Heterogeneity in Treatment Response for Patent Ductus Arteriosus: A Meta-Analysis

doi:10.21203/rs.3.rs-4991342/v1

Context:

While pharmacological interventions promote PDA closure, their impact on overall outcomes remains uncertain due to conflicting results. These inconsistent results indicate that the effectiveness of these treatments may vary considerable among preterm infants, suggesting potential heterogeneity.

Objective

This meta-analysis and meta-regression aimed to assess the effect of pharmacological interventions on mortality and PDA closure in preterm infants, while critically examining sources of heterogeneity.

Data Sources:

We searched Ovid MEDLINE and EMBASE for relevant studies.

Study Selection:

Studies comparing ibuprofen, acetaminophen, indomethacin, or placebo/expectant management in preterm infants with PDA, where the outcome of interest was either mortality or PDA closure.

Data Extraction:

We extracted data on mortality, PDA closure, study design, and patient baseline characteristics following PRISMA guidelines. We used a random-effects model to account for the heterogeneity observed in the studies.

Results

Meta-analysis of 72 RCTs revealed that while interventions significantly improved PDA closure rates (OR 5.31, p < 0.00001), they did not consistently reduce mortality (OR 1.03, p = 0.84). Notably, interventions appeared to increase mortality in infants with hemodynamically significant PDA (OR 1.45, p = 0.05). Our analysis revealed substantial heterogeneity (I² = 55%) and significant inconsistencies in outcome reporting across studies. Meta-regression models could not fully explain the observed variability.

Limitations:

Potential publication bias, incomplete patient-level data, and inconsistent definitions across studies.

Conclusions

The substantial heterogeneity underscores the complexity of PDA and the limitations of a one-size-fits-all approach. These findings strongly support a shift towards precision medicine in PDA treatment, focusing on identifying factors that predict individual response.

Our meta-analysis of 72 RCTs revealed substantial heterogeneity and significant inconsistencies in outcome reporting across studies. Meta-regression models could not fully explain the observed variability.

Patent ductus arteriosus (PDA) is a common cardiovascular condition in preterm infants, associated with increased risk of mortality and complications such as necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and bronchopulmonary dysplasia (BPD)¹. Pharmacological intervention such as ibuprofen, acetaminophen, and indomethacin, is frequently used to promote PDA closure². Despite a moderate success rate in closing PDA, pharmacological interventions have not consistently demonstrated clear survival benefits in preterm infants³. This lack of clarity leaves neonatologists facing a difficult dilemma when deciding whether or not to intervene in preterm infants with PDA. This paradox highlights a crucial knowledge gap in PDA management.

The success in outcomes of pharmacological interventions in treating PDA seems to vary significantly between preterm infants. This makes it extremely difficult for neonatologists to know which infants will truly benefit from treatment and which might be at risk of harm. The reasons for this inconsistency remain poorly understood. It’s likely that individual differences among preterm infants, along with variations in how these medications are used, significantly influence treatment success. These differences in outcomes across studies underscore the need to identify specific patient characteristics, treatment practices, and potentially other unreported factors that determine whether an infant will respond positively to PDA treatment.

A meta-analysis and meta-regression can provide a comprehensive assessment of the effect of pharmacological interventions on both PDA closure and mortality while critically examining the sources of heterogeneity in these outcomes.

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)⁴. A comprehensive search was conducted in EMBASE and Ovid MEDLINE databases for randomized clinical trials including preterm infants with patent ductus arteriosus, published until November 27th, 2023. There was no language exclusion. The search strategies were as followed: Pubmed: (("ductus arteriosus, patent[Mesh Terms]) OR (Patent Ductus Arteriosus[Title/Abstract]) AND ((random*) OR (RCT)); Filters: Humans. EMBASE: ('patent ductus arteriosus'/exp OR 'patent ductus arteriosus') AND ([controlled clinical trial]/lim OR [randomized controlled trial]/lim). Eligible studies included preterm infants (gestational age < 37 weeks) diagnosed with patent ductus arteriosus, subjected to any pharmacological intervention or conservative treatment for PDA. Included studies were randomized clinical trials reporting on patent ductus arteriosus closure rate or in-hospital mortality rate. We used Rayyan web-app⁵ for study selection, title, and abstract screening. The PRISMA flowchart is presented in eFigure 1. Two authors independently screened and reviewed titles and abstracts. In any disagreement that was not resolved, a third author was consulted.

For each study, we recorded trial characteristics, inclusion criteria, mean patient baseline characteristics, mortality, and PDA closure rate outcomes. All analyses investigating heterogeneity were conducted in two separate analyses: PDA closure rate and mortality. For trials reporting multiple PDA closure evaluations or pharmacological treatment cycles, we extracted the assessment closest to the end of the first treatment cycle. Missing observations were imputed using the mean value as a conservative estimate. If the parameter had more than 50% of missing values, we excluded the parameter from the meta-regression model.

To assess potential sources of heterogeneity, we conducted subgroup analyses was conducted based on study year, JADAD score⁶, gestational age, timing of intervention, trial size, route of administration (oral or intravenous), hemodynamically significant PDA inclusion criteria (hsPDA was defined according to each trial's definition), and PDA baseline diameter in mm. To assess heterogeneity through meta-regression models we included as potential moderators: multicenter, trial site, intervention, route of administration, hsPDA, JADAD score, mean gestational age, mean birth weight, mean days of life, female gender, antenatal corticoid and 5th minute Apgar.

We used odds ratios (ORs) with 95% confidence intervals to quantify associations for dichotomous outcomes. For studies reporting medians, we applied the Wan et al.⁷ formula to estimate mean values. Due to anticipated heterogeneity, we employed DerSimonian and Laird random-effects models for meta-analysis⁸.

The mortality and PDA closure rates across studies were analyzed using a random-effects meta-regression model with the log odds as the dependent variable. Heterogeneity was quantified using I2, and values exceeding 50% were considered statistically significant. A p-value of < 0.05 was considered statistically significant. Statistical analyses were performed using Review Manager Software (RevMan, version 5.4.1; The Cochrane Collaboration) and R Studio using the packages ‘meta’ and 'metafor’.

Systematic search

Our literature search identified 1431 articles, of which 72 randomized controlled trials (RCTs) met all our inclusion criteria (eFigure 1). Table 1, Fig. 1 (heatmap), and eTable 3 summarizes the characteristics of the included studies^3,9–78

Table 1. Characteristics of included randomized clinical trials

Number (%) or mean (SD)

Number of included trials

72

Mean total sample size

96 (63)

Multicenter trial

20 (27.7)

Trial site:

Europe

Asia

North America

Middle East

Oceania

Africa

22 (30.5)

19 (26.3)

7 (9.7)

19 (26.3)

4 (5.5)

3 (4.1)

Pharmacological treatment:

Ibuprofen

Acetaminophen

Indomethacin

Expectant/Placebo

57 (79.1)

24 (33.3)

26 (36.1)

Primary endpoint:

Mortality

PDA closure

62 (86.1)

65 (90.2)

Power analysis performed

57 (79.1)

< 28 weeks included

Yes

No/Not informed

10 (13.8)

62 (86.1)

hsPDA as inclusion criteria

Yes

No/Not informed

50 (69.4)

22 (30.5)

JADAD scale

Randomization

Randomization adequate

Blinding

Blinding adequate

Withdrawals described

74 (100)

66 (91.6)

31 (43)

20 (27.7)

28 (38.8)

Data are presented as numbers and percentages (%) or mean and standard deviation (SD)

In-Hospital Mortality (Pharmacological interventions vs. expectant management or placebo)

Overall, pharmacological interventions (ibuprofen, acetaminophen, indomethacin) did not show a clear difference in-hospital mortality for preterm infants with PDA compared to expectant management or placebo (OR 1.03, 95% CI 0.80–1.31, p = 0.84).

In the subgroup analyses, infants with hemodynamically significant PDA (hsPDA) had higher mortality odds when receiving interventions (OR 1.45, 95% CI 1.00–2.11, p = 0.05). Counterintuitively, smaller PDA baseline diameter was associated with higher mortality when received any intervention (OR 1.71, 95% CI 1.06–2.74, p = 0.03). Study quality (as assessed by the JADAD score), gestational age, timing of intervention initiation (< 3 days of life, 3–7 days of life, > 7 days of life), route of administration, and study size did not significantly influence the observed associations with mortality. Additionally, within gestational age subgroups (< 28 weeks, 28–30 weeks, 30–32 weeks), pharmacological interventions did not show a statistically significant association with survival.

Comparisons of Individual PDA interventions and Mortality

To investigate whether certain PDA medications might be more effective than others, we compared ibuprofen, acetaminophen, and indomethacin individually against their alternatives. None of these interventions demonstrated a statistically significant association with reduced mortality (eFigure 2).

Mortality and Heterogeneity

Our meta-regression model aimed to identify specific factors that could explain the variability in mortality outcomes across the studies. It included moderators such as intervention type, hsPDA status, gestational age, mean birth weight, and others. However, none of these included moderators could statistically account for the observed heterogeneity (tau2 = 0; I2 = 0%; p = 0.8849 test of heterogeneity, p = 0.0991 test for moderators) (eTable 1). This suggests that other, potentially unmeasured factors play a significant role in determining mortality outcomes in preterm infants receiving PDA treatment. These factors might include subtle differences in patient populations or variations in treatment practices.

PDA closure (Pharmacological interventions vs. expectant management or placebo)

In the overall analysis, pharmacological interventions were significantly more effective in achieving PDA closure compared to expectant management or placebo (OR 5.31, 95% CI 3.60–7.85, p < 0.00001). Ibuprofen, acetaminophen, and indomethacin all promoted closure, with varying effect sizes. Despite this overall effect, substantial heterogeneity was observed across the included studies (I2 = 55%). In the subgroup analysis, infants > 30 weeks of gestational age had the highest odds of closure with pharmacological intervention (OR 11.31, 95% CI 5.98–21.40, p < 0.00001). Earlier intervention (< 3 days of life) and later closure evaluation (> 7 days of life) increased PDA closure odds (OR 3.72 and 11.26 respectively, p < 0.00001 for both).

Comparisons of Individual PDA interventions and PDA closure rate

Comparisons between individual PDA interventions revealed mixed results. Ibuprofen demonstrated a potentially higher likelihood of PDA closure compared to acetaminophen (OR 1.28, 95% CI 0.99–1.66, p = 0.06), although the difference did not reach statistical significance. No clear advantage was observed for ibuprofen over indomethacin (OR 0.87, 95% CI 0.68–1.12, p = 0.29. However, both ibuprofen and acetaminophen appeared highly effective compared to placebo (OR 4.84 and 8.11 respectively, both p < 0.00001). Indomethacin also showed a potential benefit compared to expectant management/placebo (OR 8.89, 95% CI 1.13–68.06, p = 0.04). Comparisons showed moderate to high heterogeneity (I2 ranging from 18–71%) (Table 2).

Table 2

Effect of Pharmacological Interventions on Mortality and PDA closure
Outcome	Intervention	Comparison	OR (95% CI)	p-value	I2 (%)
Mortality	Ibuprofen	Acetaminophen	0.84 (0.57–1.25)	0.40	0
Mortality	Ibuprofen	Indomethacin	0.97 (0.64–1.46)	0.88	0
Mortality	Ibuprofen	Expectant/Placebo	1.08 (0.83–1.42)	0.55	0
Mortality	Acetaminophen	Indomethacin	0.85 (0.31–2.32)	0.76	0
Mortality	Acetaminophen	Expectant/Placebo	0.72 (0.28–1.87)	0.50	0
Mortality	Indomethacin	Expectant/Placebo	0.87 (0.42–1.82)	0.71	0
PDA closure	Ibuprofen	Acetaminophen	1.28 (0.99–1.66)	0.06	18
PDA closure	Ibuprofen	Indomethacin	0.87 (0.68–1.12)	0.29	0
PDA closure	Ibuprofen	Expectant/Placebo	4.84 (3.45–6.80)	< 0.00001	20
PDA closure	Acetaminophen	Indomethacin	0.76 (0.25–2.32)	0.63	71
PDA closure	Acetaminophen	Expectant/Placebo	8.11 (4.58–14.35)	< 0.00001	26
PDA closure	Indomethacin	Expectant/Placebo	8.89 (1.13–68.06)	0.04	58

PDA closure and heterogeneity

While pharmacological treatments increased the overall likelihood of PDA closure, there was considerable variation in how effective these treatments were across different studies (I2 = 55%). Even when we analyzed subgroups (e.g., by gestational age) the I2 values suggest moderate to high levels of heterogeneity (I2 ranging from 0–70%) (Tables 3 and 4). Our meta-regression model, while identifying important influencing factors, still left a significant portion of this variation unexplained (I2 = 49.13%, p = 0.0794) (eTable 2). This suggests that other factors, potentially related to individual patient characteristics, differences in treatment protocols, or variations in how PDA closure was measured, significantly influence the success of PDA closure interventions.

Table 3

Stratified analysis of mortality (Any intervention vs. Expectant management or Placebo)
Stratification	Subgroup	Odds Ratio	95% CI	P-value	I2 (%)
Overall Mortality	-	1.03	0.80–1.31	p = 0.84	0
Study Year	< 2013	0.83	0.60–1.15	p = 0.26	0
Study Year	2013–2018	0.66	0.32–1.35	p = 0.25	0
Study Year	2019–2023	1.74	1.13–2.67	p = 0.01	0
JADAD score	Low	0.62	0.26–1.48	p = 0.28	0
JADAD score	Moderate	1.24	0.75–2.05	p = 0.40	13
JADAD score	High	1.00	0.73–1.35	p = 0.98	0
Gestational Age	< 28 weeks	1.12	0.84–1.49	p = 0.43	0
Gestational Age	28–30 weeks	0.82	0.48–1.39	p = 0.45	0
Gestational Age	30–32 weeks	0.76	0.28–2.05	p = 0.59	0
Intervention	Ibuprofen	1.08	0.83–1.41	p = 0.58	0
Intervention	Acetaminophen	0.72	0.28–1.87	p = 0.50	0
Intervention	Indomethacin	0.87	0.42–1.82	p = 0.71	0
Time of intervention	< 3 days	1.11	0.85–1.45	p = 0.44	0
Time of intervention	3–7 days	0.51	0.23–1.12	p = 0.09	0
Time of intervention	> 7 days	1.02	0.37–2.87	p = 0.96	0
Route of administration	Oral	0.87	0.42–1.81	p = 0.72	0
Route of administration	Intravenous	1.05	0.81–1.35	p = 0.73	0
Trial size	< 100	0.99	0.59–1.68	p = 0.98	0
Trial size	> 100	1.03	0.77–1.37	p = 0.85	8
hsPDA status	With hsPDA	1.45	1.00–2.11	p = 0.05	0
hsPDA status	No hsPDA or not reported	0.80	0.58–1.10	p = 0.17	0
PDA baseline diameter	< 2.3mm	1.71	1.06–2.74	p = 0.03	0
PDA baseline diameter	> 2.3mm	1.34	0.68–2.64	p = 0.40	0

Table 4

Stratified analysis of PDA closure (Any intervention vs. Expectant management or Placebo)
Stratification	Subgroup	Odds Ratio	95% CI	P-value	I2 (%)
Overall PDA closure	-	5.31	3.60–7.85	< 0.00001	55
Year	< 2014	4.11	2.73–6.20	< 0.00001	21
Year	2014–2018	9.61	4.27–21.63	< 0.00001	41
Year	2019–2023	4.55	2.26–9.13	< 0.0001	53
Intervention	Ibuprofen	3.78	2.53–5.64	< 0.00001	41
Intervention	Acetaminophen	8.11	4.58–14.35	< 0.00001	26
Intervention	Indomethacin	8.78	1.13–68.06	0.04	58
JADAD score	High	3.21	2.37–4.35	0.00001	10
JADAD score	Moderate	6.07	2.64–13.96	< 0.0001	28
JADAD score	Low	14.37	8.05–25.66	< 0.00001	0
Gestational age	< 28 weeks	3.79	2.30–6.23	< 0.00001	41
Gestational age	28–30 weeks	4.53	2.50–8.22	< 0.00001	34
Gestational age	> 30 weeks	11.31	5.98–21.40	< 0.00001	17
Administration route	oral	7.21	4.12–12.63	< 0.00001	5
Administration route	intravenous	4.56	2.84–7.34	< 0.00001	64
Time of intervention	< 3 days	3.72	2.47–5.60	< 0.00001	46
Time of intervention	3–7 days	11.79	5.62–24.77	< 0.00001	21
Time of intervention	> 7 days	9.31	3.37–25.69	< 0.0001	0
Trial size	< 100	7.13	4.33–11.73	< 0.00001	11
Trial size	> 100	4.18	2.49–7.02	< 0.00001	69
hsPDA status	With hsPDA	6.75	2.65–17.16	< 0.0001	70
hsPDa status	No hsPDA	4.96	3.35–7.34	< 0.00001	38
Baseline PDA diameter	< 2.3mm	2.73	1.35–5.52	0.005	46
Baseline PDA diameter	> 2.3mm	6.04	3.44–10.62	< 0.00001	33
Time of closure evaluation	< 7 days of life	3.39	2.43–4.75	< 0.00001	28
Time of closure evaluation	> 7 days of life	11.26	5.89–21.52	< 0.00001	0

Dosage and Route of administration of the same intervention comparison

While a higher ibuprofen dose was linked to an increased PDA closure rate (OR 0.26, 95% CI 0.12–0.58, P = 0.001), there was no significant difference observed in survival rates between standard and higher dosages (OR 1.24, CI 95% 0.60–2.56, p = 0.56). (eFigures 4 and 5).

Oral ibuprofen was associated with higher odds of PDA closure compared to non-oral routes (OR 1.95, 95% CI 1.03–3.69, p = 0.04). However, this difference in closure did not translate to a significant increase in survival rates (OR 1.41, 95% CI 0.66–3.02, p = 0.38) (eFigures 6 and 7).

This study exposes a critical paradox in the management of patent ductus arteriosus (PDA) in preterm infants: pharmacological interventions effectively close the PDA but do not reliably translate into improved survival. Our findings highlight substantial heterogeneity in both mortality and PDA closure rates across studies, even after adjusting for common moderators. This suggests that the success of pharmacological interventions depends significantly on factors beyond those typically reported. The potential association between pharmacological interventions and increased mortality in infants with hsPDA is particularly alarming.

The substantial heterogeneity we observed poses a serious challenge for neonatologists trying to apply findings from individual PDA trials to their patients. Variations in patient characteristics, treatment practices, and inconsistent reporting of essential baseline data can profoundly impact outcomes⁷⁹. Gestational age in analyzed studies ranged widely from 22 to 37 weeks, including timing spanned from birth to 28 days of life, and many trials failed to specify hsPDA status or respiratory support needs. Basic baseline characteristics such as Apgar score, invasive mechanical ventilation, surfactant, chorioamnionitis, and baseline PDA diameter were reported only in a minority of trials. This lack of standardization and inconsistent reporting undermines the external validity of PDA trials, making it difficult to compare results or apply findings to individual patients. The discordant, even contradictory, results reported by RCTs investigating the same PDA interventions highlight this issue. It is likely that critical, yet unreported, differences in patient populations or standard-of-care practices are the primary drivers of these conflicting outcomes. Consequently, neonatologists must carefully scrutinize inclusion criteria and baseline characteristics to determine if a study population adequately reflects their own patient’s profile.

Our previous work demonstrated the profound heterogeneity of preterm infants. Using statistical cluster analyses of clinical and laboratorial data, we identified distinct PDA subphenotypes⁸¹, and subgroups within the extremely preterm infant population⁸², each carrying unique outcome risks.

Our study has some limitations. Meta-analyses are inherently dependent on the quality and completeness of available data. Potential publication bias and the lack of granular patient-level information in some studies might limit our ability to fully explain the observed heterogeneity. In particular, incomplete reporting of specific granular patient-level characteristics limits our ability to identify all the potentially influential factors in both mortality and PDA closure. Additionally, variability in how key terms like hsPDA or PDA closure were defined across studies could introduce inconsistencies. Our focus was primarily on the immediate effects of pharmacological interventions. We did not analyze other important neonatal morbidities such as necrotizing enterocolitis, bronchopulmonary dysplasia, or intraventricular hemorrhage. Long-term studies comparing closure versus conservative management, and investigating potential delayed impacts on neurodevelopment, would provide a more comprehensive understanding of treatment outcomes. Finally, our study did not address the potential influence of other treatment modalities, such as surgical ligation.

This study exposes the urgent need to move beyond the "one-size-fits-all" approach in PDA management. The unexplained heterogeneity underscores a fundamental limitation in our current understanding of PDA management. To address this, future research should focus on 1) precision medicine: identifying predictive biomarkers or patient-specific factors that can distinguish which infants are most likely to benefit from PDA interventions, and those who might be at higher risk for adverse effects. 2) standardized reporting: developing consensus on a core set of baseline patient characteristics, diagnostic criteria, and outcome measures to be reported in all PDA studies. This will enhance comparability between trials and aid in identifying the sources of heterogeneity. 3) individual patient data: encouraging the sharing of anonymized individual patient data to facilitate larger-scale analyses aimed at identifying specific subgroups and treatment effect modifiers.

This study reveals a critical paradox in managing patent ductus arteriosus (PDA) in preterm infants. While pharmacological interventions effectively achieve PDA closure, they do not consistently translate into improved survival outcomes. Our results highlight a potential trend towards increased mortality in infants with hemodynamically significant PDA who receive pharmacological treatment. Substantial heterogeneity was observed across studies for both mortality and PDA closure outcomes, and our meta-regression models could not fully account for this variability. These findings strongly indicate that factors beyond those commonly reported significantly influence treatment outcomes in preterm infants with PDA.

hsPDA: Hemodymically significant patent ductus arteriosus
OR: Odds Ratio
PDA: Patent Ductus Arteriosus
RCT: Randomized Controlled Trial

Contributors Statement

Dr Felipe Yu Matsushita conceptualized and designed the study, collected data, carried out the initial analysis, drafted the initial manuscript, and revised the manuscript

Dr Vera Lucia Jornada Krebs conceptualized and designed the study, designed the data collection instruments, carried out the initial analyses, and revised the manuscript

Prof Werther Brunow de Carvalho conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed and revised the manuscript for important intellectual content.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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No competing interests reported.

pdasupplementary.docx

Heterogeneity in Treatment Response for Patent Ductus Arteriosus: A Meta-Analysis

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Version 1

Abstract

Context:

Objective

Data Sources:

Study Selection:

Data Extraction:

Results

Limitations:

Conclusions

Figures

Summary

Introduction

Methods

Results

Systematic search

In-Hospital Mortality (Pharmacological interventions vs. expectant management or placebo)

Comparisons of Individual PDA interventions and Mortality

Mortality and Heterogeneity

PDA closure (Pharmacological interventions vs. expectant management or placebo)

Comparisons of Individual PDA interventions and PDA closure rate

PDA closure and heterogeneity

Dosage and Route of administration of the same intervention comparison

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1