Efficacy and safety of high versus standard dose ibuprofen for patent ductus arteriosus treatment in preterm infants: A systematic review and meta-analysis

Abstract

BACKGROUND:

Several small randomized controlled trials (RCTs) and observational studies have compared high (15-20/7.5-10/7.5-10 mg/kg/dose) versus standard dose (10/5/5 mg/kg/dose) ibuprofen for patent ductus arteriosus (PDA) closure, with limited evidence on efficacy and safety.

OBJECTIVE:

To systematically review and meta-analyze studies of high versus standard dose ibuprofen for the closure of PDA in preterm infants.

METHODS:

Databases were searched for RCTs and observational studies assessing high compared to standard dose of ibuprofen for PDA closure for preterm infants until August 2021. The primary outcome was failure of PDA closure after the first course of ibuprofen. The secondary outcomes were the failure of PDA closure after a second course of ibuprofen, rates of PDA ligation, all-cause mortality prior to hospital discharge, bronchopulmonary dysplasia, necrotizing enterocolitis, bleeding disorders, oliguria, and serum creatinine after treatment.

RESULTS:

There were 6 studies with 369 patients (3 RCT, N = 190; 3 observational studies, N = 179). Compared to standard dose, high dose ibuprofen did not significantly decrease the failure rate of PDA closure in preterm infants after the first course (Relative risk (RR) 0.74, 95% confidence interval (CI) 0.53 –1.03, 6 studies, N = 369). High dose ibuprofen significantly decreased the rates of PDA ligation compared to standard dose (RR 0.33, 95% CI 0.16 –0.70, 5 studies, N = 309).

INTERPRETATION:

Based on low-grade evidence, high dose ibuprofen may more effectively reduce rates of PDA ligation compared to standard dose with no increase in adverse effects, neonatal morbidities and mortality.

Keywords

Ibuprofen meta-analysis patent ductus arteriosus preterm infants

1 Introduction

In infants born at less than 28 weeks’ gestation, the patent ductus arteriosus (PDA) is associated with higher rates of death, prolonged duration of mechanical ventilation, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), acute kidney injury (AKI), intracranial hemorrhage and cerebral palsy [1 –5]; as a result, many receive treatment (60–70%) to enhance PDA closure and to mitigate the development of these morbidities [6]. Ibuprofen, a non-selective cyclo-oxygenase inhibitor, has become the mainstay of pharmacologic treatment of PDA in preterm infants due to its equivalent efficacy and superior safety profile compared to indomethacin [7, 8]. While pharmacologic intervention is successful in the majority of cases (60–70%) [9, 10], many PDAs (24–27%) fail medical therapy [9, 10]. In these cases, the standard dosage of ibuprofen (10/5/5 mg/kg/dose) is likely insufficient for PDA closure which may be due to the unique pharmacokinetics and pharmacodynamics characteristics of preterm infants [11, 12]. Desfrere et al. demonstrated that higher doses of ibuprofen (20/10/10 mg/kg/dose) have a greater probability of ductal closure for preterm infants < 27 weeks gestation [13]. However, a higher dose of ibuprofen can increase the risk of adverse events [13 –15]. Therefore, the aim of this review was to systematically review and meta-analyze high versus standard dose ibuprofen for the closure of PDA in preterm infants.

2 Methods

Guidelines from the Cochrane Neonatal Review Group [16], Centre for Reviews and Dissemination (https://www.york.ac.uk/crd/guidance/), and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement [17] were followed for undertaking and reporting this systematic review and meta-analysis. Ethics approval was not required.

2.1 Eligibility criteria

2.1.1 Types of studies

Randomized controlled trials (RCTs), quasi-RCTs and observational studies were included in this review. Narrative reviews, systematic reviews, case reports, letters, editorials, and commentaries were excluded from analysis.

2.1.2 Types of participants

Infants born preterm at less than 37 weeks’ gestation with a PDA who were treated using ibuprofen were included.

2.1.3 Intervention and comparison

The intervention group was high dose ibuprofen administered intravenously (IV) or orally (PO) at 15–20 mg/kg/dose (loading dose) followed by 7.5–10 mg/kg/dose for a total of 3 doses. The control group was standard dose ibuprofen given IV or PO at 10 mg/kg/dose for the first day followed by 5 mg/kg/dose for a total of 3 doses.

2.1.4 Outcomes

Primary outcome: Failure of PDA closure after the first course of ibuprofen treatment.

Secondary outcomes: Failure of PDA closure after a second course of ibuprofen, rates of PDA ligation, all-cause mortality prior to hospital discharge, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), bleeding disorders, oliguria, and serum creatinine after treatment.

2.2 Search strategy

The databases Medline, Embase (Excerpta Medica dataBASE), Cochrane Central Register of Controlled Trials (CENTRAL), and the Cumulative Index of Nursing and Allied Health Literature (CINAHL) were searched from inception until August 2021. Google Scholar was searched for articles that might not have been cited in the standard medical databases. The reference lists of eligible studies and review articles were searched to identify additional studies. No language restriction was applied. Only published data were used for those studies, where available. We searched PubMed for the following terms: (“ibuprofen”[MeSH Terms] OR “ibuprofen” [All Fields])) AND (“ductus arteriosus, patent” [MeSH Terms] OR (“ductus” [All Fields] AND “arteriosus” [All Fields] AND “patent” [All Fields]) OR “patent ductus arteriosus” [All Fields] OR (“patent” [All Fields] AND “ductus” [All Fields] AND “arteriosus” [All Fields] AND “preterm”[All Fields]). The other databases were searched for similar terms.

2.3 Study selection

Abstracts from the initial search were read independently by 2 reviewers (MS and TY) to identify eligible studies. Full texts of these studies were assessed by MS, TY, and BJ for inclusion. Differences in opinion were resolved by group discussion among all reviewers to reach consensus. Care was taken to ensure that multiple publications of the same study were excluded to avoid duplication of the data.

2.4 Data extraction

MS and TY extracted the data independently using a data collection form designed for this review. Information about the study design and outcomes was verified by all reviewers. Discrepancies during the data extraction process were resolved by discussion and consensus among all reviewers. We contacted authors for additional information and clarifications when details were not available in published manuscripts. We sought translation of manuscripts not published in English from three independent individuals.

2.5 Assessment of risk of bias

TY, MS and BJ independently assessed the risk of bias (ROB) by using the Cochrane “Risk of Bias Assessment Tool” [16] for RCTs in the domains of random sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of follow-up, selectivity of reporting, and other potential sources of bias. For each domain, the ROB was rated low, high, or unclear risk based on the Cochrane Collaboration guidelines [16].

For observational cohort studies, the Newcastle Ottawa Scale was applied to assess the selection of the exposed and non-exposed cohorts, the comparability of cohorts on the basis of design and analysis, and the assessment and follow up for outcome measures [18].

2.6 Data synthesis

The meta-analysis was conducted using Review Manager 5.3 (Cochrane Collaboration, Nordic Cochrane Centre, Copenhagen, Denmark). Due to heterogeneity of the study population and interventions (birth weight, gestational age, dose and mode of administration of drug), a random-effects model (REM) (Mantel–Haenszel method) was used. Effect size was expressed as relative risk (RR) and 95% confidence intervals (CI). Statistical heterogeneity was assessed with the χ² test and I2 statistic and by visual inspection of the forest plot for overlap of CIs. A P value < 0.1 on the χ² statistic was considered to indicate heterogeneity. I² statistic values were interpreted according to the guidelines of Cochrane Handbook as follows: 0% to 40%, might not be important; 30% to 60%, may represent moderate heterogeneity; 50% to 90%, may represent substantial heterogeneity; 75% to 100%, may represent considerable heterogeneity [16].

2.7 Summary of findings’ table

The key information about the certainty of evidence, the magnitude of effect of the intervention, and the sum of available data on all outcomes was presented in the summary of findings table according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) guidelines [19].

3 Results

3.1 Study selection

The literature search retrieved 74 studies from Medline, 51 studies from Embase, 93 studies from Cochrane, and 21 studies from CINAHL, of which 60 were duplicates. Sixty-four studies were considered eligible for inclusion and fifty-eight were excluded due to different interventions or controls. Three RCTs [20 –22] and three observational studies [23 –25] were included in the systematic review and meta-analysis. The flow diagram of the study selection process is illustrated in Fig. 1.

Fig. 1

Study search results.

3.2 Characteristics of included studies

3.2.1 RCTs

Three RCTs [20 –22] and three observational [23 –25] compared high and standard dose ibuprofen in PDA closure for preterm infants (Table 1). Two RCTs used the 20/10/10 mg/kg/dose regimen for high dose ibuprofen [20, 21], whereas one trial defined high dose ibuprofen as 15 mg/kg/dose for the loading dose and 7.5 mg/kg/dose for the remainder 2 doses [22]. One trial assessed IV ibuprofen [20] and two RCTs examined PO ibuprofen [21, 22]. The IV ibuprofen trial treated extremely preterm infants whereas the PO ibuprofen trials focused on very preterm infants. One manuscript was published in Farsi and translated independently by HH, NF and ZI prior to data extraction [22].

Table 1
Characteristics of Included Studies

Authors, publication year, type of study No. of participants Gestational age (weeks) Birth weight (gms) Intervention Control Outcome

Dani et al. 2012 [20] I = 35 25.6±1.8 781±225 IV ibuprofen Dose: 20|10|10 mg/kg/day (3 doses) IV ibuprofen administered as 10|5|5 mg/kg/day •Failure of PDA closure after first course •Failure of PDA closure after second course •Mortality, BPD, NEC

RCT C = 35 26.0±1.7 835±215 Timing: Within 12–24 hours of age Timing: Within 12–24 hours of age

Pourarian et al. 2015 [21] I = 30 30±2.6 1339±542 PO ibuprofen administered as 20|10|10 mg/kg/day Timing: Starting at 3–7 days of life PO ibuprofen administered as 10|5|5 mg/kg/day Timing: Starting at 3–7 days of life •Failure of PDA closure after first course •GI bleed, bleeding disorders, NEC, oliguria, serum creatinine after treatment

RCT C = 30 31.3±2.1 1493±346

Fesharaki et al. 2012 [22] I = 30 29.77 1300 PO ibuprofen administered as 15|7.5|7.5 mg/kg/day PO ibuprofen administered as 10|5|5 mg/kg/day •Failure to close PDA •Urine output less than 0.5 ml/kg after ibuprofen, GI bleeding

RCT C = 30 30.88 1324 Timing: Starting on first day of life Timing: Starting on first day of life

Meißner et al. 2012 [23] I = 23 28.9±3.9 1229±588 IV ibuprofen administered as 20|10|10 mg/kg/day Timing: Starting at 3–7 days of life IV ibuprofen administered as 10|5|5 mg/kg/day Timing: Starting at 3–7 days of life •Surgical ligation of PDA •Closure of PDA after medical therapy •Adverse outcomes (mortality, NEC > Bell stage 2, BPD, IVH, renal function, ROP)

Observational C = 19 27.7±3.2 1086±572

Dornelles et al. 2016 [24] I = 33 27.4±2.9 913±321 IV ibuprofen administered as 20|10|10 mg/kg/day IV ibuprofen administered as 10|5|5 mg/kg/day •Closure of PDA after medical therapy •Surgical ligation of PDA •Adverse outcomes (mortality, BPD, IVH, oliguria)

Observational C = 44 27.9±3.3 1002±428

Hillier et al. 2021 [25] I = 24 26.3±2.3 893±243 IV or PO ibuprofen on day of life 1–3 10|5|5 mg/kg/day; IV or PO ibuprofen administered as 10|5|5 mg/kg/day •Surgical ligation of PDA •Need for additional doses to close PDA •Adverse outcomes (mortality, NEC, BPD, IVH, GI bleed, oliguria, ROP)

Observational C = 36 26.3±2.5 901±278 day of life 3–5 15|7.5|7.5 mg/kg/day; day of life > 5 20|10|10 mg/kg/day Timing: Starting on first day of life

Authors, publication year, type of study	No. of participants	Gestational age (weeks)	Birth weight (gms)	Intervention	Control	Outcome
Dani et al. 2012 [20]	I = 35	25.6±1.8	781±225	IV ibuprofen Dose: 20\|10\|10 mg/kg/day (3 doses)	IV ibuprofen administered as 10\|5\|5 mg/kg/day	•Failure of PDA closure after first course •Failure of PDA closure after second course •Mortality, BPD, NEC
RCT	C = 35	26.0±1.7	835±215	Timing: Within 12–24 hours of age	Timing: Within 12–24 hours of age
Pourarian et al. 2015 [21]	I = 30	30±2.6	1339±542	PO ibuprofen administered as 20\|10\|10 mg/kg/day Timing: Starting at 3–7 days of life	PO ibuprofen administered as 10\|5\|5 mg/kg/day Timing: Starting at 3–7 days of life	•Failure of PDA closure after first course •GI bleed, bleeding disorders, NEC, oliguria, serum creatinine after treatment
RCT	C = 30	31.3±2.1	1493±346
Fesharaki et al. 2012 [22]	I = 30	29.77	1300	PO ibuprofen administered as 15\|7.5\|7.5 mg/kg/day	PO ibuprofen administered as 10\|5\|5 mg/kg/day	•Failure to close PDA •Urine output less than 0.5 ml/kg after ibuprofen, GI bleeding
RCT	C = 30	30.88	1324	Timing: Starting on first day of life	Timing: Starting on first day of life
Meißner et al. 2012 [23]	I = 23	28.9±3.9	1229±588	IV ibuprofen administered as 20\|10\|10 mg/kg/day Timing: Starting at 3–7 days of life	IV ibuprofen administered as 10\|5\|5 mg/kg/day Timing: Starting at 3–7 days of life	•Surgical ligation of PDA •Closure of PDA after medical therapy •Adverse outcomes (mortality, NEC > Bell stage 2, BPD, IVH, renal function, ROP)
Observational	C = 19	27.7±3.2	1086±572
Dornelles et al. 2016 [24]	I = 33	27.4±2.9	913±321	IV ibuprofen administered as 20\|10\|10 mg/kg/day	IV ibuprofen administered as 10\|5\|5 mg/kg/day	•Closure of PDA after medical therapy •Surgical ligation of PDA •Adverse outcomes (mortality, BPD, IVH, oliguria)
Observational	C = 44	27.9±3.3	1002±428
Hillier et al. 2021 [25]	I = 24	26.3±2.3	893±243	IV or PO ibuprofen on day of life 1–3 10\|5\|5 mg/kg/day;	IV or PO ibuprofen administered as 10\|5\|5 mg/kg/day	•Surgical ligation of PDA •Need for additional doses to close PDA •Adverse outcomes (mortality, NEC, BPD, IVH, GI bleed, oliguria, ROP)
Observational	C = 36	26.3±2.5	901±278	day of life 3–5 15\|7.5\|7.5 mg/kg/day; day of life > 5 20\|10\|10 mg/kg/day	Timing: Starting on first day of life

I –intervention. C –control. IV –intravenous. PO –oral. RCT –randomized controlled trial. BPD –bronchopulmonary dysplasia. NEC –necrotizing enterocolitis. IVH –intraventricular hemorrhage. GI –gastrointestinal.

3.2.2 Observational studies

Two observational studies used PO ibuprofen [23, 24]; one study included both IV and PO ibuprofen, administered at the discretion of the clinician [25]. The study by Hillier et al. [25] included infants less than 28 weeks’ gestation and the other two studies included infants less than 32 weeks’ gestation [23, 24].

3.3 Quality assessment of included studies

The three RCTs were judged to have unclear ROB for the domains of random sequence generation, blinding of the participants and personnel except for the trial by Pourarian et al. [21], which had high risk of bias in the domain of blinding of participants and personnel (Table 2A). Based on the Newcastle Ottawa Scale, two observational studies had scores of eight [24, 25] and one study had a score of nine out of a total score of nine [23] (Table 2B).

Table 2A
Assessment of the Risk of Bias (ROB) of Included RCTs

Author and publication year Random Sequence Generation (selection bias) Allocation Concealment (selection bias) Blinding of Participants and Personnel (performance bias) Blinding of Outcome Assessment (detection bias) Incomplete Outcome Data (attrition bias) Selective Reporting (reporting bias) Other Bias

Dani et al. 2012 [20] Unclear risk Low risk Unclear risk Low risk Low risk Low risk Low risk

Pourarian et al. 2015 [21] Unclear risk Low risk High risk Low risk Low risk Unclear risk Low risk

Fesharaki et al. 2012 [22] Unclear risk Unclear risk Unclear risk Unclear risk Low risk Unclear risk Low risk

Author and publication year	Random Sequence Generation (selection bias)	Allocation Concealment (selection bias)	Blinding of Participants and Personnel (performance bias)	Blinding of Outcome Assessment (detection bias)	Incomplete Outcome Data (attrition bias)	Selective Reporting (reporting bias)	Other Bias
Dani et al. 2012 [20]	Unclear risk	Low risk	Unclear risk	Low risk	Low risk	Low risk	Low risk
Pourarian et al. 2015 [21]	Unclear risk	Low risk	High risk	Low risk	Low risk	Unclear risk	Low risk
Fesharaki et al. 2012 [22]	Unclear risk	Unclear risk	Unclear risk	Unclear risk	Low risk	Unclear risk	Low risk

Table 2B

Quality Assessment using the Newcastle Ottawa Scale of Included Observational Studies

Author and publication year	Selection				Comparability	Outcome
	Representative exposed cohort	Selection of non-exposed cohort	Ascertainment of exposed cohort	Demonstrating that outcome not present at start of study	Comparability of cohorts on basis of design of analysis	Assessment of outcome	Duration of follow up	Adequacy of follow up
Meißner et al. 2012 [23]	^*	^*	^*	^*	^**	^*	^*	^*
Dornelles et al. 2016 [24]	^*	^*	^*	^*	^*	^*	^*	^*
Hillier et al. 2021 [25]	^*	^*	^*	^*	^*	^*	^*	^*

3.4 Outcome of interest

3.4.1 Primary outcome

Compared to standard dose, high dose ibuprofen did not reduce the failure rate of ductal closure after the first course of treatment (6 studies, N = 369, typical RR 0.74, 95% CI 0.53 to 1.03; p = 0.07; I² = 39%; GRADE: low certainty evidence) (Fig. 2). But among the RCTs, high dose ibuprofen significantly favored ductal closure compared to standard dosing after the first course of therapy (3 RCTs, N = 190, RR = 0.48, 95% CI 0.31 to 0.74, p = 0.001; I² = 0%; risk difference (RD) –0.29, 95% CI –0.35 to –0.10; number needed to treat (NNTB) = 5; GRADE: low certainty evidence) (Fig. 2).

Fig. 2

Failure of PDA closure in preterm infants after the first course of treatment. Comparison: High dose versus standard dose ibuprofen.

3.4.2 Secondary outcomes

There was a significant reduction in the rates of PDA ligation with high dose compared to standard dose ibuprofen (5 studies, N = 309, RR 0.33, 95% CI 0.16 to 0.70; p = 0.004; I² = 0%; RD –0.13, 95% CI –0.24 to –0.03; NNTB = 8; GRADE: low certainty evidence) (Fig. 3). All other secondary outcomes were not significantly different between the high and standard dose ibuprofen groups (Table 3).

Fig. 3

Rates of PDA ligation. Comparison: High dose versus standard dose ibuprofen for PDA treatment in preterm infants.

Table 3

Summary of Findings for High versus Standard Dose Ibuprofen

Outcomes	No. of Participants	Relative Risk or Difference (95% confidence interval)	Anticipated absolute effects		GRADE
			SD ibuprofen	HD ibuprofen
Failure of PDA closure after first course of ibuprofen	369	0.74 (0.53, 1.03)	469 per 1000	347 per 1000	Low^a,d
3 RCTs	190	0.48 (0.31, 0.74)	442 per 1000	212 per 1000	Low^a,d
3 observational studies	179	0.98 (0.72, 1.32)	485 per 1000	495 per 1000	Low^d
Failure of PDA closure after second course of ibuprofen	206	0.36 (0.13, 1.00)	365 per 1000	131 per 1000	Very low^a,b,d
3 RCTs	190	0.24 (0.10, 0.55)	321 per 1000	77 per 1000	Low^a,,d
1 observational study	16	0.83 (0.32, 2.15)	600 per 1000	498 per 1000	Very low^a,c,d
Rate of PDA ligation	309	0.33 (0.16, 0.70)	201 per 1000	66 per 1000	Low^a,d
2 RCTs	130	0.31 (0.02, 5.20)	138 per 1000	43 per 1000	Very low^a,b,c,d
3 observational studies	179	0.31 (0.14, 0.72)	242 per 1000	75 per 1000	Low^d
Mortality	369	1.03 (0.68, 1.57)	149 per 1000	154 per 1000	Very low^a,c,d
3 RCTs	190	1.31 (0.49, 3.53)	63 per 1000	83 per 1000	Very low^a,c,d
3 observational studies	179	1.42 (0.34, 5.98)	232 per 1000	330 per 1000	Very low^b,c,d
Bronchopulmonary dysplasia	249	0.80 (0.61, 1.05)	500 per 1000	400 per 1000	Low^a,d
1 RCT	70	0.63 (0.33,1.18)	457 per 1000	288 per 1000	Low^a,d
3 observational studies	179	0.84 (0.63, 1.13)	515 per 1000	433 per 1000	Low^d
Necrotizing enterocolitis	232	1.11 (0.50, 2.44)	92 per 1000	102 per 1000	Very low^a,c,d
2 RCTs	130	0.99 (0.39, 2.50)	123 per 1000	122 per 1000	Very low^a,c,d
2 observational studies	102	1.50 (0.33, 6.82)	55 per 1000	82 per 1000	Very low^c,d
Oliguria	327	1.38 (0.58, 3.29)	46 per 1000	63 per 1000	Very low^a,c,d
3 RCTs	190	1.52 (0.54, 4.25)	53 per 1000	80 per 1000	Very low^a,c,d
2 observational studies	137	1.09 (0.21, 5.52)	38 per 1000	41 per 1000	Very low^c,d
Serum creatinine after treatment (2 RCTs)	130	0.09 (-0.03, 0.21)	MD 0	MD 0.09 higher (0.03 lower to 0.21 higher)	Low^a,d
Bleeding disorder (2 RCTs)	130	0.96 (0.53, 1.73)	231 per 1000	222 per 1000	Low^a,d
Intraventricular hemorrhage	249	1.04 (0.51, 2.12)	104 per 1000	109 per 1000	Very low^a,c,d
1 RCT	70	2.00 (0.39, 10.22)	57 per 1000	114 per 1000	Very low^a,c,d
3 observational studies	179	0.89 (0.40, 1.97)	121 per 1000	108 per 1000	Very low^c,d

HD –high dose, SD –standard dose, GRADE –Grades of recommendation, assessment, development and evaluation guidelines, MD –mean difference. a. Risk of bias due to unclear allocation concealment and inconsistent utilization of random number generator for randomization. b. Inconsistency due to variation in direction of effect and heterogeneity value > 0. c. Imprecision due to wide confidence intervals. d. Publication of positive findings from multiple small studies, which may result in omission of negative studies.

3.5 Summary of findings

The certainty of evidence for all outcomes ranged from very low to low (Table 3) based on the unclear risk of bias where random sequence generation was not reported for the RCTs, inconsistency detected by the I² statistic and imprecision based on wide confidence intervals in several outcomes. No indirectness was detected. Publication bias was not assessed as there were only six studies for the primary outcome.

4 Discussion

In this systematic review and meta-analysis of 6 studies including 369 preterm infants, we found low quality evidence that high dose ibuprofen can significantly reduce rates of PDA ligation in preterm infants than standard dose ibuprofen with no significant increase in adverse events, neonatal morbidities or mortality. However, we observed no significant reduction in the failure to close the PDA with either first or second course of treatment. Interestingly there was greater reduction in failure of PDA closure after second course of treatment suggesting a cumulative dose effect with high versus standard dose ibuprofen. This trend in 2^nd course treatment is likely to explain the reduction in PDA ligation.

Using pharmacokinetic data, Hirt et al. [15] provided evidence for a modified dosed of IV ibuprofen for the treatment of PDA. In 66 preterm infants, they concluded that to achieve an effective threshold area under the curve (AUC), ibuprofen is needed beyond 70 hours of age for PDA closure in preterm infants to account for the larger clearance with increasing post-natal age. This study paved way for future studies evaluating efficacy and safety of high dose compared to standard dose ibuprofen for PDA treatment in preterm infants. Among extremely preterm infants, Dani et al. demonstrated that high dose IV ibuprofen was more favorable compared to standard dose ibuprofen for ductal closure [20]; whereas Dornelles et al., using historic controls, found no difference between high and standard dose IV ibuprofen [24]. The studies of PO ibuprofen also had varying results when high dose was compared to standard dose ibuprofen for PDA treatment in preterm infants [21, 22].

The choice of treatment for PDA closure in preterm infants amongst the various pharmacotherapeutic options remains unclear. To help address this uncertainty, a recent network meta-analysis showed that high dose oral ibuprofen was the best ranked treatment among ibuprofen, indomethacin and acetaminophen for closure of the PDA [26]. This conclusion was based on 2 RCTs enrolling 120 neonates that demonstrated oral high dose ibuprofen is superior to standard dose ibuprofen for PDA closure in very preterm infants [21, 22]. However, the participants in this trial had a mean gestation age of 30±2.6 (high dose group) and 31.3±2.1 (standard dose group) [21]; and the mean gestational ages in the second trial were 29.77 weeks (high dose group) and 30.88 weeks (standard dose group) [22]. For both studies, the participants constitute the population that are likely to have spontaneous PDA closure [27]. These factors are important to consider when assessing the results and conclusions from this network meta-analysis and extrapolating the results to bedside clinical practice. This highlights the need for a definitive trial comparing the 2 dosing regimens for PDA treatment in preterm infants.

4.1 Limitations

In this review, we identified some limitations from the six studies. Heterogeneity was present in the study population with gestational age and birth weight of included infants. Secondly, there was inconsistent documentation between studies regarding the echocardiographic criteria used to define a hemodynamically significant PDA. Thirdly, different routes of administration (PO/IV) and different doses of ibuprofen were compared for which we employed a random-effects model for analysis. Fourth, incomplete reporting of outcomes and adverse events from the RCTs such as intracranial hemorrhage or rates of BPD may confound the comparison of studies. Lastly, these studies exhibited risk of bias due to unclear random sequence generation and allocation concealment along with publication bias, resulting in low and very low quality of evidence.

4.2 Future directions

A large and adequately powered double blinded multicentre RCT comparing the 2 dosing regimens with well-defined primary and secondary outcomes including intracranial haemorrhage and long-term neurodevelopmental follow-up data will be important to determine the most effective and safe dose of ibuprofen for ductal closure in extremely preterm infants (< 28 weeks’ gestation). In addition, the route of administration, intravenous or oral, will be important considerations in early treatment of infants < 28 weeks’ gestation. Using a superiority margin of 5% with a proportion of success of 67% in the high dose group and 53% in the standard dose ibuprofen for ductal closure in preterm infants, a two-arm RCT comparing high and standard dose ibuprofen would require 359 subjects per arm (statistical power of 80% and alpha value of 0.05).

5 Conclusion

Based on low quality evidence, high dose ibuprofen may be more effective than standard dose ibuprofen with regards to reduction of PDA ligation in preterm infants without any increase in adverse events, neonatal morbidities and mortality. However, clinicians should exercise caution as no recommendations can be made on the basis of these findings; high quality and adequately powered studies are necessary to address the efficacy and safety of high dose ibuprofen in the treatment of the hemodynamically significant PDA.

Footnotes

Acknowledgments

We thank Drs. Hamid Hakak (HH), Naghmeh Forghani (NF) and Zahra Izadifar (ZI) (University of Toronto and McMaster University) for translating the Fesharaki et al. paper from Farsi to English. We also thank Eleni Philippopoulos for assistance with searching the medical databases (Sinai Health System, Library Information Services).

Contributions

TY, MS and BJ contributed to study design, data extraction, data analysis and writing. DW and AJ contributed to study design and critical editing of the manuscript.

Disclosures

The authors report no real or perceived conflicts of interest.

Funding

This work was not supported by any funding.

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