A conservative treatment of patent ductus arteriosus in very low birth weight infants

doi:10.1016/j.earlhumdev.2016.12.008

Early Human Development

Volume 104, January 2017, Pages 45-49

https://doi.org/10.1016/j.earlhumdev.2016.12.008 Get rights and content

Highlights

•
Management of patent ductus arteriosus in very low birth weight infants remains controversial.
•
Minimally invasive approach trying to avoid medical and surgical treatment seems to be feasible option.
•
Infants receiving minimally invasive management had the lowest rate of chronic lung disease.

Abstract

Background

Treatment of the patent ductus arteriosus (PDA) in the preterm infant remains contentious. There are numerous options of the PDA management from early targeted treatment, late (symptomatic) treatment to no treatment at all.

Aims

To evaluate a three different PDA management approaches in very low birth weight (VLBW) infants.

Study design

A retrospective observational time series study of three cohorts of VLBW infants born between 2004 and 2011.

Subjects

Infants in Symptomatic Treatment Group (STG) were echocardiographically evaluated when clinical signs suggestive of a PDA were present and treated if a haemodynamically significant PDA was confirmed. Early Targeted Group (ETG) underwent echocardiography within the first 48 h and infants received ibuprofen if a large PDA was present. Conservative Treatment Group (CTG) was screened by echocardiography on day seven of life; patients with PDA were managed with increased positive end expiratory pressure and fluid restriction as a first line intervention.

Outcomes

The primary outcome was medical and surgical treatment in the three time periods. Secondary outcomes included mortality, severe periventricular and intraventricular haemorrhage, respiratory distress syndrome and chronic lung disease.

Results

There were 138 infants diagnosed with PDA; 52 infants in STG, 52 infants in ETG and 34 infants in CTG. Ibuprofen therapy and ligation were less frequent in CTG. There was significantly decreased incidence of chronic lung disease in CTG compared to STG (18% vs. 51%; p = 0.003) and to ETG (18% vs. 46%; p = 0.02). There was no difference in the other short term outcomes.

Conclusion

Conservative treatment of persistent ductus arteriosus in VLBW infants is a feasible option and future randomized trials of conservative management are warranted.

Introduction

Early studies have found an association between patent ductus arteriosus (PDA) and brochopulmonary dysplasia (BPD) [1], prolonged ventilation [2], mortality [3], pulmonary haemorrhage [4], severe respiratory distress syndrome (RDS) [5], necrotizing enterocolitis (NEC) [6], intraventricular haemorrhage (IVH) [7] and death [8]. A significant left to right shunt is believed to cause pulmonary over-circulation associated with respiratory complications, and systemic hypo-perfusion with resultant reduced cerebral and gut blood flow. Due to these associations, many neonatal units have pursued a policy of active medical and surgical treatment of patients in whom PDA is identified. More than 30% of preterm infants born before 32 weeks have a PDA that fails to close after birth [9].

Medical treatment with either indomethacin or ibuprofen, and surgical closure with PDA ligation, has been the mainstay in the management of PDA. All these treatments have recognized complications and careful assessment of which babies may require treatment is vital. Ibuprofen has been associated with fewer side effects than indomethacin [10], [11].

The timing of the treatment remains controversial. There are numerous options from prophylactic treatment, early targeted treatment, late (symptomatic) treatment to no treatment at all. A conservative approach to PDA management was shown to be feasible in a prospective study by Vanhaesebrouck et al. [12]. This included adjustment of ventilation parameters (inspiratory time as low as 0.35 s and PEEP as high as 4.5 mbar) and fluid restriction (130 ml/kg/day beyond day three) [12]. Following the diagnosis of a PDA the decision to treat has therefore become more problematic [13].

In our institution three different approaches were used between 2004 and 2011. The aim of our retrospective study was to assess short term outcomes of infants treated conservatively and compare these results to infants managed by early targeted echocardiography or managed by a symptomatic approach.

Section snippets

Methods

This was a single centre study carried out in the Coombe Women and Infants University Hospital, Dublin, Ireland, which is standalone maternity hospital with approximately 8500 deliveries a year and 120 infants below 1500 g admitted to neonatal intensive care unit (NICU). The study was a retrospective time series cohort of three groups of Very Low Birth Weight (VLBW) infants born between 2004 and 2011. Data were obtained by chart review and the study was approved by the hospital Research Ethics

Results

There were 230 VLBW infants admitted in the era of STG, of whom 52 patients (23%) were clinically identified having a PDA. There was 69 VLBW infants admitted in the era of ETG, 52 infants were diagnosed with a PDA. There was 72 VLBW infants admitted in the era of CTG of whom 70 neonates were screened on day seven of life and 34 were diagnosed with a PDA (Fig. 1). There was no statistical difference in the mean gestational age, birth weight and Apgar scores between the three cohorts. The usage

Discussion

These three eras describe the natural history of the PDA in VLBW infants. Screening all VLBW infants in the first 48 h shows that approximately 75% of all VLBW infants have a PDA on echocardiography, reducing to < 50% by one week of life. These findings would be in agreement with the previous report documenting spontaneous closure of PDA in 44% of infants below 32 weeks of gestation before day seven of life [14]. This spontaneous closure rate is probably lower in extremely low birth weight infants

Sources of funding

Jana Semberova's work was supported by The HIP Trial-received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 260777.

Conflicts of interest

None declared.

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Cited by (51)

Role of patent ductus arteriosus in preterms in long-term outcome
2024, Early Human Development
This study aimed to determine long-term neurodevelopmental outcome and cerebral oxygenation in extremely preterm infants, comparing those with a hemodynamic significant patent ductus arteriosus (hsPDA) to those without.
We included infants born before 28 weeks of gestation from 2008 to 2010 with routine echocardiography. Prior to echocardiography, regional cerebral oxygen saturation was measured. At 5 years of age, we evaluated neurodevelopmental outcomes using the Movement Assessment Battery for Children 2nd Dutch edition for motor skills and the Wechsler Preschool and Primary Scale of Intelligence 3rd Dutch edition for cognition.
A total of 66 infants (gestational age 26.6 ± 0.9 weeks, birth weight 912 ± 176 g) were included, 34 infants with a hsPDA (including treatment). The group infants with hsPDA showed lower pre-closure cerebral saturation levels (58.2 % ±7.8 % versus 62.8 % ±7.0 %; p = 0.01). At 5 years, impaired motor outcome occurred more often in infants with hsPDA (17 (53 %) vs. 7 (23 %); p = 0.01). In multivariate analysis existence of hsPDA remained unfavourably related to the motor subdomain “aiming and catching”. There were no potential effects of hsPDA on cognitive performance at 5 years of age.
Treatment-receiving infants with hsPDA appear to exhibit motor deficits, specifically in “aiming and catching”, by the age 5. Persistent ductal patency could be a contributing factor.
Delayed Surgical Closure of the Patent Ductus Arteriosus: Does the Brain Pay the Price?
2023, Journal of Pediatrics
To investigate the relation between duration of hemodynamically significant patent ductus arteriosus (PDA), cerebral oxygenation, magnetic resonance imaging–determined brain growth, and 2-year neurodevelopmental outcome in a cohort of infants born preterm whose duct was closed surgically.
Infants born preterm at <30 weeks of gestational age who underwent surgical ductal closure between 2008 and 2018 (n = 106) were included in this observational study. Near infrared spectroscopy–monitored cerebral oxygen saturation during and up to 24 hours after ductal closure and a Bayley III developmental test at the corrected age of 2 years is the institutional standard of care for this patient group. Infants also had magnetic resonance imaging at term-equivalent age.
In total, 90 infants fulfilled the inclusion criteria (median [range]: 25.9 weeks [24.0-28.9]; 856 g [540-1350]. Days of a PDA ranged from 1 to 41. Multivariable linear regression analysis showed that duration of a PDA negatively influenced cerebellar growth and motor and cognitive outcome at 2 years of corrected age.
Prolonged duration of a PDA in this surgical cohort is associated with reduced cerebellar growth and suboptimal neurodevelopmental outcome.
International Variation in the Management of Patent Ductus Arteriosus and Its Association with Infant Outcomes: A Survey and Linked Cohort Study
2022, Journal of Pediatrics
Citation Excerpt :
It may indicate that the NICUs with presymptomatic PDA treatment had lower thresholds for surgical PDA treatment than the other NICUs, although we did not assess this point in our survey. Previous studies reported the lower rates of surgical PDA treatment with conservative treatment strategy likely due to greater thresholds for surgical treatment.33,34 Strengths of this study were a large sample size that increased analytical power; the inclusion of multiple countries, which enhanced generalizability; and the adjustment for potential confounders, including networks, that minimized the confounding effect.
To assess whether treating patients with a presymptomatic patent ductus arteriosus (PDA), based on early routine echocardiography, performed regardless of clinical signs, improved outcomes.
This multicenter, survey-linked retrospective cohort study used an institutional-level questionnaire and individual patient-level data and included infants of <29 weeks of gestation born in 2014-2016 and admitted to tertiary neonatal intensive care units (NICUs) of 9 population-based national or regional neonatal networks. Infants in NICUs receiving treatment of presymptomatic PDA identified by routine echocardiography and those not were compared for the primary composite outcome (early death [≤7 days after birth] or severe intraventricular hemorrhage) and secondary outcomes (any in-hospital mortality and major morbidities).
The unit survey (response rates of 86%) revealed a wide variation among networks in the treatment of presymptomatic PDA (7%-86%). Among 246 NICUs with 17 936 infants (mean gestational age of 26 weeks), 126 NICUs (51%) with 7785 infants treated presymptomatic PDA. The primary outcome of early death or severe intraventricular hemorrhage was not significantly different between the NICUs treating presymptomatic PDA and those who did not (17% vs 21%; aOR 1.00, 95% CI 0.85-1.18). The NICUs treating presymptomatic PDA had greater odds of retinopathy of prematurity treatment (13% vs 7%; aOR 1.47, 95% CI 1.01-2.12); however, it was not significant in a sensitivity analysis excluding Japanese data.
Treating presymptomatic PDA detected by routine echocardiography was commonplace but associated with no significant benefits. Well-designed trials are needed to assess the efficacy and safety of early targeted PDA treatment.
Outcomes of Extremely Premature Infants Comparing Patent Ductus Arteriosus Management Approaches
2021, Journal of Pediatrics
Citation Excerpt :
This finding was consistent across all sensitivity analyses. Although there have been sparse reports on premature infants managed conservatively,4,5,13,28 this large cohort of newborns was evaluated using a DID model, which accounts for time-invariant differences between sites and secular trends. Our overall finding of no benefit of NSAIDs for death or BPD among infants born ≥26 weeks of gestational age is consistent with the results of 2 meta-analyses that summarized the findings of several trials.2,29
To evaluate the change in the proportion of deaths/bronchopulmonary dysplasia (BPD) among premature infants (born <26 and 26-29 weeks of gestational age) following a policy change to a strict nonintervention approach, compared with standard treatment.
We examined 1249 infants (341 born <26 weeks of gestational age) at 2 comparable sites. Site 1 (control) continued medical treatment/ligation, and site 2 (exposed) changed to a nonintervention policy in late 2013. Using the difference-in-differences approach, which accounts for time-invariant differences between sites and secular trends, we assessed changes in death or BPD separately among infants born 26-29 weeks and <26 weeks of gestational age in 2 epochs (epoch 1: 2011-2013; epoch 2: 2014-2017).
Baseline characteristics were similar across sites and epochs. Medical treatment/ligation use remained stable at site 1 but declined progressively to 0% at site 2, indicating adherence to policy. We saw no difference in death/BPD among infants born at 26-29 weeks of gestational age (12%, 95% CI -1% to 24%). However, incidence of death/BPD increased by 31% among infants born <26 weeks of gestational age (95% CI 10%-51%) in site 2, whereas there was no change in outcomes in site 1. The Score for Neonatal Acute Physiology-Version II, used as a control outcome, did not change in either site, suggesting that our findings were not due to changes in patients’ severity.
Adherence to a strict conservative policy did not impact death or BPD among 26 weeks but was associated with a significant rise in infants born <26 weeks.
Patent ductus arteriosus management and the drift towards therapeutic nihilism – What is the evidence?
2021, Seminars in Fetal and Neonatal Medicine
The published literature on patent ductus arteriosus (PDA) management is challenging to interpret due to poorly designed trials with high rates of open label treatments, homogenisation of patients with varying physiological subtypes, poor treatment efficacy, and spontaneous closure in more mature infants. The perceived lack of clinical benefit has led to a drift away from medical and surgical treatment of all infants with a PDA. This therapeutic nihilism as a default response to PDA management fails to recognise the physiological relevance of a left-to-right shunt with early haemodynamic instability after birth and subsequent pulmonary volume overload with prolonged exposure. Clinicians need to know if therapeutic nihilism is safe. This review will provide an overview of the available data on the efficacy of known PDA treatments, conservative management and supportive care measures that are currently applied.
Neonatal Intensive Care Unit-Level Patent Ductus Arteriosus Treatment Rates and Outcomes in Infants Born Extremely Preterm
2020, Journal of Pediatrics
Citation Excerpt :
Although randomized controlled trials of PDA pharmacotherapies have failed to show any improvements in major clinical outcomes, studies on conservative and proactive PDA care have yielded conflicting results.21 In previous studies, authors have reported on their experiences with conservative PDA management in a small number of preterm infants, supporting the possible safety of this approach.9,11,12,31 However, these reports describe the experiences of small, single center cohorts that lack adequate power to establish the safety of prolonged exposure to ductal shunts in extremely preterm infants.
To assess associations between neonatal intensive care unit (NICU)-level patent ductus arteriosus (PDA) treatment rates (pharmacologic or surgical) and neonatal outcomes.
This cohort study included infants born at 24-28 weeks of gestation and birth weight <1500 g in 2007-2015 in NICUs caring for ≥100 eligible infants in 6 countries. The ratio of observed/expected (O/E) PDA treatment rates was derived for each NICU by estimating the expected rate using a logistic regression model adjusted for potential confounders and network. The primary composite outcome was death or severe neurologic injury (grades III-IV intraventricular hemorrhage or periventricular leukomalacia). The associations between the NICU-level O/E PDA treatment ratio and neonatal outcomes were assessed using linear regression analyses including a quadratic effect (a square term) of the O/E PDA treatment ratio.
From 139 NICUs, 39 096 infants were included. The overall PDA treatment rate was 45% in the cohort (13%-77% by NICU) and the O/E PDA treatment ratio ranged from 0.30 to 2.14. The relationship between the O/E PDA treatment ratio and primary composite outcome was U-shaped, with the nadir at a ratio of 1.13 and a significant quadratic effect (P<.001). U-shaped relationships were also identified with death, severe neurologic injury, and necrotizing enterocolitis.
Both low and high PDA treatment rates were associated with death or severe neurologic injury, whereas a moderate approach was associated with optimal outcomes.

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View full text

A conservative treatment of patent ductus arteriosus in very low birth weight infants

Highlights

Abstract

Background

Aims

Study design

Subjects

Outcomes

Results

Conclusion

Introduction

Section snippets

Methods

Results

Discussion

Sources of funding

Conflicts of interest

J. Pediatr.

J. Pediatr.

J. Pediatr.

J. Pediatr.

Semin. Perinatol.

J. Pediatr.

Lancet

Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia

N. Engl. J. Med.

Treatment of the idiopathic respiratory-distress syndrome with continuous positive airway pressure

N. Engl. J. Med.

Persistent ductus arteriosus complicating the respiratory distress syndrome

Arch. Dis. Child.

Patent ductus arteriosus, indomethacin and necrotizing enterocolitis in very low birth weight infants: a population-based study

J. Pediatr. Gastroenterol. Nutr.

Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants

Arch. Dis. Child. Fetal Neonatal Ed.

How useful are B-type natriuretic peptide measurements for monitoring changes in patent ductus arteriosus shunt magnitude?

J. Perinatol.

Treatment of patent ductus arteriosus with ibuprofen

Arch. Dis. Child. Fetal Neonatal Ed.

Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants

Cochrane Database Syst. Rev. (Online)