RT 5 WK 2 PICO Expanded into Mini-CAT

Clinical Question: 
A preterm female was born at 32 weeks gestation and presents with patent ductus arteriosus. Her parents want to proceed with non-operative management and are concerned about the many side effects of Indomethacin. They want to know which treatment between Acetaminophen or Ibuprofen is safer and more effective for closure of their daughter’s PDA.  

PICO Question:
For preterm neonates with patent ductus arteriosus, is Acetaminophen (Paracetamol) safer and more effective than Ibuprofen for PDA closure?  

P	I	C	O
Preterm infants	Acetaminophen	Ibuprofen	More efficacious
Neonates	Paracetamol	NSAIDs	Earlier closure
Patent ductus arteriosus			Safer
PDA			Better closure

  Search strategy: 

PubMed  

• Search terms: preterm infants, paracetamol, ibuprofen, patent ductus arteriosus  
  • MEDLINE indexed and published within the past 5 years: 101 results  
• Search terms: preterm infants, acetaminophen, ibuprofen, patent ductus arteriosus  
  • MEDLINE indexed and published within the past 5 years: 69 results  
• Search terms: preterm infants, paracetamol, ibuprofen, patent ductus arteriosus, more efficacious  
  • MEDLINE indexed and published within the past 5 years: 15 results  

Google Scholar   

• Search terms: preterm infants, PDA, paracetamol, ibuprofen  
  • Published within the past 5 years: 1,040 results  
• Search terms: preterm infants, PDA, paracetamol, ibuprofen, more efficacious  
  • Published within the past 5 years: 654 results  
• Search terms: preterm infants, PDA, paracetamol, ibuprofen, more efficacious, safer  
  • Published within the past 5 years: 399 results  

Cochrane Library  

• Search terms: preterm infants, PDA, paracetamol, ibuprofen  
  • Published within the past 5 years: 2 reviews, 38 trials  
• Search terms: preterm infants, PDA, paracetamol, ibuprofen, more efficacious 
  • Published within the past 5 years: 5 trials

 

I narrowed down the choices for my selected articles by evaluating which articles specifically studied the efficacy of Acetaminophen (Paracetamol) versus Ibuprofen in the management of preterm infants with PDA. I concluded that the articles selected are of high quality evidence, as they include three systematic reviews and meta-analyses and two randomized controlled trials. All of the articles provided a direct comparison between Acetaminophen (Paracetamol) and Ibuprofen as well as comparisons with Indomethacin and placebo.  All of the selected articles are also MEDLINE indexed and recently published within the past five years.   

Results found: 

1. Efficacy and safety of pharmacological treatments for patent ductusarteriosusclosure: A systematic review and network meta-analysis of clinical trials and observational studies 

Link: https://www-sciencedirect-com.york.ezproxy.cuny.edu/science/article/pii/S1043661819310205 

Efficacy and safety profiles of different pharmacological interventions used to treat patent ductus arteriosus (PDA) are relatively unexplored. Integrating the findings of randomized clinical trials (RCTs) with those from observational studies may provide key evidence on this important issue. 

We aimed at estimating the relative likelihood of failure to close the PDA, need for surgical closure, and occurrence of adverse events among preterm and full-term infants treated with indomethacin, ibuprofen, or acetaminophen, placebo, or no treatment including both RCTs and observational studies. 

We searched PubMed, Embase, and the Register of Controlled Trials from inception to October 30, 2018. We first estimated proportions of subjects with failure to close the PDA, subjects in whom surgical closure was performed after pharmacological treatment, death, and subjects with selected adverse events (AEs). These estimates were obtained using frequentist random-effect meta-analysis of arm-specific proportions. We then compared active drugs with each other and with control (either placebo or no treatment) by summarizing results at the end of treatment reported in the papers, regardless of number of administration(s), dose, route and type of administration, and study design and quality. We also summarized primary outcome results separately at first, second and third cycles of treatment. These estimates were obtained using Bayesian random-effects network meta-analysis for mixed comparisons, and frequentist random-effect pairwise meta-analysis for direct comparisons. 

We included 64 RCTs and 24 observational studies including 14,568 subjects (5339 in RCTs and 9229 in observational studies, 8292 subjects received indomethacin, 4761 ibuprofen, 574 acetaminophen, and 941 control (including placebo or no intervention). The proportion of subjects with failure to close the PDA was 0.24 (95% Confidence Interval, CI: 0.20, 0.29) for indomethacin, 0.18 (0.14, 0.22) for ibuprofen, 0.19 (0.09, 0.30) for acetaminophen, and 0.59 (0.48, 0.69) for control. At end of treatment, compared to control, we found inverse associations between all active drugs and failure to close PDA (for indomethacin Odds Ratio, OR, was 0.17 [95% Credible Interval, CrI: 0.11-0.24], ibuprofen 0.19 [0.12-0.28], and acetaminophen 0.15 [0.09-0.26]), without differences among active drugs. We showed inverse associations between effective drugs and need for surgical closure, as compared to control (for indomethacin OR was 0.28 [0.15-0.50], ibuprofen 0.30 [0.16-0.54], and acetaminophen 0.19 [0.07-0.46]), without differences among drugs. Indomethacin was directly associated with intraventricular hemorrhage (IVH) (1.27; 1.00, 1.62) compared to ibuprofen, and to oliguria as compared to ibuprofen (3.92; 1.69, 9.82) or acetaminophen (10.8; 1.86, 93.1). In conclusion, active pharmacological treatment, with indomethacin, ibuprofen, or acetaminophen, is inversely associated with failure to close the PDA compared to non-treatment. Ibuprofen should be preferred to indomethacin to avoid occurrence of IVH or oliguria, acetaminophen should be preferred to indomethacin to avoid oliguria. 

2. Efficacy and Safety of Paracetamol for Patent DuctusArteriosusClosure in Preterm Infants: An Updated Systematic Review and Meta-Analysis 

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039820/

Background: Indomethacin and ibuprofen, two commonly used prostaglandin inhibitors, are the drugs of choice for patent ductus arteriosus. However, paracetamol is an alternative choice when these drugs are ineffective or contraindicated. This study aimed to confirm paracetamol’s efficacy and safety compared with those of other drugs or placebos for patent ductus arteriosus closure in premature infants. 

Methods: We conducted a literature search using the Cochrane Library, PubMed, CINAHL, and EMBASE databases for randomized controlled trials and quasi-randomized controlled trials. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to direct the process and PICO (P, population; I, intervention/interest; C, comparator; O, outcome) principle to constitute the theme. We combined the research data through qualitative summaries or meta-analyses. 

Results: The final analyses included 15 trials (N = 1,313). No significant differences were noted between paracetamol and ibuprofen except for shorter mean days needed for patent ductus arteriosus closure, lower risk of gastrointestinal bleeding, and hyperbilirubinemia. No significant difference existed between paracetamol and indomethacin. Oral paracetamol was more effective than placebo in infants weighing 1,501–2,500 g. 

Conclusions: Our study findings tentatively conclude that paracetamol can induce early patent ductus arteriosus closure without significant side effects but that its efficacy is not superior to that of indomethacin.  

3. The efficacy and safety of oral paracetamol versus oral ibuprofen for patent ductusarteriosusclosure in preterm neonates – A systematic review and meta-analysis 

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411098/

Objective
This systematic review and meta-analysis aimed to synthesize the latest evidence on the efficacy and safety of oral acetaminophen compared to oral ibuprofen for patent ductus arteriosus (PDA) in preterm infants. 

Methods 
We performed a systematic literature search on topics that assesses the use of oral paracetamol compared to oral ibuprofen in preterm neonates diagnosed with PDA from PubMed, EuropePMC, Cochrane Central Database, ScienceDirect, ProQuest, ClinicalTrials.gov, and hand-sampling from potential articles. 

Results 
There were 1547 subjects from 10 selected studies. Primary closure rate was similar in both groups. Subgroup analysis on studies enrolling neonates with ≤30 weeks gestational age showed that ibuprofen was superior (OR 0.52 [0.31, 0.90], I2: 0%). On the other hand, paracetamol was superior neonates with ≤34 weeks gestational age (OR 1.73 [1.01, 2.94], I2: 30%). Reopening rate, surgical closure rate, mortality, intraventricular hemorrhage, and necrotizing enterocolitis were similar in both groups. Rate of renal dysfunction (OR 0.27 [0.10, 0.77], I2: 0%) and gastrointestinal bleeding (OR 0.31 [0.11, 0.88], I2: 0%) were lower in paracetamol group. Subgroup analysis of randomized controlled studies (RCTs) showed similar results. Meta-regression analysis showed that the primary closure rate was not influenced by gestational age, birth weight, and gender. GRADE demonstrates a low level of certainty for primary closure and mortality. Renal dysfunction and gastrointestinal bleeding have a moderate level of certainty. 

Conclusion 
There was no significant difference between the efficacy of oral paracetamol and oral ibuprofen. However, the rate of renal dysfunction and gastrointestinal bleeding were higher in oral ibuprofen.  

4. Oral Paracetamol vs Oral Ibuprofen in Patent DuctusArteriosus: A Randomized, Controlled,Noninferiority Trial  

Link: https://www-sciencedirect-com.york.ezproxy.cuny.edu/science/article/pii/S0022347620301311

Objective 
To test the hypothesis that oral paracetamol is non-inferior to oral ibuprofen in closing hemodynamically significant patent ductus arteriosus (hsPDA) with an a priori noninferiority (NI) margin of 15%. 

Study design 
Multicenter, randomized, controlled, NI trial conducted in level III neonatal intensive care units. Consecutively inborn preterm neonates of <32 weeks of gestation with hsPDA were included. Those with structural heart disease, major malformations, and contraindications for enteral feeding or for administration of study drugs were excluded. Interventions included oral paracetamol in the experimental arm and oral ibuprofen in the active control arm. The primary outcome was closure of hsPDA by 24 hours from the last dose of the study drug. Secondary outcome measures included closure of hsPDA by 24 hours after the first course of the study drug, rate of reopening after the first course, and adverse events associated with the study drug. 

Results 
Out of 1250 neonates screened, 161 were randomized. Oral paracetamol was noninferior to oral ibuprofen in closure of hsPDA by both per protocol analysis (62 [95.4%] vs 63 [94%]; relative risk [RR], 1.01 [95% CI, 0.94-1.1]; risk difference [RD], 1.4 [95% CI, −6 to 9]; P = .37) and intention-to-treat analysis (63 [89%] vs 65 [89%]; RR, 0.99 [95% CI, 0.89-1.12]; RD, −0.3 [95% CI, −11 to 10]; P = .47). All adverse events were comparable in the 2 study arms. 

Conclusions 
Oral paracetamol is noninferior to oral ibuprofen for the closure of hsPDA in preterm neonates of <32 weeks of gestation. No difference was observed in the adverse events studied.  

5. Comparison of the efficacy and safety of indomethacin, ibuprofen, and paracetamol in the closure of patent ductus arteriosus in preterm neonates – A randomized controlled trial 

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331836/

Introduction:
In this prospective study, we compared the efficacy and safety of ibuprofen, indomethacin, and paracetamol in the closure of patent ductus arteriosus (PDA) in preterm neonates.

Materials and Methods:
This randomized prospective study was conducted in the Division of Pediatric Cardiology, M. D. M and Umaid Hospital, Jodhpur. A total of 105 preterm neonates with gestational age <37 weeks and hemodynamically significant PDA (hs-PDA) diagnosed clinically and confirmed by echocardiography were enrolled. All neonates were randomly assigned in a ratio of 1:1:1 to oral indomethacin (Group A, 3 doses at an interval of 12 h with a starting dose of 0.2 mg/kg), oral ibuprofen (Group B, 10 mg/kg ibuprofen followed by 5 mg/kg/day for 2 days), or IV paracetamol (Group C, 15 mg/kg every 6 hourly for 3 consecutive days). After the completion of the first course, neonates were assessed clinically as well as by echocardiography to confirm PDA closure. If PDA remained open, the second course of the same drug was given and repeat assessment was done within 24 h of the last dose. In addition to an echocardiographic examination, complete blood counts, renal and liver function tests were performed.

Results:
Our study shows that there was no significant difference observed in PDA closure among all the three treatment groups after the completion of two courses of treatment. The cumulative rate of PDA closure was 68% in the indomethacin group, 77.14% in the ibuprofen group, and 71.43% in the paracetamol group (P = 0.716). There were no significant changes found in Hb, platelet, blood urea nitrogen (BUN), creatinine, and liver enzymes after treatment in the paracetamol group (P > 0.05). BUN and serum creatinine levels were significantly increased after treatment in indomethacin and ibuprofen groups (P < 0.0001 and P < 0.05, respectively).

Conclusion:
Our study shows that IV paracetamol is as effective as indomethacin and ibuprofen in promoting the closure of hs-PDA in premature infants with a better safety profile.

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting  (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Marconi E, Bettiol A, Ambrosio G, Perduca V, Vannacci A, TroianiS, Dani C, Mugelli A, Lucenteforte E (2019)	Systematic review and meta-analysis	64 RCTs and 24 observational studies including 14,568 subjects [5339 in RCTs and 9229 in observational studies, 8292 subjects received indomethacin, 4761 ibuprofen, 574 acetaminophen, and 941 control (including placebo or no intervention)]  Participants included preterm infants <37 weeks’ gestational age, full term ≥37 weeks’ gestational age, low-birth- weight <2500 g, and normal-weight infants ≥2500 g with PDA diagnosed either clinically or by echocardiographic criteria in the neonatal period of <28 days  PubMed, Embase, and the Register of Controlled Trials were searched from inception to October 30, 2018	Failure to close PDA [according to ECHO criteria and/or clinical evaluation]   Need for surgical PDA closure, death, and occurrence of selected AEs	PDA is one of the most common cardiovascular diseases in preterm infants and has been associated with increased mortality and major complications due to its role in regulating fetal circulation. Complications include metabolic acidosis, renal failure, intraventricular hemorrhage, pulmonary hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, prolonged ventilator dependence, and heart failure.   Indomethacin has been the mainstay of treatment for pharmacological closure of PDA but has been associated with adverse effects, such as renal insufficiency and necrotizing enterocolitis.   Ibuprofen has been shown to be as effective as Indomethacin in PDA closure with much less GI and renal adverse effects.   Acetaminophen, or Paracetamol, has more recently been found to be comparable to Ibuprofen in terms of efficacy with a more favorable safety profile though data is lacking in more conclusive long-term effects.   After pharmacological treatment, the proportion of patients in whom surgical closure was performed was 0.12 for Indomethacin, 0.09 for Ibuprofen, 0.03 for Acetaminophen, and 0.18 for control.   No significant differences in the odds of mortality, necrotizing enterocolitis, intraventricular hemorrhage, and oliguria were found between pharmacological treatments and control groups.   Acetaminophen showed favorable results in terms of efficacy that may be attributed to its inhibition of cyclo-oxygenase in favoring PDA closure.    Though Acetaminophen and Ibuprofen were not directly compared against each other as interventions in the pharmacologic treatment of PDA, the proportion of patients who required surgical closure was higher for Ibuprofen than for Acetaminophen, suggesting greater efficacy with Acetaminophen in non-operative PDA closure for preterm infants.	This study included term infants, which could have affected the interpretation of results as the physiology, natural history and management of PDA differ between term and preterm neonates  Variations in gestational age, birth weight, timing of treatment, co- morbidities and co-treatments may have influenced the results  Limited sample size of studies evaluating specific AEs or types of intervention may have resulted in imprecise estimated proportions
Xiao Y, Liu H, Hu R, You Q, Zeng M, Jiang X (2020)	Systematic review and meta-analysis	15 RCTs and quasi-RCTs comparing paracetamol with other drugs or placebo for PDA closure  Sample size included <37 weeks’ gestation premature infants or <2,500 g low birth weight infants with echocardiography-confirmed PDA  Cochrane Library, PubMed, CINAHL, and EMBASE databases were searched from the date of their inception to March 2018  Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA] guidelines and PICO [P, population; I, intervention/interest; C, comparator; O, outcome] principles were used	Primary PDA closure [defined as echocardiography confirmed closure of PDA after the first course of the treatment]  Overall PDA closure [defined as echocardiography confirmed closure of PDA after one or more courses of the treatment]  Neurodevelopmental impairment at any age reported  Moderate-to-severe cerebral palsy at any age reported	Paracetamol has recently been found to be an effective alternative treatment for PDA closure in patients with contraindications to Indomethacin or Ibuprofen or those who have not been successfully treated with these drugs.    Compared with the Ibuprofen group, in the Paracetamol group, the mean number of hours needed for PDA closure was significantly shorter.    The proportion of GI bleeding and hyperbilirubinemia were also significantly reduced in the Paracetamol group.  Paracetamol was found to be as efficacious as Ibuprofen in accelerating PDA closure in premature infants, as the primary closure and overall closure rates after treatment with Paracetamol were essentially similar to those after treatment with Ibuprofen.   There was a slight trend in the favoring of Paracetamol over Indomethacin in terms of primary PDA closure and overall PDA closure though the difference did not reach statistical significance.   Lastly, Paracetamol achieved more PDA closures than placebo.   While Paracetamol was not found to be superior to Indomethacin, compared to Ibuprofen, Paracetamol was more favorable in terms of time to PDA closure with fewer adverse effects.	Studies included were those only in English, possibly omitting trials published in other languages that satisfied inclusion criteria  Included trials had open-label or single-blinded or double- blinded designs, which were not always of high quality  Included studies may have had different echocardiographic criteria that may have impacted the outcomes   Due to the small number of studies, it was difficult to conduct a more detailed analysis
Pranata R, Yonas E, Vania R, Prakoso R (2020)	Systemic review and meta-analysis	1547 subjects from 10 selected studies [8 RCTs, and 2 retrospective cohort studies]  Participants included neonates ≤28 weeks [1 study], ≤30 weeks [2 studies], ≤32 weeks [2 studies], ≤34 weeks [2 studies], and ≤37 weeks [3 studies] of gestational age  Systematic literature search of PubMed, EuropePMC, Cochrane Central Database, ScienceDirect, ProQuest, ClinicalTrials.gov, and hand-sampling from potential articles	Primary closure rate defined as closure of PDA after the first course of treatment  Reopening rate [defined as reopening of PDA after previous closure with administration of paracetamol/ibuprofen], need for surgical closure, mortality, IVH, NEC, renal dysfunction, hepatic dysfunction, and GI bleeding	In both the Paracetamol and Ibuprofen groups, primary closure rate was found to be similar in neonates ≤32 weeks, neonates ≤34 weeks, and neonates ≤37 weeks of gestation.   Overall, the primary closure rate did not vary significantly with gestational age, birth weight, and male gender in percentage.   The reopening rate, need for surgical closure, rate of mortality, rate of intraventricular hemorrhage, and rate of necrotizing enterocolitis were also found to be similar in the Paracetamol and Ibuprofen groups.   However, the rate of acute renal dysfunction and the rate of GI bleeding was lower in the Paracetamol group.   Oral Paracetamol 15 mg/kg every 6 hours for 3 days administered through orogastric tube seemed to be superior in terms of safe PDA closure in preterm neonates medically.   In essence, Paracetamol was found to be as effective as Ibuprofen with lower adverse effects.	Possibility of publication bias, indicated by the asymmetrical funnel plot  Statistical power for subgroup analysis was limited due to the small study size  Incidence of safety outcomes, such as acute renal failure, might be insufficient to detect any significant difference between the paracetamol and ibuprofen groups at given sample size
Kumar A, Gosavi RS, Sundaram V, Oleti TP, Krishnan A, Kiran S, Kumar J, Murki S, Sundaram M, Saini SS, Dutta S (2020)	Randomized controlled trial	161 preterm neonates <32 weeks of gestation with hemodynamically stable PDA	Closure rate of hemodynamically stable PDA by 24 hours from the last dose of the study drug, irrespective of the course of the drug  Rate of hemodynamically stable PDA closure by 24 hours after the first course of the study drug, rate of reopening following the first course, need for surgical ligation for closure, all-cause mortality in hospital and adverse events with onset after the start of administration of the study drug	Because of its safer side effect profile, Paracetamol is suspected to be more favorable than Ibuprofen for PDA closure in hemodynamically stable preterm infants.   In this study, Paracetamol was administered orally through an orogastric tube at 15 mg/kg/dose in 6 hour intervals for 3 consecutive days whereas Ibuprofen was administered orally at 10 mg/kg/dose followed by 5 mg/kg/dose at 24 and 48 hours after the first dose.   Infants in whom the PDA remained open or reopened received a second course of the study drug or an appropriate open-label drug if any contraindication to the study drug was observed.   It was found that PDA closure was similar between the oral Paracetamol group and the oral Ibuprofen group.    While the Paracetamol group showed a lower closure rate following the first course of the drug compared to the Ibuprofen group, the difference was not statistically significant. This may, however, imply that oral Paracetamol may require a higher dosage or longer duration in order to achieve a comparable PDA closure rate as oral Ibuprofen.   Between the two groups, more patients in the oral Ibuprofen group experienced oliguria and major intraventricular hemorrhage while more definite or advanced-stage necrotizing enterocolitis was noted in the Paracetamol group. Though, these differences did not show statistical significance in terms of adverse events.    Nonetheless, the study was unable to prove that oral Paracetamol was safer than oral Ibuprofen despite the fact that it was ultimately found to be noninferior in the treatment of hsPDA closure in preterm infants.	Long-term safety of either study drug cannot be ascertained from this trial as evaluation of the long-term neurodevelopmental outcomes of the study subjects was not an objective   This study could not prove that oral paracetamol was safer than oral ibuprofen or that the  study was adequately powered to prove this hypothesis
Meena V, Meena DS, Rathore PS, Chaudhary S, Soni JP (2020)	Randomized controlled trial	105 preterm neonates <37 weeks gestation in the first 28 days of postnatal life with hemodynamically significant PDA diagnosed clinically and confirmed by echocardiography were included and randomized into 3 groups [indomethacin, ibuprofen, and paracetamol]	Rate of PDA closure after the first and second course of drugs  Number of neonates requiring rescue drug therapy for PDA closurein all groups  Side effects and complications in each group	No significant difference was observed in PDA closure among the treatment groups after the completion of two courses of treatment.  The rate of closure in the indomethacin group after the first course was 22.86%, 37.14% in the ibuprofen group, and 42.46% in the paracetamol group.  The cumulative rate of PDA closure was 68% in the indomethacin group, 77.14% in the ibuprofen group, and 71.43% in the paracetamol group.  No significant  difference was observed  in hemoglobin, platelet counts, or liver enzyme values after indomethacin treatment though BUN and serum creatinine levels were significantly increased after the treatment.  In the indomethacin group, necrotizing enterocolitis was observed in 5.71% and GI tract bleeding in 2.86%.   After oral ibuprofen treatment, no significant changes were noted in hemoglobin, platelet, and liver enzymes while BUN and serum creatinine level were significantly increased.  In the ibuprofen group, 2.86% had NEC and 2.86% had GI tract bleeding.  Patients treated with paracetamol had no significant change in hemoglobin, platelet, BUN, creatinine or liver enzymes after treatment.  No NEC or GI bleeding was observed in the paracetamol group.  Pulmonary hemorrhage was noted in 2.86% of the neonates in both the indomethacin and paracetamol groups while none occurred in the ibuprofen group.	Relatively small number of patients and a lack of blinding of the caregivers to the study intervention  Did not follow all patients to assess long-term outcomes

Conclusion(s):
Article 1: Pharmacological treatment with either indomethacin, ibuprofen or acetaminophen is effective in closing PDA and limiting PDA surgical closure in comparison with non-treatment. Ibuprofen limits the risk of IVH and oliguria in comparison to indomethacin while acetaminophen poses less risk of oliguria in comparison to indomethacin.
Article 2: Paracetamol can induce early PDA closure without noticeable side effects but was not shown to be superior to indomethacin, indicating the need for more well-designed studies to enrich the evidence of this treatment.
Article 3: There was no significant difference between the efficacy of oral paracetamol and oral ibuprofen. However, the rate of renal dysfunction and GI bleeding was higher in oral ibuprofen.
Article 4: Oral paracetamol is not inferior to oral ibuprofen in closure of hemodynamically stable PDA in preterm neonates <32 weeks gestation.
Article 5: IV Paracetamol is as effective as indomethacin and ibuprofen in promoting closure of hemodynamically stable PDA in premature infants with better safety profiles. 
Overall conclusion: While Indomethacin has traditionally been the first-line pharmacologic treatment for PDA in preterm infants, Ibuprofen, and more recently, Acetaminophen, have also been found to successfully promote PDA closure. In comparison to Ibuprofen [and Indomethacin], Acetaminophen has been shown to be equally efficacious in the treatment of PDA closure in preterm neonates with a safer side effect profile.

Weight of the Evidence
Article 1: This systematic review and meta-analysis primarily included RCTs and had a large sample size from which findings may be generalizable. Preterm infants born <37 weeks gestation were included, which is the population applicable to the patient in the case. 
Article 2: This systematic review and meta-analysis initially included original RCTs and quasi-RCTs recently published between December 2013 to March 2018. It then conducted a second updated search for studies limited to March 2018 to March 2019 using the same search strategy and searched for terms used in the first search. While almost no publication bias was found, the included trials had open-label or single-blinded or double- blinded designs, which were not always of high quality. 
Article 3: This systematic review and meta-analysis included RCTs and retrospective cohort studies that all assessed the use of oral paracetamol compared to oral ibuprofen in preterm neonates diagnosed with PDA. Though, limitations included the possibility of publication bias and a small sample size. 
Article 4: This article is a blinded RCT that included preterm neonates of <32 weeks of gestation with hemodynamically stable PDA. However, the study had a small sample size with only 161 neonates enrolled.
Article 5: This article is a RCT that included preterm neonates <37 weeks gestation where all eligible neonates were randomly assigned in a ratio of 1:1:1 among oral indomethacin, oral ibuprofen, and IV paracetamol groups. Though, only 105 neonates were enrolled.

Magnitude of Effect
Article 1: Treatment with Indomethacin resulted in a proportion of subjects with failed PDA closure of 0.24 (95% Confidence Interval, CI: 0.20, 0.29), 0.18 (0.14, 0.22) for treatment with ibuprofen, 0.19 (0.09, 0.30) for treatment with acetaminophen, and 0.59 (0.48, 0.69) for control. Following treatment, inverse associations between all active drugs and failure to close PDA were found (for indomethacin Odds Ratio, OR, was 0.17 [95% Credible Interval, CrI: 0.11-0.24], ibuprofen 0.19 [0.12-0.28], and acetaminophen 0.15 [0.09-0.26]) without differences among active drugs compared to control. Inverse associations between effective drugs and need for surgical closure, as compared to control (for indomethacin OR was 0.28 [0.15-0.50], ibuprofen 0.30 [0.16-0.54], and acetaminophen 0.19 [0.07-0.46]) were also found without differences among drugs.
Article 2: Paracetamol vs. Ibuprofen results showed no significant differences in the pooled results of the primary outcomes between the two set comparison groups regardless of whether a subgroup analysis was performed. Compared with the ibuprofen group, in the paracetamol group, the mean number of hours needed for PDA closure was significantly shorter [MD, −11.76 (95% CI, −12.88 to −10.64), P < 0.001] and the proportion of GI bleeding [RR, 0.19 95% CI, 0.07–0.56), P = 0.002] and hyperbilirubinemia [RR, 0.57 (95% CI, 0.34–0.97), P = 0.04] were significantly reduced. Paracetamol vs. Indomethacin results showed no significant intergroup differences in the pooled results of primary outcomes. Compared to those in paracetamol group, serum creatinine level [MD, −30.94 (95% CI, 34.34–27.54), P < 0.001] and BUN level [MD, −11.40 (95% CI, −12.30 to −10.50), P < 0.001] were significantly increased in the indomethacin group (P < 0.001), whereas platelet count [MD, 112.00 (95% CI, 103.02–120.98), P < 0.001] and serum bilirubin level after treatment [MD, 0.06 (95% CI, 0.01–0.11), P = 0.03] were significantly lower (P < 0.001) in the indomethacin group. Paracetamol vs. Placebo meta-analysis showed that the oral paracetamol group better promoted primary PDA closure than did the placebo group.
Article 3: The primary closure rate was similar in both paracetamol and ibuprofen group (OR 1.02 [0.77, 1.35], p = 0.89; I2:38%, p = 0.11) in studies enrolling neonates with ≤28 weeks, ≤32 weeks, and ≤37 weeks of gestational age. However, a subgroup analysis on studies enrolling neonates with ≤30 weeks of gestational age showed that ibuprofen was superior compared to paracetamol (OR 0.52 [0.31, 0.90], p = 0.02; I2: 0%, p = 0.39). Conversely, subgroup analysis on ≤34 weeks of gestational age demonstrated that paracetamol was superior to ibuprofen (OR 1.73 [1.01, 2.94], p = 0.04; I2: 30%, p = 0.23). Subgroup analysis of all studies that enrolled patients with ≤32 weeks (including ≤28 weeks, ≤30 weeks, and ≤32 weeks) of gestational age showed no significant differences between oral paracetamol and oral ibuprofen (OR 0.67 [0.43,1.05], p = 0.08; I2: 0%, p = 0.42).
Article 4: The primary outcome of PDA closure was similar in the oral paracetamol arm and oral ibuprofen arm by per-protocol analysis (62 [95.4%] vs 63 [94%]; RR, 1.01 [95% CI], 0.94-1.1]; RD, 1.4 [95% CI, -6 to 9]; P = .37). The time to closure of hemodynamically stable PDA was not different between the oral paracetamol and ibuprofen arms (median, 66 hours [95% CI, 61-71 hours] vs 49 hours [95% CI, 44- 54 hours]; P = .71, log-rank test), and no difference in adverse outcomes was observed between the study arms.
Article 5: The rate of closure after the first course was 22.86% in the indomethacin group, 37.14% in the ibuprofen group, and 42.46% in the paracetamol group. The cumulative rate of PDA closure was 68% in the indomethacin group, 77.14% in the ibuprofen group, and 71.43% in the paracetamol group (P = 0.716).

Clinical Significance
Article 1: Pharmacological treatment of PDA has changed over recent decades with the introduction of ibuprofen as an alternative to the traditional use of indomethacin. Acetaminophen is a more recent alternative that has been shown to be favorable for PDA closure.
Article 2: Paracetamol showed shorter mean days needed for closure, a lower percentage of GI bleeding, and lower risk of hyperbilirubinemia. Compared with indomethacin, paracetamol did not differ in efficacy or safety, and compared with placebo, paracetamol could promote PDA closure without adverse reactions.
Article 3: The rate of IVH, NEC, and mortality was similar in both groups. However, the incidence of renal dysfunction and GI bleeding was higher in the oral ibuprofen group. Thus, oral paracetamol 15 mg/kg every 6 h for 3 days administered through orogastric tube seems to be superior in terms of safety for PDA closure of preterm neonates.
Article 4: More neonates in the paracetamol arm required a second course of the trial drug, suggesting that a dose-response design study is needed to determine the optimum right dose, frequency, and duration of oral paracetamol therapy for effective PDA closure. 
Article 5: In the oral indomethacin group, BUN and serum creatinine levels significantly increased after treatment though no significant differences were noted with regard to hemoglobin, platelets, or liver enzymes. Similarly, BUN and serum creatinine levels were found to be significantly increased after treatment in the oral ibuprofen group with no significant differences with respect to hemoglobin, platelets, or liver enzymes. In the IV paracetamol group, however, no significant changes were found in hemoglobin, platelets, BUN, creatinine, or liver enzyme values after treatment.

Other Considerations
Article 1: No significant differences in the odds of mortality, NEC, IVH, and oliguria were found between pharmacological treatments and control groups.
Article 2: Double-blind parallel trials and cohort studies of a larger sample should be conducted to further confirm the long- and short-term efficiency and safety of the drugs used and the differences among them. 
Article 3: Larger, multi-center RCTs are needed to establish the safety outcome of oral paracetamol versus oral ibuprofen. Additionally, oral paracetamol/ibuprofen might be affected by gestational age, and further studies are necessary to confirm or deny such findings. 
Article 4: Even though the safety outcomes did not differ between the study arms, the study could not prove that oral paracetamol was safer than oral ibuprofen or that the study was adequately powered to prove this hypothesis.
Article 5: The study was limited by a relatively small number of patients and a lack of blinding of the caregivers to the study intervention. Long-term outcomes were also not assessed.

Clinical Bottom Line:  Ultimately, though evidence may be preliminary, Acetaminophen has, indeed, been found to be non-inferiorly effective for closure of PDA in preterm infants irrespective of weeks gestation or birth weight. Therefore, I would inform the parents of the patient in the case description of this current evidence regarding Acetaminophen but iterate that there is no significant difference in terms of efficacy outcomes between oral Acetaminophen and oral Ibuprofen at present. I would also add that Acetaminophen may prove to be safer for their daughter if they are worried about adverse effects, as it does not damage the GI mucosa and thus leads to much less risk of GI bleeding than Ibuprofen as well as adverse renal effects possible with Indomethacin.