SYSTEMATIC REVIEW

published: 11 September 2020

doi: 10.3389/fped.2020.00541

Spontaneous Closure of the Ductus

Arteriosus in Preterm Infants: A
Systematic Review
Johan C. A. de Klerk 1 , Aline G. J. Engbers 1,2 , Floor van Beek 1 , Robert B. Flint 1,3 ,
Irwin K. M. Reiss 1 , Swantje Völler 2,4 and Sinno H. P. Simons 1*
1
Division of Neonatology, Department of Pediatrics, Erasmus UMC—Sophia Children’s Hospital, Rotterdam, Netherlands,
2
Division of Systems Biomedicine and Pharmacology, Leiden Amsterdam Center for Drug Research (LACDR), Leiden
University, Leiden, Netherlands, 3 Department of Hospital Pharmacy, Erasmus UMC, Rotterdam, Netherlands, 4 Division of
BioTherapeutics, Leiden Amsterdam Center for Drug Research (LACDR), Leiden University, Leiden, Netherlands

The optimal management strategy for patent ductus arteriosus in preterm infants remains
a topic of debate. Available evidence for a treatment strategy might be biased by the
delayed spontaneous closure of the ductus arteriosus in preterm infants, which appears
to depend on patient characteristics. We performed a systematic review of all literature
Edited by:
Yogen Singh,
on PDA studies to collect patient characteristics and reported numbers of patients with a
Cambridge University Hospitals NHS ductus arteriosus and spontaneous closure. Spontaneous closure rates showed a high
Foundation Trust, United Kingdom variability but were lowest in studies that only included preterm infants with gestational
Reviewed by: ages below 28 weeks or birth weights below 1,000 g (34% on day 4; 41% on day 7)
Shazia Bhombal,
Stanford University, United States compared to studies that also included infants with higher gestational ages or higher birth
Christoph Bührer, weights (up to 55% on day 3 and 78% on day 7). The probability of spontaneous closure
Charité—Universitätsmedizin
Berlin, Germany
of the ductus arteriosus keeps increasing until at least 1 week after birth which favors
*Correspondence:
delayed treatment of only those infants that do not show spontaneous closure. Better
Sinno H. P. Simons prediction of the spontaneous closure of the ductus arteriosus in the individual newborn
[email protected] is a key factor to find the optimal management strategy for PDA in preterm infants.
Specialty section: Keywords: patent ductus arteriosus, spontaneous closure, preterm infants, systematic review, VLBW, ELBW
This article was submitted to
Neonatology,
a section of the journal INTRODUCTION
Frontiers in Pediatrics

Received: 20 June 2020 After preterm birth, the ductus arteriosus often remains open. Patent ductus arteriosus (PDA)
Accepted: 28 July 2020 in preterm infants has been associated with prolonged ventilation, bronchopulmonary dysplasia
Published: 11 September 2020 (BPD), and necrotizing enterocolitis potentially caused by pulmonary overcirculation and systemic
Citation: hypoperfusion (1). It is unclear if these associations reflect a causal relationship or if PDA is a
de Klerk JCA, Engbers AGJ, marker of poor condition and outcome, because outcomes of well-designed and controlled trials
van Beek F, Flint RB, Reiss IKM, are still awaited (2). Treatment options include fluid restriction, pharmacological intervention with
Völler S and Simons SHP (2020) non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol, or closing the duct by surgical
Spontaneous Closure of the Ductus
ligation or heart catheterization. All of these therapeutic options have their side-effects or specific
Arteriosus in Preterm Infants: A
Systematic Review.
risks in preterm infants. As a consequence, there is an ongoing worldwide discussion about the
Front. Pediatr. 8:541. optimal management of PDA in preterm infants (3). This discussion is complicated by the lack of
doi: 10.3389/fped.2020.00541 extensive knowledge on the (patho)physiology of the ductus arteriosus in preterm infants.

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de Klerk et al. Spontaneous PDA Closure

Intrauterine, the ductus arteriosus is needed and remains open as well as studies that reported on spontaneous closure after
due to the hypoxic fetal environment and by prostaglandins discharge. To examine spontaneous closure of the PDA, data
E2 (PGE2) produced by the placenta (4). Vasodilatation is on spontaneous closure before any intervention were collected
further enhanced by nitric oxide (NO) produced by the wall and analyzed.
of the ductus arteriosus (5). Upon term birth, the ductus
arteriosus normally closes within hours. This is the result of Search Strategy
different complex physiologic mechanisms that include changes A literature search was performed in collaboration with an
in pulmonary and systemic vascular resistance, increase in experienced librarian. The search was done in MEDLINE,
arterial oxygen pressure, decreasing levels of prostaglandins and EMBASE, Cochrane central, Web of science, and Google Scholar
changes in different mediators and growth factors (6). After until 2018 and included only English written articles. The
preterm birth, however, the ductus arteriosus frequently remains following search terms were used “patent ductus arteriosus,”
patent. Even after functional closure of the ductus arteriosus, “PDA,” “preterm,” “VLBW,” and/or “prematurity.” A more
either spontaneous or by pharmacological treatment, it might detailed search strategy for each library is available in
re-open in preterm infants afterwards caused by infection or Supplementary File 1.
increased inflammation (7). The retrieved titles, abstracts, and full text were screened
Although the high levels of prostaglandins produced by the by two independent reviewers (JdK and FvB) to assess
placenta also drop after preterm birth, the ductus arteriosus their eligibility according to pre-established criteria. Duplicate
seems to remain much more sensitive to both PGE2 and NO in publications were excluded. The data extraction was done by the
preterm infants compared to term born infants, due to increased same two independent reviewers (JdK and FvB). Discrepancies
expression of—and binding to—prostaglandin receptors in the were either resolved by discussion or by consulting a third
ductal wall (5, 8). In addition to that, oxygenation and vascular reviewer (SS).
resistance after preterm birth are hampered by an immature
cardiovascular system and insufficient breathing whereas oxygen Data Synthesis
targets are decreased to prevent retinopathy of prematurity (9). We developed a data extraction sheet, pilot-tested it on 10
A substantial part of the preterm infants with PDA still randomly-selected included studies, and refined it accordingly.
seems to show delayed ductus closure without any intervention One review author (JdK) extracted the following data from
(10). The advantage of a wait-and-see PDA treatment strategy included studies and the second author (FvB) checked the
above intervention in the 1st days after birth (<72 h) may be extracted data. Disagreements were resolved by discussion
that only those newborns without spontaneous ductus arteriosus between the two review authors; if no agreement could be
closure are exposed to treatment and its potential side effects. reached, it was planned a third author (SS) would decide. The
On the other hand, early treatment strategy may be favored data that was used included the following: total number of
because the pharmacological closure rate seems to be highest included neonates, their gestational age and birth weight, timing
on the 1st days of life (11, 12). Despite the limited studies of the echocardiographic evaluation, and the number of neonates
on delayed treatment with NSAIDs and paracetamol, this late with closed ductus arteriosus at those times. Because only
treatment seems less effective (13, 14). NSAIDs and paracetamol baseline reports of the occurrence of PDA were included, before
may enhance the spontaneous closure process. Therefore, the any intervention for PDA was initiated, no bias of individual
discussion on management of PDA in preterm infants cannot studies was expected.
neglect the spontaneous closure, although a clear overview of the Articles were categorized based on the inclusion criteria that
spontaneous closure rates is yet lacking. In this study, we aimed to were used in the studies for gestational age (GA) and birth
provide such an overview of all available data from PDA studies weight (BW). Based on frequently used inclusion cut-off values
to investigate and analyze the rates of spontaneous closure of of GA and BW, four different groups were defined prior to data
the PDA. collection: group 1: GA < 28 weeks and/or BW < 1,000 g, group
2: GA < 30 weeks and/or BW < 1,250 g, group 3: GA < 32 weeks
and/or BW < 1,500 g, and group 4: GA < 37 weeks and/or BW
METHODS < 2,500 g. If only GA or BW was given as inclusion criterion, this
determined the category of the article, if both GA and BW were
To retrieve all relevant evidence on the physiological given as inclusion criteria, GA was leading for categorization.
spontaneous ductus arteriosus closure in preterm infants, Studies were only included in one group: those included in group
we performed a thorough literature search. All studies 1 were not included in groups 2–4, studies in group 2 were not
published after 1990 that met both of the following criteria included in group 3 and 4, and studies in group 3 were not
were considered eligible: (1) trials of any form including included in group 4.
randomized controlled trials (RCTs), controlled clinical trials,
quasi experimental studies [(un)controlled before and after Data Analysis
studies], prospective and retrospective cohort studies and The primary outcome of this systematic review was the rate of
case-control studies and (2) trials with a clearly described timing spontaneous closure of the ductus arteriosus in preterm infants
of echocardiography to identify the presence or absence of a as evaluated by echocardiography. A closed ductus arteriosus is
ductus arteriosus. Case series and case reports were excluded, defined as a ductus arteriosus that shows complete closure or

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de Klerk et al. Spontaneous PDA Closure

no doppler flow on echocardiography as reported in the original 24 h until 61 days of postnatal age (15, 18). Seven of the 11 studies
reports. The closure rate was calculated as the part of patients performed their first ultrasound at day 3 after birth.
with a closed ductus within a certain cohort (number of patients Twenty articles were included in group 2 (GA < 30 weeks
with a closed ductus divided by the total number of patients) at and/or BW < 1,250 g) (11, 21–29, 67–76). The median of the
a time-point. To further explore how the observed trends were reported mean or median GA of the 2,980 patients in group 2
correlated to the maturational status of the patient, different was 28.0 (range 26.2–28.8). The median of the reported mean
subgroup analyses were performed for the different GA and or median birth weight was 1,028 (range 797–1,259) g. The
BW groups. exact gestational ages and birth weights were not available for
R Software (V 3.5.1) was used in R Studio (V 1.1.643) to group, four studies (28, 29, 69, 74). Seven of the 20 studies performed
summarize, and visualize the data. The percentage of patients multiple cardiac ultrasounds to evaluate the PDA (21, 24, 25, 27,
with PDA was plotted against postnatal age. To differentiate 67, 72, 73). The echocardiography was performed between 5 h
spontaneous closure between the different GA and BW groups, and 28 days of postnatal age in all studies.
a linear smoothed line weighted by the total number of patients Forty-nine studies that included a total of 6,946 patients were
of each study was drawn. Mean percentages of patients with eligible for group 3 (GA < 32 weeks and/or BW < 1,500 g) (30–
PDA of studies that performed an echocardiography on postnatal 45, 55–59, 77–103, 132). The median GA was 28.6 (range 26–31)
day 3 (between 72 and 95.9 h) and day 7 (between 168 and weeks. The median birth weight was 1,120 (range 794–1,595) g.
191.9 h) were calculated, and were weighted by the number of Exact gestational ages and birth weights were not available for
patients in each study. These time-points were included because nine studies (35, 38, 41, 42, 44, 85, 96, 100, 104). Multiple cardiac
the ductus is mostly evaluated during the 1st days of life (<72 h) ultrasounds where performed in 14 of the 49 studies and were
and administered courses of pharmacotherapy normally take 3 or performed between 6 and 338 h of postnatal age.
6 days. Nineteen studies used GA < 37 weeks and/or birthweight <
2,500 g as inclusion criteria (group 4), in which a total of 2,450
patients were included (46–53, 60–62, 105–112). The median
RESULTS gestational age was 30.9 (range 28.1–31.2) weeks. The median
birth weight was 1,479 (range 950–1,917) g. Gestational ages
Our literature search resulted in a retrieval of 8,173 records. After and/or birth weights were not available for six studies (47, 50, 53,
removing the duplicates 3,607 remained. Reading of the titles 105, 107, 109). Six of the 19 studies performed multiple cardiac
and abstracts resulted in 332 eligible articles. The arguments for ultrasounds at varying post-natal ages between 24 and 168 h.
exclusion of 233 articles after full text screening are listed in In Figures 3 and 4 the reported percentage of preterm infants
Supplementary File 2. The clinical characteristics of the included with PDA are presented for each subgroup with a postnatal age up
studies are summarized in Supplementary File 3. All studies to 3 and 7 days, respectively. To account for the large differences
were published between 1990 and 2018. Ninety-nine articles in number of patients (range 18–15,971), the size of the dots is
with a total of 29,532 patients were included in the analysis. In scaled by the square root of the number of patients. At postnatal
Figure 1, a flow diagram is presented of the studies retrieved age day 3 (72–95.9 h), mean percentage of PDA closure was 34%
for this review. Figure 2 presents the reported percentages of for group 1, weighted by the number of patients in each study
patients with a PDA for each individual study with increasing (range 9–71%). In group 2, this percentage was 47% (33–98%),
postnatal ages. On PNA day 3 (all reported outcomes observed and in group 3 this was 48% (22–65%). In group 4, the weighted
between 72 and 96 h of life), the mean reported percentage mean was 55% at PNA 3 (15–97%).
of patients that experienced spontaneous closure of the ductus At PNA 7, the weighted average of patients with a closed
arteriosus weighted by the number of patients was 47% (range PDA was 41% for group 1 (11–97%). Of group 2, only one
9–96%). On PNA day 7 (168–192 h) this percentage increased to study was available with a reported percentage of closure at
61% (11–100%). PNA 7, which was 77% (20 of 26 patients) (24). In group
3, the weighted average closure was 63% (38–100%) at PNA
Subgroup Analysis day 7, and for group 4 this was 78% (67–97%). Comparing
In Table 1, the reported characteristics of all studies are presented Figures 2–4 clearly show that with increasing postnatal ages the
per group, as well as the percentages of PDA closure at postnatal spontaneous closure continuous and PDA rates decrease. This is
age days 3 and 7 and the studies and number of patients these are most obvious in the studies that also included the oldest groups
based on. of infants.
Eleven different articles were included in group 1 which
contained preterm infants with a gestational age under 28 weeks
and/or birth weight under 1,000 g (15–20, 54, 63–66). The DISCUSSION
median of reported mean or median GAs of the 17,156 patients in
group 1 was 26.0 (range of mean/median 25.5–26.6) weeks. The In this review, spontaneous closure rates of the ductus arteriosus
median birth weight was 832 (range of medians 802–851) g. Exact in preterm neonates were systematically evaluated in 99 studies
numbers for gestational ages and birth weights were not available that represented 29,532 patients. As expected, we observed
for three studies (19, 63, 66). Two of the 11 studies performed increasing rates of ductus closure with post-natal age and
multiple cardiac ultrasounds to evaluate the PDA, ranging from higher spontaneous closure rates in studies that also included

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de Klerk et al. Spontaneous PDA Closure

database searching
(n = 8173)

Records a!er duplicates

removed
(n = 3607)
Screening

Records screened Records excluded

(n = 3607) (n = 3275)

Full-text ar"cles assessed for Full-text ar"cles excluded, with

Eligibility

eligibility reasons (n = 233)

(n = 332) See Supplementary File 2
Unclear when ultrasound was
performed (n=82)
PDA not described as closed
Studies included in qualita"ve (n=42)
synthesis Received treatment (n=33)
(n = 99) Commentary/editorial/review/
Included

ar"cles without pa"ents (n=26)

Full text not available (n=8)
Duplicate (n=5)
Studies included in quan"ta"ve Case report (n=4)
synthesis (meta-analysis) Number spontaneous closure
(n = 99) unknown (n=4)

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-
Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

For more informaon, visit www.prisma -statement.org.

FIGURE 1 | Flow diagram of the studies retrieved for this review.

patients with higher gestational ages. Spontaneous closure, also included in studies, these closure rates increased up to 55%.
however, occurs not only in the 1st day of life, but continues At PNA day 7 (168–192 h) the ductus arteriosus was closed in
throughout the 1st week of life. Our systematic review revealed 41% of the newborns in studies of the youngest infants and up
34% spontaneous closure on the 3rd day of life (72–96 h) in the to 78% in the studies that also included older gestational age
studies that only included the youngest group of infants (<28 groups. Because of a lack of detailed reports in the individual
weeks of GA and/or birthweight <1,000 g). If older infants were studies on subgroups of patients and the lack of longitudinal

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de Klerk et al. Spontaneous PDA Closure

FIGURE 2 | Reported percentages of closure of patent ductus arteriosus of all included studies, up to a postnatal age of 28 days. Each dot represents a reported
percentage, whose size represents the square root of the total number of patients of that observation.

assessment of the ductus arteriosus we were unable to provide a Currently, there is no international consensus on PDA
mathematical function of spontaneous ductus closure in preterm management. It is unclear if, how and when PDA in
infants. Such a function that could predict spontaneous closure preterm infants should be treated. More specifically, it is
in an individual patient would be an ultimate goal to guide unclear if PDA needs treatment because it is unknown
PDA management in individual patients. High quality datasets which preterm infants might benefit more from treatment
with repeated echocardiographic assessments of neonatal than others. Therefore, prophylaxis, early treatment (<24 h),
patients treated in current neonatal intensive care units are late treatment (72 h), symptomatic treatment and wait and
needed first. see strategies are currently used alongside each other (116).
Studies that reported on PDA showed large heterogeneity, not Better knowledge on the spontaneous closure and physiology
only in included patient populations, but also in the definition of the ductus arteriosus in preterm infants may help to
of a hemodynamically significant PDA (hsPDA) (113). It is quite determine the optimal management strategy. This is even more
clear that the significance of a PDA is not only determined by important as prophylactic as well as therapeutic treatment
the diameter of the ductus, as was used in the current review, but strategies are associated with risks for adverse effects, such
also by the pulmonary vascular resistance. The lack of consensus as intraventricular hemorrhages and decreased renal function
on the definition of a hsPDA is partly based on the lack of that might have severe consequences in these vulnerable
validated echocardiographic markers and cutoff values. van Laere patients. Treatment of the PDA, pharmacologically or surgically,
et al. (114) proposed to standardize essential echocardiographic should therefore be reserved for those patients who may
measurements for the assessment of hemodynamic significance benefit from it.
of a PDA. These consist of evaluation of the ductus arteriosus Next to the ongoing discussion on the type of drug
itself (including the diameter, flow direction, and velocity), being either ibuprofen, indomethacin, or acetaminophen (117–
indices of pulmonary overcirculation (La:Ao, left pulmonary 124), the timing of treatment initiation varies widely between
artery diastolic flow) and indices of systemic shunt effect (flow studies, and might explain reported differences in efficacy.
pattern in aorta descendens, tructus coeliacus, or middle cerebral As spontaneous ductus closure increases with PNA, part of
artery) (114). The LA:Ao ratio, ductal diameter and diastolic ductus closure reported in prophylactic and early treatment
flow in the left pulmonary artery are easy to measure and seem studies may be due to spontaneous closure rather than drug
the most accurate and easy to determine markers for a hsPDA treatment. Efficacy of PDA pharmacotherapy seems to decrease,
(115). In our aim to select those infants that would not show with post-natal age, even if dosages are increased with PNA
spontaneous closure and might actually need PDA treatment to correct for increased clearance with age (10, 13). This
these markers would be useful. suggests either a certain window of opportunity for PDA

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de Klerk et al. Spontaneous PDA Closure

TABLE 1 | Summary of reported mean or median gestational age and birthweight of the included studies, and reported percentages of PDA closure at postnatal age
days 3 and 7.

Group 1 Group 2 Group 3 Group 4 All studies

Inclusion criteria GA < 28 weeks GA < 30 weeks and/or GA < 32 weeks and/or GA < 37 weeks and/or
and/or birth weight birth weight <1,250 g birth weight <1,500 g birth weight <2,500 g
<1,000 g
Number of studies 11 20 49 19 99
Total number of 17,156 2,980 6,946 2,450 29,532
patients
Gestational Age
Mean (weeks) [median 26.0 [25.5–26.6] 28.0 [26.2–28.8] (13) 28.4 [26.0–30.0] (22) 30.8 [30.2–31.1] (7) 28.1 [25.5–31.2] (50)
(range)] (n) (8)
Median [median – 28.0 [–] (2) 29 [27–31] (15) 31.0 [28.1–31.0] (5) 29.0 [27.0–31.0] (22)
(range)]
Not reported (n) 3 5 12 7 27
Birth weight
Mean [median (range)] 818 [802–851] (8) 1,028 [(797–1,259] (13) 112 [794–1,371] (22) 1,543 [1,355–1,917] (7) 1,082 [794–1,917] (50)
Median [median – 1,060–1,062 (2) 1,160 [980–1,595] (15) 1,475 [950–1,640] (5) 1,160 [950–1,640] (22)
(range)]
Not reported (n) 3 5 12 7 27
Postnatal age of cardiac ultrasound
Median postnatal age 72 (18–1,464) 72 (5–672) 79 (6–3,864) 72 (24–1,632 72 (5–3,864)
in h (range)
Percentage of PDA closure at postnatal age 3 (72–95.9 h)
Weighted mean 34% (9–71) 47% (33–98) 48% (22–65) 55% (15–79) 47% (9–96)
percentage of patients
with PDA (range)
Number of studies with 6 9 16 8 39
reported percentage
Total number of 646 978 1,709 621 3,954
patients
Study references (15–20) (21–29) (30–45) (46–53) (15–53)
Percentage of PDA closure at postnatal age 7 (168–191.9 h)
Weighted mean 41% (11–97) 77 % (–) 63% (38–100) 78% (67–97) 61% (11–100)
percentage of patients
with PDA (range)
Number of studies with 2 1 8 5 16
reported percentage
Total number of 228 26 550 181 985
patients
Study references (18, 54) (24) (30, 33, 43, 55–59) (46, 50, 60–62) (18, 24, 30, 33, 43, 46, 50, 54–62)

Separated by groups based on inclusion criteria.

treatment during the physiological process that is involved in detailed reports of PDA for different gestational age groups in the
the spontaneous closure of the ductus arteriosus or the need included studies. While the literature was systematically reviewed
for higher drug exposures at older ages. Such a window can we were unfortunately unable to provide statistical analysis due
only be identified if the rate of spontaneous closure is well- to complexity of outcome data. This also resulted in overlap of
characterized, and efficacy studies can correct for the chance of patients in the different groups. All studies only had an upper
spontaneous closure. limit of gestational age and/or bodyweight without a lower limit
With the current review, we have summarized the evidence for gestational age/weight. As a consequence, the gestational
that spontaneous closure is less likely to occur in preterm age/weight range of inclusion criteria of the included studies
neonates with the lowest gestational ages. Nevertheless, in increases from group 1 to 4. Therefore, the actual difference
another significant number of preterm infants the ductus in the occurrence of spontaneous closure between different
arteriosus although delayed, closes spontaneously within the first GA groups is bigger than observed in the present study. As
150 h of life. The presented review was limited by the lack of other widely used measures for ductus closure, such as LA:Ao

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de Klerk et al. Spontaneous PDA Closure

FIGURE 3 | Reported percentages of patients with patent ductus arteriosus up to a postnatal age of 4 days, grouped by mean or median gestational age or
birthweight if gestational age was unreported. Each dot represents one observation at the reported postnatal age. The size of the dots represents square root of the
number of patients of each observation. Lines represent a linear smooth weighted by the number of patients of each observation.

ratio were mostly missing, we defined a closed ductus as a role in the occurrence of PDA in preterm infants. In a large
ductus that was visually closed or when there was no doppler cohort of 1,013 preterm neonates Dagle et al. (125) found that
flow visible on echocardiography. As discussed previously, a several single nucleotide polymorphisms that were associated
better definition of a hsPDA might be desirable and might with PDA. For future meta-analyses, it might thus be of interest
lead to a more precise estimation of incidence- and closure- to include genetic variations to determine their influence on
rates. In this study, we presented the relationships between spontaneous closure.
spontaneous closure rate and PNA as linear relationships. In Our systematic review was based on the assumption that
reality, the spontaneous closure rate is probably highest on gestational age is a more important factor compared to
the 1st day and decreases with an asymptotic shape since in birthweight for patent ductus arteriosus in preterm infants.
some patients the spontaneous closure will not occur, or the Villamor-Martinez et al. (126) showed that small for gestational
percentage of patients with PDA might even go up if the age (SGA) infants showed a significantly reduced risk of PDA,
ductus arteriosus reopens. With the available data, it is not but their review was complicated by the heterogeneity of studies.
possible to determine whether the reported numbers of PDA As SGA infants also show a much higher clearance of ibuprofen
at high postnatal ages (Figure 2) are due to non-closure or compared to appropriate weight for age newborns these patients
re-opening because seventy of the 99 articles performed only form a special population that need additional attention in future
one echocardiography. Therefore, there were insufficient data to PDA studies (127).
study potential reopening of the ductus arteriosus in this review. A next step could be to find markers to repeatedly monitor
The patency of the ductus arteriosus is regulated by the balance of closure and pathophysiology of the ductus arteriosus. These
vasodilating (prostaglandin E2, nitric oxide) and vasoconstrictor could include the continuously available perfusion index to
(oxygen) factors (6). Preterm neonates are more sensitive to the identify a hemodynamic significant PDA (51, 128) or urinary
vasodilating factors compared to the term neonates (5). There prostaglandine levels (129). Neutrophil gelatinase-associated
is some evidence suggesting that genetic variations may play a lipocalin and heart-type fatty acid-binding protein are two

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de Klerk et al. Spontaneous PDA Closure

FIGURE 4 | Reported percentages of patients with patent ductus arteriosus up to a postnatal age of 8 days, grouped by mean or median gestational age or
birthweight if gestational age was unreported. Each dot represents one observation at the reported postnatal age. The size of the dots represents square root of the
number of patients of each observation. Lines represent a linear smooth weighted by the number of patients of each observation.

peptides that can be measured in urine and also appear to be AUTHOR CONTRIBUTIONS
promising future markers to quantify the effect of a PDA on
systemic perfusion, which makes the ductus arteriosus more JK is responsible for the study design, data collection and
hemodynamic significant (130, 131). Relevant risk factors could extraction, and writing and editing the article. AE is responsible
help to predict those patients whose ductus arteriosus will for the data analysis and writing the article. SV helped with
remain open and for whom pharmacological treatment might the analysis and edited the manuscript. FB performed the data
be needed. collection and extraction. RF supervised the design and edited the
Spontaneous closure rates increase with both gestational age manuscript. IR supervised the design and edited the manuscript.
and postnatal age. This review showed that in 34% of the most SS supervised the study design, data collection, and contributed
premature infants (GA < 28 weeks and/or BW < 1,000 g), the with the editing of the article. All authors contributed to the
ductus arteriosus had spontaneously closed on the 3rd day of article and approved the submitted version.
life (72–96 h). This increased to 41% at PNA day 7. As patients
with a GA < 28 weeks have the lowest chance of spontaneous ACKNOWLEDGMENTS
closure of the ductus arteriosus in the 1st days of life, studies
on PDA management should therefore focus on these most We would like to thank W. G. Kramer for his help in the
premature patients. literature search.

DATA AVAILABILITY STATEMENT SUPPLEMENTARY MATERIAL

The original contributions presented in the study are included The Supplementary Material for this article can be found
in the article’s Supplementary Material, further inquiries can be online at: https://www.frontiersin.org/articles/10.3389/fped.
directed to the corresponding author. 2020.00541/full#supplementary-material

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de Klerk et al. Spontaneous PDA Closure

REFERENCES arteriosus closure: a randomised controlled trial in extremely low

birthweight infants. Arch Dis Child Fetal Neonatal Ed. (2012)
1. Clyman RI. The role of patent ductus arteriosus and its treatments in 97:F279–83. doi: 10.1136/archdischild-2011-300532
the development of bronchopulmonary dysplasia. Semin Perinatol. (2013) 20. Polat TB, Celik IH, Erdeve O. Early predictive echocardiographic features
37:102–7. doi: 10.1053/j.semperi.2013.01.006 of hemodynamically significant patent ductus arteriosus in preterm VLBW
2. Hundscheid T, Onland W, Overmeire B Van, Dijk P, Kaam AHLC Van, infants. Pediatr Int. (2016) 58:589–94. doi: 10.1111/ped.12915
Dijkman KP, et al. Early treatment versus expectative management of 21. Reller MD, Laird MR, Rice MJ, McDonald RW. Timing of ductal closure
patent ductus arteriosus in preterm infants: a multicentre, randomised, in very low birth weight premature infants without respiratory distress. J
non-inferiority trial in Europe (BeNeDuctus trial). BMC Pediatr. (2018) Pediatr. (1991) 119:976–7. doi: 10.1016/S0022-3476(05)83060-4
18:262. doi: 10.1186/s12887-018-1215-7 22. Parikh R, Negrine RJS, Chikermane A, Rasiah SV, Ewer AK.
3. Laughon M, Bose C, Clark R. Treatment strategies to prevent or close a Assessment of myocardial function in preterm infants with patent
patent ductus arteriosus in preterm infants and outcomes. J Perinatol. (2007) ductus arteriosus using tissue Doppler imaging. Cardiol Young. (2014)
27:164–70. doi: 10.1038/sj.jp.7211662 25:70–5. doi: 10.1017/S1047951113001595
4. Hung YC, Yeh JL, Hsu JH. Molecular mechanisms for regulating 23. Bin-Nun A, Mimouni FB, Fink D, Sela H, Hammerman C.
postnatal ductus arteriosus closure. Int J Mol Sci. (2018) Elevated nucleated red blood cells at birth predict hemodynamically
19:1861. doi: 10.3390/ijms19071861 significant patent ductus arteriosus. J Pediatr. (2016) 177:313–
5. Hundscheid T, van den Broek M, van der Lee R, de Boode WP. 5. doi: 10.1016/j.jpeds.2016.07.005
Understanding the pathobiology in patent ductus arteriosus in 24. De Waal K, Phad N, Lakkundi A, Tan P. Post-transitional adaptation of
prematurity-beyond prostaglandins and oxygen. Pediatr Res. (2019) the left heart in uncomplicated, very preterm infants. Cardiol Young. (2017)
86:28–38. doi: 10.1038/s41390-019-0387-7 27:1167–73. doi: 10.1017/S1047951116002687
6. Chiruvolu A, Jaleel MA. Pathophysiology of patent ductus 25. de Waal K, Phad N, Boyle A. Left atrium function and deformation in very
arteriosus in premature neonates. Early Hum Dev. (2009) preterm infants with and without volume load. Echocardiography. (2018)
85:143–6. doi: 10.1016/j.earlhumdev.2008.12.006 35:1818–26. doi: 10.1111/echo.14140
7. Gonzalez A, Sosenko IRS, Chandar J, Hummler H, Claure N, Bancalari 26. Kahvecioglu D, Erdeve O, Akduman H, Ucar T, Alan S, Çakir U, et al.
E. Influence of infection on patent ductus arteriosus and chronic lung Influence of platelet count, platelet mass index, and platelet function on
disease in premature infants weighing 1000 grams or less. J Pediatr. (1996) the spontaneous closure of ductus arteriosus in the prematurity. Pediatr
128:470–8. doi: 10.1016/S0022-3476(96)70356-6 Neonatol. (2018) 59:53–7. doi: 10.1016/j.pedneo.2017.01.006
8. Bardanzellu F, Neroni P, Dessì A, Fanos V. Paracetamol in patent 27. Van Overmeire B, Allegaert K, Casaer A, Debauche C, Decaluwé
ductus arteriosus treatment: efficacious and safe? Biomed Res Int. (2017) W, Jespers A, et al. Prophylactic ibuprofen in premature infants: a
2017:1438038. doi: 10.1155/2017/1438038 multicentre, randomised, double-blind, placebo-controlled trial. Lancet.
9. Askie LM, Darlow BA, Davis PG, Finer N, Stenson B, Vento M, et al. (2004) 364:1945–9. doi: 10.1016/S0140-6736(04)17477-1
Effects of targeting lower versus higher arterial oxygen saturations on 28. Braulio R, Gelape CL, Araújo FD da R, Brandão KN, Abreu LDG, Costa
death or disability in preterm infants. Cochrane Database Syst Rev. (2017) PHN, et al. Indicadores para o tratamento cirúrgico na persistência do
2017:CD011190. doi: 10.1002/14651858.CD011190.pub2 ducto arterial em neonatos prematuros na primeira semana de vida.
10. Benitz WE, Fetus CON. Patent ductus arteriosus in preterm infants. Braz J Cardiovasc Surg. (2013) 28:504–8. doi: 10.5935/1678-9741.201
Pediatrics. (2016) 137:1–6. doi: 10.1542/peds.2015-3730 30082
11. Aranda JV, Clyman R, Cox B, Van Overmeire B, Wozniak P, Sosenko I, 29. Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS,
et al. A randomized, double-blind, placebo- controlled trial on intravenous et al. Oral paracetamol versus oral ibuprofen in the management
ibuprofen L-lysine for the early closure of nonsymptomatic patent ductus of patent ductus arteriosus in preterm infants: A randomized
arteriosus within 72 hours of birth in extremely low-birth-weight infants. controlled trial. J Pediatr. (2014) 164:510–4.e1. doi: 10.1016/j.jpeds.2013.
Am J Perinatol. (2009) 26:235–46. doi: 10.1055/s-0028-1103515 11.008
12. Kluckow M, Jeffery M, Gill A, Evans N. A randomised placebo-controlled 30. Skelton R, Evans N, Smythe J. A blinded comparison of
trial of early treatment of the patent ductus arteriosus. Arch Dis Child Fetal clinical and echocardiographic evaluation of the preterm infant
Neonatal Ed. (2014) 99:F99–104. doi: 10.1136/archdischild-2013-304695 for patent ductus arteriosus. J Paediatr Child Health. (1994)
13. de Klerk JCA, van Paassen N, van Beynum IM, Flint RB, Reiss IKM, 30:406–11. doi: 10.1111/j.1440-1754.1994.tb00689.x
Simons SHP. Ibuprofen treatment after the first days of life in preterm 31. Su BH, Watanabe T, Shimizu M, Yanagisawa M. Echocardiographic
neonates with patent ductus arteriosus. J Matern Neonatal Med. (2019) assessment of patent ductus arteriosus shunt flow pattern in
1–7. doi: 10.1080/14767058.2019.1667323. [Epub ahead of print]. premature infants. Arch Dis Child Fetal Neonatal Ed. (1997)
14. Roofthooft DWE, Van Beynum IM, Helbing WA, Reiss IKM, Simons 77:36–40. doi: 10.1136/fn.77.1.F36
SHP. Paracetamol for ductus arteriosus closure: not always a success story. 32. El-Khuffash A, Barry D, Walsh K, Davis PG, Molloy EJ. Biochemical markers
Neonatology. (2013) 104:170. doi: 10.1159/000353451 may identify preterm infants with a patent ductus arteriosus at high risk of
15. Rolland A, Shankar-Aguilera S, Diomandé D, Zupan-Simunek V, Boileau death or severe intraventricular haemorrhage. Arch Dis Child Fetal Neonatal
P. Natural evolution of patent ductus arteriosus in the extremely Ed. (2008) 93:407–13. doi: 10.1136/adc.2007.133140
preterm infant. Arch Dis Child Fetal Neonatal Ed. (2015) 100:F55– 33. Nemerofsky SL, Parravicini E, Bateman D, Kleinman C, Polin RA,
8. doi: 10.1136/archdischild-2014-306339 Lorenz JM. The ductus arteriosus rarely requires treatment in infants
16. Narayanan M, Cooper B, Weiss H, Clyman RI. Prophylactic indomethacin: > 1000 grams. Am J Perinatol. (2008) 25:661–6. doi: 10.1055/s-0028-10
factors determining permanent ductus arteriosus closure. J Pediatr. (2000) 90594
136:330–7. doi: 10.1067/mpd.2000.103414 34. Sangtawesin C, Sangtawesin V, Lertsutthiwong W, Kanjanapattanakul W,
17. Gournay V, Roze JC, Kuster A, Daoud P, Cambonie G, Hascoet Khorana M, Ayudhaya JKN. Prophylaxis of symptomatic patent ductus
JM, et al. Prophylactic ibuprofen versus placebo in very premature arteriosus with oral ibuprofen in very low birth weight infants. J Med Assoc
infants: a randomised, double-blind, placebo-controlled trial. Lancet. (2004) Thai. (2008) 91(Suppl 3):28–34.
364:1939–44. doi: 10.1016/S0140-6736(04)17476-X 35. Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy
18. Dani C, Bertini G, Pezzati M, Poggi C, Guerrini P, Martano C, et al. and safety of oral versus intravenous ibuprofen in very low birth weight
Prophylactic ibuprofen for the prevention of intraventricular hemorrhage preterm infants with patent ductus arteriosus. J Pediatr. (2011) 158:549–
among preterm infants: a multicenter, randomized study. Pediatrics. (2005) 54. doi: 10.1016/j.jpeds.2010.10.008
115:1529–35. doi: 10.1542/peds.2004-1178 36. De Carolis MP, Romagnoli C, Polimeni V, Piersigilli F, Zecca E, Papacci P,
19. Erdeve O, Yurttutan S, Altug N, Ozdemir R, Gokmen T, Dilmen et al. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm
U, et al. Oral versus intravenous ibuprofen for patent ductus infants. Eur J Pediatr. (2000) 159:364–8. doi: 10.1007/s004310051288

Frontiers in Pediatrics | www.frontiersin.org 9 September 2020 | Volume 8 | Article 541

de Klerk et al. Spontaneous PDA Closure

37. Sellmer A, Bjerre JV, Schmidt MR, McNamara PJ, Hjortdal VE, Høst B, 55. Vieux R, Desandes R, Boubred F, Semama D, Guillemin F,
et al. Morbidity and mortality in preterm neonates with patent ductus Buchweiller MC, et al. Ibuprofen in very preterm infants impairs
arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed. (2013) 98:F505– renal function for the first month of life. Pediatr Nephrol. (2010)
10. doi: 10.1136/archdischild-2013-303816 25:267–74. doi: 10.1007/s00467-009-1349-9
38. Akar S, Karadag N, Gokmen Yildirim T, Toptan HH, Dincer E, Tuten A, 56. Martinovici D, Vanden Eijnden S, Unger P, Najem B, Gulbis B, Maréchal Y.
et al. Does platelet mass influence the effectiveness of ibuprofen treatment for Early NT-proBNP is able to predict spontaneous closure of patent ductus
patent ductus arteriosus in preterm infants? J Matern Neonatal Med. (2016) arteriosus in preterm neonates, but not the need of its treatment. Pediatr
29:3786–9. doi: 10.3109/14767058.2016.1145207 Cardiol. (2011) 32:953–7. doi: 10.1007/s00246-011-0020-y
39. Härkin P, Härmä A, Aikio O, Valkama M, Leskinen M, Saarela 57. Letshwiti JB, Sirc J, O’Kelly R, Miletin J. Serial N-terminal pro-brain
T, et al. Paracetamol accelerates closure of the ductus arteriosus natriuretic peptide measurement as a predictor of significant patent ductus
after premature birth: a randomized trial. J Pediatr. (2016) 177:72– arteriosus in preterm infants beyond the first week of life. Eur J Pediatr.
7.e2. doi: 10.1016/j.jpeds.2016.04.066 (2014) 173:1491–6. doi: 10.1007/s00431-014-2350-2
40. Van Der Laan ME, Roofthooft MTR, Fries MWA, Berger RMF, Schat TE, Van 58. Chen HL, Yang RC, Lee W-T, Lee PL, Hsu JH, Wu JR, et al. Lung
Zoonen AGJF, et al. A hemodynamically significant patent ductus arteriosus function in very preterm infants with patent ductus arteriosus under
does not affect cerebral or renal tissue oxygenation in preterm infants. conservative management: an observational study. BMC Pediatr. (2015)
Neonatology. (2016) 110:141–7. doi: 10.1159/000445101 15:1–6. doi: 10.1186/s12887-015-0480-y
41. Demir N, Peker E, Ece I, Balahoroglu R, Tuncer O. Efficacy and safety 59. Suzumura H, Nitta A, Tanaka G, Arisaka O. Diastolic flow velocity of the left
of rectal ibuprofen for patent ductus arteriosus closure in very low pulmonary artery of patent ductus arteriosus in preterm infants. Pediatr Int.
birth weight preterm infants. J Matern Neonatal Med. (2017) 30:2119– (2001) 43:146–51. doi: 10.1046/j.1442-200x.2001.01365.x
25. doi: 10.1080/14767058.2016.1238897 60. Nuntnarumit P, Chongkongkiat P, Khositseth A. N-terminal-pro-
42. Sellmer A, Bech BH, Bjerre JV, Schmidt MR, Hjortdal VE, Esberg G, et al. brain natriuretic peptide: a guide for early targeted indomethacin
Urinary neutrophil gelatinase-associated lipocalin in the evaluation of patent therapy for patent ductus arteriosus in preterm infants. Acta Paediatr
ductus arteriosus and AKI in very preterm neonates: a cohort study. BMC Int J Paediatr. (2011) 100:1217–21. doi: 10.1111/j.1651-2227.2011.
Pediatr. (2017) 17:7. doi: 10.1186/s12887-016-0761-0 02304.x
43. Yum SK, Moon CJ, Youn YA, Lee JY, Sung IK. Echocardiographic assessment 61. Ding YJ, Han B, Yang B, Zhu M. NT-proBNP plays an important role in the
of patent ductus arteriosus in very low birthweight infants over time: effect of ibuprofen on preterm infants with patent ductus arteriosus. Eur Rev
prospective observational study. J Matern Neonatal Med. (2018) 31:164– Med Pharmacol Sci. (2014) 18:2596–8.
72. doi: 10.1080/14767058.2016.1278207 62. Puddy VF, Amirmansour C, Williams AF, Singer DRJ. Plasma brain
44. Heyman E, Morag I, Batash D, Keidar R, Baram S, Berkovitch natriuretic peptide as a predictor of haemodynamically significant
M. Closure of patent ductus arteriosus with oral ibuprofen patent ductus arteriosus in preterm infants. Clin Sci. (2002) 103:75–
suspension in premature newborns: a pilot study. Pediatrics. (2003) 7. doi: 10.1042/cs1030075
112(5). doi: 10.1542/peds.112.5.e354 63. Su BH, Lin HC, Chiu HY, Hsieh HY, Chen HH, Tsai YC.
45. Schmitz L, Stiller B, Koch H, Koehne P, Lange P. Diastolic left Comparison of ibuprofen and indometacin for early-targeted
ventricular function in preterm infants with a patent ductus arteriosus: treatment of patent ductus arteriosus in extremely premature infants:
a serial Doppler echocardiography study. Early Hum Dev. (2004) 76:91– a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. (2008)
100. doi: 10.1016/j.earlhumdev.2003.11.002 93:F94–9. doi: 10.1136/adc.2007.120584
46. Shortland DB, Gibson NA, Levene MI, Archer LNJ, Evans DH, Shaw DE. 64. Candel-Pau J, Sillo Á, Salinas F, Redon E, Menduiña Q, Albert DC. Early
Patent ductus arteriosus and cerebral circulation in preterm infants. Dev Med versus conventional treatment for patent ductus arteriosus in preterm
Child Neurol. (1990) 32:386–93. doi: 10.1111/j.1469-8749.1990.tb16957.x infants. Am J Perinatol. (2013) 30:289–96. doi: 10.1055/s-0032-1324696
47. Kulkarni VV, Dutta S, Sundaram V, Saini SS. Preterm thrombocytopenia 65. Steiner M, Salzer-Muhar U, Swoboda V, Unterasinger L, Baumgartner S,
and delay of ductus arteriosus closure. Pediatrics. (2016) Waldhoer T, et al. Preterm infants who later require duct ligation show
138:e20161627. doi: 10.1542/peds.2016-1627 different vital signs and pH in early postnatal life. Acta Paediatr Int J Paediatr.
48. Babaei H, Nemati R, Daryoshi H. Closure of patent ductus arteriosus with (2015) 104:e7–13. doi: 10.1111/apa.12814
oral acetaminophen in preterm neonates: a randomized trial. Biomed Res 66. Lee JH, Greenberg RG, Quek BH, Clark RH, Laughon MM, Smith PB,
Ther. (2018) 5:2034–44. doi: 10.15419/bmrat.v5i02.418 et al. Association between early echocardiography, therapy for patent ductus
49. Bagheri MM, Bahman-Bijari B, Torabi-Nejad MH, Niknafs P, Mousavi H, arteriosus, and outcomes in very low birth weight infants. Cardiol Young.
Sabzevari F, et al. Is prophylactic parenteral paracetamol effective to diminish (2017) 27:1732–9. doi: 10.1017/S1047951117001081
incidence of PDA in preterm neonates? A randomized trial. Iran J Pediatr. 67. Breatnach CR, Franklin O, James AT, McCallion N, El-Khuffash
(2018) 28:10–3. doi: 10.5812/ijp.11735 A. The impact of a hyperdynamic left ventricle on right
50. Ding Y, Wang X, Wu Y, Li H, Xu J, Wang X. Effects of prophylactic ventricular function measurements in preterm infants with a
oral ibuprofen on the closure rate of patent ductus arteriosus in patent ductus arteriosus. Arch Dis Child Fetal Neonatal Ed. (2017)
premature infants. Medicine. (2018) 97:1–8. doi: 10.1097/MD.00000000000 102:F446–50. doi: 10.1136/archdischild-2016-311189
12206 68. Elsayed Y, Seshia M, Baier RJ, Dakshinamurti S. Serial serum brain-type
51. Khositseth A, Muangyod N, Nuntnarumit P. Perfusion index as a diagnostic natriuretic peptide (BNP) identifies compromised blood flow in infants with
tool for patent ductus arteriosus in preterm infants. (2013) 104:250– hemodynamically significant patent ductus arteriosus. J Pediatr Neonatal
4. doi: 10.1159/000353862 Individ Med. (2017) 6:1–10.
52. Byung MC, Kee HL, Baik LE, Kee HY, Young SH, Chang SS, et al. Utility 69. Gomez-Pomar E, Makhoul M, Westgate PM, Ibonia KT, Patwardhan
of rapid B-type natriuretic peptide assay for diagnosis of symptomatic A, Giannone PJ, et al. Relationship between perfusion index and
patent ductus arteriosus in preterm infants. Pediatrics. (2005) 115:e255– patent ductus arteriosus in preterm infants. Pediatr Res. (2017) 81:775–
61. doi: 10.1542/peds.2004-1837 9. doi: 10.1038/pr.2017.10
53. van Overmeire B, Brus F, van Acker KJ, van der Auwera JC, Schasfoort M, 70. Romagnoli V, Pedini A, Santoni M, Scutti G, Colaneri M, Pozzi M, et al.
Elzenga NJ, et al. Aspirin versus indomethacin treatment of patent ductus Patent ductus arteriosus in preterm infants born before 30 weeks’ gestation:
arteriosus in preterm infants with respiratory distress syndrome. Pediatr Res. high rate of spontaneous closure after hospital discharge. Cardiol Young.
(1995) 38:886–91. doi: 10.1203/00006450-199512000-00010 (2018) 28:995–1000. doi: 10.1017/S1047951118000641
54. Liebowitz M, Clyman RI. Prophylactic indomethacin compared with delayed 71. Küçük M, Bagci O, IGde M. The fate of patent ductus arteriosus is
conservative management of the patent ductus arteriosus in extremely not affected by platelet count and mean platelet volume in premature
preterm infants: effects on neonatal outcomes. J Pediatr. (2017) 187:119– infants < 32 gestational weeks. Turkiye Klin Cardiovasc Sci. (2018) 30:53–
26.e1. doi: 10.1016/j.jpeds.2017.03.021 7. doi: 10.5336/cardiosci.2018-62380

Frontiers in Pediatrics | www.frontiersin.org 10 September 2020 | Volume 8 | Article 541

de Klerk et al. Spontaneous PDA Closure

72. Ment LR, Oh W, Ehrenkranz RA, Philip AGS, Vohr B, Allan W, et al. arteriosus in very preterm infants. Acta Paediatr Int J Paediatr. (2015)
Low-dose indomethacin and prevention of intraventricular hemorrhage: a 104:e139–42. doi: 10.1111/apa.12892
multicenter randomized trial. Pediatrics. (1994) 93:543–50. 90. Breatnach CR, Franklin O, McCallion N, EL-Khuffash A. The effect of a
73. Groves AM, Kuschel CA, Knight DB, Skinner JR. Does retrograde diastolic significant patent ductus arteriosus on doppler flow patterns of preductal
flow in the descending aorta signify impaired systemic perfusion in preterm vessels: an assessment of the brachiocephalic artery. J Pediatr. (2017)
infants? Pediatr Res. (2008) 63:89–94. doi: 10.1203/PDR.0b013e31815b4830 180:279–81.e1. doi: 10.1016/j.jpeds.2016.09.029
74. Kalra VK, DeBari VA, Zauk A, Kataria P, Myridakis D, Kiblawi F. Point-of- 91. Demir N, Peker E, Ece I, Agengin K, Bulan KA, Tuncer O. Is platelet
care testing for B-type natriuretic peptide in premature neonates with patent mass a more significant indicator than platelet count of closure of
ductus arteriosus. Ann Clin Lab Sci. (2011) 41:131–7. patent ductus arteriosus? J Matern Neonatal Med. (2016) 29:1915–
75. Alan S, Karadeniz C, Okulu E, Kilic A, Erdeve O, Ucar T, et al. 8. doi: 10.3109/14767058.2015.1067296
Management of patent ductus arteriosus in preterm infants: clinical 92. Dix L, Molenschot M, Breur J, de Vries W, Vijlbrief D,
judgment might be a fair option. J Matern Neonatal Med. (2013) 26:1850– Groenendaal F, et al. Cerebral oxygenation and echocardiographic
4. doi: 10.3109/14767058.2013.801956 parameters in preterm neonates with a patent ductus arteriosus:
76. Dani C, Poggi C, Fontanelli G. Relationship between platelet an observational study. Arch Dis Child Fetal Neonatal Ed. (2016)
count and volume and spontaneous and pharmacological closure 101:F520–6. doi: 10.1136/archdischild-2015-309192
of ductus arteriosus in preterm infants. Am J Perinatol. (2013) 93. Elsayed Y, Seshia M, Soni R, Buffo I, Baier RJ, McNamara PJ, et al. Pre-
30:359–64. doi: 10.1055/s-0032-1324702 symptomatic prediction of morbitidies in preterm infants with patent ductus
77. Koch J, Hensley G, Roy L, Brown S, Ramaciotti C, Rosenfeld CR. arteriosus by targeted neonatal echocardiography and brain-type natriuretic
Prevalence of spontaneous closure of the ductus arteriosus in neonates peptide. J Pediatr Neonatal Individ Med. (2016) 5:1–10.
at a birth weight of 1000 grams or less. Pediatrics. (2006) 117:1113– 94. Engür D, Deveci M, Türkmen MK. Early signs that predict later
21. doi: 10.1542/peds.2005-1528 haemodynamically significant patent ductus arteriosus. Cardiol Young.
78. Rakza T, Magnenant E, Klosowski S, Tourneux P, Bachiri A, Storme L. (2016) 26:439–45. doi: 10.1017/S1047951115000372
Early hemodynamic consequences of patent ductus arteriosus in preterm 95. Mochammading, Kaban RK, Yanuarso PB, Djer MM. Prostaglandin
infants with intrauterine growth restriction. J Pediatr. (2007) 151:624– E2 and patent ductus arteriosus in premature infants. (2016) 56:8–
8. doi: 10.1016/j.jpeds.2007.04.058 14. doi: 10.14238/pi56.1.2016.02
79. Strauss T, Pessach I, Jacoby E, Schushan-Eisen I, Mazkereth R, Kuint J. 96. Arlettaz R, Archer N, Wilkinson AR. Closure of the ductus arteriosus
Carina angle measurements for diagnosis of patent ductus arteriosus in and development of pulmonary branch stenosis in babies of less
preterm infants. Neonatology. (2011) 99:224–30. doi: 10.1159/000315862 than 32 weeks gestation. Arch Dis Child Fetal Neonatal Ed. (2001)
80. Dhuper S, Kim R, Weichbrod L, Mahdi E, Shah N, Kona S, et al. NT-proBNP 85. doi: 10.1136/fn.85.3.F197
levels improve the ability of predicting a hemodynamically significant patent 97. Oliveira AGS, Soares P, Flor-de-Lima F, Neves AL, Guimarães H. PDA
ductus arteriosus in very low-birth-weight infants. J Clin Neonatol. (2012) management in VLBW infants: experience of a level III NICU. J Pediatr
1:82. doi: 10.4103/2249-4847.96758 Neonatal Individ Med. (2016) 5:1–9.
81. Desandes R, Jellimann JM, Rouabah M, Haddad F, Desandes E, Boubred F, 98. Tauber K, Granina E, Doyle R, Munshi U. Gestational and postnatal
et al. Echocardiography as a guide for patent ductus arteriosus ibuprofen age influence B-type natriuretic peptide level used in diagnosis of
treatment and efficacy prediction. Pediatr Crit Care Med. (2012) 13:324– a hemodynamically significant patent ductus arteriosus in preterm
7. doi: 10.1097/PCC.0b013e31822882b5 infants. J Clin Neonatol. (2016) 5:143. doi: 10.4103/2249-4847.
82. Alyamac Dizdar E, Ozdemir R, Nur Sari F, Yurttutan S, Gokmen 191241
T, Erdeve O, et al. Low platelet count is associated with ductus 99. Valerio E, Valente MR, Salvadori S, Frigo AC, Baraldi E, Lago P.
arteriosus patency in preterm newborns. Early Hum Dev. (2012) 88:813– Intravenous paracetamol for PDA closure in the preterm: a single-center
6. doi: 10.1016/j.earlhumdev.2012.05.007 experience. Eur J Pediatr. (2016) 175:953–66. doi: 10.1007/s00431-016-
83. Sallmon H, Weber SC, Hüning B, Stein A, Horn PA, Metze 2731-9
BC, et al. Thrombocytopenia in the first 24 hours after birth 100. Ledo A, Aguar M, Núñez-Ramiro A, Saénz P, Vento M. Abdominal near-
and incidence of patent ductus arteriosus. Pediatrics. (2012) infrared spectroscopy detects low mesenteric perfusion early in preterm
130:e623–30. doi: 10.1542/peds.2012-0499 infants with hemodynamic significant ductus arteriosus. Neonatology. (2017)
84. Brunner B, Hoeck M, Schermer E, Streif W, Kiechl-Kohlendorfer U. 112:238–45. doi: 10.1159/000475933
Patent ductus arteriosus, low platelets, cyclooxygenase inhibitors, and 101. Demirel G, Yılmaz A, Vatansever B, Tastekin A. Is high platelet distribution
intraventricular hemorrhage in very low birth weight preterm infants. J width in the first hours of life can predict hemodynamically significant patent
Pediatr. (2013) 163:23–8. doi: 10.1016/j.jpeds.2012.12.035 ductus arteriosus in preterm newborns? J Matern Fetal Neonatal Med. (2020)
85. Visconti LF, Morhy SS, Deutsch ADA, Tavares GMP, Wilberg TJM, 33:2049–53. doi: 10.1080/14767058.2018.1536743
Rossi F de S. Clinical and echocardiographic characteristics associated 102. Van Overmeire B, Van De Broek H, Van Laer P, Weyler J, Vanhaesebrouck
with the evolution of the ductus arteriosus in the neonate with P. Early versus late indomethacin treatment for patent ductus arteriosus
birth weight lower than 1,500g. Einstein (Sao Paulo). (2013) 11:317– in premature infants with respiratory distress syndrome. J Pediatr. (2001)
23. doi: 10.1590/S1679-45082013000300010 138:205–11. doi: 10.1067/mpd.2001.110528
86. Grass B, Baumann P, Arlettaz R, Fouzas S, Meyer P, Spanaus K, 103. Sanjeev S, Pettersen M, Lua J, Thomas R, Shankaran S, L’Ecuyer T. Role
et al. Cardiovascular biomarkers pro-atrial natriuretic peptide and pro- of plasma B-type natriuretic peptide in screening for hemodynamically
endothelin-1 to monitor ductus arteriosus evolution in very preterm infants. significant patent ductus arteriosus in preterm neonates. J Perinatol. (2005)
Early Hum Dev. (2014) 90:293–8. doi: 10.1016/j.earlhumdev.2014.03.002 25:709–13. doi: 10.1038/sj.jp.7211383
87. Occhipinti F, De Carolis MP, De Rosa G, Bersani I, Lacerenza S, Cota 104. Dix LML, Blok CA, Lemmers PMA, Van Der Aa N, Molenschot MC,
F, et al. Correlation analysis between echocardiographic flow pattern Vreman HJ, et al. Early end-tidal carbon monoxide levels, patency of the
and N-terminal-pro-brain natriuretic peptide for early targeted treatment ductus arteriosus and regional cerebral oxygenation in preterm infants.
of patent ductus arteriosus. J Matern Neonatal Med. (2014) 27:1800– Neonatology. (2014) 105:161–5. doi: 10.1159/000356167
4. doi: 10.3109/14767058.2014.880879 105. Olukman O, Ozdemir R, Karadeniz C, Calkavur S, Mese T, Vergin C. Is
88. Trevisanuto D, Zaninotto M, Lachin M, Altinier S, Plebani M, Ferrarese there a relationship between platelet parameters and patency of ductus
P, et al. Effect of patent ductus arteriosus and indomethacin treatment on arteriosus in preterm infants? Blood Coagul Fibrinolysis. (2017) 28:8–
serum cardiac troponin T levels in preterm infants with respiratory distress 13. doi: 10.1097/MBC.0000000000000520
syndrome. Eur J Pediatr. (2000) 159:273–6. doi: 10.1007/s004310050069 106. Khositseth A, Nuntnarumit P, Chongkongkiat P. Echocardiographic
89. König K, Guy KJ, Drew SM, Barfield CP. B-type and N-terminal pro- parameters of patent ductus arteriosus in preterm infants. Indian Pediatr.
B-type natriuretic peptides are equally useful in assessing patent ductus (2011) 48:773–8. doi: 10.1007/s13312-011-0127-5

Frontiers in Pediatrics | www.frontiersin.org 11 September 2020 | Volume 8 | Article 541

de Klerk et al. Spontaneous PDA Closure

107. Lago P, Bettiol T, Salvadori S, Pitassi I, Vianello A, Chiandetti L, et al. Safety 123. Mitra S, Florez ID, Tamayo ME, Mbuagbaw L, Vanniyasingam T,
and efficacy of ibuprofen versus indomethacin in preterm infants treated for Veroniki AA, et al. Association of placebo, indomethacin, ibuprofen,
patent ductus arteriosus: a randomised controlled trial. Eur J Pediatr. (2002) and acetaminophen with closure of hemodynamically significant patent
161:202–7. doi: 10.1007/s00431-002-0915-y ductus arteriosus in preterm infants a systematic review and meta-
108. Khosroshahi AJ, Kianfar A, Aharanjani BM, Zanjani KS. Usefulness of serum analysis. JAMA J Am Med Assoc. (2018) 319:1221–38. doi: 10.1001/jama.
brain natriuretic peptide level for screening hemodynamically significant 2018.1896
patent ductus arteriosus in preterm neonates. Iran J Pediatr. (2014) 24:766–9. 124. Aikio O, Härkin P, Saarela T, Hallman M. Early paracetamol
109. Van Overmeire B, Follens I, Hartmann S, Creten WL, Van Acker KJ. treatment associated with lowered risk of persistent ductus
Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child Fetal arteriosus in very preterm infants. J Matern Neonatal Med. (2014)
Neonatal Ed. (1997) 76:1–6. doi: 10.1136/fn.76.3.F179 27:1252–6. doi: 10.3109/14767058.2013.854327
110. Nuntnarumit P, Khositseth A, Thanomsingh P. N-terminal probrain 125. Dagle JM, Ryckman KK, Spracklen CN, Momany M, Cotten CM, Levy J,
natriuretic peptide and patent ductus arteriosus in preterm infants. J et al. Genetic variants associated with patent ductus arteriosus in extremely
Perinatol. (2009) 29:137–42. doi: 10.1038/jp.2008.185 preterm infants. (2019) 39:401–8. doi: 10.1038/s41372-018-0285-6
111. Terek D, Yalaz M, Ulger Z, Koroglu OA, Kultursay N. Medical closure 126. Villamor-Martinez E, Kilani MA, Degraeuwe PL, Clyman RI, Villamor E.
of patent ductus arteriosus does not reduce mortality and development Intrauterine growth restriction and patent ductus arteriosus in very and
of bronchopulmonary dysplasia in preterm infants. J Res Med Sci. extremely preterm infants: a systematic review and meta-analysis. Front
(2014) 19:1074–9. Endocrinol. (2019) 10:1–11. doi: 10.3389/fendo.2019.00058
112. Mine K, Ohashi A, Tsuji S, Nakashima JI, Hirabayashi M, Kaneko K. B-type 127. Engbers AGJ, Klerk JCA De Flint RB, Völler S, Reiss IKM, Andriessen P, et al.
natriuretic peptide for assessment of haemodynamically significant patent Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates
ductus arteriosus in premature infants. Acta Paediatr Int J Paediatr. (2013) with patent ductus arteriosus. (2020) 1–12. doi: 10.1111/bcp.14298. [Epub
102:347–52. doi: 10.1111/apa.12273 ahead of print].
113. Zonnenberg I, De Waal K. The definition of a haemodynamic significant duct 128. Terek D, Altun Koroglu O, Ulger Z, Yalaz M, Kultursay N. The
in randomized controlled trials: A systematic literature review. Acta Paediatr serial changes of perfusion index in preterm infants with patent ductus
Int J Paediatr. (2012) 101:247–51. doi: 10.1111/j.1651-2227.2011.02468.x arteriosus: is perfusion index clinically significant? Minerva Pediatr. (2016)
114. van Laere D, van Overmeire B, Gupta S, El Khuffash A, Savoia M, McNamara 68:250–5.
PJ, et al. Application of NPE in the assessment of a patent ductus arteriosus. 129. Antonucci R, Cuzzolin L, Arceri A, Dessì A, Fanos V. Changes
Pediatr Res. (2018) 84:46–56. doi: 10.1038/s41390-018-0077-x in urinary PGE2 after ibuprofen treatment in preterm infants
115. El Hajjar M, Vaksmann G, Rakza T, Kongolo G, Storme L. Severity of with patent ductus arteriosus. Eur J Clin Pharmacol. (2009)
the ductal shunt: a comparison of different markers. Arch Dis Child Fetal 65:223–30. doi: 10.1007/s00228-008-0586-3
Neonatal Ed. (2005) 90:419–22. doi: 10.1136/adc.2003.027698 130. Tosse V, Pillekamp F, Verde P, Hadzik B, Sabir H, Mayatepek E, et al. Urinary
116. Ngo S, Profit J, Gould JB, Lee HC. Trends in patent ductus arteriosus NT-proBNP, NGAL, and H-FABP may predict hemodynamic relevance of
diagnosis and management for very low birth weight infants. Pediatrics. patent ductus arteriosus in very low birth weight infants. Neonatology. (2012)
(2017) 139:e20162390. doi: 10.1542/peds.2016-2390 101:260–6. doi: 10.1159/000334826
117. Lamp KC, Reynolds MS. Indomethacin for prevention of 131. Lavery AP, Meinzen-Derr JK, Anderson E, Ma Q, Bennett MR, Devarajan
neonatal intraventricular hemorrhage. DICP. (1991) 25:1344– P, et al. Urinary NGAL in premature infants. Pediatr Res. (2008) 64:423–
8. doi: 10.1177/106002809102501213 8. doi: 10.1203/PDR.0b013e318181b3b2
118. Fowlie PW, Davis PG. Cochrane review: prophylactic intravenous 132. El-Khuffash A, Higgins M, Walsh K, Molloy EJ. Quantitative assessment
indomethacin for preventing mortality and morbidity in preterm of the degree of ductal steal using celiac artery blood flow to left
infants. Evidence Based Child Health A Cochrane Rev J. (2010) ventricular output ratio in preterm infants. Neonatology. (2008) 93:206–
5:416–71. doi: 10.1002/ebch.526 12. doi: 10.1159/000110869
119. Jensen EA, Dysart KC, Gantz MG, Carper B, Higgins RD, Keszler M, et al.
Association between use of prophylactic indomethacin and the risk for Conflict of Interest: The authors declare that the research was conducted in the
bronchopulmonary dysplasia in extremely preterm infants. J Pediatr. (2017) absence of any commercial or financial relationships that could be construed as a
186:34–40.e2. doi: 10.1016/j.jpeds.2017.02.003 potential conflict of interest.
120. Pacifici GM. Differential renal adverse effects of ibuprofen and indomethacin
in preterm infants: a review. Clin Pharmacol Adv Appl. (2014) 6:111– Copyright © 2020 de Klerk, Engbers, van Beek, Flint, Reiss, Völler and
6. doi: 10.2147/CPAA.S59376 Simons. This is an open-access article distributed under the terms of the
121. Ferguson JM. Pharmacotherapy for patent ductus arteriosus Creative Commons Attribution License (CC BY). The use, distribution or
closure. Congenit Heart Dis. (2018) 14:52–6. doi: 10.1111/chd. reproduction in other forums is permitted, provided the original author(s)
12715 and the copyright owner(s) are credited and that the original publication in
122. Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus this journal is cited, in accordance with accepted academic practice. No use,
in preterm and/or low birth weight infants. Cochrane Database Syst Rev. distribution or reproduction is permitted which does not comply with these
(2020) 2020:1–60. doi: 10.1002/14651858.CD004213.pub5 terms.

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