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Seminars in Fetal and Neonatal Medicine

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Prophylactic and early targeted treatment of patent ductus arteriosus 7

a,b,∗ b,c
Jonathan P. Wyllie , Samir Gupta
a
Department of Neonatology, The James Cook University Hospital, Middlesbrough, UK
b
Durham University, Stockton-on-Tees, UK
c
Department of Paediatrics and Neonatology, University Hospital of North Tees, Stockton-on-Tees, UK

A R T I C LE I N FO A B S T R A C T

Keywords: Treatment of a haemodynamically significant patent ductus arteriosus (PDA) in the very preterm infant has been
Preterm an accepted approach for several decades. However, the rationale for closure of PDA has recently been chal-
Patent ductus arteriosus lenged due to reports of success with conservative approaches and the lack of evidence for longer-term benefits
Early targeted treatment from treatment. In this article, we address an approach to assess treatment of those babies most likely to benefit.
Prophylactic treatment
Ibuprofen
Indomethacin

1. Introduction increases pulmonary vasodilatation [3]. The exact mechanisms of

oxygen-induced pulmonary vasodilatation during the transition remain
An understanding of perinatal cardiovascular ductal anatomy and unclear. The increase in alveolar or arterial oxygen tension may de-
physiology is essential if subsequent interventions are to be logical ra- crease pulmonary vascular resistance, either directly by dilating the
ther than merely treating “numbers”, as still occurs in neonatal in- small pulmonary arteries, or indirectly by stimulating the production of
tensive care. The patent ductus arteriosus (PDA) seems to be a con- vasodilator substances such as prostacyclin (PGI2), bradykinin, and
tinuum of transitional physiology and pathophysiology affected importantly, nitric oxide [4,5].
primarily by gestational age and severity of surfactant-deficient lung More blood flows through the lungs returning to the left atrium,
disease. Several other perinatal factors may lead to persistence of the where the pressure rises, causing the foramen ovale to close, usually
ductus arteriosus, then called PDA. As the initial closure of the ductus within minutes of birth. The ductus arteriosus initially remains open
arteriosus is functional rather than structural, neonatal disease states with flow first ceasing and then reversing (left to right) when systemic
such as infection and haemodynamic disturbances may cause a func- pressure exceeds pulmonary pressure. This is the postnatal part of the
tionally closed ductus to reopen. transitional phase of the perinatal circulation. Although most of the
A PDA in term babies persisting after the first week of life is usually decline in pulmonary vascular resistance occurs during the first day at
pathological and often associated with congenital heart disease. In term, it may not be complete for several weeks in preterm infants [5–8].
these cases, the direction of ductal shunting reflects underlying pa-
thology. Discussions of PDA in term babies will be covered in other 3. Physiological closure of the ductus arteriosus
sections and this monograph is limited to the management of PDA in
preterm babies during early postnatal life. Closure is normally initiated by constriction of the spiral medial
muscle layer with shortening and thickening of the ductus, disruption of
2. Early postnatal physiology the intima and formation of intimal cushions [9]. Intimal cushions,
which are identifiable by echocardiography as echo-dense protrusions
After birth, the pulmonary vascular resistance falls due to lung into the ductal lumen, have been shown to be the first signs of im-
aeration and increasing oxygenation [1,2], and the peripheral vascular pending ductal closure. Lack of these within the first few hours of life is
resistance increases due to the removal of the low-resistance placenta associated with ductal patency [10]. The sequence of closure usually
and exposure to the outside environment. Ventilation of the newborn starts at the pulmonary end with functional closure usually complete by
mammal without changing oxygenation produces only partial pul- 72 h of age in healthy term infants [11,12] but this may take longer in
monary vasodilatation, whereas ventilation with air or oxygen the preterm infant [13–15]. In normal newborn infants > 36 weeks

∗
Corresponding author. South Tees NHS Foundation Trust, Marton Road, Middlesbrough TS4 3BW, UK.
E-mail address: [email protected] (J.P. Wyllie).

https://doi.org/10.1016/j.siny.2018.03.005

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J.P. Wyllie, S. Gupta 6HPLQDUVLQ)HWDODQG1HRQDWDO0HGLFLQH  ²

gestation, functional PDA closure has occurred in 42% by 24 h after seem that, if infants lose 1–2% of birth weight per day for the first five
birth, 78% by 40 h, 90% by 48 h and in all by 96 h [12]. Closure is often days after birth, there is no increased risk of symptomatic PDA [34].
delayed in preterm babies and 48% with birth weight < 1000 g have a The use of furosemide to initiate and maintain urine output in the first
symptomatic PDA [13]. It is important to realize that functional closure few days of life has been associated with increased incidence of PDA, an
of the ductus arteriosus may predate anatomical closure by several effect not seen with chlorothiazide [35]. Phototherapy may also be
weeks. Early ductal closure is initiated after birth, by a complex inter- associated with PDA in infants < 1000 g [36]. Where possible, avoid-
action between oxygen, local and circulating neuro-humoral factors and ance of factors that are associated with PDA seems sensible.
the ductus smooth muscle. Increasing oxygen tension causes ductal
constriction and hypoxaemia relaxation [16]. This sensitivity to oxygen 6. Prophylactic treatment of PDA
is greatest at term and diminishes within 24 h of birth [17]. In contrast,
as the fetus approaches term, the duct becomes less sensitive to the The ductus is usually silent in the first 48–72 h after birth and the
dilating effects of prostaglandins [18–21] whereas the preterm infant signs and symptoms of an open DA are usually absent due to the
demonstrates increased sensitivity even after initial constriction [22], transitional circulation and minimal pressure differences between the
and paradoxically, there is some evidence that oxygen metabolites may two sides of circulation connected by the ductus. With limitations of
stimulate prostaglandin E2 production and ductus dilatation. The clo- clinical diagnosis of PDA during early postnatal life, bedside echo-
sure mechanism is usually fully mature after 35 weeks gestation. cardiography is required for diagnosing a ‘significant’ PDA and under-
However, in a large number of preterm babies, the vessel does not close standing transitional PDA haemodynamics. There is growing interest in
spontaneously, resulting in continued patency known as PDA. Around exploring other biomarkers for diagnosing PDA, such as pro-brain na-
7000 extremely preterm babies (< 29 weeks of gestation) are born in triuretic peptide, near-infrared spectroscopy, etc., in this period, but
the UK every year and in ∼40% the duct will fail to close spontaneously these tests are limited by their sensitivity and specificity.
even by four months of age [3,23]. Prophylactic treatment of PDA incorporates all-inclusive treatment
of babies for closure of PDA without excluding those who do not have
4. Associations of continued ductal patency in preterm babies PDA or in whom the PDA could close spontaneously. Non-steroidal anti-
inflammatory drugs (NSAIDs) such as indomethacin and ibuprofen,
PDA in the preterm has long been associated with pulmonary hae- ethamsylate, and surgery have been proposed as prophylactic treat-
morrhage, intraventricular haemorrhage (IVH), necrotizing en- ments for PDA in low birth weight and gestation babies.
terocolitis (NEC), bronchopulmonary dysplasia (BPD), and mortality as One study indicated a reduction in PDA brought about by etham-
well as early hypotension [24]. However, a recent literature review sylate but the criteria for diagnosis of PDA were not published [37]. A
suggested that whereas PDA is a risk factor for IVH, a significant as- controlled trial of prophylactic surgical ligation within 24 h of birth in
sociation between PDA and mortality, BPD, NEC, or retinopathy is preterm infants who were < 1000 g and requiring supplemental oxygen
unlikely [39]. Sellmer et al. reported that persistence of PDA at 72 h in showed no effect on chronic lung disease or IVH, which were the main
extreme preterm babies is associated with increased odds of compli- outcome measures. There was, of course, an effect on PDA but in no
cations of prematurity and mortality [24]. In another observational other outcome except NEC, which was reduced [38]. A review of pro-
study, Noori et al. reported an eight-fold increase in mortality asso- phylactic indomethacin analysed 19 trials with 2872 infants and de-
ciated with persistent ductus arteriosus after controlling for con- monstrated immediate short-term benefits in symptomatic PDA, the
founding factors [26]. The decision about when or whether to treat PDA need for surgical ligation and IVH without evidence for harm except
remains uncertain, with reports of satisfactory outcomes with a con- reduced renal output during treatment [39]. Disappointingly, there was
servative approach towards PDA treatment [27,28]. no difference in mortality or pulmonary outcomes. There is therefore no
proven role for prophylactic indomethacin in terms of long-term out-
5. Factors affecting ductal patency comes.
Despite the apparent lack of association between indomethacin and
Patency and significance are related to gestation and the presence of NEC [39], ibuprofen has superseded it because of a better safety profile
respiratory distress; however, other factors have also been implicated. since it does not reduce the blood flow velocity to the brain, gut or
Two non-randomized clinical trials have suggested that antenatal ad- kidneys and appears to reduce NEC [40]. Reviewing prophylactic ibu-
ministration of steroids may be protective [29,30]. Such an effect might profen, seven studies with 931 infants demonstrated similar short-term
be explained in terms of the known effect upon the course and severity benefits to indomethacin [41].
of RDS. Morales et al. evaluated this effect in a randomized controlled However, there remain concerns in treating infants unnecessarily, as
trial of 165 infants between 26 and 34 weeks gestation [31]. They there may be long-term renal side-effects: extremely low birth weight
found that steroids given more than 24 h before birth significantly re- infants treated with NSAIDs and aminoglycosides have been found to
duced symptomatic PDA (relative risk (RR) 0.32: 95% (confidence in- have a renal volume less than the 10th percentile at seven years of age
terval (CI): 0.12 to 0.85 as well as improving the course of RDS. Other in 40% of cases, which is associated with α1-microglobinuria [42].
antenatal drugs administered to the mother such as magnesium, sul- Paracetamol remains to be assessed as a prophylactic treatment but
phate, terbutaline and salbutamol do not appear to affect ductal pa- appears to have a good short-term safety profile [43], although pro-
tency. phylactic efficacy remains uncertain [44].
Excessive fluid intake is widely quoted as predisposing to PDA, but
this is based on relatively little evidence. Rapid volume expansion may 7. Spontaneous PDA closure
cause release of renal prostaglandin with potential but unproven effects
upon PDA [32]. If parenteral fluid exceeds an average of 169 mL/kg/ Since the Trial of Indomethacin Prophylaxis in Preterms (TIPP) re-
day (SD: 20) from day 3 of life, PDA is more likely (RR: 30.6%; 95% CI: sults were published in 2001, increasing numbers of neonatal units
18.3, 42.9) [29]. In a small study, De Buyst reported the effect of fluid adopted the practice of prophylactic treatment for closure of PDA, as it
restriction on PDA dimension. They fluid restricted preterm babies also reduced the incidence of IVH. There has, however, been a growing
aged > 10 days, from 145 to 108 mL/kg/day, but failed to see any uncertainty around treatment for closure of PDA over the last decade.
change in ductal dimension on echo before and after restriction. There This has primarily been due to concerns around the unnecessary ex-
was, however, a significant reduction in superior vena cava flow [33]. posure of babies to the side-effects of cyclooxygenase (COX) inhibitor
Therefore, there is no evidence for restricting fluid to facilitate ductal treatment who might otherwise have closed the ductus spontaneously.
closure, and no evidence for the restriction of enteral intake. It would With the improvements in perinatal care, fewer babies > 28 weeks


J.P. Wyllie, S. Gupta 6HPLQDUVLQ)HWDODQG1HRQDWDO0HGLFLQH  ²

are now mechanically ventilated, and the associated neonatal morbid- 10. Early targeted treatment approach
ities are also less in this group of babies. We analysed a cohort of babies
born at < 32 weeks gestation in a single unit over three years. The There are limited data on outcomes using this treatment approach.
study cohort was divided into two subgroups, those born at < 29 (up to This is partly because the bedside echocardiography has not been
28+6) weeks gestation and babies born at 29 to 31+6 weeks gestation. available in the past to diagnose PDA before it is symptomatic in the
There were significant differences in short-term pre-discharge outcomes first two or three days of life. Early echocardiography in preterm infants
between the two study groups. Babies < 29 weeks gestation had sig- has now improved our understanding of transitional circulation and
nificantly fewer deaths, fewer complications of prematurity, and fewer physiology of ductal shunts. It is now known that immediate postnatal
had persistence of PDA. Further, babies < 29 weeks gestation who were circulation through a ductus is not right to left but mainly left to right.
diagnosed with PDA were analysed according to whether they had re- Additionally, the ductus may have varied degrees of constriction even
ceived treatment for closure of PDA or were managed conservatively. In in the extreme preterm babies.
this group, babies who were treated for PDA had significantly less There is little evidence using this approach, with few studies, all of
death, less necrotizing enterocolitis and less pulmonary haemorrhage, small sample size, from the 1980s. These three small trials have a
albeit a higher incidence of chronic lung disease [45]. Nemerofsky et al. combined size of 97 infants. The meta-analysis reported that treatment
also reported that 40% of babies born with birth weight of < 1000 g did of an asymptomatic PDA with indomethacin significantly reduced the
not close their PDA spontaneously even by four months of age com- incidence of symptomatic PDA (RR: 0.36; 95% CI: 0.19, 0.68) and
pared to those born > 1000 g in whom all ducts closed spontaneously duration of supplemental oxygen (weighted mean difference: −12.5;
by two months of age [46]. This suggests that selection of babies for 95% CI: −23.8, −1.26). There was no evidence of effect on mortality,
treatment or study is important, as it is possible that treatment of PDA chronic lung disease, intraventricular haemorrhage, retinopathy of
may be helpful in some groups but not in others. The group of ba- prematurity, and length of ventilation [48]. Similarly, one trial eval-
bies < 1000 g, which will always have higher morbidity, is a particular uated the use of ibuprofen for early-targeted treatment of PDA in 136
focus for attention, especially as this group is under-represented in preterm infants < 30 weeks gestation from 11 sites. The primary out-
earlier research. comes for this study were mortality, rescue treatment or drop-out
through study day 14 and showed a significantly higher PDA closure
rate when using ibuprofen at standard dose compared to placebo. There
8. Treatment options for closure of PDA
were no significant differences in other short-term outcomes of interest
pre-discharge. With these limited data and the absence of long-term
Broadly the treatment options for PDA have been grouped into
outcomes it is difficult to draw any meaningful conclusions.
conservative and active, with the latter sub-divided into medical and
The results of the Australian double-blind randomized controlled
surgical. The timing of active treatment may be prophylactic, sympto-
DETECT trial [49] using early targeted treatment approach within 12 h
matic, or early targeted treatment. The details of various treatment
with indomethacin as an active drug versus placebo were published
approaches are discussed by [COMPLETE ON PROOF] in this issue of
recently. The trial was stopped prematurely due to non-availability of
Seminars. However, there is growing consensus that treating PDA before
indomethacin as it was withdrawn from the market. In this double-
it is symptomatic, usually before age 72 h, may offer potential benefits
blind randomized multicentre trial, babies < 29 weeks were enrolled
[39]. Treatment of babies soon after birth in the first 24–72 h, who are
within 12 h, meeting echocardiography criteria of eligibility. The active
unlikely to undergo spontaneous closure, offers potential benefits of the
drug indomethacin was given at a dose of 0.2 mg/kg as loading dose
prophylactic approach without exposing the babies in whom sponta-
followed by two further doses of 0.1 mg/kg. The primary outcome was
neous ductal closure is likely due to the side-effects of COX inhibitors.
death/abnormal cranial ultrasound (Grade 2–4 IVH and/or PVL). The
The selection of babies for this early targeted treatment is dependent on
trial was stopped after screening 157 babies from three centres, of
availability of bedside echocardiography screening, as the symptoms
whom 94 (60%) were recruited. The primary outcome was available for
and signs are usually not present. With the increasing availability of
92 babies. There was no difference in the primary outcome between the
echocardiography on the neonatal units, this approach can now be
two study groups. In the indomethacin group eight out of 44 babies and
evaluated for clinical outcomes of interest.
in the placebo group nine out of 48 babies achieved primary outcome.
The contamination rate (open treatment for closure of PDA) was 20% in
9. Echocardiography for early targeted treatment of PDA the indomethacin group and 40% in the placebo group but there were
fewer babies with pulmonary haemorrhage in the indomethacin group
Early targeted treatment is an attractive potential option, as only (9% vs 23%; P = 0.06). The premature termination of the study and
those infants likely to develop a significant PDA are treated. The high contamination rates pose challenges in interpreting the data, so
echocardiography in extreme preterm infants in the first 72 h should the question posed by the study remains unanswered.
use criteria that have a high sensitivity for diagnosing PDA that is un-
likely to close spontaneously. It should take account of the transitional 11. Trials on the horizon using early targeted treatment
circulation and be able to identify babies who have impending or es-
tablished pulmonary hypertension. Any concerns about congenital Several trials are currently using an early targeted treatment ap-
heart disease clinically or on echocardiogram should be discussed with proach for PDA. The multicentre TRIOCAPI trial from France is ran-
paediatric cardiologists, and babies with duct-dependent congenital domizing babies with a large PDA within 12 h of birth using echo cri-
heart disease should not be prescribed treatment for closure of PDA. teria and using ibuprofen as an active drug at standard doses. The study
The other principles of neonatal echocardiography and guidance on recruited 363 extreme preterm babies and the primary outcome is
who should perform are beyond the scope of this article and discussed survival without cerebral palsy at two years of age. This trial is cur-
elsewhere but follow the same principles. The use of more than one rently in follow-up phase and the results are awaited with estimated
criterion improves the sensitivity (Box 1). completion date in February 2019 (http://clinicaltrials.gov/ct2/show/
In a recent publication by Khuffash et al., scoring criteria have been study/NCT01630278).
suggested [47] with high sensitivity. This score uses duct dimension, The Baby OSCAR trial from the UK is an NIHR-HTA-funded multi-
flow velocity in PDA, left ventricular output, and left ventricular late centre, masked, randomized placebo-controlled trial investigating
diastolic velocity (a′ wave) on tissue Doppler imaging. This approach short- and long-term health and economic outcomes of the treatment of
requires a greater expertise and the findings have not been replicated a large PDA with ibuprofen in extremely preterm babies within 72 h of
from other centres. birth. Extremely premature babies born at or before 28 weeks of


J.P. Wyllie, S. Gupta 6HPLQDUVLQ)HWDODQG1HRQDWDO0HGLFLQH  ²

Box 1
Widely used echocardiography criteria for early diagnosis of patent ductus arteriosus.

• Duct dimension ≥1.5 mm (some prefer a cut-off of 2 mm)

• Pulsatile flow pattern (or a growing pattern with < 30% right to left flow)
• No concerns about pulmonary hypertension
• Absence of duct-dependent congenital heart disease
gestation are eligible for inclusion into the trial in the first 72 h fol- 12. Conclusions
lowing birth, if they have a large PDA diagnosed using bedside echo-
cardiography. The echocardiography criteria identify babies in whom Prophylactic and early targeted treatments have the potential of
PDAs are unlikely to close spontaneously. Babies are randomized to closing the PDA before it is symptomatic. The prophylactic treatment,
receive either the active drug (ibuprofen) used for medical closure of once popular, has now become controversial as it unnecessarily exposes
PDA or a matched placebo (normal saline). This aims to answer the a large proportion of preterm babies to the side effects of treatment who
clinical question as to whether to treat an asymptomatic ‘significant’ would have closed the PDA spontaneously. Persistence of PDA is,
PDA identified in the first 72 h of life. The success of the trial depends however, associated with increase in morbidity and mortality. Early
on meeting recruitment and retention targets, and, for a fair compar- targeted treatment seems promising as it allows selection of babies who
ison, open label treatment needs to be kept to a minimum. This has are less likely to close the PDA spontaneously and it has the benefits of a
been one of the weaknesses of the trials conducted to date. To minimize prophylactic approach. This approach is currently being tested in large
this ‘contamination’, the trial protocol sets clinical and echocardio- randomized trials awaiting results.
graphy thresholds that need to be met before considering treatment of a
symptomatic PDA. The trial aims to recruit around 730 babies over 12.1. Practice points
three years. Unlike previous studies, this trial is using a primary out-
come of mortality or moderate-to-severe chronic lung disease, plus a • Uncertainty remains as to when or if to treat PDA.
number of secondary outcomes including short- and long-term health • Infants likely to develop significant PDA can be identified using
outcomes at two years of age and health economic evaluation. echocardiography before it is symptomatic.
BeNeDuctus trial is a Dutch multicentre, randomized, non-in- • Early targeted treatment could have benefits of prophylactic treat-
feriority trial of early treatment versus expectant management of PDA ment without exposing babies to side-effects of treatment un-
in preterm infants. The objective of the trial is to investigate whether in necessarily.
preterm infants, born at a gestational age < 28 completed weeks, with • Early targeted treatment approach should be studied to determine
a PDA on echo of > 1.5 mm an expectative management is not inferior whether it alters clinical outcomes and longer-term morbidity.
to early treatment with regard to the composite of mortality and/or
NEC and/or BPD at a PMA of 36 weeks. The planned sample size is 564 12.2. Research directions
babies with a non-inferiority margin of 10%. This trial is currently re-
cruiting. • The results of ongoing randomized trials evaluating early targeted
The U-PDA trial is recruiting from Australia, enrolling extreme treatment are awaited to provide data on short-term and long-term
preterm infants < 29 weeks gestation in < 72 h with an aim that PDA outcomes.
management using supportive care without NSAIDs is equally effective • Further studies evaluating bedside echocardiography to improve
compared to standard PDA treatment with supportive care and NSAIDs. sensitivity of parameters to predict non-closure of PDA are required.
The primary outcome of this pilot study is death and/or chronic lung • Other biomarkers are currently being evaluated including N-term-
disease (oxygen dependency at 36 weeks corrected gestational age) and inal brain natriuretic peptide, and near-infrared spectroscopy, for
evaluating NSAID therapy with supportive care versus supportive care early diagnosis of PDA.
alone in the management of PDA. Both widely used NSAID preparations
can be used in this trial according to current local guidelines. The References
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