Paracetamol (acetaminofeno) para el conducto arterial persistente en lactantes prematuros o de bajo peso al nacer
Appendices
Appendix 1. 2021 CENTRAL search strategy
Cochrane CENTRAL
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| Cochrane CENTRAL via CRS (October 13, 2021) |
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| ID | Search | Hits |
| #1 | MeSH descriptor: [Acetaminophen] this term only | 3340 |
| #2 | (paracetamol* or acetaminophen*):ti,ab,kw | 11072 |
| #3 | #1 OR #2 | 11072 |
| #4 | MeSH descriptor: [Ductus Arteriosus, Patent] this term only | 294 |
| #5 | ((patent or patency or persistence or persistent or presistens) NEAR/2 (duct* botalli or ductus arteriosus)):ti,ab,kw | 1060 |
| #6 | (ductus arteriosus obliteration or open ductus botalli or truncus arteriosus persistens):ti,ab,kw | 18 |
| #7 | (PDA or "P.D.A."):ti,ab,kw | 1058 |
| #8 | #4 OR #5 OR #6 OR #7 | 1679 |
| #9 | infant or infants or infant's or "infant s" or infantile or infancy or newborn* or "new born" or "new borns" or "newly born" or neonat* or baby* or babies or premature or prematures or prematurity or preterm or preterms or "pre term" or premies or "low birth weight" or "low birthweight" or VLBW or LBW or ELBW or NICU | 94134 |
| #10 | MeSH descriptor: [Infant, Newborn] explode all trees | 16442 |
| #11 | #9 OR #10 | 94134 |
| #12 | #3 AND #8 AND #11 | 121 |
Appendix 2. 2021 MEDLINE search strategy
MEDLINE (OVID)
| Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process, In‐Data‐Review & Other Non‐Indexed Citations, Daily and Versions(R) <1946 to October 13, 2021> |
|
|
| 1 Acetaminophen/ (19218) |
| 2 (paracetamol* or acetaminophen*).mp. (30917) |
| 3 or/1‐2 [Paracetamol] (30917) |
| 4 Ductus Arteriosus, Patent/ (9328) |
| 5 ((patent or patency or persisten*) adj2 ductus*).ti,ab,kw,kf. (10157) |
| 6 ((ductus adj2 (arteriosus* or obliteration* or truncus*)) or ductus botalli*).ti,ab,kw,kf. (12696) |
| 7 (PDA or "P.D.A.").ti,ab,kw,kf. (13786) |
| 8 or/4‐7 [PDA] (26215) |
| 9 exp infant, newborn/ or Intensive Care, Neonatal/ or Intensive Care Units, Neonatal/ (638294) |
| 10 (baby* or babies or infant or infants or infant? or infantile or infancy or low birth weight or low birthweight or neonat* or newborn* or new born or new borns or newly born or premature or prematures or prematurity or preterm or preterms or pre term or preemie or preemies or premies or premie or VLBW or LBW or ELBW or NICU).ti,ab,kw,kf. (945715) |
| Annotation: added PREEMIE July 2021 |
| 11 or/9‐10 [Filter: Neonatal Population 2021‐‐MEDLINE] (1224190) |
| 12 randomized controlled trial.pt. (546116) |
| 13 controlled clinical trial.pt. (94450) |
| 14 (randomized or randomised).ti,ab. (693527) |
| 15 placebo.ab. (222200) |
| 16 drug therapy.fs. (2385186) |
| 17 randomly.ab. (367680) |
| 18 trial.ab. (571622) |
| 19 groups.ab. (2258288) |
| 20 (quasirandom* or quasi‐random*).ti,ab. (5232) |
| 21 exp animals/ not humans/ (4897471) |
| 22 (or/12‐20) not 21 [RCT Filter‐Based on Cochrane‐ Box 6.4.c: Cochrane Highly Sensitive Search Strategy] (4504513) |
| 23 meta‐analysis/ or "systematic review"/ or network meta‐analysis/ [/ finds same as.pt. syntax] (242441) |
| 24 ((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab,kf,kw. (243488) |
| 25 ((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab,kf,kw. (32055) |
| 26 (data synthes* or data extraction* or data abstraction*).ti,ab,kf,kw. (32434) |
| 27 (hand search* or handsearch*).ti,ab,kf,kw. (10090) |
| 28 (mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab,kf,kw. (30189) |
| 29 meta‐analysis as topic/ or network meta‐analysis/ (23127) |
| 30 (met analy* or metanaly* or meta regression* or metaregression*).ti,ab,kf,kw. (11889) |
| 31 (medline or cochrane or pubmed or medlars or embase or cinahl).ab. (264680) |
| 32 (cochrane or systematic review?).jw. (18785) |
| 33 or/23‐32 [SR filter‐Medline; based on CADTHhttps://www.cadth.ca/strings‐attached‐cadths‐database‐search‐filters] (475171) |
| 34 3 and 8 and 11 [Results before filters] (198) |
| 35 3 and 8 and 11 and 22 [RCT Results] (139) |
| 36 3 and 8 and 11 and 33 [SR Results] (17) |
| 37 or/35‐36 [All results Medline] (140) |
Appendix 3. 2021 EMBASE search strategy
EMBASE (OVID)
| Embase <1974 to 2021 October 13> |
|
|
| 1 paracetamol/ (98647) |
| 2 (paracetamol* or acetaminophen*).mp. (105519) |
| 3 or/1‐2 [Paracetamol] (105519) |
| 4 patent ductus arteriosus/ or ductus arteriosus obliteration/ (17592) |
| 5 ((patent or patency or persisten*) adj2 ductus*).ti,ab,kw,kf. (12197) |
| 6 ((ductus adj2 (arteriosus* or obliteration* or truncus*)) or ductus botalli*).ti,ab,kw,kf. (14797) |
| 7 (PDA or "P.D.A.").ti,ab,kw. (18699) |
| 8 or/4‐7 [PDA] (36452) |
| 9 newborn/ or prematurity/ or newborn intensive care/ or newborn care/ (630424) |
| 10 (infant or infants or infant? or infantile or infancy or newborn* or new born or new borns or newly born or neonat* or baby* or babies or premature or prematures or prematurity or preterm or preterms or pre term or preemie or preemies or premies or low birth weight or low birthweight or VLBW or LBW or ELBW or NICU).ti,ab,kw. (1098383) |
| 11 or/9‐10 [Filter: Neonatal Population 2021‐OVID EMBASE] (1313774) |
| 12 Randomized controlled trial/ or Controlled clinical study/ (868285) |
| 13 random$.ti,ab,kw. (1719791) |
| 14 Randomization/ (92009) |
| 15 placebo.ti,ab,kw. (331129) |
| 16 ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab,kw. (249306) |
| 17 double blind procedure/ (188665) |
| 18 (controlled adj7 (study or design or trial)).ti,ab,kw. (390062) |
| 19 parallel group$1.ti,ab. (28229) |
| 20 (crossover or cross over).ti,ab. (113029) |
| 21 ((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab. (364685) |
| 22 (open adj label).ti,ab. (91644) |
| 23 or/12‐22 [ Terms based on Cochrane Central strategy‐https://www.cochranelibrary.com/central/central‐creation] (2468486) |
| 24 (exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/) and (human/ or normal human/ or human cell/) (22852627) |
| 25 exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/ (29614480) |
| 26 25 not 24 [Animal Exclusion‐Anne Eisinga, Cochrane UK] (6761853) |
| 27 23 not 26 [Filter: RCT‐EMBASE] (2204346) |
| 28 meta‐analysis/ or "systematic review"/ or "meta analysis (topic)"/ [EMTREE] (464244) |
| 29 ((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab,kw. (298228) |
| 30 ((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab,kw. (45337) |
| 31 (data synthes* or data extraction* or data abstraction*).ti,ab,kw. (39889) |
| 32 (hand search* or handsearch*).ti,ab,kw. (12296) |
| 33 (mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab,kw. (39963) |
| 34 (met analy* or metanaly* or meta regression* or metaregression*).ti,ab,kw. (15275) |
| 35 (medline or cochrane or pubmed or medlars or embase or cinahl).ab. (335516) |
| 36 (cochrane or systematic review?).jn,jx. (29835) |
| 37 (overview adj2 reviews).ti. (96) |
| 38 or/28‐37 [SR Filter: EMBASE based on CADTH filter: https://www.cadth.ca/strings‐attached‐cadths‐database‐search‐filters] (692402) |
| 39 3 and 8 and 11 [Results before filters] (419) |
| 40 3 and 8 and 11 and 27 [RCT Results] (117) |
| 41 3 and 8 and 11 and 38 [SR Results] (49) |
| 42 or/40‐41 [All results EMBASE] (137) |
Appendix 4. 2022 CINAHL search strategy
Note: CINAHL was searched prior to publication of this review on 1 March 2022.
| # | Query | Results |
| 1 | (MH "Acetaminophen") | 6,144 |
| 2 | (paracetamol* or acetaminophen*) | 9,043 |
| 3 | S1 OR S2 | 9,043 |
| 4 | (MH "Ductus Arteriosus, Patent") | 1,812 |
| 5 | ((patent or patency or persisten*) N2 ductus*) | 2,640 |
| 6 | ((ductus N2 (arteriosus* or obliteration* or truncus*)) or ductus botalli*) | 2,842 |
| 7 | S4 OR S5 OR S6 | 2,895 |
| 8 | S3 AND S7 | 118 |
| 9 | (MH "Infant, Newborn+") OR (MH "Infant, Large for Gestational Age") OR (MH "Infant, Low Birth Weight+") OR (MH "Infant, Postmature") OR (MH "Infant, Premature") | 152,974 |
| 10 | (MH "Intensive Care, Neonatal+") OR (MH "Intensive Care Units, Neonatal") | 19,598 |
| 11 | TI (baby* or babies or infant? or infantile or infancy or low birth weight or low birthweight or neonat* or neo‐nat* or newborn* or new born? or newly born or premature or pre‐mature or pre‐matures or prematures or prematurity or pre‐maturity or preterm or preterms or pre term? or preemie or preemies or premies or premie or VLBW or LBW or ELBW or NICU) OR AB (baby* or babies or infant? or infantile or infancy or low birth weight or low birthweight or neonat* or neo‐nat* or newborn* or new born? or newly born or premature or pre‐mature or pre‐matures or prematures or prematurity or pre‐maturity or preterm or preterms or pre term? or preemie or preemies or premies or premie or VLBW or LBW or ELBW or NICU) | 244,086 |
| 12 | S9 OR S10 OR S11 | 303,174 |
| 13 | (MH "Single‐Blind Studies") OR (MH "Triple‐Blind Studies") OR (MH "Randomized Controlled Trials+") OR (MH "Double‐Blind Studies") | 166,983 |
| 14 | (MH "Clinical Trials+") | 335,050 |
| 15 | TI (randomized or randomised) OR AB (randomized or randomised) OR SU (randomized or randomised) | 318,519 |
| 16 | AB randomly | 102,144 |
| 17 | AB placebo | 63,624 |
| 18 | AB (trial) | 320,155 |
| 19 | AB groups | 848,546 |
| 20 | TI (quasirandom* or quasi‐random*) OR AB (quasirandom* or quasi‐random*) | 2,167 |
| 21 | S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 | 1,245,653 |
| 22 | (MH "Animal Studies") | 145,201 |
| 23 | (MH "Human") | 2,522,835 |
| 24 | S22 NOT S23 | 121,023 |
| 25 | S21 NOT S24 | 1,207,597 |
| 26 | (MH "Systematic Review") | 107,441 |
| 27 | (MH "Meta Analysis") | 60,814 |
| 28 | (TI ((systematic* N3 (review* or overview*)) or (methodologic* N3 (review* or overview*))) ) OR ( AB ((systematic* N3 (review* or overview*)) or (methodologic* N3 (review* or overview*)))) | 130,752 |
| 29 | (TI ((integrative N3 (review* or overview*)) or (collaborative N3 (review* or overview*)) or (pool* N3 analy*))) OR (AB ((integrative N3 (review* or overview*)) or (collaborative N3 (review* or overview*)) or (pool* N3 analy*))) | 17,575 |
| 30 | (TI (data synthes* or data extraction* or data abstraction*)) OR (AB (data synthes* or data extraction* or data abstraction*)) | 13,094 |
| 31 | AB (hand search* or handsearch*) | 4,762 |
| 32 | AB (mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*) | 9,059 |
| 33 | (TI met analy* or metanaly* or meta regression* or metaregression*)) OR (AB met analy* or metanaly* or meta regression* or metaregression*)) | 4,525 |
| 34 | AB (medline or cochrane or pubmed or medlars or embase OR CINAHL) | 109,986 |
| 35 | S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 | 233,326 |
| 36 | S8 AND S12 | 108 |
| 37 | (S25 OR S35) AND S36 | 51 |
Appendix 5. Search methods used for the 2020 published version
We used the criteria and standard methods of Cochrane and Cochrane Neonatal.
We conducted a comprehensive search including: Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 10) in the Cochrane Library; MEDLINE via PubMed (1966 to 6 November 2017); Embase (1980 to 6 November 2017); and CINAHL (1982 to 6 November 2017) using the following search terms: (Acetaminophen[Mesh] OR paracetamol OR acetaminophen) AND (Ductus Arteriosus, Patent[Mesh] OR patent ductus arteriosus or PDA), plus database‐specific limiters for RCTs and neonates (see below for the full search strategies for each database). We did not apply language restrictions. Conference proceedings were not specifically searched but we identified some by the other searches.
We searched clinical trial registries for ongoing or recently completed trials (ClinicalTrials.gov; the World Health Organization’s International Trials Registry and Platform, and the ISRCTN Registry).
PubMed: ((infant, newborn[MeSH] OR infan* OR newborn OR neonat* OR premature OR low birth weight OR VLBW OR LBW) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh]))
Embase: ((exp infant) OR (infan* OR newborn or neonat* OR premature or very low birth weight or low birth weight or VLBW or LBW).mp AND (human not animal) AND (randomized controlled trial or controlled clinical trial or randomized or placebo or clinical trials as topic or randomly or trial or clinical trial).mp
CINAHL: (infan* OR newborn OR neonat* OR premature OR low birth weight OR VLBW OR LBW) AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)
Cochrane Library: (infan* or newborn or neonat* or premature or preterm or very low birth weight or low birth weight or VLBW or LBW)
Appendix 6. Search methods used for the 2015 published version
For the 2015 review, we used the standard search strategy of the Cochrane Neonatal Review Group as outlined in the Cochrane Library. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library), MEDLINE (1966 to December 2013), EMBASE (1980 to December 2013) and CINAHL (1982 to December 2013). Ms Colleen Ovelman, Trials Search Co‐ordinator, Cochrane Neonatal Review Group, conducted the searches modified as needed for the different databases. For MEDLINE the following search string was used: (paracetamol OR acetaminophen) AND (patent ductus arteriosus or PDA) AND ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomised controlled trial [pt] OR controlled clinical trial [pt] OR Clinical Trial[ptyp] OR randomised [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh])). Relevant reviews related to the topic were identified. No language restrictions were applied.
We conducted electronic searches of abstracts from the meetings of the Pediatric Academic Societies 2000 to 2013 and the Perinatal Society of Australia and New Zealand 2000 to 2013.
We searched the following clinical trials registries for ongoing or recently completed trials: clinicaltrials.gov; controlled‐trials.com; anzctr.org.au; who.int/ictrp in December 2013. We searched the Web of Science for articles quoting identified RCTs in December 2013.
We searched the first 200 hits on Google Scholar to identify grey literature. We limited the Google Scholar search to the first 200 hits as in our experience the yield is poor after 200 hits.
We repeated the search of MEDLINE in August 2014 and did not identify any new trials.
Appendix 7. 2021 Trial registry searches
| Trial Registers |
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| Search terms: (acetaminophen OR paracetamol) AND patent ductus |
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| ISRCTN; No date limit: October 18,2021 | 2 |
| Clinicaltrials.gov: October 18, 2021: (acetaminophen OR paracetamol) AND patent ductus | 27 |
| ICTRP: October 18, 2021; no date limit | 67 |
| Subtotal | 96 |
| Duplicates | 27 |
| Net | 69 |
Appendix 8. 'Risk of bias' tool
1. Random sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?
For each included study, we categorised the method used to generate the allocation sequence as:
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low risk (any truly random process e.g. random number table; computer random number generator);
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high risk (any non‐random process e.g. odd or even date of birth; hospital or clinic record number); or
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unclear risk.
2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?
For each included study, we categorised the method used to conceal the allocation sequence as:
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low risk (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);
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high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or
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unclear risk
3. Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?
For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or class of outcomes. We categorised the methods as:
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low risk, high risk or unclear risk for participants; and
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low risk, high risk or unclear risk for personnel.
4. Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?
For each included study, we categorised the methods used to blind outcome assessment. Blinding was assessed separately for different outcomes or class of outcomes. We categorised the methods as:
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low risk for outcome assessors;
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high risk for outcome assessors; or
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unclear risk for outcome assessors.
5. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?
For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re‐included missing data in the analyses. We categorised the methods as:
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low risk (< 20% missing data);
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high risk (≥ 20% missing data); or
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unclear risk.
6. Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?
For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. For studies in which study protocols were published in advance, we compared prespecified outcomes versus outcomes eventually reported in the published results. If the study protocol was not published in advance, we contacted study authors to gain access to the study protocol. We assessed the methods as:
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low risk (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);
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high risk (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified outcomes of interest and are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); or
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unclear risk.
7. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?
For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data‐dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:
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low risk;
-
high risk;
-
unclear risk.
If needed, we explored the impact of the level of bias through undertaking sensitivity analyses.
Study flow diagram for 2022 review update
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Funnel plot: failure of PDA closure after first course of treatment for comparison 'Paracetamol (oral or IV) versus ibuprofen (oral or IV)'
Funnel plot: failure of PDA closure after second course of treatment for comparison 'Paracetamol (oral or IV) versus ibuprofen (oral or IV)'
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 1: Failure of PDA closure after first course of treatment
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 2: Neurodevelopmental impairment
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 3: All‐cause mortality during initial hospital stay
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 4: Neonatal mortality (deaths during the first 28 days of life)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 5: Re‐opening of the ductus arteriosus
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 6: Failure of PDA closure after second course of treatment
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 7: Surgical closure of the PDA
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 8: Duration of ventilator support (days)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 9: Duration of need for supplementary oxygen (days)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 10: Pulmonary hemorrhage
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 11: Pulmonary hypertension
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 12: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 13: Moderate to severe BPD (according to the new criteria)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 14: Severe BPD (according to the new criteria)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 15: Intraventricular hemorrhage (IVH, Grade I‐IV)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 16: Severe IVH (Grade III‐IV)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 17: Periventricular leukomalacia
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 18: Necrotizing enterocolitis (NEC)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 19: Intestinal perforation
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 20: Gastrointestinal bleed
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 21: Retinopathy of prematurity stage ≥ 3
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 22: Retinopathy of prematurity requiring treatment
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 23: Oliguria (< 1 mL/kg/h)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 24: Sepsis
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 25: Post‐pre difference in serum or plasma levels of creatinine (mg/dL)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 26: Serum levels of aspartate transaminase (AST) IU/L
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 27: Post‐pre difference in serum levels of alanine aminotransferase (ALT) (IU/L)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 28: Serum bilirubin following treatment (µmol/L)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 29: Hyperbilirubinemia (serum bilirubin level higher than the exchange level according to the postnatal age and BW)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 30: Duration of hospitalization (days)
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 31: Mental developmental index (MDI) < 70
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 32: Psychomotor developmental index (PDI) < 70
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 33: Moderate to severe cerebral palsy
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 34: Deafness
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 35: Blindness
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 36: Mental developmental index
Comparison 1: Paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 37: Psychomotor developmental index
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 1: Failure of PDA closure after first course of treatment
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 2: All‐cause mortality during initial hospital stay
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 3: Failure of PDA closure after second course of treatment
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 4: Surgical closure of the PDA
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 5: Pulmonary hemorrhage
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 6: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 7: Intraventricular hemorrhage (IVH, Grade I‐IV)
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 8: IVH (Grade III‐IV)
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 9: Periventricular leukomalacia
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 10: Necrotizing enterocolitis (NEC)
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 11: Gastrointestinal bleed
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 12: Retinopathy of prematurity requiring treatment
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 13: Acute kidney injury
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 14: Sepsis
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 15: Post‐pre difference in serum creatinine (mg/dL)
Comparison 2: Paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 16: Serum bilirubin following treatment (µmol/L)
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 1: Failure of PDA closure after first course of prophylaxis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 2: All‐cause mortality during initial hospital stay
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 3: Duration of need for supplementary oxygen (days)
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 4: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 5: Intraventricular hemorrhage (IVH, Grade I‐IV)
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 6: Severe IVH (Grade III‐IV)
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 7: Intestinal perforation
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 8: Retinopathy of prematurity requiring treatment
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 9: Oliguria (< 1 mL/kg/h)
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 10: Sepsis
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 11: Cerebral palsy (5 years' follow‐up)
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 12: Autism spectrum disorder (5 years' follow‐up)
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 13: Attention deficit hyperactivity disorder (5 years' follow‐up)
Comparison 3: Prophylactic paracetamol (oral or IV) versus placebo (IV) or no intervention, Outcome 14: Pervasive developmental disorder (5 years' follow‐up)
Comparison 4: Early paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 1: Failure of PDA closure after first course of treatment
Comparison 4: Early paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 2: Failure of PDA closure after two courses of treatment
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 1: Failure of PDA closure after one course of treatment
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 2: Surgical closure of PDA
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 3: Pulmonary hemorrhage
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 4: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 5: Necrotizing enterocolitis (NEC)
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 6: Retinopathy of prematurity requiring treatment
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 7: Acute kidney injury
Comparison 5: Late paracetamol (oral or IV) versus placebo (oral or IV) or no intervention, Outcome 8: Failure of PDA closure/non‐significant PDA after treatment
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 1: Failure of PDA closure after first course of treatment
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 2: Failure of PDA closure after two courses of treatment
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 3: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 4: Intraventricular hemorrhage (IVH, Grade I‐IV)
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 5: Severe IVH (Grade III‐IV)
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 6: Periventricular leukomalacia
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 7: Necrotizing enterocolitis (NEC)
Comparison 6: Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention, Outcome 8: Oliguria (< 1 mL/kg/h)
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 1: Failure of PDA closure after first course of treatment
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 2: All‐cause mortality during initial hospital stay
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 3: Failure of PDA closure after two courses of treatment
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 4: Surgical closure of PDA
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 5: Intraventricular hemorrhage (IVH, Grade I‐IV)
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 6: Severe IVH (Grade III‐IV)
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 7: Necrotizing enterocolitis (NEC)
Comparison 7: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus ibuprofen (oral or IV), Outcome 8: Gastrointestinal bleed
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 1: Failure of PDA closure after first course of treatment
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 2: All‐cause mortality during initial hospital stay
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 3: Failure of PDA closure after two courses of treatment
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 4: Surgical closure of PDA
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 5: Intraventricular hemorrhage (IVH, Grade I‐IV)
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 6: Severe IVH (Grade III‐IV)
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 7: Necrotizing enterocolitis (NEC)
Comparison 8: Subgroup analysis (< 32 weeks' GA): paracetamol (oral or IV) versus indomethacin (oral or IV), Outcome 8: Gastrointestinal bleed
| Paracetamol (oral or IV) versus ibuprofen (oral or IV) for PDA in preterm or low birth weight infants | ||||||
| Patient or population: preterm or low birth weight infants with PDA | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Oral/IV ibuprofen | Oral/IV paracetamol | |||||
| Failure of PDA closure after first course of treatment (assessed by post‐treatment ECHO) | High‐risk study population | RR 1.02 | 1535 | ⊕⊕⊕⊝ |
| |
| 299 per 1000 | 308 per 1000 | |||||
| All‐cause mortality during initial hospital stay | High‐risk study population | RR 1.09 | 734 | ⊕⊕⊕⊝ |
| |
| 166 per 1000 | 181 per 1000 | |||||
| Necrotizing enterocolitisduring initial hospital stay (by radiological diagnosis) | 70 per 1000 | 91 per 1000 (61 to 136) | RR 1.30 | 1015 | ⊕⊕⊕⊝ |
|
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| aFor all three key critical outcomes, we downgraded the evidence by one level to moderate certainty, due to concerns regarding blinding of personnel and outcome assessment. | ||||||
| Paracetamol (oral or IV) versus indomethacin (IV) for PDA in preterm or low birth weight infants | ||||||
| Patient or population: preterm infants with PDA Settings: neonatal intensive care unit in India, Egypt, and the USA Intervention: paracetamol Comparison: indomethacin | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Indomethacin | Paracetamol | |||||
| Failure of PDA closure after first course of treatment (assessed by post‐treatment ECHO) | High‐risk study population | RR 1.02 (0.78 to 1.33) | 380 | ⊕⊕⊝⊝ Lowa
|
| |
| 297 per 1000 | 303 per 1000 | |||||
| All‐cause mortality during initial hospital stay (by clinical assessment) | 186 per 1000 | 160 per 1000 (73 to 358) | RR 0.86 (0.39 to 1.92) | 114 (2 studies) | ⊕⊕⊝⊝ Lowb |
|
| Necrotizing enterocolitis during initial hospital stay (by radiological diagnosis) | 93 per 1000 | 39 per 1000 (18 to 89) | RR 0.42 (0.19 to 0.96) | 384 (4 studies) | ⊕⊕⊝⊝ |
|
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| aWe downgraded evidence by two levels to low certainty due to concerns regarding blinding of personnel and outcome assessment, and high heterogeneity. | ||||||
| Prophylactic administration of paracetamol (oral or IV) versus placebo (IV) or no intervention for PDA in preterm or low birth weight infants | ||||||
| Patient or population: preterm infants with PDA Settings: neonatal intensive care units in Finland and Iran Intervention: paracetamol Comparison: placebo or no intervention | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo or no intervention | Paracetamol | |||||
| Failure of PDA closure after first course (assessed by post‐treatment ECHO) | High‐risk study population | RR 0.27 (0.18 to 0.42) | 240 | ⊕⊕⊝⊝
|
| |
| 612 per 1000 | 165 per 1000 | |||||
| All‐cause mortality during initial hospital stay (by clinical assessment) | High‐risk study population | RR 0.59 (0.24 to 1.44) | 240 | ⊕⊕⊝⊝
|
| |
| 91 per 1000 | 54 per 1000 | |||||
| Necrotizing enterocolitis during initial hospital stay (by radiological diagnosis)
| High‐risk study population | Not reported | Not reported | Not reported | Not reported | |
| Data not available | Data not available | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| aWe downgraded the evidence by two levels to low certainty due to concerns regarding selection bias, blinding of personnel, and high heterogeneity. | ||||||
| Early paracetamol (oral or IV, < 14 days postnatal age) versus placebo (oral or IV) or no intervention for PDA in preterm or low birth weight infants | ||||||
| Patient or population: preterm or low birth weight infants with PDA | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo/no intervention | Oral/IV paracetamol | |||||
| Failure of PDA closure after first course of treatment (by post‐treatment ECHO) | High‐risk study population | RR 0.35 (0.23 TO 0.53) | 127 (2 studies) | ⊕⊕⊝⊝
|
| |
| 790 per 1000 | 277 per 1000 (182 to 419) | |||||
| All‐cause mortality during initial hospital stay (by clinical assessment) | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
| Necrotizing enterocolitis during initial hospital stay (by radiological diagnosis) | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| aWe downgraded the evidence by two levels to low certainty due to concerns regarding selection bias, blinding of personnel and outcome assessors, and high heterogeneity. | ||||||
| Late paracetamol (oral or IV, ≥ 14 days postnatal age) versus placebo (oral or IV) or no intervention for PDA in preterm or low birth weight infants | ||||||
| Patient or population: preterm or low birth weight infants with PDA | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo/no intervention | Oral/IV paracetamol | |||||
| Failure of PDA closure after first course of treatment (assessed by post‐treatment ECHO) | High‐risk study population | RR 0.85 (0.72 to 1.01) | 55 (1 study) | ⊕⊕⊝⊝ |
| |
| 1000 per 1000 | 850 per 1000 (720 to 1000) | |||||
| All‐cause mortality during initial hospital stay (by clinical assessment) | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
| Necrotizing enterocolitis during initial hospital stay (by radiological diagnosis) | 36 per 1000 | 37 per 1000 (3 to 563) | RR 1.04 (0.07 to 15.76) | 55 (1 study) | ⊕⊕⊝⊝ |
|
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| aWe downgraded the evidence for both failure of PDA closure after first course of treatment and NEC by two levels to low certainty due to concerns regarding indirectness and imprecision. | ||||||
| Paracetamol plus ibuprofen (oral or IV) versus ibuprofen plus placebo (oral or IV) or no intervention for PDA in preterm or low birth weight infants | ||||||
| Patient or population: preterm or low birth weight infants with PDA | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Ibuprofen plus placebo | Paracetamol plus ibuprofen | |||||
| Failure of PDA closure after first course of treatment (assessed by post‐treatment ECHO) | 313 per 1000 | 241 per 1000 (134 to 425) | RR 0.77 (0.43 to 1.36) | 111 (2 studies) | ⊕⊕⊝⊝ | |
| All‐cause mortality during initial hospital stay (by clinical assessment) | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
| Necrotizing enterocolitis during initial hospital stay (radiological diagnosis) | 83 per 1000 | 28 per 1000 (1 to 621) | RR 0.33 (0.01 to 7.45)
| 24 (1 study) | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| aWe downgraded the evidence for both failure of PDA closure after first course of treatment and NEC by two levels to low certainty due to concerns regarding selection bias, blinding of personnel, outcome assessment, and imprecision. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Failure of PDA closure after first course of treatment Show forest plot | 18 | 1535 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.88, 1.18] |
| 1.2 Neurodevelopmental impairment Show forest plot | 1 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.44, 1.96] |
| 1.3 All‐cause mortality during initial hospital stay Show forest plot | 8 | 734 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.80, 1.48] |
| 1.4 Neonatal mortality (deaths during the first 28 days of life) Show forest plot | 1 | 90 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.43, 3.20] |
| 1.5 Re‐opening of the ductus arteriosus Show forest plot | 5 | 458 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.35 [0.85, 2.12] |
| 1.6 Failure of PDA closure after second course of treatment Show forest plot | 13 | 393 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.78, 1.21] |
| 1.7 Surgical closure of the PDA Show forest plot | 6 | 603 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.34, 1.08] |
| 1.8 Duration of ventilator support (days) Show forest plot | 3 | 260 | Mean Difference (IV, Fixed, 95% CI) | ‐0.56 [‐1.19, 0.08] |
| 1.9 Duration of need for supplementary oxygen (days) Show forest plot | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐12.40 [‐22.97, ‐1.83] |
| 1.10 Pulmonary hemorrhage Show forest plot | 5 | 442 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.36, 2.09] |
| 1.11 Pulmonary hypertension Show forest plot | 1 | 90 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.97] |
| 1.12 Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA Show forest plot | 2 | 141 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.45, 1.38] |
| 1.13 Moderate to severe BPD (according to the new criteria) Show forest plot | 1 | 160 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.22, 2.87] |
| 1.14 Severe BPD (according to the new criteria) Show forest plot | 1 | 90 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.32, 1.23] |
| 1.15 Intraventricular hemorrhage (IVH, Grade I‐IV) Show forest plot | 8 | 800 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.77, 1.22] |
| 1.16 Severe IVH (Grade III‐IV) Show forest plot | 6 | 544 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.63 [0.28, 1.43] |
| 1.17 Periventricular leukomalacia Show forest plot | 4 | 421 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.40 [0.56, 3.50] |
| 1.18 Necrotizing enterocolitis (NEC) Show forest plot | 10 | 1015 | Risk Difference (M‐H, Fixed, 95% CI) | 0.02 [‐0.01, 0.05] |
| 1.19 Intestinal perforation Show forest plot | 2 | 191 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.83 [0.12, 67.87] |
| 1.20 Gastrointestinal bleed Show forest plot | 7 | 693 | Risk Difference (M‐H, Fixed, 95% CI) | ‐0.05 [‐0.09, ‐0.02] |
| 1.21 Retinopathy of prematurity stage ≥ 3 Show forest plot | 2 | 191 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.43 [0.12, 1.55] |
| 1.22 Retinopathy of prematurity requiring treatment Show forest plot | 3 | 353 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.48, 1.85] |
| 1.23 Oliguria (< 1 mL/kg/h) Show forest plot | 5 | 608 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.47 [0.30, 0.76] |
| 1.24 Sepsis Show forest plot | 7 | 844 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.72, 1.22] |
| 1.25 Post‐pre difference in serum or plasma levels of creatinine (mg/dL) Show forest plot | 6 | 557 | Mean Difference (IV, Fixed, 95% CI) | ‐0.12 [‐0.13, ‐0.10] |
| 1.26 Serum levels of aspartate transaminase (AST) IU/L Show forest plot | 4 | 270 | Mean Difference (IV, Fixed, 95% CI) | 1.08 [‐0.16, 2.32] |
| 1.27 Post‐pre difference in serum levels of alanine aminotransferase (ALT) (IU/L) Show forest plot | 6 | 557 | Mean Difference (IV, Fixed, 95% CI) | 0.52 [0.00, 1.05] |
| 1.28 Serum bilirubin following treatment (µmol/L) Show forest plot | 4 | 400 | Mean Difference (IV, Fixed, 95% CI) | ‐10.56 [‐13.16, ‐7.96] |
| 1.29 Hyperbilirubinemia (serum bilirubin level higher than the exchange level according to the postnatal age and BW) Show forest plot | 1 | 160 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.57 [0.34, 0.97] |
| 1.30 Duration of hospitalization (days) Show forest plot | 4 | 361 | Mean Difference (IV, Fixed, 95% CI) | 2.79 [0.34, 5.24] |
| 1.31 Mental developmental index (MDI) < 70 Show forest plot | 1 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.41, 2.59] |
| 1.32 Psychomotor developmental index (PDI) < 70 Show forest plot | 1 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.33, 3.21] |
| 1.33 Moderate to severe cerebral palsy Show forest plot | 1 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.07 [0.41, 10.46] |
| 1.34 Deafness Show forest plot | 1 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.34 [0.01, 8.13] |
| 1.35 Blindness Show forest plot | 1 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.34 [0.01, 8.13] |
| 1.36 Mental developmental index Show forest plot | 1 | 61 | Mean Difference (IV, Fixed, 95% CI) | ‐0.40 [‐8.19, 7.39] |
| 1.37 Psychomotor developmental index Show forest plot | 1 | 61 | Mean Difference (IV, Fixed, 95% CI) | ‐0.20 [‐7.44, 7.04] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Failure of PDA closure after first course of treatment Show forest plot | 4 | 380 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.78, 1.33] |
| 2.2 All‐cause mortality during initial hospital stay Show forest plot | 2 | 114 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.39, 1.92] |
| 2.3 Failure of PDA closure after second course of treatment Show forest plot | 2 | 86 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.70, 1.50] |
| 2.4 Surgical closure of the PDA Show forest plot | 2 | 237 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.31 [0.72, 2.38] |
| 2.5 Pulmonary hemorrhage Show forest plot | 3 | 347 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.28, 2.10] |
| 2.6 Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA Show forest plot | 2 | 94 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.16 [0.77, 1.75] |
| 2.7 Intraventricular hemorrhage (IVH, Grade I‐IV) Show forest plot | 2 | 275 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.42, 1.63] |
| 2.8 IVH (Grade III‐IV) Show forest plot | 2 | 112 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.28, 4.31] |
| 2.9 Periventricular leukomalacia Show forest plot | 1 | 75 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.34 [0.01, 8.14] |
| 2.10 Necrotizing enterocolitis (NEC) Show forest plot | 4 | 384 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.42 [0.19, 0.96] |
| 2.11 Gastrointestinal bleed Show forest plot | 3 | 347 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.63 [0.32, 1.25] |
| 2.12 Retinopathy of prematurity requiring treatment Show forest plot | 2 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.32 [0.58, 2.99] |
| 2.13 Acute kidney injury Show forest plot | 1 | 77 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.08 [0.13, 73.26] |
| 2.14 Sepsis Show forest plot | 3 | 314 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.59, 1.82] |
| 2.15 Post‐pre difference in serum creatinine (mg/dL) Show forest plot | 2 | 270 | Mean Difference (IV, Fixed, 95% CI) | ‐0.37 [‐0.40, ‐0.34] |
| 2.16 Serum bilirubin following treatment (µmol/L) Show forest plot | 1 | 200 | Mean Difference (IV, Fixed, 95% CI) | 1.03 [0.13, 1.93] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Failure of PDA closure after first course of prophylaxis Show forest plot | 3 | 240 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.27 [0.18, 0.42] |
| 3.2 All‐cause mortality during initial hospital stay Show forest plot | 3 | 240 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.59 [0.24, 1.44] |
| 3.3 Duration of need for supplementary oxygen (days) Show forest plot | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | ‐2.40 [‐16.41, 11.61] |
| 3.4 Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA Show forest plot | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.02, 8.45] |
| 3.5 Intraventricular hemorrhage (IVH, Grade I‐IV) Show forest plot | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.65 [0.28, 1.51] |
| 3.6 Severe IVH (Grade III‐IV) Show forest plot | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.07, 16.39] |
| 3.7 Intestinal perforation Show forest plot | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.02, 8.45] |
| 3.8 Retinopathy of prematurity requiring treatment Show forest plot | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.25 [0.14, 76.01] |
| 3.9 Oliguria (< 1 mL/kg/h) Show forest plot | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.29, 2.11] |
| 3.10 Sepsis Show forest plot | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.45 [0.36, 5.79] |
| 3.11 Cerebral palsy (5 years' follow‐up) Show forest plot | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.07, 15.66] |
| 3.12 Autism spectrum disorder (5 years' follow‐up) Show forest plot | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.13 Attention deficit hyperactivity disorder (5 years' follow‐up) Show forest plot | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.35 [0.02, 8.10] |
| 3.14 Pervasive developmental disorder (5 years' follow‐up) Show forest plot | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.35 [0.02, 8.10] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Failure of PDA closure after first course of treatment Show forest plot | 2 | 127 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.35 [0.23, 0.53] |
| 4.2 Failure of PDA closure after two courses of treatment Show forest plot | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.07 [0.02, 0.25] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Failure of PDA closure after one course of treatment Show forest plot | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.72, 1.01] |
| 5.2 Surgical closure of PDA Show forest plot | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.11 [0.13, 73.11] |
| 5.3 Pulmonary hemorrhage Show forest plot | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.07 [0.20, 21.56] |
| 5.4 Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA Show forest plot | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.61, 1.40] |
| 5.5 Necrotizing enterocolitis (NEC) Show forest plot | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.07, 15.76] |
| 5.6 Retinopathy of prematurity requiring treatment Show forest plot | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.11 [0.34, 28.09] |
| 5.7 Acute kidney injury Show forest plot | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 5.8 Failure of PDA closure/non‐significant PDA after treatment Show forest plot | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.29, 0.84] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 6.1 Failure of PDA closure after first course of treatment Show forest plot | 2 | 111 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.43, 1.36] |
| 6.2 Failure of PDA closure after two courses of treatment Show forest plot | 2 | 111 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.28 [0.08, 0.99] |
| 6.3 Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA Show forest plot | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.28, 2.27] |
| 6.4 Intraventricular hemorrhage (IVH, Grade I‐IV) Show forest plot | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.33 [0.38, 4.72] |
| 6.5 Severe IVH (Grade III‐IV) Show forest plot | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.50 [0.30, 7.43] |
| 6.6 Periventricular leukomalacia Show forest plot | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.45] |
| 6.7 Necrotizing enterocolitis (NEC) Show forest plot | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.45] |
| 6.8 Oliguria (< 1 mL/kg/h) Show forest plot | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.50 [0.05, 4.81] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 7.1 Failure of PDA closure after first course of treatment Show forest plot | 6 | 584 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.29 [1.00, 1.66] |
| 7.2 All‐cause mortality during initial hospital stay Show forest plot | 4 | 374 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.28 [0.85, 1.91] |
| 7.3 Failure of PDA closure after two courses of treatment Show forest plot | 4 | 86 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.48, 1.01] |
| 7.4 Surgical closure of PDA Show forest plot | 5 | 543 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.65 [0.36, 1.16] |
| 7.5 Intraventricular hemorrhage (IVH, Grade I‐IV) Show forest plot | 4 | 413 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.75, 1.19] |
| 7.6 Severe IVH (Grade III‐IV) Show forest plot | 4 | 354 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.42 [0.14, 1.24] |
| 7.7 Necrotizing enterocolitis (NEC) Show forest plot | 5 | 552 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.34 [0.71, 2.51] |
| 7.8 Gastrointestinal bleed Show forest plot | 2 | 290 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.22 [0.05, 1.01] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 8.1 Failure of PDA closure after first course of treatment Show forest plot | 3 | 310 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.27 [0.86, 1.87] |
| 8.2 All‐cause mortality during initial hospital stay Show forest plot | 2 | 114 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.39, 1.92] |
| 8.3 Failure of PDA closure after two courses of treatment Show forest plot | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.55, 1.40] |
| 8.4 Surgical closure of PDA Show forest plot | 2 | 237 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.31 [0.72, 2.38] |
| 8.5 Intraventricular hemorrhage (IVH, Grade I‐IV) Show forest plot | 2 | 275 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.42, 1.63] |
| 8.6 Severe IVH (Grade III‐IV) Show forest plot | 2 | 112 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.28, 4.31] |
| 8.7 Necrotizing enterocolitis (NEC) Show forest plot | 3 | 314 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.46 [0.20, 1.07] |
| 8.8 Gastrointestinal bleed Show forest plot | 2 | 277 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.33, 1.33] |
