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October 2017Volume 189, Pages 13–17

Treatment and Nontreatment of the Patent Ductus

Arteriosus: Identifying Their Roles in Neonatal
Morbidity
Ronald I. Clyman, MD Correspondence information about the author MD Ronald I. Clyman Email
the author MD Ronald I. Clyman
Department of Pediatrics Cardiovascular Research Institute
Melissa Liebowitz, MD
 Department of Pediatrics University of California San Francisco San Francisco, California

PlumX Metrics
DOI: http://dx.doi.org/10.1016/j.jpeds.2017.06.054
|
Article Info
 Abstract
 Full Text
 References
Abbreviations:
BPD (Bronchopulmonary dysplasia), PDA (Patent ductus arteriosus), RCT (Randomized controlled trial)

Unlabelled box
-
See related article, p 105

In this volume of The Journal, Bixler et al report their study of 61 520 infants (delivered before 31 weeks'

gestation) in the Pediatrix Clinical Data Warehouse; they found that both the incidence of patent ductus

arteriosus (PDA) reported and the number of infants receiving PDA treatment (either medical or surgical)

declined significantly between 2006 and 2015. 1 Their findings are similar to the results reported by Lokku et al

from the Canadian Neonatal Network and by Hagadorn et al from the Pediatric Hospital Information System

database.2,3 Although these studies demonstrate that there has been a decline in both the desire to investigate

the presence of a PDA, as well as to treat it when present, they cannot tell us whether this trend toward

nontreatment (or conservative management) has been applied primarily to infants with small, insignificant left-to-

right PDA shunts or whether infants with moderate/large PDA shunts also have been included in this approach.

This is an important consideration. Although there is no association between the presence of small PDA shunts

and neonatal morbidity, there is evidence for a direct association between moderate/large shunts and serious

morbidities.4 The heterogeneity in shunt size among the infants included in these studies makes it impossible to

tell whether nontreatment of infants with moderate/large PDA shunts has had a positive or negative impact on
neonatal morbidity.

The trend toward nontreatment of the PDA appears to be driven by the belief that treatment to induce PDA

closure does not improve long-term neonatal outcomes.5, 6 The evidence to support this claim comes from

controlled clinical trials that compared infants who received treatment to close the PDA with those who received

no treatment. However, interpreting the results of these clinical trials requires that one recognize the basic

assumptions behind the clinical trial study design. If these are not appreciated, the study results can be

misinterpreted. For example, although we may question whether a moderate/large PDA shunt is responsible for

specific neonatal morbidities, there is no question that a moderate/large PDA shunt has significant hemodynamic

consequences for the infant. A moderate/large left-to-right PDA shunt causes a decrease in systemic blood

pressure, a reduction in blood flow to the systemic organs, an increase in pulmonary blood pressure and flow, an

increase in lung water, and a decrease in lung compliance.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18 Every infant with a

moderate/large PDA shunt is challenged by these hemodynamic changes. 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 of the PDA has to include the recognition that “other” treatment modalities are

being used to offset the hemodynamic consequences of the PDA (eg, inotropic support, fluid restriction, or

increased end-expiratory pressure).19, 20, 21, 22 Therefore, if morbidities are found in the no-treatment arm of these

studies, one has to ask the following: Are they due to the persistent PDA shunt itself, or are they due to the

“other” treatments used to stabilize the infants while awaiting spontaneous closure? Although most trials describe

in detail what is being done to infants in the treatment arm, virtually no study describes the “other” treatments

used to deal with the PDA's hemodynamic effects in the no-treatment arm of the study. The outcomes of these

trials depend as much (or even more so) on the “other” treatments used in the no-treatment arm as they do on

those used in the treatment arm. Stated another way, the treatment vs no- treatment trials do not really tell us

about the morbid effects of the PDA on the newborn, they just tell us about 2 different treatment choices: one
designed to close the ductus and one designed to treat its hemodynamic consequences.

There is probably no better example to illustrate this point than to consider the question: should infants with a

moderate/large PDA shunt be ligated within the first 2 weeks after birth? Consider first the seminal randomized

controlled trial (RCT) of early surgical closure vs no treatment reported by Cotton et al in 1978.23 In this study,

ventilated infants born preterm were randomized at the end of the first week to either surgical PDA ligation or no

treatment. Despite the fact that performing a surgical ligation increases the risk for pulmonary morbidity, the

authors found that infants in the surgical treatment arm had a lower incidence of pulmonary morbidity than infants
with a persistent PDA in the no-treatment arm of the study.24, 25, 26, 27, 28, 29, 30, 31, 32, 33

In contrast to the findings of Cotton et al, recent controlled clinical trials report the opposite results, namely, less

morbidity in the no-treatment arm compared with the arm that underwent early surgical closure. 23, 34, 35 The

beneficial effects of no treatment appeared to be attributable to the elimination of ligation from the no-treatment

arm of the study because the difference between the study arms disappeared when the analyses were adjusted
for the different ligation rates.32

So, what's the difference between the earlier study of Cotton et al and the more recent studies? In both studies,

the investigators had 2 choices: either to close the ductus itself (treatment) or to mitigate its hemodynamic effects

(no treatment). In the study of Cotton et al, the no treatment group received long-term, high-volume, and high-

pressure mechanical ventilation, which was the prevalent form of ventilation in the 1970s, to control PDA-induced

pulmonary edema.23, 36 One needs to ask: were the pulmonary morbidities in the no-treatment arm due to the

persistent PDA itself, or were they due to the treatments used to stabilize the infants while awaiting spontaneous
closure?23, 36

In contrast, the more recent surgical closure trials managed infants in the no-treatment group with a “gentler”

ventilator approach, which avoided intubation and tolerated hypercarbia. With this type of respiratory

management, there is no evidence that early surgical PDA closure prevents the evolution of BPD. 24, 34, 37, 38, 39In

fact, many morbidities associated with ligation (postligation hypotension, vocal cord paralysis, bronchopulmonary
dysplasia [BPD], and abnormal neurocognitive development) appear to be reduced when ligation is delayed for at
least several weeks.24, 31, 32, 33, 40 At this point in time, avoiding surgical 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 determine which infants are most likely to benefit from later surgical ligation and which infants
might best be left untreated.

Let's turn now to the trials that used indomethacin or ibuprofen to study the effects of pharmacologic PDA closure

on neonatal morbidity. Although more than 30 placebo-controlled RCTs have examined this question, the

evidence for long-term benefits from pharmacologic PDA closure still appears to be in doubt.11, 41, 42, 43, 44,45, 46 Most

of these trials were performed more than 17 years ago, and as with the surgical treatment trials, 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 group was used as a surrogate for PDA closure, and the no-

treatment group 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 previous pharmacologic-treatment

RCTs enrolled patients based on whether the PDA was present or absent, without considering the magnitude of

the shunt.47 This was made worse by the fact that 40%-75% of 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 treatment group. The average time before infants in the no-treatment group were crossed-

over, and received treatment, was 2-5 days. This imperfect correlation between no treatment and persistent

ductus patency minimized the difference in length of PDA exposure between the groups and resulted in a

misclassification that biased the results toward the null hypothesis. As a result, it would be a mistake to assume

that these RCTs really can address the effects of prolonged exposure to a moderate/large PDA shunt. At best,

one might conclude that the risk of serious neonatal morbidity is not increased by exposure to a moderate/large

PDA that lasts for just a few days.41, 42, 44, 45, 46 In contrast, if one examines RCTs in which the difference in PDA

exposure between the groups is at least 7 days, early treatment of the PDA (within the first 3 days of birth)

reduced the incidence of BPD and BPD or death (BPD/death) compared with starting treatment after 8-10
days.46, 48

Recently, several prospective cohort controlled trials specifically have examined the effects of exposure to a

moderate/large PDA for greater than 8 days.49, 50 In these trials, infants were treated with indomethacin to close

the PDA either prophylactically or early in the first week and compared with infants in a no-treatment group. As in

the previous RCTs, infants in the no-treatment group were allowed to be rescued or crossed-over to the

treatment group. However, in contrast with the previous RCTs (where the infants were rescued at 2-5 days), in

the more recent trials the median time before infants were rescued was 12-15 days. As was seen in the earlier

RCTs, there were no differences between the treatment and no-treatment groups in the rates of death,

necrotizing enterocolitis, and severe retinopathy of prematurity. In contrast, when PDA rescue treatment was
delayed beyond 8 days, there was a significant increase in the need for ventilator and inotropic support at the end

of the first week, as well as an increase in the incidence of BPD and BPD/death in the no-treatment
 group.49, 50, 51 Although “treating” the PDA early in the first week had a significant effect on decreasing the

incidence of BPD and BPD/death, each week that rescue treatment was delayed reduced its effectiveness in
preventing the occurrence of BPD and BPD/death.49

The relationship between persistence of a moderate/large PDA beyond the first week and BPD helps to explain

several recent clinical observations. During the past decade, improvements in clinical care have been associated

with a decrease in the incidence of neonatal morbidities that have not been linked causally to the persistence of a

PDA (eg, death, severe intraventricular hemorrhage, necrotizing enterocolitis, and severe retinopathy of

prematurity).1, 52 In contrast, during the same period, the incidence of BPD (which has been linked causally to the

presence of a PDA) has remained the same or even increased. 1, 3, 12, 13, 16, 49, 50, 52Although many factors contribute

to the lack of improvement in the incidence of BPD, it is interesting to note that this has occurred during the same

time interval that PDA treatment has been in decline.1, 2, 3, 52 It also is noteworthy that neonatal centers that

regularly use prophylactic indomethacin as part of their admission care have significantly lower rates of BPD and
BPD/death than centers that only consider PDA treatment later in the neonatal hospitalization. 53

In summary, it is unlikely that clinical trials examining pharmacologic treatment vs nontreatment can really tell us

whether PDA-related morbidities are due to the hemodynamic effects of a persistent PDA itself or to the

treatments used to stabilize infants while they are awaiting spontaneous closure. Several short-term benefits

(decreased intraventricular hemorrhage, pulmonary hemorrhage, and ligation) may result from prophylactic

indomethacin or prophylactic treatment of the PDA, but there is little evidence to suggest that delaying treatment

for the first few days after birth has any detrimental effects on later morbidities. In contrast, there is growing

evidence that delaying treatment of a moderate/large PDA beyond the first week may contribute to the
development of BPD and BPD/death.

Currently there are several ongoing RCTs examining the effects of PDA treatment starting at different times after
birth (NCT01630278, NCT02884219, EudraCT:2013-005336-23, NCT01958320, and NCT02128191). Hopefully

these studies have been designed so that the timing of spontaneous closure or rescue treatment in the no-

treatment arm is delayed beyond 8-10 days. If so, these trials should give us important information about the
effects of timing of treatment and prolonged PDA exposure on neonatal morbidity.

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Supported by the US Public Health Service and the National Heart, Lung, and Blood Institute ( HL109199 ) and
by a gift from the Jamie and Bobby Gates Foundation. The authors declare no conflicts of interest.

© 2017 Elsevier Inc. All rights reserved.

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