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Position statement

CPS

Management of the patent ductus arteriosus in preterm infants

Posted: Feb 1, 2022

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Principal author(s)

Souvik Mitra, Dany Weisz, Amish Jain, Geert ‘t Jong; Canadian Paediatric Society, Fetus and Newborn Committee, Drug Therapy Committee

Paediatr Child Health 2022 27(1): 63 (Abstract)

Abstract

Management of the patent ductus arteriosus (PDA) is one of the most contentious topics in the care of preterm infants. PDA management can be broadly divided into prophylactic and symptomatic therapy. Prophylaxis with intravenous indomethacin in extremely low birth weight infants may reduce severe intraventricular hemorrhage. Echocardiography should be routinely used to confirm the presence of a PDA before considering symptomatic therapy. A symptomatic PDA can be managed conservatively, using pharmacotherapy or with procedural closure. Ibuprofen should be considered as the pharmacotherapy of choice for a symptomatic PDA. High-dose ibuprofen may be preferable, especially for preterm infants beyond the first 3 to 5 days of age. If pharmacotherapy fails (after two courses) or is contraindicated, procedural closure may be considered for infants with a persistent PDA with significant clinical symptoms in addition to echocardiographic signs of a large PDA shunt volume and pulmonary over-circulation.

 

Keywords: Cyclo-oxygenase inhibitors (COX-I); Hemodynamically significant (hs)-PDA; Patent ductus arteriosus (PDA); Preterm infants; Procedural PDA closure

Background

Management of the patent ductus arteriosus (PDA) in preterm infants is one of the most contentious topics in neonatal intensive care. PDAs have been associated without proof of causation with numerous adverse outcomes, including prolongation of assisted ventilation, pulmonary hemorrhage, chronic lung disease (CLD), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and death [1][2].

The clinical decision to provide prophylactic PDA treatment using cyclooxygenase-inhibitor (COX-I) drugs has primarily been driven by the perceived benefits versus potential risks as determined by the treating physician. Randomized controlled trials (RCTs) have not shown a clear benefit of symptomatic PDA treatment, partially due to major methodological challenges such as high rates of open-label backup treatment in the experimental and control arms, and a lack of high quality data on clinically important outcomes, such as NEC, CLD, IVH, and mortality. Controversy remains whether a  PDA should be treated, and if so, in whom, when, and which pharmacotherapeutic agent to use as well as when to consider procedural closure of the PDA.

Data from the Canadian Neonatal Network suggest an increase in conservative, non-pharmacological management of PDAs in preterm infants in recent years [3]. However, there is no consensus on what conservative management entails and which infants are appropriate candidates. Furthermore, with an increase in conservative PDA management, more infants who are repatriated back to non-tertiary neonatal care units tend to have a persistent PDA. Persistent PDA often poses a management dilemma among physicians caring for these infants, who are otherwise well but may have ongoing respiratory symptoms due to CLD.

This position statement systematically addresses the most important questions that may be a source of variation in clinical practice related to PDA management.

Statement development methods

A comprehensive search was conducted including the Cochrane Central Register of Controlled Trials (CENTRAL 2020, issue 12) in the Cochrane Library; MEDLINE (1996 to December 14, 2020); Embase (1980 to December 14, 2020); and CINAHL (1982 to December 14, 2020), using the following search terms: preterm/premature, patent ductus arteriosus, PDA, indomethacin, ibuprofen, paracetamol, acetaminophen, surgery, transcatheter, ligation, and applicable MeSH terms. RCTs, cohort studies, and systematic reviews were specifically sought. Searches were not restricted by language.

The GRADE (Grading of Recommendations, Assessment, Development and Evaluations) Evidence to Decision (EtD) framework was used to formulate the recommendations [4]. The detailed EtDs for each question are available in the online appendix.

Leading questions affecting PDA management

1. Should prophylactic COX-I drugs (indomethacin, ibuprofen, or acetaminophen) be used for PDA closure?

Nineteen RCTs (2872 infants) have evaluated use of prophylactic indomethacin. The largest single 2001 trial restricted participation to extremely low birth weight (ELBW; <1000 g) infants [5]. Prophylactic indomethacin significantly reduced rates of severe IVH, PDA ligation, and symptomatic PDA. However, this strategy did not appeare to improve rates of  CLD, severe neurodevelopmental impairment, and cerebral palsy among survivors [6] (Table 1). Furthermore, there are concerns regarding the association of prophylactic indomethacin and gastrointestinal (GI) perforation in extremely preterm infants, especially when prophylactic hydrocortisone is used concomitantly [7][8]. Therefore, prophylactic use of indomethacin may only be considered in infants with risk factors predictive of severe IVH, such as extremely low gestational age (GA), lack of antenatal corticosteroids, and being born outside a tertiary care centre [9][10].

Prophylactic ibuprofen (seven RCTs; 931 infants) may marginally reduce severe IVH and PDA ligation [11]. However, use of ibuprofen prophylaxis in preterm infants is not recommended due to its minimal benefits, possible harm related to increased GI hemorrhage, and reports of associated acute severe pulmonary hypertension [11][12]. Prophylactic acetaminophen has not been shown to appreciably improve any patient-important clinical outcomes (two RCTs; 80 infants) [13].

Summary: Selective prophylaxis with intravenous (IV) indomethacin may be considered in ELBW infants at high risk for severe IVH (conditional recommendation). There is insufficient evidence to recommend prophylactic ibuprofen or acetaminophen in extremely preterm or ELBW infants.

RCT evidence on prophylactic COX-I use is summarized in Table 1.

Table 1. Summary of RCT evidence on PDA pharmacoprophylaxis in preterm infants
Author, year Type of study Interventions

Main results (with GRADE certainty of evidence, when available)
Fowlie 2010 [6] Systematic review (19 RCTs;2872 infants) Indomethacin
  • Severe IVH: RR 0.66 (95% CI 0.53 to 0.82) (High)
  • PDA ligation: RR 0.51 (95% CI 0.37 to 0.71) (Moderate)
  • Symptomatic PDA: RR 0.44 (95% CI 0.38 to 0.50) (High)
  • NEC: RR 1.09 (95% CI 0.82 to 1.46) (High)
  • CLD: RR 1.06 (95% CI 0.92 to1.22) (Moderate)
  • Severe neurodevelopmental impairment: RR 0.96 (95% CI 0.79 to 1.17) (Moderate)
Ohlsson 2019 [11] Systematic review (7 RCTs;931 infants) Ibuprofen 
  • Severe IVH: RR 0.67 (95% CI 0.45 to 1.00) (Low)
  • PDA ligation: RR 0.46 (95% CI 0.22 to 0.96) (Moderate)
  • Symptomatic PDA: RR 0.17 (95% CI 0.11 to 0.26) (Moderate)
  • NEC: RR 0.96 (95% CI 0.61 to 1.50) (Moderate)
  • CLD: RR 1.06 (95% CI 0.89 to 1.26) (Moderate)
Ohlsson 2020 [13] Systematic review (2 RCTs;80 infants) Acetaminophen
  • Severe IVH: RR 1.09 (95% CI 0.07 to 16.39) (Low)
  • Persistent PDA: RR 0.49 (95% CI 0.24 to 1.00) (Moderate)
  • CLD: RR 0.36 (95% CI 0.02 to 8.45) (Low)

CLD chronic lung disease, IVH intraventricular hemorrhage, NEC necrotizing enterocolitis, PDA patent ductus arteriosus, RCT randomized controlled trial

2. How should a hemodynamically significant (hs)-PDA be defined?

There is limited consensus on the definition of an hs-PDA [2][14][15]. Clinical signs of a symptomatic PDA, which include precordial murmur in addition to one or more of hyperdynamic precordial impulse, tachycardia, bounding pulses, widened pulse pressure, or worsening respiratory status, are generally unreliable in determining the PDA shunt volume and thereby the need for treatment [16][17]. Treatment of a symptomatic PDA, therefore, should never be initiated based on clinical examination alone [16][18]. Several echocardiographic parameters are used to quantify the PDA shunt volume. A PDA size of >1.5 mm and a left atrium to aortic root ratio >1.4 are the two echocardiographic measures most commonly used in RCTs to define hemodynamic significance [2]. Of these common echocardiographic parameters, a PDA diameter of <1.5 mm can fairly reliably rule out a large volume PDA shunt in most infants [17]. Studies have attempted to define the degree of shunt volume based on clinical and echocardiography-based classification or scoring systems [19][20]. However, the utility of such PDA-severity scores have not been validated through large RCTs.

Summary: Echocardiography should be used to confirm the presence of a left-to-right PDA shunt before considering treatment (strong recommendation). There is insufficient evidence to suggest a set of echocardiographic criteria to define hemodynamic significance of the PDA. A PDA with a diameter of <1.5 mm is unlikely to result in a hemodynamically significant shunt, and therefore may be conservatively managed without pharmacotherapy (conditional recommendation). 

3. Should early pharmacotherapy or conservative management be used as the initial management approach for a symptomatic PDA?

Seven RCTs (n=526) have compared early treatment (initiated within 7 days) and seven RCTs (n=384) have compared very early treatment (initiated within 3 days) to early conservative (i.e., non-pharamocological) management of a PDA [21][22]. (Conservative management is reviewed below, following the Summary). Early (or very early) PDA treatment appears to increase overall COX-I exposure in preterm infants without reducing death, severe IVH, CLD, surgical PDA ligation, or neurodevelopmental impairment [21][22]. Two further RCTs that compared treatment initiation between 6 to 14 days of age with conservative management also failed to demonstrate any significant differences in clinical outcomes [23][24]. However, only six trials to date have exclusively enrolled extremely preterm infants [22][23][25]-[28].

Interestingly, a follow-up analysis of eligible infants who were not enrolled in one of the recent (PDA-TOLERATE) trials due to lack of physician equipoise showed that the group treated before 6 days postnatal age had a significantly lower incidence of CLD and/or death, despite having a significantly lower GA and substantially higher initial respiratory morbidity [29]. Furthermore, other observational studies have shown that a persistent, symptomatic PDA in extremely preterm infants is associated with increased risk for mortality, while routine early screening echocardiography before day 3 of age is associated with lower in-hospital mortality and a lower likelihood of pulmonary hemorrhage [30]-[32].

Summary: Clinicians may choose to conservatively manage a symptomatic PDA within the first 1 to 2 weeks after birth (conditional recommendation). However, they should exercise caution with conservative management in clinically unstable extremely preterm infants (<26 weeks GA), for whom earlier pharmacotherapy may be considered.

Conservative management of the PDA: There is little consensus on what conservative PDA management entails. Prophylactic restriction of IV fluids may reduce incidence of symptomatic PDA in older infants, but the benefits of this practice remain unclear for very low birth weight (VLBW) infants [33][34]. There is no evidence to support restricting fluids to treat a symptomatic PDA. Moreover, there are concerns that aggressive fluid restriction (restricting fluids to <120 mL/kg/day) may significantly worsen regional blood flow, and this practice therefore cannot be recommended [35]. Loop diuretics such as furosemide are often used to reduce pulmonary edema and improve lung function [36]. Earlier concerns that renal upregulation of prostaglandin E2 (PGE2) induced by furosemide would inhibit ductal closure have not been substantiated by recent studies [37][38]. One recent large observational study (n=43,576) demonstrated that exposure to furosemide decreased the odds of PDA treatment (adjusted odds ratio (OR)=0.72, 95% CI, 0.65 to 0.79), lending further credence to furosemide use as part of conservative management strategy [39]. Other physiological manoeuvres, such as increasing the positive end-expiratory pressure (PEEP), have also been shown to reduce left-to-right shunting without significantly affecting cerebral perfusion or oxygenation [40].

Summary: Use of diuretics and PEEP modulation may be considered for conservative PDA management in preterm infants (conditional recommendation). Given the unclear benefits and potential harms of restricting fluids in VLBW infants, aggressive fluid restriction as a management strategy for symptomatic PDA is not suggested (conditional recommendation).

4. Which COX-I drug should be the pharmacotherapy of choice to treat a symptomatic PDA?

At least eighty RCTs have been conducted comparing different COX-I medications, doses, and routes to treat symptomatic PDA. Standard-dose ibuprofen (10 mg/kg followed by two doses of 5 mg/kg at 24 h-intervals) is the most common regimen and has a significantly better safety profile than indomethacin (the previous gold standard) [41]. Acetaminophen has also emerged as a potential treatment option for PDA closure, with its enteral formulation being as effective as standard-dose ibuprofen or indomethacin, and a significantly better GI/renal safety profile [13]. However, recent RCTs have suggested that PDA closure with IV acetaminophen is significantly lower than with either indomethacin or ibuprofen [42]-[44].

One recent network meta-analysis of sixty-eight RCTs (4802 infants) showed that higher doses of ibuprofen (15 mg/kg to 20 mg/kg followed by two doses of 7.5 mg/kg to 10 mg/kg at 24 h-intervals), especially when given enterally, may achieve better PDA closure without increasing risk for adverse outcomes (such as NEC) compared with standard-dose ibuprofen, indomethacin, or acetaminophen (low certainty) [15]. These data are consistent with recent studies suggesting that higher doses of ibuprofen may be required beyond the first 3 to 5 days post-birth to achieve therapeutic serum levels [24][45][46]. However, the effect estimates for high-dose ibuprofen were derived from four small RCTs (n=319), three of which enrolled infants with a mean GA ≥30 weeks. Therefore, the effectiveness and safety of high-dose ibuprofen use in extremely preterm infants remains unknown, which has resulted in widely variable clinical practice among Canadian NICUs. RCT evidence on pharmacotherapy for symptomatic PDA is summarized in Table 2.

Summary: Ibuprofen should be considered the pharmacotherapy of choice for a symptomatic PDA (strong recommendation). High-dose ibuprofen may be considered as the preferred dosage, especially for preterm infants beyond the first 3 to 5 days of age (conditional recommendation). Exercise caution when treating extremely preterm infants (<26 weeks GA) with high-dose ibuprofen due to limited safety and efficacy data.

Table 2. Summary of RCT evidence on pharmacotherapy for symptomatic PDA in preterm infants
Author, year Type of study Interventions

Main results (with GRADE certainty of evidence, when available)
Mitra 2018 [15] Systematic review and network meta-analysis (68 RCTs;4802 infants) Compared indomethacin, ibuprofen, or acetaminophen with another medication, placebo, or no treatment
  • Likelihood of PDA closure: High-dose oral ibuprofen followed by high-dose IV ibuprofen, acetaminophen, standard-dose oral ibuprofen, IV indomethacin, standard-dose IV ibuprofen (in order from best to worst)
  • No statistically significant difference in NEC, IVH, or mortality noted with any intervention
Ohlsson 2020 [41] Systematic review (39 RCTs;2843 infants) Compared ibuprofen in different doses and by different routes of administration, and against indomethacin or placebo

Ibuprofen versus indomethacin

  • Failure to close PDA: RR 1.07 (95% CI 0.92 to 1.24) (Moderate)
  • NEC: RR 0.68 (95% CI 0.49 to 0.94) (Moderate)

High-dose versus standard-dose ibuprofen

  • Failure to close PDA: RR 0.37 (95% CI 0.22 to 0.61) (Moderate)
  • NEC: RR 1.0 (95% CI 0.4 to 2.5) (Low)

Oral versus IV standard-dose ibuprofen

  • Failure to close PDA: RR 0.38 (95% CI 0.26 to 0.56) (Moderate)
Ohlsson 2020 [13] Systematic review (8 RCTs;916 infants) Acetaminophen compared against ibuprofen or indomethacin

Acetaminophen versus ibuprofen

  • Failure to close PDA: RR 0.95 (95% CI 0.75 to 1.21) (Moderate)
  • Gastrointestinal bleeding: RR 0.28 (95% CI 0.12 to 0.69) (Moderate)

Acetaminophen versus indomethacin

  • Failure to close PDA: RR 0.96 (95% CI 0.55 to 1.65) (Moderate)

CLD chronic lung disease, IVH intraventricular hemorrhage, NEC necrotizing enterocolitis, PDA patent ductus arteriosus, RCT randomized controlled trial

5. Should invasive management (surgical or percutaneous catheter closure) or repeat pharmacotherapy be used for a persistent, symptomatic PDA?

There is insufficient evidence regarding the efficacy and safety of repeat courses of pharmacotherapy for a persistent PDA. Observational studies have demonstrated that a second course of ibuprofen may significantly improve overall PDA closure rates as compared with the initial course, without increasing adverse effects, while benefits of a third course have not been consistently demonstrated [47]-[50]. Similarly, repeat courses of indomethacin have also shown improving, cumulative PDA closure rates. However, increased rates of periventricular leukomalacia have been reported in infants receiving more than two courses of indomethacin [51].  

Given the better safety profile of acetaminophen, some centres may choose to use a third course of pharmacotherapy using acetaminophen while contemplating procedural PDA closure. A recent retrospective observational study showed that extremely preterm infants with a persistent symptomatic PDA who were treated with a 3 to 7-day course of oral acetaminophen following two failed courses with indomethacin or ibuprofen had significantly reduced surgical ligation but increased rates of CLD [52].

Summary: A second course of COX-I therapy should be considered over invasive management for a persistent, symptomatic PDA when there are no contraindications (strong recommendation). The benefit of a third course of pharmacotherapy with enteral acetaminophen is unclear but may be considered after discussion with the infant’s parents or guardians, especially while awaiting invasive PDA closure (conditional recommendation).

Procedural closure of the PDA: There is considerable debate regarding the usefulness and timing of invasive PDA closure in preterm infants. It has been shown that persistence of a symptomatic PDA is associated with increased risk for death or CLD [53][54]. However, outcomes following surgical PDA ligation are controversial because most evidence for and against the procedure is obtained from studies that failed to address confounding by indication. One recent Canadian observational study (n=166) showed that a pre-ligation PDA diameter >2.5 mm and left ventricular dilatation (z score ≥2) predicted earlier extubation following surgical ligation in ventilator-dependent preterm infants. This finding suggests possible short-term respiratory benefit of procedural PDA closure in the subgroup of preterm infants with echocardiographic markers of large shunt volume and pulmonary overcirculation [55].

Summary: Procedural closure may be considered for infants with  persistent PDA, even after two courses of pharmacotherapy or with contraindications to pharmacotherapy, when clinical symptoms are significant and echocardiography shows signs of large shunt volume and pulmonary overcirculation (conditional recommendation).

6. Should surgical closure or percutaneous catheter closure be the intervention of choice for invasive management of a persistently symptomatic PDA?

PDA ligation has been associated with complications such as post-PDA ligation syndrome, vocal cord paresis, phrenic nerve palsy, thoracic scoliosis, and inadvertent ligation of the left pulmonary artery (LPA) and aorta, with substantial variation in reported rates among centres [56][57]. One systematic review estimated the incidence of left vocal cord paralysis after PDA ligation in extremely preterm infants at 9% (95% CI, 5 to 15) with a wide variability among studies [58].

Percutaneous transcatheter PDA closure is an emerging option for preterm infants. A recent systematic review reported a technical success rate of 96% (95% CI, 93 to 98) in preterm infants ≤1.5 kg. However, this finding is balanced by an overall adverse event rate of 27% (95% CI, 17 to 38), a clinically significant adverse event rate (e.g., cardiac or vascular perforation, device embolization, and LPA stenosis requiring intervention) of 8% (95% CI, 5 to 10), and a procedure-related mortality rate of 2% (95% CI, 1 to 4) [59]. No RCTs have yet compared the efficacy and safety of these two approaches. Data on the cost-effectiveness of catheter-based PDA closure in preterm infants are also limited.

Summary: If institutional expertise is available and patient characteristics are suitable, percutaneous transcatheter PDA closure may be considered as an alternative to surgical PDA ligation (conditional recommendation). Further data on safety and cost-effectiveness are required before a strong recommendation can be made for this procedure to replace surgical PDA ligation as the invasive procedure of choice.

7. When should referral to a tertiary care centre be considered for a preterm infant with persistent PDA?

A persistent low-volume PDA shunt in stable and growing preterm infants who are not experiencing cardiorespiratory compromise is unlikely to affect clinical outcomes [60]. Most milder PDA shunts close spontaneously before term-corrected gestation [61][62]. However, there have been reports of preterm infants developing chronic pulmonary hypertension from prolonged exposure to large PDA shunts [63][64].

Summary:  Routine referral to a tertiary care centre for echocardiographic evaluation of a persistent PDA in an otherwise clinically stable, growing, preterm infant before term-corrected GA is not recommended (strong recommendation). Paediatric cardiology referral should be sought for ongoing evaluation and follow-up when the PDA is deemed to be present at discharge (strong recommendation).

Key recommendations

  1. Selective prophylaxis with intravenous (IV) indomethacin may be considered for extremely low birth weight (ELBW) infants at high risk for severe intraventriculare hemorrhage (IVH) (conditional recommendation).
  2. Echocardiography should be used to confirm the presence of a left-to-right patent ductus arteriosis (PDA) shunt before considering treatment (strong recommendation).
  3. Clinicians may choose to conservatively manage a PDA in the first 1 to 2 weeks post-birth, especially with clinically stable preterm infants (conditional recommendation).
  4. Ibuprofen should be considered the pharmacotherapy of choice for symptomatic PDA (strong recommendation). High-dose ibuprofen may be considered as the preferred dosage, especially for preterm infants beyond the first 3 to 5 days of age (conditional recommendation). Caution should be exercised when treating extremely preterm infants (<26 weeks gestational age (GA)) with high-dose ibuprofen, due to limited safety and efficacy data.
  5. A second course of pharmacotherapy should be considered over invasive management for a persistent, symptomatic PDA if not contraindicated (strong recommendation). 
  6. Procedural closure may be considered for infants with persistent PDA even after two courses of pharmacotherapy, or for those with contraindications to pharmacotherapy, especially when their clinical symptoms are significant and echocardiography shows signs of large shunt volume and pulmonary overcirculation (conditional recommendation).
  7. Percutaneous transcatheter PDA closure may be considered as an alternative to surgical PDA ligation when institutional expertise is available and patient characteristics are appropriate (conditional recommendation).
  8. Routine referral to a tertiary care centre for echocardiographic evaluation of a persistent PDA in an otherwise clinically stable, growing, preterm infant before term-corrected GA is not recommended (strong recommendation).  
  9. Paediatric cardiology referral should be sought for ongoing evaluation and follow-up when the PDA is present at discharge (strong recommendation).

Note that conditional recommendations are opportunities for shared decision-making with an infant’s parents or guardians, with choices based on thorough discussion of the benefits and risks, prospective health outcomes, and the family’s values and preferences. Conditional recommendations also imply that the strength and the direction of recommendations may change as new evidence emerges.

Acknowledgements

This statement was reviewed by the Canadian Paediatric Society’s Community Paediatrics Committee as well as by members of the Canadian Targeted Neonatal Echocardiography Consortium (CANTEC).

CANADIAN PAEDIATRIC SOCIETY FETUS AND NEWBORN COMMITTEE (2020-2021)

Members: Gabriel Altit MD, Nicole Anderson MD (Resident Member), Heidi Budden MD (Board Representative), Leonora Hendson MD (past member), Souvik Mitra MD, Michael R. Narvey MD (Chair), Eugene Ng MD, Nicole Radziminski MD, Vibhuti Shah MD (past member)

Liaisons: Radha Chari MD (The Society of Obstetricians and Gynaecologists of Canada), James Cummings MD (Committee on Fetus and Newborn, American Academy of Pediatrics), William Ehman MD (College of Family Physicians of Canada), Danica Hamilton RN (Canadian Association of Neonatal Nurses), Chloë Joynt MD (CPS Neonatal-Perinatal Medicine Section Executive), Chantal Nelson PhD (Public Health Agency of Canada)

CANADIAN PAEDIATRIC SOCIETY DRUG THERAPY AND HAZARDOUS SUBSTANCES COMMITTEE (2020-2021)

Members: Jean-François Turcotte MD (Board Representative), Yaron Finkelstein MD, Shinya Ito, Geert ‘t Jong MD (Chair), Tom McLaughlin MD, Shahrad Rassekh MD, Smita Roychoudhury MD (Resident Member)

Liaison: Michael J. Rieder MD PhD (Canadian Society of Pharmacology and Therapeutics)

Principal authors: Souvik Mitra MD, MSc, Dany Weisz MD, Amish Jain MBBS, MRCPCH, PhD, Geert ‘t Jong MD

References

  1. Benitz WE: American Academy of Pediatrics, Committee on Fetus and Newborn. Patent ductus arteriosus in preterm infants. Pediatrics 2016;137(1). doi: 10.1542/peds.2015-3730. Epub 2015 Dec 15.
  2. Mitra S, McNamara PJ. Patent ductus arteriosus—Time for a definitive trial. Clin Perinatol 2020;47(3):617-39.
  3. Lokku A, Mirea L, Lee SK, Shah PS; Canadian Neonatal Network. Trends and outcomes of patent ductus arteriosus treatment in very preterm infants in Canada. Am J Perinatol2017;34(5):441–50.
  4. Alonso-Coello P, Schünemann HJ, Moberg J, et al. GRADE Evidence to Decision (EtD) frameworks: A systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ 2016;353:i2016.
  5. Schmidt B, Davis P, Moddemann D, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med 2001;344(26):1966–72.
  6. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 2010;2010(7):CD000174.
  7. Stavel M, Wong J, Cieslak Z, Sherlock R, Claveau M, Shah PS. Effect of prophylactic indomethacin administration and early feeding on spontaneous intestinal perforation in extremely low-birth-weight infants. J Perinatol 2017;37(2):188–93.
  8. Shaffer ML, Baud O, Lacaze-Masmonteil T, Peltoniemi OM, Bonsante F, Watterberg KL. Effect of prophylaxis for early adrenal insufficiency using low-dose hydrocortisone in very preterm infants: An individual patient data meta-analysis. J Pediatr 2019;207:136-142.e5.
  9. Singh R, Gorstein SV, Bednarek F, Chou JH, McGowan EC, Visintainer PF. A predictive model for SIVH risk in preterm infants and targeted indomethacin therapy for prevention. Sci Rep 2013;3:2539.
  10. Ryan M, Lacaze-Masmonteil T, Mohammad K. Neuroprotection from acute brain injury in preterm infants. Paediatr Child Health 2019;24(4):276–90.
  11. Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2019;6(6):CD004213.
  12. Gournay V, Roze JC, Kuster A, et al. Prophylactic ibuprofen versus placebo in very premature infants: A randomised, double-blind, placebo-controlled trial. Lancet 2004;364(9449):1939–44.
  13. Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database Syst Rev 2020;1(1):CD010061.
  14. Zonnenberg I, de Waal K. The definition of a haemodynamic significant duct in randomized controlled trials: A systematic literature review. Acta Paediatr 2012;101(3):247–51.
  15. Mitra S, Florez ID, Tamayo ME, et al. Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of hemodynamically significant patent ductus arteriosus in preterm infants: A systematic review. JAMA 2018;319(12):1221–38.
  16. Shepherd JL, Noori S. What is a hemodynamically significant PDA in preterm infants? Congenit Heart Dis 2019;14(1):21–26.
  17. Jain A, Shah PS. Diagnosis, evaluation, and management of patent ductus arteriosus in preterm neonates. JAMA Pediatr 2015;169(9):863–72.
  18. Smith A, El-Khuffash AF. Defining “haemodynamic significance” of the patent ductus arteriosus: Do we have all the answers? Neonatology 2020;117(2):225–32.
  19. McNamara PJ, Sehgal A. Towards rational management of the patent ductus arteriosus: The need for disease staging. Arch Dis Child Fetal Neonatal Ed 2007;92(6):F424–7.
  20. El-Khuffash A, James AT, Corcoran JD, et al. A patent ductus arteriosus severity score predicts chronic lung disease or death before discharge. J Pediatr 2015;167(6):1354-61.e2.
  21. Mitra S, Scrivens A, von Kursell AM, Disher T. Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants. Cochrane Database Syst Rev 2020;12:CD013278.
  22. Rozé J-C, Cambonie G, Le Thuaut A, et al. Effect of early targeted treatment of ductus arteriosus with ibuprofen on survival without cerebral palsy at 2 years in infants with extreme prematurity: A randomized clinical trial. J Pediatr 2021;233:33-42.e2.
  23. Clyman RI, Liebowitz M, Kaempf J, et al. PDA-TOLERATE trial: An exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at 1 week of age. J Pediatr 2019;205:41–48.e6.
  24. Sung SI, Lee MH, Ahn SY, Chang YS, Park WS. Effect of nonintervention vs oral ibuprofen in patent ductus arteriosus in preterm infants: A randomized clinical trial. JAMA Pediatr 2020;174(8):755–63.
  25. Kluckow M, Jeffery M, Gill A, Evans N. A randomised placebo-controlled trial of early treatment of the patent ductus arteriosus. Arch Dis Child Fetal Neonatal Ed 2014;99(2):F99–F104.
  26. El-Khuffash A, Bussmann N, Breatnach CR, et al. A pilot randomized controlled trial of early targeted patent ductus arteriosus treatment using a risk based severity score (The PDA RCT). J Pediatr 2021;229:127-33.
  27. de Waal K, Phad N, Stubbs M, Chen Y, Kluckow M. A randomized placebo-controlled pilot trial of early targeted nonsteroidal anti-inflammatory drugs in preterm infants with a patent ductus arteriosus. J Pediatr 2021;228:82-86.e2
  28. Knight D, Alkindi S, Buksh M, Kuschel C, Skinner J. Placebo-controlled pilot trial of indomethacin in preterm infants with a patent ductus arteriosus. J Paediatr Child Health 2011;47(suppl 1):88.
  29. Liebowitz M, Katheria A, Sauberan J, et al. Lack of equipoise in the PDA-TOLERATE Trial: A comparison of eligible infants enrolled in the trial and those treated outside the trial. J Pediatr 2019;213:222-26.e2.
  30. Brooks JM, Travadi JN, Patole SK, Doherty DA, Simmer K. Is surgical ligation of patent ductus arteriosus necessary? The Western Australian experience of conservative management. Arch Dis Child Fetal Neonatal Ed 2005;90(3):F235-39.
  31. Sellmer A, Bjerre JV, Schmidt MR, et al. Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed 2013;98(6):F505-10.
  32. Rozé J-C, Cambonie G, Marchand-Martin L, et al. Association between early screening for patent ductus arteriosus and in-hospital mortality among extremely preterm infants. JAMA 2015;313(24):2441–8.
  33. Kavvadia V, Greenough A, Dimitriou G, Hooper R. Randomised trial of fluid restriction in ventilated very low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2000;83(2):F91-96.
  34. Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2014;2014(12):CD000503.
  35. De Buyst J, Rakza T, Pennaforte T, Johansson A-B, Storme L. Hemodynamic effects of fluid restriction in preterm infants with significant patent ductus arteriosus. J Pediatr 2012;161(3):404–8.
  36. Laughon MM, Chantala K, Aliaga S, et al. Diuretic exposure in premature infants from 1997 to 2011. Am J Perinatol 2015;32(1):49–56.
  37. Green TP, Thompson TR, Johnson DE, Lock JE. Furosemide promotes patent ductus arteriosus in premature infants with the respiratory-distress syndrome. N Engl J Med 1983;308(13):743–8.
  38. Lee BS, Byun SY, Chung ML, et al. Effect of furosemide on ductal closure and renal function in indomethacin-treated preterm infants during the early neonatal period. Neonatology 2010;98(2):191–9.
  39. Thompson EJ, Greenberg RG, Kumar K, et al. Association between furosemide exposure and patent ductus arteriosus in hospitalized very low birth weight infants. J Pediatr 2018;199:231–36.
  40. Fajardo MF, Claure N, Swaminathan S, et al. Effect of positive end-expiratory pressure on ductal shunting and systemic blood flow in preterm infants with patent ductus arteriosus. Neonatology 2014;105(1):9–13.
  41. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev 2020;2(2):CD003481.
  42. Davidson JM, Ferguson J, Ivey E, Philip R, Weems MF, Talati AJ. A randomized trial of intravenous acetaminophen versus indomethacin for treatment of hemodynamically significant PDAs in VLBW infants. J Perinatol 2021;41(1):93-99.
  43. Dani C, Lista G, Bianchi S, et al. Intravenous paracetamol in comparison with ibuprofen for the treatment of patent ductus arteriosus in preterm infants: A randomized controlled trial. Eur J Pediatr 2021;180(3):807-16.
  44. Liebowitz M, Kaempf J, Erdeve O, et al. Comparative effectiveness of drugs used to constrict the patent ductus arteriosus: A secondary analysis of the PDA-TOLERATE trial (NCT01958320). J Perinatol 2019;39(5):599–607.
  45. Hirt D, Van Overmeire B, Treluyer J-M, et al. An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study. Br J Clinl Pharmacol 2008;65(5):629–36.
  46. Desfrere L, Zohar S, Morville P, et al. Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. J Clin Pharm Ther 2005;30(2):121–32.
  47. van der Lugt NM, Lopriore E, Bökenkamp R, Smits-Wintjens VE, Steggerda SJ, Walther FJ. Repeated courses of ibuprofen are effective in closure of a patent ductus arteriosus. Eur J Pediatr 2012;171(11):1673–77.
  48. Richards J, Johnson A, Fox G, Campbell M. A second course of ibuprofen is effective in the closure of a clinically significant PDA in ELBW infants. Pediatrics 2009;124(2):e287-93.
  49. Olgun H, Ceviz N, Kartal İ, et al. Repeated courses of oral ibuprofen in premature infants with patent ductus arteriosus: Efficacy and safety. Pediatr Neonatol.2017;58(1):29–35.
  50. Yen T-A, Wang C-C. Efficacy of repeated courses of ibuprofen in the closure of patent ductus arteriosus in premature infants. Pediatr Neonatol 2017;58(1):1–2.
  51. Sangem M, Asthana S, Amin S. Multiple courses of indomethacin and neonatal outcomes in premature infants. Pediatr Cardiol 2008;29(5):878–84.
  52. Mashally S, Nield LE, McNamara PJ, et al. Late oral acetaminophen versus immediate surgical ligation in preterm infants with persistent large patent ductus arteriosus. J Thorac Cardiovasc Surg 2018;156(5):1937–44.
  53. Schena F, Francescato G, Cappelleri A, et al. Association between hemodynamically significant patent ductus arteriosus and bronchopulmonary dysplasia. J Pediatr 2015;166(6):1488–92.
  54. Kaempf JW, Huston R, Wu Y, et al. Permissive Tolerance of the Patent Ductus Arteriosus may Increase the Risk of Chronic Lung Disease [Internet]. Vol. 3, Research and Reports in Neonatology. Dovepress 2013:5-10: (Accessed May 31, 2021).
  55. Krishnappa S, Shah PS, Jain A, Resende MH, McNamara PJ, Weisz DE. Predictors of early extubation after patent ductus arteriosus ligation among infants born extremely preterm dependent on mechanical ventilation. J Pediatr 2019;214:222-226.e3.
  56. Ghani SA, Hashim R. Surgical management of patent ductus arteriosus. A review of 413 cases. J R Coll Surg Edinb 1989;34(1):33–36.
  57. Mavroudis C, Backer CL, Gevitz M. Forty-six years of patient ductus arteriosus division at Children’s Memorial Hospital of Chicago. Standards for comparison. Ann Surg 1994;220(3):402–10.
  58. Engeseth MS, Olsen NR, Maeland S, Halvorsen T, Goode A, Røksund OD. Left vocal cord paralysis after patent ductus arteriosus ligation: A systematic review. Paediatr Respir Rev 2018;27:74–85.
  59. Bischoff AR, Jasani B, Sathanandam SK, Backes C, Weisz DE, McNamara PJ. Percutaneous closure of patent ductus arteriosus in infants ≤1.5 kg: A meta-analysis. J Pediatr 2021;230:84-92.e14.
  60. Sung SI, Chang YS, Chun JY, et al. Mandatory closure versus nonintervention for patent ductus arteriosus in very preterm infants. J Pediatr 2016;177:66-71.e1.
  61. Clyman RI, Couto J, Murphy GM. Patent ductus arteriosus: Are current neonatal treatment options better or worse than no treatment at all? Semin Perinatol. 2012;36(2):123–29.
  62. Semberova J, Sirc J, Miletin J, , et al. Spontaneous closure of patent ductus arteriosus in infants ≤1500 g. Pediatrics 2017;140(2):e20164258.
  63. Philip R, Nathaniel Johnson J, Naik R, et al. Effect of patent ductus arteriosus on pulmonary vascular disease. Congenit Heart Dis 2019;14(1):37–41.
  64. Philip R, Waller BR, Chilakala S, et al. Hemodynamic and clinical consequences of early versus delayed closure of patent ductus arteriosus in extremely low birth weight infants. J Perinatol 2021;41(1):100-08

Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.

Last updated: Feb 8, 2024

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