SE M I N A R S I N P E R I N A T O L O G Y ] (]]]]) ]]]–]]]

Available online at www.sciencedirect.com

Seminars in Perinatology

www.seminperinat.com

Patent ductus arteriosus, its treatments, and the

risks of pulmonary morbidity
Ronald I. Clyman, MDn
Cardiovascular Research Institute, Departments of Pediatrics and the Cardiovascular Research Institute, University of
California, San Francisco, UCSF Box 1346, HSW 1408, 513 Parnassus Ave, San Francisco, CA 94143-1346

article info abstra ct

Keywords: A persistent left-to-right shunt through a patent ductus arteriosus (PDA) increases the rate of
Patent ductus arteriosus hydrostatic fluid filtration into the lung’s interstitium, impairs pulmonary mechanics, and
Indomethacin prolongs the need for mechanical ventilation. In preclinical trials, pharmacologic PDA closure
Ibuprofen leads to improved alveolarization and minimizes the impaired postnatal alveolar development
Bronchopulmonary dysplasia that is the pathologic hallmark of bronchopulmonary dysplasia (BPD). Although routine
Chronic lung disease prophylactic treatment of a PDA on the day of birth does not appear to offer any more
Pulmonary edema protection against BPD than delaying treatment for 2–3 days, recent evidence from quality
improvement trials suggests that early pharmacologic treatment decreases the incidence of BPD
compared with a treatment approach that exposes infants to a moderate-to-large PDA shunt for
the first 7–10 days after birth. After the first week, routine pharmacologic treatment (compared
with continued PDA exposure) no longer appears to alter the course of BPD development.
Evidence from epidemiologic, preclinical, and randomized controlled trials demonstrate that
early ductus ligation is an independent risk factor for the development of BPD.
& 2018 Published by Elsevier Inc.

Introduction interstitium, a decrease in interstitial protein concentration,

Patent ductus arteriosus (PDA) are present in up to 70% of
preterm infants born before 28 weeks gestation. While there
is general agreement that a moderate-to-large left-to-right
PDA shunt should be closed by the time a child is 1–2 years
old, there is great uncertainty about whether it needs to be
closed during the neonatal period. Both the high rate of
spontaneous ductus closure during the neonatal hospital-
ization and the absence of appropriate randomized controlled
trials (RCTs) that specifically address the risks of prolonged
shunt exposure, have created the current confusion.
A persistent PDA increases hydraulic pressures on both the
arterial and venous sides of the pulmonary capillary bed.
This, in turn, leads to an increase in fluid filtration into the
and “hydraulic” pulmonary edema. Although numerous epi-
demiologic studies show an association between the pres-
ence of a PDA and bronchopulmonary dysplasia (BPD), clear
evidence demonstrating a causal role for the PDA in the
development of BPD is lacking. This chapter will examine the
evidence linking a PDA and its forms of treatment to the
development of BPD.
PDA: pulmonary edema, pulmonary mechanics,
and alveolar growth
The pathophysiologic features of a PDA depend on the
magnitude of the left-to-right shunt and on the cardiac and

Supported in part by a grant from U.S. Public Health Service (NIH HL109199), the Gerber Foundation, and by a gift from the Jamie and
Bobby Gates Foundation.
n
Tel.: þ1 415 443 9305.
E-mail address: clymanr@peds.ucsf.edu

https://doi.org/10.1053/j.semperi.2018.05.006
0146-0005/& 2018 Published by Elsevier Inc.
2 SE M I N A R S I N P E R I N A T O L O G Y
pulmonary responses to the shunt. The immature fetal
ventricles are less distensible than at term.1 As a result, left
ventricular distension, secondary to the left-to-right PDA
shunt, produces higher left ventricular end-diastolic pres-
sures at smaller ventricular volumes in preterm infants than
at term. The increase in left ventricular pressure increases
pulmonary venous pressure, which contributes to pulmonary
congestion. Because the pulmonary vascular bed in the
preterm newborn is already fully recruited,2 the increase in
pulmonary blood flow from the left-to-right PDA shunt
produces an increase in pulmonary arterial pressure and a
shift in the pulmonary pressure head downstream towards
the capillary fluid filtration sites.3 This, in turn, increases the
rate of fluid transudation into the pulmonary interstitium.4
Depending on the gestational age and the species examined,
changes in pulmonary mechanics may occur as early as 1 day
after birth (as they do in mice with a PDA),5 or not before
several days of exposure to the left-to-right PDA shunt.3,6 In
preterm newborns, the decreased ability to maintain active
precapillary pulmonary arterial tone7 allows the intravascular
hydraulic pressure to distribute more of its force towards the
downstream capillary fluid filtration sites.3 Anything that
decreases precapillary tone (e.g., intrauterine growth restric-
tion8 or surfactant administration9–11) can exacerbate the
amount of left-to-right shunt, alter the distribution of pulmo-
nary hydraulic pressures to downstream filtration sites, and
lead to earlier pulmonary edema and pulmonary hemor-
rhage.8,11,12 Conversely, therapies that increase precapillary
vasoconstriction (e.g., dopamine13) or precapillary resistance
(e.g., red blood cell transfusions and increased blood viscos-
ity14) can decrease the left-to-right PDA shunt and redistrib-
ute the pressure head upstream, away from the capillary bed.
Increased microvascular pressure in preterm infants with
respiratory distress syndrome has an exaggerated effect on
interstitial and alveolar fluid accumulation due to their low
plasma oncotic pressures and increased capillary permeabil-
ity. Subsequent leakage of plasma proteins into the alveolar
space inhibits surfactant function and increases surface
tension in the immature air sacs,15 which are already com-
promised by surfactant deficiency.
Even though preterm animals with a PDA have increased
fluid and, to a lesser extent, protein filtration into the lung’s
interstitium, the excess fluid and protein appear to be cleared
by a simultaneous increase in lung lymph flow.4 This com-
pensatory increase in lung lymph acts as an “edema safety
factor”, which inhibits fluid accumulation in the lungs and
minimizes changes in pulmonary mechanics.3,16–19 The del-
icate balance between PDA-induced fluid filtration and lym-
phatic fluid clearance probably accounts for the observation,
that PDA patency or closure during the first day after birth in
human infants, has little effect on pulmonary mechanics and
need for ventilatory support. However, if lung lymphatic
drainage is overwhelmed or impaired, as it is in the presence
of pulmonary interstitial emphysema or fibrosis, the like-
lihood of edema increases dramatically.
After several days of exposure to mechanical ventilation
there is a decrease in pulmonary capillary surface area, which
causes both an increase in pulmonary microvascular pres-
sure and an increase in hydraulic fluid filtration.20 As a result,
it is not uncommon for infants with a persistent PDA to
] (]]]]) ]]]–]]]
develop pulmonary edema and alterations in pulmonary
mechanics at 7–10 days after birth from the same size PDA
shunt that could be accommodated on the first day after
delivery. In these infants, closure of the PDA consistently
results in improvement in lung compliance.16,21–25
The preterm baboon newborn (delivered at 67% term
gestation) has been used as a preclinical model to examine
the role of the PDA in the development of BPD.6,26–28 Prema-
ture delivery and mechanical ventilation of the newborn
baboon decrease the expression of genes involved with new
vessel growth and lung remodeling and increase the expres-
sion of genes involved with pulmonary inflammation.6,29–40
Although numerous changes in gene expression occur during
the first 2 weeks after birth, the presence of an open ductus
does not appear to alter the expression of any of the pro-
inflammatory or tissue remodeling genes that have been
examined.6 Nor does persistent exposure to the PDA alter
surfactant secretion, pulmonary epithelial protein permeabil-
ity, or presence of surfactant inhibitory proteins.6
In addition to its effects on pulmonary vascular fluid
filtration,4 pharmacologic PDA closure alters fluid clearance
from the alveolar space. Clearance of fluid from the newborn
lung requires the presence of amiloride-sensitive alveolar
epithelial sodium (ENaC) channels.41 In contrast with full-
term newborns, preterm baboons have diminished expres-
sion of ENaC channels and slow rates of fluid clearance from
their lungs.6,42,43 Pharmacologic closure of the PDA (with
ibuprofen or indomethacin) is associated with a small but
significant decrease in lung water compared with baboons
with an open ductus.6 The improvement in pulmonary
mechanics that follows pharmacologic closure of the PDA is
associated with increased pulmonary expression of ENaC
channels and increased lung water clearance.6 The effects
of ibuprofen and indomethacin on ENaC expression appear to
be due to their inhibition of cyclooxygenase activity, rather
than their effect on ductus closure.6 This finding may account
for the decreased incidence of significant pulmonary edema/
hemorrhage in infants that are treated prophylactically with
indomethacin or ibuprofen shortly after birth.44–48
Pharmacologic closure of the PDA is also associated with
improved alveolar development in preterm baboons. In con-
trast to animals with an open ductus, where impaired alveolar
development (the hallmark of the BPD) is noticeable by 2
weeks after birth, pharmacological closure of the PDA leads to
improved alveolarization.6 Whether the improvement in
alveolarization is due to closure of the PDA or to the pharma-
cologic agents (indomethacin and ibuprofen) used to close it is
uncertain at this time. Inflammation plays a significant role in
the development of BPD.33,49 Infants with a PDA have elevated
concentrations of activated neutrophils in their tracheal fluid
and indomethacin-induced closure of the PDA is associated
with a decline in activated neutrophils.50 However, the
decrease in neutrophil concentration occurs in both those
who close their ductus after indomethacin as well as in those
whose PDA fails to close after indomethacin.51
The improvements in pulmonary mechanics and alveolar
surface area that accompany pharmacologic closure of the
PDA have not been observed after surgical ligation of the PDA.
In premature baboons surgical PDA closure decreases the
expression of genes involved in angiogenesis (angiopoietin-2
 SE M I N A R S I N
and TGF beta 3)52 and increases the expression of pro-
inflammatory mediators (cyclooxygenase 2, TNF-alpha, and
cells expressing CD14).53 Surgical PDA closure also decreases
the expression of pulmonary ENaC channels. The decrease in
ENaC expression may contribute to the pulmonary edema,
delayed fluid clearance and lack of improvement in pulmo-
nary mechanics after PDA ligation.53 Early surgical ligation
also impedes lung alveolarization.54 These findings raise the
possibility that early ductus ligation, while eliminating the
detrimental effects of a PDA on lung development, may
create its own set of problems that counteract the benefits
derived from ductus closure.55
PDA and BPD: interpreting the
results of clinical trials
Early pharmacologic treatment is effective in closing the PDA
and decreasing the incidence of hemorrhagic pulmonary
edema,44,46,56 hypotension, and need for early inotropic and
ventilator support.57,58 Whether the PDA plays a causal role in
the development of BPD in human infants is still a matter of
debate.
Prior retrospective observational studies demonstrate an
association between the presence of a PDA and bronchopul-
monary dysplasia. However, caution must be used when
trying to link causation to association in these observational
studies. Both the presence of a PDA and its perceived need for
treatment are excellent biomarkers for infant immaturity and
illness. Although statistical models may adjust for multiple
factors, they cannot adjust for bias or for potential unmeas-
ured confounders. Unfortunately, in all of the retrospective
observational studies, PDA treatment assignment was deter-
mined by the physicians’ perceived need for treatment rather
than by a specific mandated, unbiased treatment protocol.
In contrast with the associations found in the observational
studies, none of the randomized controlled trials (RCTs) that
have explored the relationship between ductus patency and
BPD have found an association between the two.56,57,59–62 As a
result, recent reviews have concluded that “routine treatment
to induce closure of the ductus, either medically or surgically,
in the first 2 weeks after birth does not improve long-term
outcomes” like BPD.63,64
Although the aforementioned RCTs failed to show any
long-term benefits, it might be a mistake to conclude that
exposure to a PDA during the first 2 weeks might not have
any long-term consequences. Interpreting the results of
clinical trials requires that one recognize the basic assump-
tions behind the clinical trial study design. As discussed
above, infants with a moderate-to-large PDA shunt are
challenged by the hemodynamic alterations that accompany
the shunt (decreased systemic blood pressure, reduction in
blood flow to the systemic organs, increased pulmonary
blood pressure and flow, increased lung water, and decreased
lung compliance).3,4,6,8,11,19,25,44,56,65–67 How an infant adapts
to these hemodynamic changes determines how clinicians
respond to the infant. Any study that compares “treatment”
(to close the PDA) with “no treatment” (and persistent ductus
patency) has to recognize that “other” treatment modalities
are being used to offset the hemodynamic consequences of
P E R I N A T O L O G Y ] (]]]]) ]]]–]]] 3
the PDA. Although treatments like inotropic support,13 fluid
restriction68,69, and end-expiratory pressure70 may have no
effect on the size of the PDA, they are frequently used to
minimize the effects of the shunt. Therefore, if morbidities
are found in the “no treatment” arm of a study, one has to
ask: are the morbidities due to the persistent PDA shunt
itself, or are they due to the “other” treatments used to
stabilize the infants while awaiting spontaneous closure?
While most trials describe in detail what is done to infants
in the “treatment” arm, virtually none of the studies describe
the “other” treatments used in the “no treatment” arm to deal
with the PDA’s hemodynamic effects. The trials’ outcomes
depend as much (or even more so) on the “other” treatments
as they do on those used in the “treatment” arm.
Consider, for example, the trials that examined whether
moderate-to-large PDA shunts should be ligated within the first
2 weeks after birth. In the seminal randomized controlled trial of
“early surgical closure” versus “no treatment” reported by Cotton
et al. in 197871 ventilated preterm infants were randomized at
the end of the first week to either surgical PDA ligation or “no
treatment”. Despite the known complications that can accom-
pany surgical ligation (pneumothorax, chylothorax, scoliosis,
infection, vocal cord paralysis, and post-operative cardiopulmo-
nary deterioration),53–55,72–83 the authors found that infants in the
surgical treatment arm had a lower incidence of pulmonary
morbidity than infants in the “no treatment” arm. In contrast to
the findings of Cotton et al.,71 recent controlled clinical trials
report the opposite results—namely, that the “no treatment”
group has less morbidity compared with the early surgical
closure group.84,85
How can we explain the difference between the study of
Cotton et al. and the more recent studies? In both sets of
studies, the investigators had two choices: either to close the
ductus itself (“treatment”), or to mitigate its hemodynamic
effects (“no treatment”). In the study by Cotton et al. the “no
treatment” group required long-term, high volume and high
pressure mechanical ventilation, which was the prevalent
form of ventilation in the 1970s, to control the PDA-induced
pulmonary edema.71,86 Even when they reported their results,
Cotton et al. questioned whether the pulmonary morbidity in
the “no treatment” group might be due to the mechanical
ventilation rather than to the ductus shunt.86
In contrast with the study by Cotton et al., the more recent
surgical closure trials managed infants in the “no treatment”
group with a “gentler” respiratory approach—where intuba-
tions were avoided and hypercarbia tolerated. With this type
of respiratory management the opposite results were found—
namely, less morbidity in the “no treatment” arm.55,84,87–89
The increased morbidity in the “treatment” arm appeared to
be due to the surgery itself since the difference between the
study arms disappeared when the analyses were adjusted for
the different ligation rates.82 Similarly, the one RCT that
compared the effects of prophylactic PDA ligation with
delayed ligation found a higher incidence of BPD in the group
that was ligated prophylactically.55 We now know that many
of the morbidities associated with ligation (post-ligation
hypotension,81 vocal cord paralysis,73 and bronchopulmonary
dysplasia55 and abnormal neurocognitive development82)
appear to be reduced when ligation is avoided or delayed
for several weeks.83 At this point in time, avoiding surgical
4 SE M I N A R S I N P E R I N A T O L O G Y
Table – Comparison of neonatal morbidities detected in different PDA treatment trials.
Prophylactic versus early
Rx RCTs*
Day of Rx (mean) Day 0 versus Day 3
Duration of exposure to a moderate-to-large 2 days versus 4 days
PDA (median)
IVH (grades 3 & 4) Decreased
Pulmonary hemorrhage Decreased
Ventilatory support (at end of first week) No effect
Dopamine-dependent hypotension No effect
BPD No effect
NEC No effect
Late onset bacteremia No effect
Death No effect
⁎
See Refs.56,57,59–62,90
§
See Refs.58,94
¶
See PDA-TOLERATE trial (unpublished results).
ligation or delaying it until late in the neonatal course
appears to be preferable to ligating the PDA within the first
2–3 weeks. Unfortunately, there is no information to deter-
mine which infants are most likely to benefit from later
surgical ligation and which infants might best be left
untreated.
Similar problems exist when one examines the trials used to
study the effects of pharmacologic PDA closure on neonatal
morbidity. More than 30 placebo controlled RCTs have exam-
ined this question.56,57,59–62,90 Most of these trials were per-
formed more than 17 years ago and as with the surgical
“treatment” trials discussed above, interpreting the results of
the pharmacologic RCTs requires an understanding of how
infants in the “no treatment” arm were handled. In these trials,
the pharmacologic “treatment” was used as a surrogate for
PDA closure, and conversely, “no treatment” was used as a
surrogate for persistent ductus patency. Unfortunately, the
correlation between “no treatment” and persistent ductus
patency was quite imperfect. Most of the RCTs enrolled
patients based on whether the PDA was present or absent,
without considering the magnitude of the shunt.91 This is a
significant problem since, although there is an association
between the development of BPD and the persistence of
moderate-to-large PDA shunts, there does not appear to be
any association between BPD and small, insignificant
shunts.92,93 Including infants with small, insignificant PDAs in
the “no treatment” group minimizes the difference in PDA
exposure between the two groups. The lack of correlation
between “no treatment” and “persistent PDA exposure” was
made even worse by the fact that 40–75% of the infants in the
“no treatment” group closed their PDA spontaneously before
the end of the first week. In addition, infants in the no
treatment group could be rescued or crossed-over to the treat-
ment group. The average time before infants in the “no-treat-
ment” group were crossed-over and treated was 2–5 days.
This imperfect correlation between “no treatment” and
persistent ductus patency results in a misclassification that
biases the results of the RCTs towards the null hypothesis. As
] (]]]]) ]]]–]]]
Quality improvement trials§ PDA-TOLERATE RCT¶
Day 0 versus Day 8 Day 8 versus Day 20
2 days versus 14 days 16 days versus 30 days
Decreased (only in infants No effect
≤24 weeks)
Decreased No effect
Decreased No effect
Decreased Decreased
Decreased No effect
No effect No effect
No effect Increased (in infants ≥26
weeks)
No effect Increased (in infants ≥26
weeks)
a result, it would be a mistake to assume that these RCTs can
really address the effects of prolonged exposure to a moderate-
to-large PDA shunt. The best that one can conclude from
these trials is that the risk of serious neonatal morbidity is
not increased by exposure to a moderate-to-large PDA that
lasts for just a few days.57,59,61,62,90
Fortunately, new information is starting to appear from
studies that were specifically designed to examine the role of
prolonged PDA exposure in the development of BPD (Table).
Recent quality improvement trials have compared infants
that were born in an era where all infants received indome-
thacin within 3 days of birth (“treatment” era), with infants
born in a “no treatment” era, where infants could only be
treated with indomethacin if a moderate-to-large PDA per-
sisted beyond 7 days and specific rescue criteria were
present.94,95 Although these studies were not RCTs, they were
done prospectively and the planned change in the use of
indomethacin was by design and not confounded by indica-
tion, as had been the case in the retrospective observational
studies mentioned above. In the quality improvement trials,
73% of the infants in the “no treatment” era still had a
moderate-to-large PDA at the end of the first week.94,95
Although infants in the “no treatment” era could be “res-
cued”, the median age of rescue was 12–15 days (in contrast
with the earlier RCTs, discussed above, where infants were
rescued at 2–5 days). The quality improvement studies found
that infants in the early “treatment” era required less ven-
tilator and inotropic support at the end of the first week,58
and had a lower incidence of BPD and BPD/Death than infants
in the “no treatment” era.94,95 These findings are consistent
with the findings of several small RCTs in which infants
treated within 3 days of birth were compared with infants
treated after 8–10 days.16,90 In these trials, infants in the early
treatment group had a reduced incidence of pulmonary
morbidity compared with delayed PDA treatment. These
findings are also consistent with a recent report from the
National Institute of Child Health and Human Development
Neonatal Research Network. Network centers that regularly
 SE M I N A R S I N
used prophylactic indomethacin as part of their admission
care had significantly lower rates of BPD and BPD/Death than
centers that never used prophylactic treatment.96
Unfortunately, studies that enroll infants within the first
days after birth run the risk of enrolling and treating infants
who might spontaneously close their ductus before the end
of the first week.97,98 In the RCTs discussed above the
incidence of spontaneous closure within the first week
ranged from 40% to 75%. To avoid including infants who
might constrict their PDA spontaneously, an alternate
approach might be to wait until the end of the first week
before evaluating and enrolling infants. The recently con-
cluded PDA-TOLERATE RCT used this type of approach (Cly-
man et al., unpublished results) to test the hypothesis that
routine treatment of a moderate-to-large PDA, present at the
end of the first postnatal week in infants o28 weeks
gestation, would decrease the incidence of neonatal morbid-
ities compared with a Conservative “no treatment”
approach. The Conservative “no treatment” approach only
used PDA treatment if pre-specified respiratory and hemo-
dynamic “Rescue” criteria were present. Infants in the PDA-
TOLERATE RCT were enrolled at 8 ± 2 (mean ± sd) days: the
median age of PDA constriction in the routine “treatment”
group was 16 days (7.5 days after randomization), whereas
the median age of PDA constriction in the Conservative “no
treatment” group was 30 days (22 days after randomization).
The PDA-TOLERATE trial found that routine PDA “treat-
ment”, at the end of the first week, decreased the need for
inotropic support and incidence of PDA at discharge among
infants o26 weeks gestation. However, it failed to reduce the
incidence of BPD, BPD/Death or other neonatal morbidities.
In addition, routine PDA “treatment” appeared to increase
the incidence of late-onset bacteremia and death among
infants ≥26 weeks gestation.
Taken together, the data from the quality improvement
studies and the PDA-TOLERATE trial suggest that there may
be a critical window, during the first 10 days after birth,
during which exposure to a persistent PDA might increase the
risk of BPD. In contrast, waiting until the end of the first week
before initiating treatment, as was done in the PDA-TOLER-
ATE trial, may be like closing the barn door after the horse
has already escaped. In the PDA-TOLERATE trial routine
treatment of moderate-to-large PDAs after the first week
had no effect on the incidence of BPD compared with waiting
for more severe respiratory or hemodynamic symptoms to
develop. It appears that after the first week, continued
exposure to a moderate-to-large PDA may no longer contrib-
ute to the burden of BPD. This observation is supported by a
recent study examining the relationship between ductus
patency during the first week and the incidence of BPD in
infants born before 28 weeks gestation (Liebowitz, Jhong,
Clyman, unpublished results). In this study, infants with a
persistent small PDA at 7 days had the same incidence of BPD
as infants with a closed ductus; whereas infants with a
moderate-to-large PDA at 7 days had a 2–3 fold higher
incidence of BPD than infants with a closed ductus. This is
similar to previous reports.92,93 What is interesting about this
study is that some of the infants with a small PDA at 7 days
subsequently reopened their PDA and developed a moderate-
to-large shunt that persisted for several weeks. In contrast
P E R I N A T O L O G Y ] (]]]]) ]]]–]]] 5
with the infants who had a moderate-to-large PDA during the
first week, infants with a moderate-to-large PDA that first
appeared after 7 days had the same low incidence of BPD as
infants with a closed ductus at 7 days.
Currently there are several ongoing RCTs examining
the effects of PDA treatment starting at different times after
birth (NCT01630278, NCT02884219, EudraCT:2013–005336–23,
NCT02128191). Hopefully these studies have been designed so
the timing of spontaneous or “rescue” PDA closure in the “no
treatment” arm is delayed at least 8–10 days. If so, these trials
should give us important information about the effects of
timing of treatment and prolonged PDA exposure on BPD and
other neonatal morbidities.
Conclusions
1) Moderate-to-large PDAs decrease systemic blood pressure,
decrease systemic organ perfusion, increase pulmonary
blood flow, pulmonary pressure, and lung water, and
decrease lung compliance.
2) The “treatment” versus “no treatment” trials do not really
tell us about the morbid effects of the PDA. They just tell us
about two different treatment choices: one designed to
close the ductus and one designed to deal with its hemo-
dynamic consequences. As the “other” treatment choices
used in these studies change in the future, so will the
outcomes of future “treatment” trials.
3) PDA ligation, especially early PDA ligation, should be
considered a morbidity in and of itself. Our primary
strategy should be to avoid, or at least delay, surgical
ligation.
4) Although delaying pharmacologic PDA treatment for 2–3
days after birth does not increase the incidence of BPD,
there is growing evidence from quality improvement trials
that delaying treatment until after the first week may be
associated with an increased incidence of BPD and BPD/
Death. After the first week, routine pharmacologic treat-
ment (compared with continued PDA exposure) no longer
appears to alter the course of BPD development.
Disclosure
Dr Clyman has no proprietary or commercial interest in any
product mentioned or concept discussed in this article.
refere nces
1. Friedman WF. The intrinsic physiologic properties of the
developing heart. In: Friedman WF, Lesch M, Sonnenblick
EH, et al., eds. Neonatal Heart Disease. New York: Grune and
Stratton; 1972. 21–49.
2. Nelin LD, Wearden ME, Welty SE, Hansen TN. The effect of
blood flow and left atrial pressure on the DLCO in lambs and
sheep. Respir Physiol. 1992;88(3):333–342.
3. Perez Fontan JJ, Clyman RI, Mauray F, Heymann MA, Roman
C. Respiratory effects of a patent ductus arteriosus in pre-
mature newborn lambs. J Appl Physiol. 1987;63(6):2315–2324.
6 SE M I N A R S I N P E R I N A T O L O G Y
4. Alpan G, Scheerer R, Bland RD, Clyman R. Patent ductus
arteriosus increases lung fluid filtration in preterm lambs.
Pediatr Res. 1991;30:616–621.
5. Loftin CD, Trivedi DB, Tiano HF, et al. Failure of ductus
arteriosus closure and remodeling in neonatal mice deficient
in cyclooxygenase-1 and cyclooxygenase-2. Proc Natl Acad Sci
U S A. 2001;98(3):1059–1064.
6. McCurnin D, Seidner S, Chang LY, et al. Ibuprofen-induced
patent ductus arteriosus closure: physiologic, histologic, and
biochemical effects on the premature lung. Pediatrics. 2008;121
(5):945–956.
7. Lewis AB, Heymann MA, Rudolph AM. Gestational changes in
pulmonary vascular responses in fetal lambs in utero. Circ
Res. 1976;39:536–541.
8. Rakza T, Magnenant E, Klosowski S, Tourneux P, Bachiri A,
Storme L. Early hemodynamic consequences of patent ductus
arteriosus in preterm infants with intrauterine growth restric-
tion. J Pediatr. 2007;151(6):624–628.
9. Clyman RI, Jobe A, Heymann MA, et al. Increased shunt
through the patent ductus arteriosus after surfactant replace-
ment therapy. J Pediatr. 1982;100:101–107.
10. Soll R, Ozek E. Prophylactic protein free synthetic surfactant
for preventing morbidity and mortality in preterm infants.
Cochrane Database Syst Rev. 2010(1)): CD001079.
11. Alpan G, Clyman RI. Cardiovascular effects of surfactant
replacement with special reference to the patent ductus
arteriosus. In: Robertson B, Taeusch HW, et al., eds. Surfactant
Therapy for Lung Disease: Lung Biology in Health and Disease. 84.
New York: Marcel Dekker, Inc; 1995. 531–545.
12. Raju TNK, Langenberg P. Pulmonary hemorrhage and exoge-
nous surfactant therapy—a metaanalysis. J Pediatr. 1993;123
(4):603–610.
13. Bouissou A, Rakza T, Klosowski S, Tourneux P, Vanderborght
M, Storme L. Hypotension in preterm infants with significant
patent ductus arteriosus: effects of dopamine. J Pediatr.
2008;153(6):790–794.
14. Fouron JC, Bard H, Riopel L, de Muylder X, Van Ameringen MR,
Urfer F. Circulatory changes in newborn lambs with exper-
imental polycythemia: comparison between fetal and adult
type blood. Pediatrics. 1985;75(6):1054–1060.
15. Ikegami M, Jacobs H, Jobe A. Surfactant function in respira-
tory distress syndrome. J Pediatr. 1983;102:443–447.
16. Clyman RI. Commentary: Recommendations for the postnatal
use of indomethacin. An analysis of four separate treatment
strategies. J Pediatr. 1996;128:601–607.
17. Shimada S, Raju TNK, Bhat R, Maeta H, Vidyasagar D. Treat-
ment of patent ductus arteriosus after exogenous surfactant
in baboons with hyaline membrane disease. Pediatr Res.
1989;26:565–569.
18. Krauss AN, Fatica N, Lewis BS, et al. Pulmonary function in
preterm infants following treatment with intravenous indo-
methacin. Am J Dis Child. 1989;143:78–81.
19. Alpan G, Mauray F, Clyman RI. Effect of patent ductus
arteriosus on water accumulation and protein permeability
in the premature lungs of mechanically ventilated premature
lambs. Pediatr Res. 1989;26:570–575.
20. Mokres LM, Parai K, Hilgendorff A, et al. Prolonged mechan-
ical ventilation with air induces apoptosis and causes failure
of alveolar septation and angiogenesis in lungs of newborn
mice. Am J Physiol Lung Cell Mol Physiol. 2010;298(1):L23–L35.
21. Gerhardt T, Bancalari E. Lung compliance in newborns with
patent ductus arteriosus before and after surgical ligation. Biol
Neonate. 1980;38:96–105.
22. Naulty CM, Horn S, Conry J, Avery GB. Improved lung com-
pliance after ligation of patent ductus arteriosus in hyaline
membrane disease. J Pediatr. 1978;93:682–684.
23. Stefano JL, Abbasi S, Pearlman SA, Spear ML, Esterly KL, Bhutani
VK. Closure of the ductus arteriosus with indomethacin in
] (]]]]) ]]]–]]]
ventilated neonates with respiratory distress syndrome. Effects
of pulmonary compliance and ventilation. Am Rev Respir Dis.
1991;143(2):236–239.
24. Yeh TF, Thalji A, Luken L, Lilien L, Carr I, Pildes RS. Improved
lung compliance following indomethacin therapy in prema-
ture infants with persistent ductus arteriosus. Chest. 1981;80
(6):698–700.
25. Szymankiewicz M, Hodgman JE, Siassi B, Gadzinowski J.
Mechanics of breathing after surgical ligation of patent
ductus arteriosus in newborns with respiratory distress
syndrome. Biol Neonate. 2004;85(1):32–36.
26. Coalson JJ, Winter VT, Siler-Khodr T, Yoder BA. Neonatal
chronic lung disease in extremely immature baboons. Am J
Respir Crit Care Med. 1999;160(4):1333–1346.
27. Yoder BA, Siler-Khodr T, Winter VT, Coalson JJ. High-fre-
quency oscillatory ventilation: effects on lung function,
mechanics, and airway cytokines in the immature baboon
model for neonatal chronic lung disease. Am J Respir Crit Care
Med. 2000;162(5):1867–1876.
28. Bhatt AJ, Pryhuber GS, Huyck H, Watkins RH, Metlay LA,
Maniscalco WM. Disrupted pulmonary vasculature
and decreased vascular endothelial growth factor, Flt-1,
and TIE-2 in human infants dying with bronchopulmonary
dysplasia. Am J Respir Crit Care Med. 2001;164(10 Pt 1):
1971–1980.
29. McCurnin DC, Pierce RA, Willis BC, et al. Postnatal estradiol
up-regulates lung nitric oxide synthases and improves lung
function in bronchopulmonary dysplasia. Am J Respir Crit Care
Med. 2009;179(6):492–500.
30. Pierce RA, Joyce B, Officer S, et al. Retinoids increase lung
elastin expression but fail to alter morphology or angio-
genesis genes in premature ventilated baboons. Pediatr Res.
2007;61(6):703–709.
31. Maniscalco WM, Watkins RH, Pryhuber GS, Bhatt A, Shea C,
Huyck H. Angiogenic factors and alveolar vasculature: devel-
opment and alterations by injury in very premature baboons.
Am J Physiol Lung Cell Mol Physiol. 2002;282(4):L811–L823.
32. Naik AS, Kallapur SG, Bachurski CJ, et al. Effects of ventilation
with different positive end-expiratory pressures on cytokine
expression in the preterm lamb lung. Am J Respir Crit Care Med.
2001;164(3):494–498.
33. Speer CP. Inflammation and bronchopulmonary dysplasia: a
continuing story. Semin Fetal Neonatal Med. 2006;11(5):354–362.
34. Vozzelli MA, Mason SN, Whorton MH, Auten RL Jr. Antima-
crophage chemokine treatment prevents neutrophil and
macrophage influx in hyperoxia-exposed newborn rat lung.
Am J Physiol Lung Cell Mol Physiol. 2004;286(3):L488–L493.
35. Kotecha S, Wilson L, Wangoo A, Silverman M, Shaw RJ.
Increase in interleukin (IL)-1 beta and IL-6 in bronchoalveolar
lavage fluid obtained from infants with chronic lung disease
of prematurity. Pediatr Res. 1996;40(2):250–256.
36. Tullus K, Noack GW, Burman LG, Nilsson R, Wretlind B,
Brauner A. Elevated cytokine levels in tracheobronchial aspi-
rate fluids from ventilator treated neonates with broncho-
pulmonary dysplasia. Eur J Pediatr. 1996;155(2):112–116.
37. Groneck P, Gotze-Speer B, Oppermann M, Eiffert H, Speer CP.
Association of pulmonary inflammation and increased micro-
vascular permeability during the development of broncho-
pulmonary dysplasia: a sequential analysis of inflammatory
mediators in respiratory fluids of high-risk preterm neonates.
Pediatrics. 1994;93(5):712–718.
38. Ikegami M, Jobe AH. Postnatal lung inflammation increased
by ventilation of preterm lambs exposed antenatally to
Escherichia coli endotoxin. Pediatr Res. 2002;52(3):356–362.
39. Jobe AH, Kramer BW, Moss TJ, Newnham JP, Ikegami M.
Decreased indicators of lung injury with continuous positive
expiratory pressure in preterm lambs. Pediatr Res. 2002;52(3):
387–392.
 SE M I N A R S I N P E R I N A T O L O G Y
40. Thebaud B, Abman SH. Bronchopulmonary dysplasia: where
have all the vessels gone? Roles of angiogenic growth factors
in chronic lung disease. Am J Respir Crit Care Med. 2007;175
(10):978–985.
41. Hummler E, Barker P, Gatzy J, et al. Early death due to
defective neonatal lung liquid clearance in alpha-ENaC-defi-
cient mice. Nat Genet. 1996;12(3):325–328.
42. Helve O, Pitkanen O, Janer C, Andersson S. Pulmonary fluid
balance in the human newborn infant. Neonatology. 2009;95
(4):347–352.
43. Copetti R, Cattarossi L, Macagno F, Violino M, Furlan R. Lung
ultrasound in respiratory distress syndrome: a useful tool for
early diagnosis. Neonatology. 2008;94(1):52–59.
44. Al Faleh K, Smyth J, Roberts R, Solimano A, Asztalos E,
Schmidt B. Prevention and 18-month outcome of serious
pulmonary hemorrhage in extremely low birth weight
infants: results from the triall of indomethacin prophylaxis
in preterms. Pediatrics. 2008;121(2):e233–e238.
45. Clyman RI, Chorne N. PDA treatment: effects on pulmonary
hemorrhage and pulmonary morbidity. J Pediatr. 2008;152
(3):447–448.
46. 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.
47. Domanico RS, Waldman JD, Lester LA, McPhillips HA, Catram-
bone JE, Covert RF. Prophylactic indomethacin reduces the
incidence of pulmonary hemorrhage and patent ductus
arteriosus in surfactant treated infants o1250 grams. Pediatr
Res. 1994;35:331.
48. Kluckow M, Gill A, Jeffery M, Evans N. Ductal Echocardio-
graphic Targeting and Early Closure Trial (DETECT): a pilot
randomized controlled trial. E-PAS. 2012 1675.5.
49. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J
Respir Crit Care Med. 2001;163(7):1723–1729.
50. Varsila E, Hallman M, Venge P, Andersson S. Closure of patent
ductus arteriosus decreases pulmonary myeloperoxidase in
premature infants with respiratory distress syndrome. Biol
Neonate. 1995;67(3):167–171.
51. Nakamura T, Takasaki J, Ogawa Y. Inflammatory changes in
the lungs of premature infants with symptomaticpatent
ductus arteriosus. Pediatr Int. 2002;44(4):363–367.
52. Jain RK. Molecular regulation of vessel maturation. Nat Med.
2003;9(6):685–693.
53. Waleh N, McCurnin DC, Yoder BA, Shaul PW, Clyman RI. Patent
ductus arteriosus ligation alters pulmonary gene expression in
preterm baboons. Pediatr Res. 2011;69(3):212–216.
54. Chang LY, McCurnin D, Yoder B, Shaul PW, Clyman RI. Ductus
arteriosus ligation and alveolar growth in preterm baboons with
a patent ductus arteriosus. Pediatr Res. 2008;63(3):299–302.
55. Clyman R, Cassady G, Kirklin JK, Collins M, Philips JB. The role
of patent ductus arteriosus ligation in bronchopulmonary
dysplasia: reexamining a randomized controlled trial.
J Pediatr. 2009;154(6):873–876.
56. Kluckow M, Jeffery M, Gill A, Evans N. A randomised placebo-
controlled trial of early treatment of the patent ductus
arteriosus. Arch Dis Child Fetal Neonatal Ed. 2014;99(2):F99–F104.
57. Cooke L, Steer P, Woodgate P. Indomethacin for asympto-
matic patent ductus arteriosus in preterm infants. Cochrane
Database Syst Rev. 2003(2)): CD003745.
58. Liebowitz M, Koo J, Wickremasinghe A, Allen IE, Clyman RI.
Effects of prophylactic indomethacin on vasopressor-depend-
ent hypotension in extremely preterm infants. J Pediatr. 2017;
182:21–27 e2.
59. Fowlie PW, Davis PG. Prophylactic intravenous indomethacin
for preventing mortality and morbidity in preterm infants.
Cochrane Database Syst Rev. 2010(7): CD000174.
] (]]]]) ]]]–]]] 7
60. Sosenko IR, Fajardo MF, Claure N, Bancalari E. Timing of
patent ductus arteriosus treatment and respiratory outcome
in premature infants: a double-blind randomized controlled
trial. J Pediatr. 2012;160(6):929–935 e1.
61. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of
patent ductus arteriosus in preterm or low birth weight (or
both) infants. Cochrane Database Syst Rev. 2015;2 CD003481.
62. Ohlsson A, Shah SS. Ibuprofen for the prevention of patent
ductus arteriosus in preterm and/or low birth weight infants.
Cochrane Database Syst Rev. 2011(7): CD004213.
63. Bose CL, Laughon M. Treatment to prevent patency of the
ductus arteriosus: beneficial or harmful? J Pediatr. 2006;148
(6):713–714.
64. Benitz WE, Committee On F, Newborn. Patent ductus arterio-
sus in preterm infants. Pediatrics. 2016;137(1):1–6.
65. Clyman RI, Mauray F, Heymann MA, Roman C. Cardiovascular
effects of a patent ductus arteriosus in preterm lambs with
respiratory distress. J Pediatr. 1987;111:579–587.
66. Shimada S, Kasai T, Konishi M, Fujiwara T. Effects of
patent ductus arteriosus on left ventricular output and organ
blood flows in preterm infants with respiratory distress
syndrome treated with surfactant. J Pediatr. 1994;125(2):
270–277.
67. Lemmers PM, Molenschot MC, Evens J, Toet MC, van Bel F.
Is cerebral oxygen supply compromised in preterm infants
undergoing surgical closure for patent ductus arteriosus? Arch
Dis Child Fetal Neonatal Ed. 2010;95(6):F429–F434.
68. Bell EF, Acarregui MJ. Restricted versus liberal water intake for
preventing morbidity and mortality in preterm infants
(Cochrane Review). Cochrane Database Syst Rev. 2001;3.
69. De Buyst J, Rakza T, Pennaforte T, Johansson AB, Storme L.
Hemodynamic effects of fluid restriction in preterm infants
with significant patent ductus arteriosus. J Pediatr. 2012;161
(3):404–408.
70. Fajardo MF, Claure N, Swaminathan S, et al. Effect of positive
end-expiratory pressure on ductal shunting and systemic
blood flow in preterm infants with patent ductus arteriosus.
Neonatology. 2014;105(1):9–13.
71. Cotton RB, Stahlman MT, Berder HW, Graham TP, Catterton
WZ, Kover I. Randomized trial of early closure of sympto-
matic patent ductus arteriosus in small preterm infants.
J Pediatr. 1978;93:647–651.
72. Roclawski M, Sabiniewicz R, Potaz P, et al. Scoliosis in patients
with aortic coarctation and patent ductus arteriosus: does
standard posterolateral thoracotomy play a role in the devel-
opment of the lateral curve of the spine? Pediatr Cardiol.
2009;30:941–945.
73. Smith ME, King JD, Elsherif A, Muntz HR, Park AH, Kouretas
PC. Should all newborns who undergo patent ductus arterio-
sus ligation be examined for vocal fold mobility? Laryngoscope.
2009;119(8):1606–1609.
74. Clement WA, El-Hakim H, Phillipos EZ, Cote JJ. Unilateral
vocal cord paralysis following patent ductus arteriosus liga-
tion in extremely low-birth-weight infants. Arch Otolaryngol
Head Neck Surg. 2008;134(1):28–33.
75. Moin F, Kennedy KA, Moya FR. Risk factors predicting vaso-
pressor use after patent ductus arteriosus ligation. Am J
Perinatol. 2003;20:313–320.
76. Noori S, Friedlich P, Seri I, Wong P. Changes in myocardial
function and hemodynamics after ligation of the
ductus arteriosus in preterm infants. J Pediatr. 2007;150(6):
597–602.
77. Strychowsky JE, Rukholm G, Gupta MK, Reid D. Unilateral
vocal fold paralysis after congenital cardiothoracic surgery:
a meta-analysis. Pediatrics. 2014;133(6):e1708–e1723.
78. Nichols BG, Jabbour J, Hehir DA, et al. Recovery of vocal fold
immobility following isolated patent ductus arteriosus liga-
tion. Int J Pediatr Otorhinolaryngol. 2014;78(8):1316–1319.
8 SE M I N A R S I N P E R I N A T O L O G Y
79. Clyman RI, Wickremasinghe A, Merritt TA, et al. Hypotension
following patent ductus arteriosus ligation: the role of adre-
nal hormones. J Pediatr. 2014;164:1449–1455.
80. Noori S, McNamara P, Jain A, et al. Catecholamine-resistant
hypotension and myocardial performance following patent
ductus arteriosus ligation. J Perinatol. 2015;35(2):123–127.
81. Teixeira LS, Shivananda SP, Stephens D, Van Arsdell G,
McNamara PJ. Postoperative cardiorespiratory instability fol-
lowing ligation of the preterm ductus arteriosus is related to
early need for intervention. J Perinatol. 2008;28(12):803–810.
82. Wickremasinghe AC, Rogers EE, Piecuch RE, et al. Neuro-
developmental outcomes following two different treatment
approaches (early ligation and selective ligation) for patent
ductus arteriosus. J Pediatr. 2012;161(6):1065–1072.
83. Sung SI, Choi SY, Park JH, et al. The timing of surgical ligation
for patent ductus arteriosus is associated with neonatal
morbidity in extremely preterm infants born at 23–25 weeks
of gestation. J Korean Med Sci. 2014;29(4):581–586.
84. Jhaveri N, Moon-Grady A, Clyman RI. Early surgical ligation
versus a conservative approach for management of patent
ductus arteriosus that fails to close after indomethacin treat-
ment. J Pediatr. 2010;157(3):381–387 7 e1.
85. Sung SI, Chang YS, Chun JY, et al. Mandatory closure versus
nonintervention for patent ductus arteriosus in very preterm
infants. J Pediatr. 2016;177:66–71 e1.
86. Cotton RB, Stahlman MT, Kover I, Catterton W-Z. Medical
management of small preterm infants with symptomatic
patent ductus arteriosus. J Pediatr. 1978;92:467–473.
87. 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;102:895–906.
88. Chorne N, Leonard C, Piecuch R, Clyman RI. Patent ductus
arteriosus and its treatment as risk factors for neonatal and
neurodevelopmental morbidity. Pediatrics. 2007;119:1165–1174.
89. Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff
A. Neurosensory impairment after surgical closure of patent
] (]]]]) ]]]–]]]
ductus arteriosus in extremely low birth weight infants:
results from the trial of indomethacin prophylaxis in pre-
terms. J Pediatr. 2007;150(3):229–234.
90. Benitz WE. Treatment of persistent patent ductus arteriosus
in preterm infants: time to accept the null hypothesis? J
Perinatol. 2010;30(4):241–252.
91. Zonnenberg I, de Waal K. The definition of a haemodynamic
significant duct in randomized controlled trials: a systematic
literature review. Acta Paediatr. 2012;101(3):247–251.
92. Schena F, Francescato G, Cappelleri A, et al. Association
between hemodynamically significant patent ductus arterio-
sus and bronchopulmonary dysplasia. J Pediatr. 2015;166(6):
1488–1492.
93. Sellmer A, Bjerre JV, Schmidt MR, et al. Morbidity and
mortality in preterm neonates with patent ductus arteriosus
on day 3. Arch Dis Child Fetal Neonatal Ed. 2013;98(6):
F505–F510.
94. Liebowitz M, Clyman RI. Prophylactic indomethacin com-
pared with delayed conservative management of the patent
ductus arteriosus in extremely preterm infants: effects on
neonatal outcomes. J Pediatr. 2017;187:119–126.
95. 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.
96. Jensen EA, Dysart KC, Gantz MG, et al. Association between
use of prophylactic indomethacin and the risk for broncho-
pulmonary dysplasia in extremely preterm infants. J Pediatr.
2017 [Epub ahead of print].
97. 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.
98. Nemerofsky SL, Parravicini E, Bateman D, Kleinman C, Polin
RA, Lorenz JM. The ductus arteriosus rarely requires treat-
ment in infants 4 1000 grams. Am J Perinatol. 2008;25(10):
661–666.