et al (51)(52)c 22 — 1.2 – 0.1d — Piccolo
Sathanandam et al (53) 11 4–1 weeks 1.1–0.2 — MVP
Narin et al (54), Pamokcu et al 22 20.4–8.1 days 1.13–0.3 Midazolam, ketamine Piccolo
(55), Narin et al (56)c
Zahn et al (33)c (57) 16 24.3–9.5 days 1.07 – 0.19 — AVP II
Philip et al (37) 14 6 (4–16) weeks 1.6 (1.1–2.5) — AVP II, AVP IV
Baspinar et al (58) 7 18–5 days 1.4–0.2 — Piccolo
Sungur et al (59) 2 0.6–0.2 months 1.4–0.2 — Piccolo
Francis et al (60) 7 5.3–2.6 weeks 1.1–0.1 Midazolam, ketamine Cook Coils

The mean age and weight at time of procedure were calculated for eligible cases, when known (using patient-level data) or the overall reported mean – SD,
median (range). AVP II: AmplatzerTM Vascular Plug 2; AVP IV: AmplatzerTM Vascular Plug 4; GA¼general anesthesia, not otherwise specified; MVP: Medtronic
Microvascular Plug; — ¼ not reported or not available; Piccolo: Amplatzer PiccoloTM Occluder (previously referred to in cited literature as ADO-II AS:
AmplatzerTM Ductal Occluder II Additional Sizes).
a
For infants in the <1 kg subgroup; infants in 1–2 kg subgroup were also included as mean weight £1.5 kg, however, patient-level data were not available.
b
Only range reported.
c
Articles with overlapping cases; nonoverlapping cases meeting criteria were included, and overlapping cases were counted only once.
d
Calculated for reported weights only (n¼20).

CURRENT GAPS IN THE UNDERSTANDING OF
PERCUTANEOUS PDA CLOSURE AMONG LOWER-
WEIGHT INFANTS
Percutaneous PDA closure has emerged as a viable treatment
option for definitive closure among very preterm and very-
low-weight infants. In view of the increasing numbers of
percutaneous closures, the neonatal community is now
tasked with defining research goals and priorities for this
novel procedure in this vulnerable subgroup of infants.
Recent device and procedural modifications have provided
an acceptable safety profile for percutaneous closure in single-
arm studies, but the effectiveness in improving short- and
longer-term clinical outcomes has never been evaluated via
randomized clinical trials. In the absence of prospective,
comparative studies, health care practitioners are unable to
weigh the risks of percutaneous closure versus those of
alternative treatments, including conservative management.
Historically, trials of infants with PDA have been focused
on the most expeditious way to close the ductus, rather than
the more fundamental question of whether closing the ductus
improves outcomes. To date, only 4 procedural trials of
closure (interventional) versus nonclosure of the ductus have
been conducted, all of which evaluated open surgical ligation
rather than percutaneous closure. (61)(62)(63)(64)(65)(66)
Moreover, the extensive and ongoing evolution in neonatal
intensive care raises questions about the applicability of
previous studies on PDA closure in contemporary practice.
While prospective trials comparing PDA closure (percutane-
ous) versus conservative treatment are clearly needed to
inform the practice of evidence-based medicine, concerns
regarding a lack of physician equipoise for enrollment of very
preterm infants into randomized controlled trials remains.
(67) Therefore, strategies to optimize informed consent and
recruitment strategies will be essential. (68)
Traditionally, clinical trials of PDA treatment were con-
ducted without attention to the heterogeneity in clinical and
echocardiographic markers of ductal patency. In contrast to
infants with small (<1.5 mm) PDAs without clinical sequa-
lae, some infants have large (‡1.5 mm) PDAs with echocar-
diographic signs of hemodynamic significance, including

Vol. 21 No. 7 JULY 2020 e475

Downloaded from http://neoreviews.aappublications.org/ at Ukraine:AAP Sponsored on July 1, 2020
 pulmonary hypertension and/or volume overloading of
their immature hearts (left atrial/ventricular dilation) and
lungs, and PDA-associated clinical symptoms, including
worsening respiratory failure. (10) Rather than an all-or-
none approach in the treatment of a PDA, efforts to classify a
PDA based on clinical and echocardiographic criteria may
provide a more individualized approach to care and identify
infants most likely to benefit from treatment. In addition,
previous studies have defined hemodynamically significant
PDA based solely on ductal size or left heart dimensions
(ratio or left atrium to aorta). In an effort to develop more
robust models for outcome prediction, recent investigators
have championed “PDA scoring systems” that take into
account both clinical and echocardiographic data. (69)
Realizing that treatment is not likely to benefit all infants
with PDAs, targeted treatment of subgroups of infants
meeting predetermined criteria for adverse ductal conse-
quences may enable clinicians and investigators to mini-
mize risk and yield the greatest benefit. (70)
Summary
• Treatment strategies for very-low-weight infants with PDAs vary
markedly among institutions and individual providers.
• Health care professionals should question widespread
acceptance of percutaneous PDA closure among very-low-weight
infants in the absence of comparative studies and necessary
evidence base.
• Efforts to optimize anesthesia practices during percutaneous
closure are needed.
• Percutaneous PDA closure in very-low-weight infants should be
limited to centers with the requisite interdisciplinary
(interventional pediatric cardiology, pediatric cardiology
imaging, neonatology, anesthesiology) expertise.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the evaluation and medical and/or surgical management
and associated potential complications or adverse effects
of such management for a preterm neonate with a patent
ductus arteriosus.
e476 NeoReviews
Downloaded from http://neoreviews.aappublications.org/ at Ukraine:AAP Sponsored on July 1, 2020
References
1. Deshpande P, Baczynski M, McNamara PJ, Jain A. Patent ductus
arteriosus: The physiology of transition. Semin Fetal Neonatal Med.
2018;23(4):225–231
2. Jain A, Mohamed A, El-Khuffash A, et al. A comprehensive
echocardiographic protocol for assessing neonatal right ventricular
dimensions and function in the transitional period: normative data
and z scores. J Am Soc Echocardiogr. 2014;27(12):1293–1304
3. Yu VY. Patent ductus arteriosus in the preterm infant. Early Hum
Dev. 1993;35(1):1–14
4. Koch J, Hensley G, Roy L, Brown S, Ramaciotti C, Rosenfeld CR.
Prevalence of spontaneous closure of the ductus arteriosus in
neonates at a birth weight of 1000 grams or less. Pediatrics.
2006;117(4):1113–1121
5. Clyman RI, Couto J, Murphy GM. Patent ductus arteriosus: are
current neonatal treatment options better or worse than no
treatment at all? Semin Perinatol. 2012;36(2):123–129
6. Havranek T, Rahimi M, Hall H, Armbrecht E. Feeding preterm
neonates with patent ductus arteriosus (PDA): intestinal blood flow
characteristics and clinical outcomes. J Matern Fetal Neonatal Med.
2015;28(5):526–530
7. Noori S, McCoy M, Friedlich P, et al. Failure of ductus arteriosus
closure is associated with increased mortality in preterm infants.
Pediatrics. 2009;123(1):e138–e144
8. Brown ER. Increased risk of bronchopulmonary dysplasia in infants
with patent ductus arteriosus. J Pediatr. 1979;95(5 Pt 2):865–866
9. Lemmers PM, Benders MJ, D’Ascenzo R, et al. Patent ductus
arteriosus and brain volume. Pediatrics. 2016;137(4):e20153090
10. Reese J, Laughon MM. The patent ductus arteriosus problem:
infants who still need treatment. J Pediatr. 2015;167(5):954–956
11. Benitz WE. Treatment of persistent patent ductus arteriosus in
preterm infants: time to accept the null hypothesis? J Perinatol.
2010;30(4):241–252
12. Benitz WE; Committee on Fetus and Newborn, American Academy
of Pediatrics. Patent ductus arteriosus in preterm infants. Pediatrics.
2016;137(1):e20153730. doi: 10.1542/peds.2015-3758
13. Grover A, Barnes N, Chadwick C, Thompson F, Adams E, Wilson N.
Neonatal infective endarteritis complicating patent ductus
arteriosus. Acta Paediatr. 2008;97(5):663–665
14. Aranda JV, Clyman R, Cox B, et al. A randomized, double-blind,
placebo-controlled trial on intravenous ibuprofen L-lysine for the
early closure of nonsymptomatic patent ductus arteriosus within 72
hours of birth in extremely low-birth-weight infants. Am J Perinatol.
2009;26(3):235–245
15. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous
indomethacin for preventing mortality and morbidity in preterm
infants. Cochrane Database Syst Rev. 2010; (7):CD000174
16. Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent
ductus arteriosus in preterm or low-birth-weight infants. Cochrane
Database Syst Rev. 2015; (3):CD010061
17. Knight DB, Laughon MM. Evidence for active closure of patent
ductus arteriosus in very preterm infants. J Pediatr.
2008;152(3):446–447, author reply 447–448
18. Bixler GM, Powers GC, Clark RH, Walker MW, Tolia VN. Changes in the
diagnosis and management of patent ductus arteriosus from 2006 to 2015
in United States neonatal intensive care units. J Pediatr. 2017;189:105–112
19. Susheel Kumar TK. Surgical management of patent ductus
arteriosus. Congenit Heart Dis. 2019;14(1):57–59
20. Benjamin JR, Smith PB, Cotten CM, Jaggers J, Goldstein RF,
Malcolm WF. Long-term morbidities associated with vocal cord
paralysis after surgical closure of a patent ductus arteriosus in
extremely low birth weight infants. J Perinatol. 2010;30(6):408–413
21. El-Khuffash AF, Jain A, Dragulescu A, McNamara PJ, Mertens L. Acute
changes in myocardial systolic function in preterm infants undergoing
patent ductus arteriosus ligation: a tissue Doppler and myocardial
deformation study. J Am Soc Echocardiogr. 2012;25(10):1058–1067
22. Weisz DE, Giesinger RE. Surgical management of a patent ductus
arteriosus: Is this still an option? Semin Fetal Neonatal Med.
2018;23(4):255–266
23. Weisz DE, Mirea L, Rosenberg E, et al. Association of patent ductus
arteriosus ligation with death or neurodevelopmental impairment
among extremely preterm infants. JAMA Pediatr.
2017;171(5):443–449
24. Kaempf JW, Wu YX, Kaempf AJ, Kaempf AM, Wang L,
Grunkemeier G. What happens when the patent ductus arteriosus
is treated less aggressively in very low birth weight infants?
J Perinatol. 2012;32(5):344–348
25. Rolland A, Shankar-Aguilera S, Diomandé D, Zupan-Simunek V,
Boileau P. Natural evolution of patent ductus arteriosus in the
extremely preterm infant. Arch Dis Child Fetal Neonatal Ed.
2015;100(1):F55–F58
26. Letshwiti JB, Semberova J, Pichova K, Dempsey EM, Franklin OM,
Miletin J. A conservative treatment of patent ductus arteriosus in
very low birth weight infants. Early Hum Dev. 2017;104:45–49
27. Elhoff JJ, Ebeling M, Hulsey TC, Atz AM. Potential unintended
consequences of a conservative management strategy for patent
ductus arteriosus. Congenit Heart Dis. 2016;11(1):52–57
28. Mirza H, Garcia J, McKinley G, et al. Duration of significant patent
ductus arteriosus and bronchopulmonary dysplasia in extremely
preterm infants. J Perinatol. 2019;39(12):1648–1655
29. Sathanandam S, Agrawal H, Chilakala S, et al. Can transcatheter
PDA closure be performed in neonates £1000 grams? The
Memphis experience. Congenit Heart Dis. 2019;14(1):79–84
30. Moore JW, Greene J, Palomares S, et al; Pivotal and Continuing Access
Studies of the Nit Occlud PDA Investigators. Results of the combined
U.S. Multicenter Pivotal Study and the Continuing Access Study of the
Nit-Occlud PDA device for percutaneous closure of patent ductus
arteriosus. JACC Cardiovasc Interv. 2014;7(12):1430–1436
31. Baruteau AE, Hascoët S, Baruteau J, et al. Transcatheter closure of
patent ductus arteriosus: past, present and future. Arch Cardiovasc
Dis. 2014;107(2):122–132
32. Backes CH, Rivera BK, Bridge JA, et al. Percutaneous patent ductus
arteriosus (PDA) closure during infancy: a meta-analysis. Pediatrics.
2017;139(2):e20162927
33. Zahn EM, Nevin P, Simmons C, Garg R. A novel technique for
transcatheter patent ductus arteriosus closure in extremely preterm
infants using commercially available technology. Catheter
Cardiovasc Interv. 2015;85(2):240–248
34. Backes CH, Cheatham SL, Deyo GM, et al. Percutaneous patent
ductus arteriosus (PDA) closure in very preterm infants: feasibility
and complications. J Am Heart Assoc. 2016;5(2):e002923
35. Backes CH, Kennedy KF, Locke M, et al. transcatheter occlusion of
the patent ductus arteriosus in 747 infants <6 kg: insights from the
NCDR IMPACT Registry. JACC Cardiovasc Interv.
2017;10(17):1729–1737
36. Moodie DS, Sathanandam S, Qureshi AM. Proceedings of the
International PDA Symposium [published online ahead of print
February 27, 2019]. Congenit Heart Dis. 2019;14(1):5
Downloaded from http://neoreviews.aappublications.org/ at Ukraine:AAP Sponsored on July 1, 2020
37. Mitchell CC, Rivera BK, Cooper JN, et al. Percutaneous closure of
the patent ductus arteriosus: opportunities moving forward.
Congenit Heart Dis. 2019;14(1):95–99
38. Philip R, Waller BR III, Agrawal V, et al. Morphologic
characterization of the patent ductus arteriosus in the premature
infant and the choice of transcatheter occlusion device. Catheter
Cardiovasc Interv. 2016;87(2):310–317
39. Zahn EM. Transcatheter PDA Closure: Results of the Piccolo Trial.
Presented at the International PDA Symposium; Memphis, TN;
April 11, 2019
40. National Institutes of Health. AMPLATZER Duct Occluder II
Additional Sizes (ADO II AS). ClinicalTrials.gov Identifier:
NCT03055858. Available at: https://clinicaltrials.gov/ct2/
show/NCT03055858?term¼ADOþII&rank¼1. Accessed April 9,
2020
41. Johnson JN, Sathanandam S, Naik R, Philip R. Echocardiographic
guidance for transcatheter patent ductus arteriosus closure in
extremely low birth weight infants. Congenit Heart Dis.
2019;14(1):74–78
42. Bentham J, Meur S, Hudsmith L, Archer N, Wilson N.
Echocardiographically guided catheter closure of arterial ducts in
small preterm infants on the neonatal intensive care unit. Catheter
Cardiovasc Interv. 2011;77(3):409–415
43. Nealon E, Rivera BK, Cua CL, et al. Follow-up after percutaneous
patent ductus arteriosus occlusion in lower weight infants. J Pediatr.
2019;212:144–150.e3
44. Bass JL, Wilson N. Transcatheter occlusion of the patent ductus
arteriosus in infants: experimental testing of a new Amplatzer
device. Catheter Cardiovasc Interv. 2014;83(2):250–255
45. Wilson W, Taubert KA, Gewitz M, et al; American Heart Association
Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee;
American Heart Association Council on Cardiovascular Disease in
the Young; American Heart Association Council on Clinical
Cardiology; American Heart Association Council on Cardiovascular
Surgery and Anesthesia; Quality of Care and Outcomes Research
Interdisciplinary Working Group. Prevention of infective
endocarditis: guidelines from the American Heart Association: a
guideline from the American Heart Association Rheumatic Fever,
Endocarditis, and Kawasaki Disease Committee, Council on
Cardiovascular Disease in the Young, and the Council on Clinical
Cardiology, Council on Cardiovascular Surgery and Anesthesia, and
the Quality of Care and Outcomes Research Interdisciplinary
Working Group. Circulation. 2007;116(15):1736–1754
46. El-Said HG, Bratincsak A, Foerster SR, et al. Safety of percutaneous
patent ductus arteriosus closure: an unselected multicenter
population experience. J Am Heart Assoc. 2013;2(6):e000424
47. Malekzadeh-Milani S, Akhavi A, Douchin S, et al. Percutaneous
closure of patent ductus arteriosus in premature infants: A French
national survey. Catheter Cardiovasc Interv. 2019;95(1):71–77
48. Serrano RM, Madison M, Lorant D, Hoyer M, Alexy R. Comparison
of ‘post-patent ductus arteriosus ligation syndrome’ in premature
infants after surgical ligation vs. percutaneous closure. J Perinatol.
2020;40(2):324–329
49. Morville P, Douchin S, Bouvaist H, Dauphin C. Transcatheter
occlusion of the patent ductus arteriosus in premature infants
weighing less than 1200 g. Arch Dis Child Fetal Neonatal Ed.
2018;103(3):F198–F201
50. Morville P, Akhavi A. Transcatheter closure of hemodynamic
significant patent ductus arteriosus in 32 premature infants by
Vol. 21 No. 7 JULY 2020 e477
 amplatzer ductal occluder additional size-ADOIIAS. Catheter
Cardiovasc Interv. 2017;90(4):612–617
51. Rodríguez Ogando A, Planelles Asensio I, de la Blanca ARS, et al.
Surgical ligation versus percutaneous closure of patent ductus
arteriosus in very low-weight preterm infants: which are the real
benefits of the percutaneous approach? Pediatr Cardiol.
2018;39(2):398–410
52. Rodríguez Ogando A, Ballesteros Tejerizo F, Blanco Bravo D,
Sánchez Luna M, Zunzunegui Martínez JL. transcatheter occlusion
of patent ductus arteriosus in preterm infants weighing less than 2
kg with the Amplatzer Duct Occluder II Additional Sizes Device.
Rev Esp Cardiol (Engl Ed). 2018;71(10):865–866
53. Sathanandam S, Justino H, Waller BR III, Radtke W, Qureshi AM.
Initial clinical experience with the Medtronic Micro Vascular
PlugTM in transcatheter occlusion of PDAs in extremely premature
infants. Catheter Cardiovasc Interv. 2017;89(6):1051–1058
54. Narin N, Pamukçu Ö, Baykan A, et al. Transcatheter closure of PDA
in premature babies less than 2 kg. Anatol J Cardiol.
2017;17(2):147–153
55. Pamukcu O, Tuncay A, Narin N, et al. Patent Ductus Arteriosus
closure in preterms less than 2kg: Surgery versus transcatheter. Int J
Cardiol. 2018;250:110–115
56. Narin N, Pamukcu O, Baykan A, Sunkak S, Ulgey A, Uzum K.
Percutaneous PDA closure in extremely low birth weight babies.
J Interv Cardiol. 2016;29(6):654–660
57. Zahn EM, Peck D, Phillips A, et al. Transcatheter closure of patent
ductus arteriosus in extremely preterm newborns: early results and
midterm follow-up. JACC Cardiovasc Interv. 2016;9(23):2429–2437
58. Baspinar O, Sahin DA, Sulu A, et al. Transcatheter closure of patent
ductus arteriosus in under 6 kg and premature infants. J Interv
Cardiol. 2015;28(2):180–189
59. Sungur M, Karakurt C, Ozbarlas N, Baspinar O. Closure of patent
ductus arteriosus in children, small infants, and premature babies
with Amplatzer Duct Occluder II additional sizes: multicenter
study. Catheter Cardiovasc Interv. 2013;82(2):245–252
60. Francis E, Singhi AK, Lakshmivenkateshaiah S, Kumar RK.
Transcatheter occlusion of patent ductus arteriosus in pre-term
infants. JACC Cardiovasc Interv. 2010;3(5):550–555
61. Peckham GJ, Miettinen OS, Ellison RC, et al. Clinical course to 1
year of age in premature infants with patent ductus arteriosus:
e478 NeoReviews
Downloaded from http://neoreviews.aappublications.org/ at Ukraine:AAP Sponsored on July 1, 2020
results of a multicenter randomized trial of indomethacin. J Pediatr.
1984;105(2):285–291
62. Gersony WM, Peckham GJ, Ellison RC, Miettinen OS, Nadas AS.
Effects of indomethacin in premature infants with patent ductus
arteriosus: results of a national collaborative study. J Pediatr.
1983;102(6):895–906
63. Cassady G, Crouse DT, Kirklin JW, et al. A randomized, controlled
trial of very early prophylactic ligation of the ductus arteriosus in
babies who weighed 1000 g or less at birth. N Engl J Med.
1989;320(23):1511–1516
64. Clyman R, Cassady G, Kirklin JK, Collins M, Philips JB III. The role
of patent ductus arteriosus ligation in bronchopulmonary dysplasia:
reexamining a randomized controlled trial. J Pediatr.
2009;154(6):873–876
65. Malviya MN, Ohlsson A, Shah SS. Surgical versus medical
treatment with cyclooxygenase inhibitors for symptomatic patent
ductus arteriosus in preterm infants. Cochrane Database Syst Rev.
2013;(3):CD003951
66. Mosalli R, Alfaleh K. Prophylactic surgical ligation of patent ductus
arteriosus for prevention of mortality and morbidity in extremely
low birth weight infants. Cochrane Database Syst Rev.
2008;(1):CD006181
67. Liebowitz M, Katheria A, Sauberan J, et al; PDA-TOLERATE (PDA:
TOLEave it alone or Respond And Treat Early) Trial Investigators.
Lack of Equipoise in the PDA-TOLERATE Trial: A Comparison of
Eligible Infants Enrolled in the Trial and Those Treated Outside the
Trial. J Pediatr. 2019;213:222–226.e2 doi: 10.1016/
j.jpeds.2019.05.049
68. Backes CH, Donovan JL, Slaughter JL. Catheter-based closure of the
patent ductus arteriosus in preterm infants: considerations in the
design of a randomized trial. J Perinatol. 2019;39(11):1437–1438
69. McNamara PJ, Sehgal A. Towards rational management of the
patent ductus arteriosus: the need for disease staging. Arch Dis
Child Fetal Neonatal Ed. 2007;92(6):F424–F427
70. Slaughter JL, Cua CL, Notestine JL, et al. Early prediction of
spontaneous Patent Ductus Arteriosus (PDA) closure and PDA-
associated outcomes: a prospective cohort investigation. BMC
Pediatr. 2019;19(1):333
 Percutaneous Closure of the Patent Ductus Arteriosus in Very-Low-Weight
Infants
Danielle Scerbo, Clifford L. Cua, Brian K. Rivera, Laura C. Marzec, Charles V.
Smith, Jonathan L. Slaughter, Darren P. Berman and Carl H. Backes
NeoReviews 2020;21;e469
DOI: 10.1542/neo.21-7-e469

Updated Information & including high resolution figures, can be found at:
Services http://neoreviews.aappublications.org/content/21/7/e469
References This article cites 64 articles, 14 of which you can access for free at:
http://neoreviews.aappublications.org/content/21/7/e469.full#ref-list-
1
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Pediatric Drug Labeling Update
http://classic.neoreviews.aappublications.org/cgi/collection/pediatric
_drug_labeling_update
Permissions & Licensing Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
https://shop.aap.org/licensing-permissions/
Reprints Information about ordering reprints can be found online:
http://classic.neoreviews.aappublications.org/content/reprints

Downloaded from http://neoreviews.aappublications.org/ at Ukraine:AAP Sponsored on July 1, 2020

 Percutaneous Closure of the Patent Ductus Arteriosus in Very-Low-Weight
Infants
Danielle Scerbo, Clifford L. Cua, Brian K. Rivera, Laura C. Marzec, Charles V.
Smith, Jonathan L. Slaughter, Darren P. Berman and Carl H. Backes
NeoReviews 2020;21;e469
DOI: 10.1542/neo.21-7-e469

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/21/7/e469

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication,
it has been published continuously since 2000. Neoreviews is owned, published, and trademarked
by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,
Illinois, 60007. Copyright © 2020 by the American Academy of Pediatrics. All rights reserved.
Online ISSN: 1526-9906.

Downloaded from http://neoreviews.aappublications.org/ at Ukraine:AAP Sponsored on July 1, 2020