Abstract
Background
Echocardiogram is the reference standard for the diagnosis of haemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. A simple blood assay for brain natriuretic peptide (BNP) or amino‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) may be useful in the diagnosis and management of hsPDA, but a summary of the diagnostic accuracy has not been reviewed recently.
Objectives
Primary objective: To determine the diagnostic accuracy of the cardiac biomarkers BNP and NT‐proBNP for diagnosis of haemodynamically significant patent ductus arteriosus (hsPDA) in preterm neonates. Our secondary objectives were: to compare the accuracy of BNP and NT‐proBNP; and to explore possible sources of heterogeneity among studies evaluating BNP and NT‐proBNP, including type of commercial assay, chronological age of the infant at testing, gestational age at birth, whether used to initiate medical or surgical treatment, test threshold, and criteria of the reference standard (type of echocardiographic parameter used for diagnosis, clinical symptoms or physical signs if data were available).
Search methods
We searched the following databases in September 2021: MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Web of Science. We also searched clinical trial registries and conference abstracts. We checked references of included studies and conducted cited reference searches of included studies. We did not apply any language or date restrictions to the electronic searches or use methodological filters, so as to maximise sensitivity.
Selection criteria
We included prospective or retrospective, cohort or cross‐sectional studies, which evaluated BNP or NT‐proBNP (index tests) in preterm infants (participants) with suspected hsPDA (target condition) in comparison with echocardiogram (reference standard).
Data collection and analysis
Two authors independently screened title/abstracts and full‐texts, resolving any inclusion disagreements through discussion or with a third reviewer. We extracted data from included studies to create 2 × 2 tables. Two independent assessors performed quality assessment using the Quality Assessment of Diagnostic‐Accuracy Studies‐2 (QUADAS 2) tool. We excluded studies that did not report data in sufficient detail to construct 2 × 2 tables, and where this information was not available from the primary investigators. We used bivariate and hierarchical summary receiver operating characteristic (HSROC) random‐effects models for meta‐analysis and generated summary receiver operating characteristic space (ROC) curves. Since both BNP and NTproBNP are continuous variables, sensitivity and specificity were reported at multiple thresholds. We dealt with the threshold effect by reporting summary ROC curves without summary points.
Main results
We included 34 studies: 13 evaluated BNP and 21 evaluated NT‐proBNP in the diagnosis of hsPDA. Studies varied by methodological quality, type of commercial assay, thresholds, age at testing, gestational age and whether the assay was used to initiate medical or surgical therapy. We noted some variability in the definition of hsPDA among the included studies.
For BNP, the summary curve is reported in the ROC space (13 studies, 768 infants, low‐certainty evidence). The estimated specificities from the ROC curve at fixed values of sensitivities at median (83%), lower and upper quartiles (79% and 92%) were 93.6% (95% confidence interval (CI) 77.8 to 98.4), 95.5% (95% CI 83.6 to 98.9) and 81.1% (95% CI 50.6 to 94.7), respectively. Subgroup comparisons revealed differences by type of assay and better diagnostic accuracy at lower threshold cut‐offs (< 250 pg/ml compared to ≥ 250 pg/ml), testing at gestational age < 30 weeks and chronological age at testing at one to three days. Data were insufficient for subgroup analysis of whether the BNP testing was indicated for medical or surgical management of PDA.
For NT‐proBNP, the summary ROC curve is reported in the ROC space (21 studies, 1459 infants, low‐certainty evidence). The estimated specificities from the ROC curve at fixed values of sensitivities at median (92%), lower and upper quartiles (85% and 94%) were 83.6% (95% CI 73.3 to 90.5), 90.6% (95% CI 83.8 to 94.7) and 79.4% (95% CI 67.5 to 87.8), respectively. Subgroup analyses by threshold (< 6000 pg/ml and ≥ 6000 pg/ml) did not reveal any differences. Subgroup analysis by mean gestational age (< 30 weeks vs 30 weeks and above) showed better accuracy with < 30 weeks, and chronological age at testing (days one to three vs over three) showed testing at days one to three had better diagnostic accuracy. Data were insufficient for subgroup analysis of whether the NTproBNP testing was indicated for medical or surgical management of PDA.
We performed meta‐regression for BNP and NT‐proBNP using the covariates: assay type, threshold, mean gestational age and chronological age; none of the covariates significantly affected summary sensitivity and specificity.
Authors' conclusions
Low‐certainty evidence suggests that BNP and NT‐proBNP have moderate accuracy in diagnosing hsPDA and may work best as a triage test to select infants for echocardiography. The studies evaluating the diagnostic accuracy of BNP and NT‐proBNP for hsPDA varied considerably by assay characteristics (assay kit and threshold) and infant characteristics (gestational and chronological age); hence, generalisability between centres is not possible. We recommend that BNP or NT‐proBNP assays be locally validated for specific populations and outcomes, to initiate therapy or follow response to therapy.
Keywords: Humans; Infant; Infant, Newborn; Cross-Sectional Studies; Infant, Premature; Natriuretic Peptide, Brain; Prospective Studies; Retrospective Studies
Plain language summary
In preterm infants, how accurate are the blood tests BNP and NT‐proBNP in identifying PDAs (patent ductus arteriosus) that require further treatment?
A number of preterm infants have a heart condition called patent ductus arteriosus (PDA). A PDA is a blood vessel that usually closes spontaneously in term and most preterm infants, but in some the PDA tends to remain open longer. Preterm infants who have an open PDA often remain stable; but in some, the large blood flow through the PDA can cause breathing and blood pressure problems and may need treatment. Usually, a large PDA is identified by a scan of the heart called an echocardiogram (echo). Performing an echo is time consuming and requires several resources; equipment, personnel trained to operate it and a paediatric cardiologist to review the images. Given how challenging it can be for many hospitals to have all these resources in place, alternate blood tests (BNP and NT‐proBNP) that can identify a large PDA in a timelier fashion may be useful.
What is the aim of this review?
To see if BNP and NT‐proBNP can identify a large PDA accurately so an echo need not be performed in all infants.
What was studied in the review?
The review looked at studies, which measured blood levels of BNP and NT‐proBNP in preterm infants and compared results to an echo.
What are the main results of the review?
We identified a total of 34 studies (13 studies for BNP and 21 studies for NT‐proBNP) to answer this question.
The results of these studies suggest that if the BNP blood test was performed in a group of 100 preterm infants who may have a large problematic PDA, the BNP blood test would miss only two of these infants but may wrongly detect large PDA in 13 of the 100 infants. Similarly, if the NT‐proBNP blood test was performed in a group of 100 preterm infants who may have a large problematic PDA, the NT‐proBNP blood test would miss only two of these infants but may wrongly detect large PDA in 11 of the 100 infants.
How reliable are the results of the studies in this review?
We have little confidence in the evidence because the results of the studies were inconsistent and variable.
Who do the results of this review apply to?
Preterm infants who are in the hospital for prematurity and are suspected to have a large PDA.
What are the implications of this review?
The blood tests were accurate enough to consider being used as first‐line tests, even though they were variable. Depending on the results, an echo could then be considered if needed. Such an approach may decrease the need for echo, which can be expensive and time consuming, requiring specialised equipment and trained personnel.
How up‐to‐date is this review?
The review included studies published up to September 2021.
Summary of findings
Summary of findings 1. BNP Summary of findings table.
| Review question: what is the accuracy of BNP used to diagnose haemodynamically significant PDA in preterm infants? | ||||||
| Population: preterm neonates with clinically suspected haemodynamically significant PDA | ||||||
| Settings: preterm neonates in the neonatal unit | ||||||
| Index test: brain natriuretic peptide (BNP) | ||||||
| Reference standard: echocardiogram | ||||||
| Study design: prospective or retrospective, cohort or cross‐sectional studies | ||||||
| № of studies (№ of infants): 13 studies (768 infants) | ||||||
| Specificity and likelihood ratios for BNP for fixed values of sensitivity (median and quartiles reported by included studies) in the diagnosis of a hsPDA | ||||||
| Statistic | Fixed value of sensitivity % | Estimated specificity % (95% CI) | Positive likelihood ratio (95% CI) | Negative likelihood ratio (95% CI) | ||
| Lower quartile | 79 | 95.5 (83.6 to 98.9) | 17.56 (4.82 to 71.82) | 0.22 (0.21 to 0.25) | ||
| Median | 83 | 93.6 (77.8 to 98.4) | 12.97 (3.74 to 51.88) | 0.18 (0.17 to 0.22) | ||
| Upper quartile | 92 | 81.1 (50.6 to 94.7) | 4.87 (1.86 to 17.36) | 0.10 (0.08 to 0.16) | ||
| Factors that may decrease certainty of evidence | Test accuracy CoE | |||||
| Risk of bias | Indirectness | Inconsistency | Imprecision | Publication bias | ||
|
GRADE rating of certainty of evidence |
not serious | not serious | serious | serious | none | ⊕⊕⊝⊝ Lowa |
CI: confidence interval; BNP: brain natriuretic peptide; CoE: certainty of evidence; hsPDA: haemodynamically significant patent ductus arteriosus; PDA: patent ductus arteriosus, aCertainty of evidence was downgraded to low due to inconsistency (variability in the estimated sensitivities and specificities among studies) and imprecision (wide 95% confidence intervals of the summary estimates of sensitivity and specificity).
Summary of findings 2. NT‐proBNP Summary of findings table.
| Review question: what is the accuracy of NT‐proBNP used to diagnose haemodynamically significant PDA in preterm infants? | ||||||
| Population: preterm neonates with clinically suspected haemodynamically significant PDA | ||||||
| Settings: preterm neonates in the neonatal unit | ||||||
| Index test: NT‐proBNP | ||||||
| Reference standard: echocardiogram | ||||||
| Study design: prospective or retrospective, cohort or cross‐sectional studies | ||||||
| № of studies (№ of infants): 21 studies (1459 infants) | ||||||
| Specificity and likelihood ratios for NT‐proBNP for fixed values of sensitivity (median and quartiles reported by included studies) in the diagnosis of a hsPDA | ||||||
| Statistic | Fixed value of sensitivity % | Estimated specificity % (95% CI) | Positive likelihood ratio (95% CI) | Negative likelihood ratio (95% CI) | ||
| Lower quartile | 85 | 90.6 (83.8 to 94.7) | 9.04 (5.24 to 16.04) | 0.17 (0.16 to 0.18) | ||
| Median | 92 | 83.6 (73.3 to 90.5) | 5.61 (3.44 to 9.68) | 0.10 (0.09 to 0.11) | ||
| Upper quartile | 94 | 79.4 (67.5 to 87.8) | 4.56 (2.89 to 7.70) | 0.08 (0.07 to 0.09) | ||
| Factors that may decrease certainty of evidence | Test accuracy CoE | |||||
| Risk of bias | Indirectness | Inconsistency | Imprecision | Publication bias | ||
|
GRADE rating of certainty of evidence |
not serious | not serious | serious | serious | none | ⊕⊕⊝⊝ Lowa |
CI: confidence interval; CoE: certainty of evidence; hsPDA: haemodynamically significant patent ductus arteriosus; NT‐proBNP: amino‐terminal pro‐B‐type natriuretic peptide; PDA: patent ductus arteriosus, aCertainty of evidence was downgraded to low due to inconsistency (variability in the estimated sensitivities and specificities among studies) and imprecision (wide 95% confidence intervals of the summary estimates of sensitivity and specificity).
Background
Haemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants is associated with significant mortality and morbidity (Hamrick 2010). Left‐to‐right shunting across the patent ductus arteriosus (PDA) results in pulmonary over‐circulation, which leads to respiratory decompensation, increasing risk of bronchopulmonary dysplasia (BPD) (Marshall 1999), intraventricular haemorrhage (IVH) (Dykes 1980; Evans 1996), necrotising enterocolitis (NEC) (Dollberg 2005), pulmonary haemorrhage and death (Cotton 1978; Dudell 1984; Noori 2009; Sellmer 2013). An international consensus has not been reached on the definition of an hsPDA (Zonnenberg 2012); however, most studies use a combination of clinical signs and echocardiographic criteria to define this disorder. The sensitivity of various clinical signs has been shown to be poor (Jain 2015). An hsPDA is suspected by clinical manifestations, but echocardiography remains the mainstay for diagnosis.
Early diagnosis and management of hsPDA in preterm neonates may improve clinical outcomes, including in‐hospital mortality and risk of pulmonary haemorrhage (Kluckow 2014; Roze 2015). However, current evidence is not clear as to whether treating an hsPDA is beneficial, and this ambiguity is reflected in the variations in practice reported among neonatologists (Clyman 2012). Moreover, use of medical and surgical treatment for managing hsPDA has decreased over the past decade (Hagadorn 2016;McNamara 2007). The reduction of medical and surgical treatments is supported by evidence which reveals a large percentage of spontaneous closure of PDAs in very low birth weight (VLBW) infants (born at < 1500 grams) close to and before discharge (Semberova 2017). Echocardiography is expensive and personnel‐intensive, and may not be available in all settings. Hence, assays for the cardiac biomarkers brain natriuretic peptide (BNP) and amino‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) have been used for early diagnosis of hsPDA in preterm infants.
Target condition being diagnosed
The incidence of hsPDA depends on the characteristics of the study population and is inversely proportional to postmenstrual age and birth weight. Other factors that may influence the incidence of hsPDA include chronological age at diagnosis and the echocardiographic diagnostic criteria used. The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network reports PDA diagnosis among 46% of VLBW babies and preterm infants born at < 28 weeks of gestation (Stoll 2010). Of VLBW infants with a diagnosis of PDA, 71% were treated with indomethacin, 13% with ibuprofen, and 27% with surgical closure. In other cohorts, the incidence of PDA was approximately 33% in VLBW infants in the Vermont Oxford Network (VON 1993), and approximately 55% in extremely low birth weight (ELBW) infants (birth weight < 1000 grams) (Koch 2006). In a French national cohort of preterm infants born between 24 and 28 weeks, 32.9% required Ibuprofen treatment or surgery for PDA (Roze 2015). Recent reports suggest that spontaneous closure of PDA is very frequent in the VLBW population with conservative management (Semberova 2017).
Although clinical manifestations and physical examination findings have long been used to determine the presence and magnitude of PDA in premature infants, use of such signs has been shown to be unreliable (Jain 2015). Hence echocardiography is used to document the haemodynamic significance of PDA shunting. In this review, the haemodynamic significance of a PDA in preterm neonates will be defined by at least one or a combination of (1) general clinical signs (clinical signs of hyperdynamic circulation, which include respiratory signs (increased respiratory support, inability to wean, need for oxygen support)); (2) cardiac physical signs (a hyperdynamic precordium or bounding pulses, increased pulse pressure (difference between systolic and diastolic blood pressures), signs of congestive heart failure); or (3) echocardiographic parameters (left atrium‐to‐aortic root (LA/Ao) ratio > 1.5, ductal diameter > 1.5 mm (using colour Doppler)).
Index test(s)
BNP and NT‐proBNP cardiac biomarker assays are two different index tests that have been used to diagnose hsPDA in preterm infants. BNP is synthesised in the body as a prohormone, proBNP, which is then cleaved into the active fragment BNP (32‐amino‐acid, C‐terminal fragment) and the inactive fragment NT‐proBNP (inactive 72‐amino‐acid, N‐terminal fragment), both of which can be measured in the plasma. BNP and NT‐proBNP are synthesised and released into the circulation by cardiac ventricular myocytes in response to pressure overload, volume expansion, and increased myocardial wall stress. Both plasma BNP and NT‐proBNP are cleared by the kidneys, but NT‐proBNP has a longer half‐life (mean 120 minutes vs mean 20 minutes) (Holmes 1993; Vanderheyden 2004), and it is more stable than BNP in vitro. Serum levels vary with chronological age, gestational age, test kit, PDA, and renal function. In adults and children, BNP and NT‐proBNP are well‐established markers of heart failure (Clerico 2007; Kantor 2013; Koulouri 2004). Many commercial kits are available for assessment of BNP and NT‐proBNP.
Various studies have reported normative values of BNP and NT‐proBNP in neonates (Kulkarni 2015). BNP and NT‐proBNP values peak in the first three days of life and decline progressively thereafter. At birth, concentrations in preterm neonates are higher than in full‐term neonates and reach similar values by one month of life. Plasma levels of BNP and NT‐proBNP vary with postmenstrual age, presence or absence of PDA, and renal function. Many commercial kits are available, and measurements may vary by the kit used. Kits available for the BNP assay include Triage (Biosite Diagnostics Inc., San Diego, California, USA), Shionospot (Shionogi, Response Biomedical, Osaka, Japan), AxSYM (Abbott Laboratories, Abbott Park, Illinois, USA), and ADVIA Centaur (Siemens Healthcare GmbH, Erlangen, Germany); and for the NT‐proBNP assay, Elecsys 2010 (Roche Diagnostics, Indianapolis, Indiana, USA), VITROS (Ortho Clinical Diagnostics, Raritan, New Jersey, USA), RxL Dimensions (Dade Behring, Ramsey, Minnesota, USA), and BRAHMS (Thermo‐Fisher, Brahms, Germany).
Clinical pathway
In preterm infants where a hsPDA is suspected clinically, an echocardiogram is the routine method to diagnose hsPDA. An echocardiogram may also be required to rule out other cardiac lesions, especially ductal‐dependent lesions (e.g. severe coarctation of the aorta, pulmonary atresia), before PDA closure therapy is initiated. BNP and NT‐proBNP testing may be useful to triage cases of suspected hsPDA to decrease the need for echocardiograms, especially in resource‐poor settings. This review will focus on use of the index test as a triaging tool to aid in determination of whether a subsequent echocardiogram needs to be obtained as part of further evaluation.
Alternative test(s)
No alternative test is currently available for the diagnosis of hsPDA, apart from the reference standard (the echocardiogram) and the index test (cardiac biomarkers: BNP and NT‐proBNP).
Rationale
Echocardiogram is the reference standard for the diagnosis of hsPDA, but it is resource intensive, requires interpretation by a cardiologist, and may not be available in resource‐limited settings. A simple blood assay of BNP or NT‐proBNP that can diagnose hsPDA reliably may be useful to clinicians, especially in low‐resource settings. A decrease in the need for echocardiograms will decrease utilisation of resources, including personnel and equipment. This can have a significant impact on healthcare costs in that the cost of an echocardiogram is more than 10‐fold greater than the cost of BNP or NT‐proBNP assays. BNP and NT‐proBNP assays have been used in preterm infants both for diagnosis and for initiation of medical or surgical treatment for hsPDA. Serial estimations of BNP or NT‐proBNP dictated by the clinical condition may also help in the diagnosis and follow‐up of hsPDA. We have previously systematically reviewed the diagnostic accuracy of BNP and NT‐proBNP for the diagnosis of hsPDA and found considerable variability in diagnostic accuracy by assay kit and infant characteristics (Kulkarni 2015). NT‐proBNP had higher sensitivity but BNP had higher specificity in the diagnosis of a haemodynamically significant PDA. Advances in assay technology may introduce newer optimal methods for measurement of BNP and NT‐proBNP that may change the diagnostic accuracy of these tests. In our view, a Cochrane Review is justified, as new literature may have accumulated since our last published review, and updates will be needed as new studies are performed in the future. We are not aware of any other systematic review or meta‐analysis on this topic in preterm infants, although narrative reviews have been published (El‐Khuffash 2009; Hammerman 2012; Hamrick 2010).
Objectives
Primary objective
To determine the diagnostic accuracy of the cardiac biomarkers BNP and NT‐proBNP for diagnosis of haemodynamically significant patent ductus arteriosus (hsPDA) in preterm neonates.
Secondary objectives
To compare the accuracy of BNP and NT‐proBNP.
To explore possible sources of heterogeneity among studies evaluating BNP and NT‐proBNP, including type of commercial assay, chronological age of the infant at testing, gestational age at birth, whether used to initiate medical or surgical treatment, test threshold, and criteria of the reference standard (type of echocardiographic parameter used for diagnosis, clinical symptoms or physical signs if data were available).
Methods
Criteria for considering studies for this review
Types of studies
Prospective or retrospective, cohort or cross‐sectional studies that evaluated the diagnostic accuracy of plasma BNP or NT‐proBNP (index tests) in the diagnosis of hsPDA (target condition) among preterm neonates in conjunction with an echocardiogram (reference standard) were eligible for inclusion. We excluded studies that assessed the diagnostic accuracy of the test using only positive samples or healthy controls (case‐control study design) and not in the clinical context of hsPDA.
Participants
Studies evaluated preterm neonates with clinically suspected hsPDA. Clinical signs and symptoms of hsPDAs in preterm neonates relate to hyperdynamic circulation such as respiratory insufficiency, active precordium, bounding pulses, widened pulse pressure on blood pressure measurements, and congestive heart failure. Neonates are defined as newborns ≤ 28 days of age, and preterm neonates as neonates born at < 37 completed weeks of gestation.
Index tests
We included studies that performed the index tests (plasma BNP and NT‐proBNP assays) using any kit and method of assay. We reported these index tests as positive or negative on the basis of study threshold cutoffs. For BNP, we chose two arbitrary ranges: < 250 pg/mL and ≥ 250 pg/mL. For NT‐proBNP, we used < 6000 pg/ml and ≥ 6000 pg/ml for subgroup analyses. We planned to include studies that evaluated both BNP and NT‐proBNP in the same study population, but did not find any studies of this type.
Target conditions
The target condition is a PDA that is considered haemodynamically significant, as defined by the criteria mentioned below in Reference standards. The incidence of PDA was approximately 33% in VLBW (birth weight < 1500 grams) infants in the Vermont Oxford Network (VON 1993), and approximately 55% in extremely low birth weight (ELBW) infants (birth weight < 1000 grams) (Koch 2006).
Reference standards
Echocardiogram is the reference standard for the diagnosis of a hsPDA. No consensus is available on echocardiographic criteria for hsPDA, but based on the best available evidence, we used either of two echocardiographic criteria to define hsPDA in preterm infants: LA/Ao ratio > 1.5 or ductal diameter > 1.5 mm (using colour Doppler) (Iyer 1994; Jain 2015; Kluckow 1995; Kluckow 2014; Silverman 1974;Zonnenberg 2012). LA/Ao ratio is estimated from the diameter of the left atrium (LA) and from the aortic root diameter (Ao) in the parasternal long‐axis view at the level of the aortic valve. We included echocardiography performed by any qualified user, as well as targeted neonatal echo (tnEcho).
Search methods for identification of studies
We conducted searches on 29 September 2021, without limits on date, language or publication type.
Electronic searches
We searched the following databases.
Ovid MEDLINE (R) and Epub Ahead of Print, In‐Process, In‐Data‐Review & Other Non‐Indexed Citations and Daily < 1946 to 29 September 2021
Cumulative Index to Nursing and Allied Health Literature (CINAHL), EbscoHost, 1982 to 29 September 2021)
Embase via embase.com, Elsevier, 1982 to 29 September 2021
Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Issue 9, 2021
Web of Science, 29 September 2021
Searching other resources
Abstracts of conferences: we searched proceedings of Paediatric Academic Societies (American Pediatric Society, Society for Pediatric Research, and European Society for Paediatric Research) from 1990 in the journal Pediatric Research, and in abstracts2view online from the year 2000 to 29 September 2021.
We searched the following trial registries on 29 September 2021.
US National Library of Medicine's www.clinicaltrials.gov
www.controlled-trials.com (now known as ISRCTN: www.isrctn.com)
World Health Organization (WHO) International Clinical Trials Platform (ICTRP): www.who.int/ctrp/en
We used Web of Science to search for articles cited by the included studies using the 'cited reference search', and the 'related citations' feature in PubMed to identify relevant articles.
We searched for ongoing and unpublished studies by contacting experts in this field. We conducted additional searches of the reference lists of identified studies and of the review authors’ personal files.
Data collection and analysis
Selection of studies
Review authors (MP and GG) screened all titles and abstracts identified by our search strategy for relevance to the inclusion criteria of this review. MP and GG retrieved in full all identified articles that were relevant to the review and independently evaluated them for inclusion eligibility, as detailed under Criteria for considering studies for this review. We compared results and resolved disagreements by mutual discussion.
Data extraction and management
We extracted the following data.
Author, year of publication, journal.
Study design, including sample size, whether prospective or retrospective, and whether a cohort or cross‐sectional study.
Study population characteristics and the clinical context in which the test was evaluated.
Reference standard and performance of the reference standard and criteria used to diagnose haemodynamically significant PDA.
Index tests and performance of the index tests, type of assay, manufacturer, positivity thresholds, time between performance of index and reference tests.
Information regarding quality assessment items based on the Quality Assessment of Diagnostic‐Accuracy Studies (QUADAS‐2) assessment system (Whiting 2011).
Data for a 2 × 2 table for calculation of diagnostic accuracy measures.
If necessary, we sought additional information from study authors to clarify study design and data via at least three email attempts. Review authors (GG and MK) independently entered all data electronically using Microsoft Excel spreadsheets. We compared the data extracted by each review author and resolved discrepancies by mutual discussion with input from a third review author (MP or CF).
Assessment of methodological quality
We assessed the methodological quality of each study as recommended by the Cochrane DTA Working Group and adapted from QUADAS‐2 by review authors GG and MK (Whiting 2011). We tailored the QUADAS‐2 tool to the review question by modifying specific signalling questions. We assessed four domains for risk of bias: patient selection, index test, reference test, and flow and timing. We assessed applicability concerns in the first three domains (patient selection, index test, and reference test). For each domain, we answered questions with a Yes/No/Unclear answer and we assessed risk of bias as Low/High/Unclear (Appendix 1). We assessed for risk of bias and clinical applicability related to neonates, the index test and the reference test and data analysis.
Statistical analysis and data synthesis
We performed analyses separately for BNP and NT‐proBNP. In the included studies, the reference standard (echocardiogram) had dichotomous outcomes and the index tests had thresholds at which we calculated diagnostic accuracy measures. We constructed 2 × 2 tables for all studies at the threshold reported in the study, and enumerated true positives (TP), false positives (FP), false negatives (FN), and true negatives (TN). When studies reported diagnostic accuracy measures at multiple thresholds, we chose a representative threshold (optimal threshold for sensitivity and specificity as deemed by authors) for meta‐analyses as recommended by Leeflang 2008. Based on published data on normative values of BNP and NT‐proBNP for preterm infants (Kulkarni 2015), we chose arbitrary cutoff levels. For BNP, we chose two arbitrary ranges: < 250 pg/mL and ≥ 249 pg/mL. For NT‐proBNP, we used < 6000 pg/ml and ≥ 6000 pg/ml for subgroup analyses. We entered data in RevMan 5.4 (Review Manager 2020), and created forest plots with 95% confidence intervals (CIs) for sensitivity and specificity for each study. We also plotted results in the receiver operating characteristic space (ROC) and estimated the summary ROC curve without summary estimates of sensitivity and specificity.
We performed meta‐analysis using the METANDI and MIDAS packages for STATA (Stata), and used the parameters of the hierarchical summary receiver operating characteristic (HSROC) model to report on the performance of the tests. MIDAS performs primary data synthesis within the bivariate mixed‐effects regression framework focused on making inferences about average sensitivity and specificity. An exact binomial rendition of the bivariate model assumes independent binomial distributions for the true positives and true negatives conditional on the sensitivity and specificity in each study (Arends 2008; Chu 2006; Riley 2007). Additionally, MIDAS facilitates exploratory analysis of heterogeneity (unobserved, threshold‐related and covariate etc.), publication and other precision‐related biases. Bayes’ nomograms, likelihood‐ratio matrices, and probability modifying plots may be derived and used to guide neonate‐based diagnostic decision making.
We expected the included studies to use different threshold cutoffs for estimations of sensitivity and specificity, as no consensus has been reached regarding the optimal threshold cutoff for BNP or NT‐proBNP for diagnosis of hsPDA. We dealt with the threshold effect by estimating summary curves instead of summary points of sensitivity and specificity and used meta‐regression of covariates using threshold as continuous variable (Macaskill 2010). We estimated the summary ROC curve by using the HSROC model, which accounts for variability of thresholds across studies.
If we found studies which evaluated both BNP and NT‐proBNP in the same infants, we planned to do a direct comparison of BNP and NT‐proBNP. However, we did not find any studies where this applied. We plotted the summary ROC curves for both BNP and NT‐proBNP in the same ROC space to facilitate indirect comparisons visually.
Investigations of heterogeneity
We investigated heterogeneity by subgroup analyses and meta‐regression of covariates for both index tests, BNP and NT‐proBNP.
We explored possible sources of heterogeneity by the following subgroup analyses when data were available:
type of commercial test assay used for BNP and NT‐proBNP, as measurements may vary with each commercial assay;
effects of postmenstrual age (in days) and chronological age at testing: BNP and NT‐proBNP levels are higher at birth and then decline over time and vary by gestational age at birth;
whether test results were used to initiate medical or surgical treatment for PDA; and
index test threshold and criteria of the reference standard (type of echocardiographic parameter used for diagnosis, clinical symptoms or physical signs, if data were available).
We explored categorical variables in the following subgroup analyses:
assay type
threshold cut‐offs (< 250 pg/ml and ≥250 pg/ml for BNP; and < 6000 pg/ml and ≥ 6000 pg/ml for NTproBNP);
mean gestational age (< 30 weeks vs 30 weeks and above);
chronological age at testing (days 1 to 3 vs > 3 days); and
whether BNP was used for medical or surgical management of PDA.
We explored the following continuous variables as covariates in meta‐regression: threshold, mean gestational age and chronological age.
We used the package MIDAS in STATA (Stata) for evaluation of heterogeneity by meta‐regression.
Sensitivity analyses
We planned to perform sensitivity analysis to investigate the effects of potential sources of bias by excluding studies with high or unclear risk of bias from the total set of studies and re‐analysing this new set. We refrained from doing so as most included studies were of similar methodological quality.
Assessment of reporting bias
Quantitative methods for exploring reporting bias are not well established for studies of DTA. Specifically, funnel plots of the diagnostic odds ratio (DOR) versus the standard error of this estimate were not considered.
Summary of findings and assessment of the certainty of the evidence
We assessed the certainty of evidence according to GRADE for diagnostic test studies (Gopalakrishna 2014; Schuneman 2020a; Schuneman 2020b). We used GradePro software to generate a summary of findings (SoF) table (GradePro).
Results
Results of the search
Searches identified 498 references; after removing eight duplicates, 490 records were available for screening. We excluded 411 based on title/abstract and reviewed 79 full‐texts. We included 34 studies (Characteristics of included studies); excluded 38 (Characteristics of excluded studies); and categorised seven studies awaiting assessment (Characteristics of studies awaiting classification); details are available in Figure 1.
1.
PRISMA Flow diagram depicting the study inclusion process
Thirteen included studies evaluated BNP and 21 included studies evaluated NT‐proBNP in the diagnosis of hsPDA.
Methodological quality of included studies
Methodological assessment of included studies by an adapted QUADAS 2 tool revealed study deficiencies in the following domains (Figure 2; Figure 3).
2.
Authors' judgements about each domain of risk of bias and applicability concerns summary of the 34 included studies that evaluated BNP or NT‐proBNP for the evaluation of a hemodynamically significant PDA
3.
Authors' judgements about each domain of risk of bias and applicability concerns summary of the 34 included studies that evaluated BNP or NT‐proBNP for the evaluation of a hemodynamically significant PDA. Each domain is presented as percentages across included studies.
1. Patient selection
Exclusion criteria in the individual studies were variable and were not defined in some studies, which may have introduced bias. Some studies were retrospective in design. Inclusion criteria differed and most studies had restrictive inclusion criteria by birth weight and gestational age. For patient selection we noticed high risk of bias in about 10% of studies, and 50% of studies had applicability concerns.
2. Index test
Only one study had a predefined threshold (Sellmer 2020), and some studies did not blind the clinician. Two studies by Elsayed and colleagues used BNP in addition to a clinical PDA score as the index test (Elsayed 2011; Elsayed 2012). The PDA score incorporated echocardiographic parameters reflective of both volume and pressure overload (maximum score 15), and clinical, radiological and laboratory features of both pulmonary over‐circulation and systemic hypo‐perfusion (maximum score 13). For the index test, we noticed high risk of bias in about 20% of studies, and less than 5% had applicability concerns.
3. Reference standard
All studies used an acceptable reference standard, the echocardiogram, but echocardiogram criteria to define hsPDA were variable, which may have introduced bias. There was absence of blinding of the cardiologists to the BNP assay in a few studies. We did not rate any of the studies as having high risk of bias or having applicability concerns.
4. Flow and timing
We noted longer or unclear time intervals between the blood test (index test) and echocardiogram (reference standard) in some studies, most notably in the study by Kim 2012, where the time interval between the index and reference standard was as long as 48 hours. We noted 5% of the included studies to have high risk of bias for flow and timing.
Findings
Included studies for both BNP and NT‐proBNP reported sensitivity and specificity at variable threshold cut‐offs, and we chose one representative threshold reported in the studies deemed optimal at the authors' discretion. BNP and NT‐proBNP are tests with continuous outcomes, and because diagnostic accuracy parameters were reported at variable thresholds, we chose to report summary curves without summary points. All studies enrolled preterm neonates, but some of them were more restrictive in terms of gestational age compared to others. BNP levels vary by gestational age, and this could affect threshold values used to diagnose hsPDA. Some of the studies had additional inclusion criteria, e.g. ventilator support and surfactant, and this might introduce applicability concerns. All the included studies evaluating NT‐proBNP were prospective in design and more uniform in respect to inclusion criteria based on gestational age compared to studies evaluating BNP.
Diagnostic performance of BNP
For BNP, we report analysis from 13 studies that included 768 infants (all outcomes with low‐certainty evidence due to imprecision and inconsistency). Forest plots using a single threshold from each study show that sensitivity across studies ranged from 0.60 to 1.00 for BNP and specificity from 0.74 to 1.0 (Figure 4). We plotted the included studies for both BNP and NT‐proBNP in the receiver operator characteristic (ROC) space to give a sense of the distribution of the sensitivity and specificity of the studies (Figure 5). The estimated specificities from the ROC curve at fixed values of sensitivities at median (83%), lower and upper quartiles (79% and 92%) were 93.6% (95% CI 77.8 to 98.4), 95.5% (95% CI 83.6 to 98.9) and 81.1% (95% CI 50.6 to 94.7), respectively (Table 3).
4.
Forest plot of the 13 studies evaluating BNP for a haemodynamically significant PDA. The studies are arranged alphabetically.
5.
Receiver operating characteristic plot of the summary curves along with the 95% confidence regions of BNP and NT‐proBNP. Black circles and the black summary curve correspond to BNP and the red diamonds and red summary curve correspond to NT‐proBNP. The black circles and red diamonds are scaled according to sample size.
1. Specificity and likelihood ratios for BNP and NT‐proBNP for fixed values of sensitivity (median and quartiles reported by included studies) in the diagnosis of a hsPDA.
| Statistic | Fixed value of sensitivity % | Estimated specificity % (95% CI) | Positive likelihood ratio (95% CI) | Negative likelihood ratio (95% CI) |
| BNP studies – 13 studies (768 participants) | ||||
| Lower quartile | 79 | 95.5 (83.6 to 98.9) | 17.56 (4.82 to 71.82) | 0.22 (0.21 to 0.25) |
| Median | 83 | 93.6 (77.8 to 98.4) | 12.97 (3.74 to 51.88) | 0.18 (0.17 to 0.22) |
| Upper quartile | 92 | 81.1 (50.6 to 94.7) | 4.87 (1.86 to 17.36) | 0.10 (0.08 to 0.16) |
| NT‐proBNP studies – 21 studies (1459 participants) | ||||
| Lower quartile | 85 | 90.6 (83.8 to 94.7) | 9.04 (5.24 to 16.04) | 0.17 (0.16 to 0.18) |
| Median | 92 | 83.6 (73.3 to 90.5) | 5.61 (3.44 to 9.68) | 0.10 (0.09 to 0.11) |
| Upper quartile | 94 | 79.4 (67.5 to 87.8) | 4.56 (2.89 to 7.70) | 0.08 (0.07 to 0.09) |
BNP: brain natriuretic peptide; CI: confidence interval; hsPDA: haemodynamically significant patent ductus arteriosus; NT‐proBNP: amino‐terminal pro‐B‐type natriuretic peptide
Subgroup analyses by type of assay showed that testing by Aggot (1 study) was better compared to Triage (8 studies), with the curve more towards the left upper corner of the ROC space (Figure 6). Subgroup analyses by threshold (< 250 pg/ml and ≥ 250 pg/ml) showed better accuracy with < 250 pg/ml. The subgroup analysis by mean gestational age (< 30 weeks vs 30 weeks and above) showed better accuracy with < 30 weeks, and subgroup analysis of chronological age at testing (days 1 to 3 vs > 3 days) showed testing at 1 to 3 days had better diagnostic accuracy. There were very few data on whether the tests were performed for medical or surgical indications of PDA management. We performed meta‐regression of covariates, namely assay type, threshold, mean gestational age and chronological age. None of the covariates significantly affected summary sensitivity and specificity (Table 4).
6.
BNP subgroup comparisons. A: subgroups by Assay type. B: subgroup comparisons by threshold; threshold < 250 pg/ml and threshold ⩾ 250 pg/ml, C: subgroups by mean gestational age (< 30 weeks vs 30 weeks and above) and D:subgroups by chronological age at testing (days 1 to 3 vs > 3 days)
2. Metaregression of Covariates.
| Covariate | Sensitivity | Specificity | P value |
| BNP | |||
| Assay type | 0.85 (95% CI 0.60 to 0.96) | 0.95 (95% CI 0.77 to 0.99) | 0.45 |
| Threshold | 0.87 (95% CI 0.78 to 0.92) | 0.91 (95% CI 0.82 to 0.95) | 0.75 |
| Gestational age | 0.92 (95% CI 0.59 to 0.99) | 0.95 (95% CI 0.67 to 0.99) | 0.77 |
| Chronological age | 0.87 (95% CI 0.73 to 0.95) | 0.86 (95% CI 0.66 to 0.95) | 0.45 |
| NT‐proBNP | |||
| Assay type | 0.89 (95% CI 0.75 to 0.96) | 0.82 (95% CI 0.67 to 0.91) | 0.59 |
| Threshold | 0.90 (95% CI 0.85 to 0.93) | 0.87 (95% CI 0.82 to 0.91) | 0.20 |
| Gestational age | 0.93 (95% CI 0.83 to 0.98) | 0.89 (95% CI 0.78 to 0.95) | 0.54 |
| Chronological age | 0.95 (95% CI 0.85 to 0.98) | 0.87 (95% CI 0.72 to 0.94) | 0.40 |
Diagnostic performance of NT‐proBNP
For NT‐proBNP, we report analysis from 21 studies that included 1459 infants (all outcomes with low‐certainty evidence due to imprecision and inconsistency). Forest plots using a single threshold from each study show that sensitivity across studies ranged from 0.58 to 1.00, and specificity from 0.57 to 1.0 (Figure 7). We also plotted the included studies in the receiver operator characteristic (ROC) space to give a sense of the distribution of the sensitivity and specificity of the studies (Figure 5). The estimated specificities from the ROC curve at fixed values of sensitivities at median (92%), lower and upper quartiles (85% and 94%) were 83.6% (95% CI 73.3 to 90.5), 90.6% (95% CI 83.8 to 94.7) and 79.4% (95% CI 67.5 to 87.8), respectively (Table 3).
7.
Forest plot of the 21 studies evaluating NT‐proBNP for a haemodynamically significant PDA. The studies are arranged alphabetically.
Subgroup analyses by type of assay showed that testing by Vitros (1 study) was better compared to Roche (14 studies), with the curve more towards the left upper corner of the ROC space (Figure 8). Subgroup analyses by threshold (< 6000 pg/ml and ≥ 6000 pg/ml) did not reveal any differences. Subgroups by mean gestational age (< 30 weeks vs 30 weeks and above) showed better accuracy with < 30 weeks; and chronological age at testing (days 1 to 3 vs > 3 days) showed testing at 1 to 3 days had better diagnostic accuracy. There were very few data on whether the tests were performed for medical or surgical indications of PDA management. We performed meta‐regression of covariates, namely assay type, threshold, mean gestational age and chronological age. None of the covariates significantly affected summary sensitivity and specificity (Table 4).
8.
NT‐proBNP subgroup comparisons. A: subgroups by Assay type. B: subgroup comparisons by threshold; threshold < 6000 pg/ml and threshold ⩾6000 pg/ml, C: subgroups by mean gestational age (< 30 weeks vs 30 weeks and above) and D: subgroups by chronological age at testing (days 1 to 3 vs > 3 days)
Discussion
Summary of main results
We included 13 studies that evaluated BNP and 21 studies that evaluated NT‐proBNP in the diagnosis of hsPDA in preterm neonates. We found considerable variation in sensitivity and specificity across the studies, and some variation in how hsPDA was defined by echocardiogram, the reference standard. For BNP, the estimated specificities from the ROC curve at fixed values of sensitivities at median (83%), lower and upper quartiles (79% and 92%) were 93.6% (95% CI 77.8 to 98.4), 95.5% (95% CI 83.6 to 98.9) and 81.1% (95% CI 50.6 to 94.7), respectively. For NT‐proBNP, the estimated specificities from the ROC curve at fixed values of sensitivities at median (92%), lower and upper quartiles (85% and 94%) were 83.6% (95% CI 73.3 to 90.5), 90.6% (95% CI 83.8 to 94.7) and 79.4% (95% CI 67.5 to 87.8), respectively The summary curves of BNP and NT‐proBNP were similar, without significant differences in diagnostic accuracy. However, studies evaluating NTproBNP were all prospective by study design and had better study methodology.
We explored heterogeneity by subgroup analyses and meta‐regression by type of assay, threshold cut‐offs, mean gestational age, chronological age and medical or surgical indication of PDA management. Some heterogeneity can be explained by the type of assay, gestational age and chronological age at the time of testing. There were considerable variations in the threshold cut‐offs in both studies of BNP and of NT‐proBNP, possibly due to differences in assay characteristics or infant's characteristics, or both, which preclude recommendation of a specific threshold value of BNP or NT‐proBNP for the diagnosis of hsPDA.
We assessed the methodological quality of studies using the four domains of the QUADAS‐2 checklist: patient selection, index test, reference standard, and flow and timing. Patient selection scored poorly, with high risk of bias noticed in about 10% of studies and applicability concerns affecting 50% of studies. All studies enrolled preterm neonates, but some of them were more restrictive than others. BNP levels vary by gestational age, and this could affect threshold values used to diagnose hsPDA. Some of the studies had additional inclusion criteria, e.g. ventilator support and surfactant, and this might introduce applicability concerns. Failure to report exclusion criteria or variable exclusion criteria may further add bias. Some studies had a retrospective design but had comparable inclusion and exclusion criteria and definition for hsPDA. As described by Zonnenberg 2012, there were considerable variations in the definition of hsPDA in the included studies. This raises applicability concerns, as a neonate with hsPDA in one study may be labelled as non‐hsPDA in another. All the included studies evaluating NT‐proBNP were prospective in design, and were more uniform in respect to inclusion criteria based on gestational age compared to studies evaluating BNP.
BNP and NT‐proBNP assays are widely available and used in children and adults, both in hospitals and in the community, to diagnose or monitor cardiac failure in at‐risk populations (Cantinotti 2010;Dunlay 2009). Many studies of BNP and NT‐proBNP have been reported from low‐ and middle‐income countries, in resource‐limited settings (Deorari 2011; Letzner 2012; Nuntnarumit 2009). The easy availability and its potential to complement echocardiography in the diagnosis of hsPDA or cardiac dysfunction in infants with bronchopulmonary dysplasia is likely to increase its usage in neonatal units (Xiong 2020), especially in resource‐limited areas. In adults, use of serial NT‐proBNP estimations to guide therapy decreases mortality, hospitalisations and healthcare costs (Dunlay 2009; Ferrandis 2013; Khezri 2014; Moertl 2013). However, studies that evaluated cost‐effectiveness of BNP or NT‐proBNP have not been reported in the neonatal population.
Strengths and weaknesses of the review
Strengths
Our systematic review follows the methodology recommended by the Cochrane Screening and Diagnostic Tests Methods Group (SDTM) (methods.cochrane.org/sdt/; Reitsma 2009). We searched comprehensively for all eligible studies using clinically relevant inclusion criteria. We used the bivariate and HSROC random‐effects models for meta‐analyses of the included studies, and strove to explain the sources of heterogeneity by subgroup analyses based on type of commercial assay, test threshold, age of the neonate at testing, gestational age and whether the test was used for medical or surgical treatment of the PDA. To our knowledge, our group published the first systematic review to evaluate the diagnostic accuracy of BNP and NT‐proBNP in the diagnosis of hsPDA (Kulkarni 2015). Other authors have reviewed the role of natriuretic peptides in the diagnosis of hsPDA without synthesising data by meta‐analyses (Chiruvolu 2009; El‐Khuffash 2007; Evans 2012; Weisz 2017) .
Weaknesses
Unlike meta‐analyses of randomised control trials, heterogeneity is a well‐recognised problem in reviews of diagnostic test accuracy (Reitsma 2009). In spite of our extensive search strategy, we may have missed potential studies, as diagnotic accuracy studies are poorly tagged in electronic databases. Publication bias in studies reporting diagnostic test accuracy has been poorly studied (Leeflang 2008). Poor reporting of study design, method of enrolment and infant characteristics may hamper methodological assessment and external validity of the studies. Another limitation of our review might be that echocardiogram (reference standard) parameters to diagnose hsPDA were not consistent among studies. A systematic review on the definition of hsPDA by echocardiogram highlights this issue in detail (Zonnenberg 2012). An ideal reference standard in the diagnosis of hsPDA may be a composite of echocardiographic, clinical and radiographic findings, which needs to be evaluated and validated. The seven studies awaiting classification, if included, may or may not affect the conclusions of this review. We acknowledge that the search is over one year old, but the editorial processes for DTA reviews takes six months longer than usual editorial assessment.
Applicability of findings to the review question
New diagnostic tests can assume the following roles in a diagnostic pathway: 1) replacement of the existing test, 2) triage, or 3) add‐on to an existing test (Bossyt 2006). In the context of hsPDA, it is not reasonable to replace echocardiogram with BNP or NT‐proBNP testing. The standard of care is to confirm the presence of hsPDA and rule out ductal‐dependent lesions with an echocardiogram before initiating therapy. BNP and NT‐proBNP testing may be useful to triage cases of suspected hsPDA to decrease the need for echocardiograms, especially in resource poor settings. A sensitivity of over 90% would be preferable in this setting; at optimal thresholds, the estimates of sensitivity of BNP and NT‐proBNP were over 85%, which indicate that both BNP and NT‐proBNP would be very useful in triaging infants who need an echocardiogram. This would be an advantage in low‐resource settings, where echocardiograms and paediatric cardiologists to interpret the echocardiograms are not readily available.
For screening of hsPDA, a sensitivity of 90% and above would be ideal so that only a few infants with HsPDA are missed, but at the cost of having a small number of false positives.
For BNP studies (Table 3), the upper quartile of sensitivity is 92%, with a corresponding specificity of 81%. Assuming a prevalence of hsPDA of 30% in VLBW infants, using BNP in 100 preterm neonates with suspected hsPDA would miss only two infants with hsPDA where echocardiogram would be indicated, and have 13 false positives who would have an unnecessary echocardiogram.
For NT‐proBNP studies (Table 3), the median sensitivity is 92% with a corresponding specificity of 84%. Assuming a prevalence of hsPDA of 30% in VLBW infants, using NT‐proBNP in 100 preterm neonates with suspected hsPDA would miss only two infants with hsPDA where echocardiogram would be indicated, and have 11 false positives who would have an unnecessary echocardiogram.
Serial estimations dictated by the clinical condition may diagnose hsPDA in the missed neonates. BNP or NT‐proBNP levels do not decline with the worsening or persistence of hsPDA, and echocardiogram can be performed later. Decrease in the need for echocardiograms will decrease utilisation of resources, including personnel and equipment, in addition to avoiding discomfort. Paediatric cardiologists are not readily available to perform and interpret echocardiograms. This can have a huge impact on the healthcare costs, as the cost of one echocardiogram is more than 10‐fold the cost of a BNP or NT‐proBNP test.
BNP can also be used as an add‐on test to echocardiogram, and has the advantage of allowing serial testing for trends before or after initiating medical therapy, to guide management without the need for serial echocardiograms. Threshold cut‐offs should be based on the normative values at different gestational and chronological ages, validated locally for the type of commercial assay used and the population being investigated. Costs of the BNP and NT‐proBNP assays need to be balanced with their ability to impact clinical outcomes before widespread acceptance in clinical practice.
Authors' conclusions
Implications for practice.
Low‐certainty evidence suggests that BNP and NT‐proBNP have moderate accuracy in diagnosing hsPDA and may work best as a triage test to select infants for echocardiography. Heterogeneity in test results may be due to both the characteristics of the assay (type of assay or thresholds used) and infant characteristics (gestational and chronological age) and hence generalisability is limited. We recommend that the type of assay should be locally validated in the specified population for the specified outcome (to initiate therapy or follow response after therapy) for diagnostic accuracy before being used to guide clinical decisions.
Implications for research.
Future studies should be designed that satisfy the methodological quality items expounded in the QUADAS‐2 evaluation system, so that studies are of high methodological quality with minimal bias, Studies reporting diagnostic test accuracy should explicitly state the method of enrolment (prospective or retrospective), characteristics of the population assessed (such as gestational age, birth weight, comorbidity), blinding of reference standard and index tests and explanation of withdrawals. There is a real need for international consensus for defining hsPDA based on echocardiographic and objective clinical parameters. Studies should explicitly state the details of the clinical setting and infant characteristics so that clinicians can determine the generalisability of the diagnostic test to their infant population. A composite scoring system that includes gestational and chronological age‐specific BNP and NT‐proBNP values in addition to clinical parameters may improve diagnostic accuracy and generalisability, but needs evaluation.
History
Protocol first published: Issue 10, 2018
Acknowledgements
The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
We acknowledge the following investigators for providing data for their studies: Maria Pia de Carolis, Jan Miletin, Johannes Letshwiti, Gilles Cambonie, Sven Wellmann, JB Letzner, Henrik Holmstrom, Atsushi Ohashi (K Mine), Arun Sasi and Afif El‐Khuffash.
We acknowledge the services of Joseph Hagan ScD, statistician, in estimating paired sensitivities and specificities from the ROC curve for this revised version of the review.
We thank the Cochrane Neonatal editorial base for editorial support: Roger Soll and William McGuire, Co‐ordinating Editors; Michelle Fiander and Jane Cracknell, Managing Editors.
We thank the Cochrane Diagnostic Test Accuracy Group for reviewing this manuscript and providing feedback.
We acknowledge Jack Price, who provided critical intellectual input and participated in revision of the protocol.
We thank Andrea Takeda for copy editing and proofreading this review.
Appendices
Appendix 1. Appendix: QUADAS‐2 method of assessment of methodological quality of included studies
QUADAS‐2 is structured so that each of four key domains is rated in terms of risk of bias and concern regarding applicability to the research question (as defined above). Each key domain has a set of signalling questions to help reach judgements regarding bias and applicability.
DOMAIN 1: PATIENT SELECTION
A. Risk of bias
Was a consecutive or random sample of infants enrolled?
YES: if the article clearly states that a consecutive or random samples have been enrolled.
NO: if it is clear that this was not the case (e.g. if a study includes infants ‘at the discretion of the clinician’).
UNCLEAR: in other cases where it is not clear if consecutive or random samples have been enrolled.
Was a case‐control design avoided?
YES: if the enrolled sample was a random or consecutive enrolment of preterm neonates with suspected hsPDA prospectively.
NO: if the study design is retrospective.
UNCLEAR: if the sampling regarding case‐control design was not clear.
Did the study avoid inappropriate exclusions?
Inappropriate exclusions might include neonates with PDA on ventilator or neonates with PDA who received indomethacin prophylaxis.
YES is scored if inappropriate exclusions were not found in the included study.
NO if reasons for inappropriate exclusion were found.
UNCLEAR if there was no description of inclusion and exclusion criteria and inappropriate exclusion could not be ascertained.
Could the selection of infants have introduced bias?
LOW RISK: if all questions were scored 'YES', or a maximum of one question was scored as 'UNCLEAR'.
HIGH RISK: if at least one question was scored as ‘NO’.
UNCLEAR RISK: if at least two questions were scored as 'UNCLEAR' and one as ‘NO’.
B. Concerns regarding applicability
Is there concern that the included infants do not match the review question?
If the inclusion criteria do not match our review question, we will exclude those studies from the meta‐analysis.
LOW CONCERN: for studies with the inclusion criterion of preterm infants < 37 weeks GA, they will be marked as low concern.
HIGH CONCERN: if studies are more restrictive in terms of BW or GA, or have additional inclusion criteria that would make the patient population more selective, they will be marked as high concern.
UNCLEAR CONCERN: if it is unclear whether studies fulfilled either criteria for low concern or for high concern, they will be marked as unclear concern.
DOMAIN 2: INDEX TEST(S)
If more than one index test was used, please complete for each test.
A. Risk of bias
Describe the index test and how it was conducted and interpreted:
Were the index test results interpreted without knowledge of results of the reference standard?
YES: if the clinician was blinded OR If the index test was conducted and interpreted before the reference standard.
NO: if the clinician was not blinded.
UNCLEAR: if the study does not explicitly describe how the index test was conducted and interpreted.
If a threshold was used, was it prespecified?
YES: if threshold was pre‐specified.
NO: if threshold was not pre‐specified.
Could the conduct or interpretation of the index test have introduced bias?
LOW RISK: if the study was performed blinded to results of the reference standard and threshold was not prespecified.
HIGH RISK: if there was prior knowledge of results of the reference standard and threshold was prespecified.
UNCLEAR RISK: if there was no clear description of how tests were conducted and interpreted.
B. Concerns regarding applicability
Is there concern that the index test, its conduct, or its interpretation differ from the review question?
LOW CONCERN: if the index test used for diagnosis of hsPDA was a blood BNP or NT‐proBNP assay as defined in our protocol, and if the index test was interpreted without knowledge of results of the reference standard.
HIGH CONCERN: if the index test used for diagnosis of hsPDA varies from what was defined in the protocol (e.g. other cardiac biomarkers like ANP, or urine NT‐proBNP or BNP ‐ these studies will be excluded from the meta‐analysis), and if the index test was interpreted with knowledge of results of the reference standard.
UNCLEAR CONCERN: if it is unclear whether the study fulfils criteria for low concern or high concern, or if the study provided limited information regarding the conduct and interpretation of the index test.
DOMAIN 3: REFERENCE STANDARD
A. Risk of bias
Describe the reference standard and how it was conducted and interpreted.
Is the reference standard likely to correctly classify the target condition?
YES: if the reference standard described in the study is the same cutoff for LA:Ao ratio and ductal diameter in echocardiogram as described in the methods in the diagnosis of hsPDA.
NO: if the test used as reference standard is a test other than echocardiogram.
UNCLEAR: if there is no description of the reference standard, or if other echocardiogram parameters alone or in addition to clinical parameters are used to define hsPDA.
Were the reference standard results interpreted without knowledge of results of the index test?
YES: if the cardiologist is blinded.
NO: if not blinded.
UNCLEAR: if the study does not explicitly describe how the reference standard was conducted and interpreted.
Could the reference standard, its conduct, or its interpretation have introduced bias?
LOW RISK: if the reference standard used meets the definition described in the protocol and is performed and evaluated without knowledge of results of the index test.
HIGH RISK: if the reference standard does not meet the definition described in the protocol or was evaluated with knowledge of results of the index test.
UNCLEAR RISK: if no clear description of the reference standard was used, or how it was performed and interpreted in relation to results of the index test.
B. Concerns regarding applicability
Is there concern that the target condition as defined by the reference standard does not match the review question?
LOW CONCERN: if echocardiographic criteria are similar to our defined criteria, it will be marked as low concern.
HIGH CONCERN: if echocardiographic criteria are different or use clinical criteria in addition to echocardiographic criteria to define hsPDA, it will be marked as unclear concern.
UNCLEAR CONCERN: if it was unclear whether the study fulfilled the criteria for low concern or for high concern.
DOMAIN 4: FLOW AND TIMING
A. Risk of bias
Describe any infants who did not receive the index test(s) and/or reference standard, or who were excluded from the 2 × 2 table (refer to flow diagram).
Describe the time interval and any interventions between index test(s) and reference standard.
Was there an appropriate interval between index test(s) and reference standard?
YES: if the interval between index test and reference standard is less than 6 hours (arbitrarily chosen based on practicality of getting an echo).
NO: if the interval between index test and reference standard is more than 24 hours.
UNCLEAR: if there was no description of how and when samples for both the index text and the reference standard were collected, or if the time interval between two tests is 6 to 24 hours.
Did all infants receive a reference standard?
YES: if all infants had echocardiogram.
NO: if at least 1 patient did not have the reference standard performed.
UNCLEAR: if the study does not describe clearly which patients received the reference standard and which ones did not.
Did infants receive the same reference standard?
YES: if all infants had the echocardiogram read by the same cardiologist.
NO: if different cardiologists read the echocardiogram for neonates.
UNCLEAR: if the study does not describe clearly how many cardiologists read the echocardiogram.
Were all infants included in the analysis?
YES: if all enrolled infants with the target condition who underwent testing using the index test and the reference standard were included in the analysis
NO: if all enrolled patients were not accounted for in the analysis.
UNCLEAR: if it is unclear from the study how many enrolled infants were included in the analysis.
Could the patient flow have introduced bias?
LOW CONCERN: if answers to the above questions were all YES, which means that all infants enrolled in the study were subjected to the same reference standard and index test, clinical samples for testing were drawn concurrently from the same patient, and all infants were included in the final analysis.
HIGH CONCERN: if at least two questions had a NO answer.
UNCLEAR CONCERN: if at least one question had a NO answer or it was unclear whether the study fulfilled the criteria for low concern or for high concern.
Appendix 2. Search strategies
Medline Ovid
1. Ductus Arteriosus/ or Ductus Arteriosus, Patent/
2. (PDA or ductus*).ti,ab,kw,kf.
3. 1 or 2
4. Natriuretic Peptide, Brain/
5. ("brain natriuretic peptide*" or ntprobnp* or probnp* or bnp or bnps).ti,ab,kw,kf.
6. 4 or 5
7. exp Infant, Newborn/
8. (newborn* or "new‐born*" or neonat* or "neo‐nat*" or prematu* or "pre‐matur*" or preterm* or "pre‐term*" or preemie*).ti,ab,kw,kf.
9. 7 or 8
10. 3 and 6 and 9
Embase
1. 'patent ductus arteriosus'/exp OR 'ductus arteriosus'/de
2. pda:ti,ab,kw OR ductus*:ti,ab,kw
3. #1 OR #2
4. 'brain natriuretic peptide'/de
5. 'brain natriuretic peptide*':ti,ab,kw OR ntprobnp*:ti,ab,kw OR probnp*:ti,ab,kw OR bnp:ti,ab,kw OR bnps:ti,ab,kw
6. #4 OR #5
7. 'newborn'/exp
8. newborn*:ti,ab,kw OR 'new‐born*':ti,ab,kw OR neonat*:ti,ab,kw OR 'neo‐nat*':ti,ab,kw OR prematu*:ti,ab,kw OR 'pre‐matur*':ti,ab,kw OR preterm*:ti,ab,kw OR 'pre‐term*':ti,ab,kw OR preemie*:ti,ab,kw
9. #7 OR #8
10. #3 AND #6 AND #9
CINAHL
1. (MH "Ductus Arteriosus, Patent")
2. TI ( PDA or ductus* ) OR AB ( PDA or ductus* )
3. S1 OR S2
4. (MH "Natriuretic Peptide, Brain")
5. TI ( "brain natriuretic peptide*" or ntprobnp* or probnp* or bnp or bnps ) OR AB ( "brain natriuretic peptide*" or ntprobnp* or probnp* or bnp or bnps )
6. S4 OR S5
7. (MH "Infant, Newborn+")
8. TI ( newborn* or "new‐born*" or neonat* or "neo‐nat*" or prematu* or "pre‐matur*" or preterm* or "pre‐term*" or preemie* ) OR AB ( newborn* or "new‐born*" or neonat* or "neo‐nat*" or prematu* or "pre‐matur*" or preterm* or "pre‐term*" or preemie* ) TI ( newborn* or "new‐born*" or neonat* or "neo‐nat*" or prematu* or "pre‐matur*" or preterm* or "pre‐term*" or preemie* ) OR AB ( newborn* or "new‐born*" or neonat* or "neo‐nat*" or prematu* or "pre‐matur*" or preterm* or "pre‐term*" or preemie* )
9. S7 OR S8
10. S3 AND S6 AND S9
Web of Science
1. TOPIC: (PDA or ductus*)
2. TOPIC: ("brain natriuretic peptide*" or ntprobnp* or probnp* or bnp or bnps)
3. TOPIC: (newborn* or "new‐born*" or neonat* or "neo‐nat*" or prematu* or "pre‐matur*" or preterm* or "pre‐term*" or preemie*)
4. #3 AND #2 AND #1
Data
Presented below are all the data for all of the tests entered into the review.
Tests. Data tables by test.
| Test | No. of studies | No. of participants |
|---|---|---|
| 1 BNP | 13 | 768 |
| 2 NT‐proBNP | 21 | 1459 |
1. Test.
BNP
2. Test.
NT‐proBNP
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Asrani 2018.
| Study characteristics | |||
| Patient Sampling | Prospective observational study, unclear if random or consecutive sampling was performed | ||
| Patient characteristics and setting | Preterm infants weighing < 1500 g and < 34 weeks gestation | ||
| Index tests | NT‐proBNP measured using Roche assay. Clinical team, sonographers and cardiologists blinded to index test | ||
| Target condition and reference standard(s) | hsPDA defined as PDA diameter > 1.5 mm and LA/Ao ratio > 1.2 | ||
| Flow and timing | Index test performed within 30 minutes of echo | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Low risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Yes | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | No | ||
| Could the patient flow have introduced bias? | Low risk | ||
Buddhe 2012.
| Study characteristics | |||
| Patient Sampling | Prospective observational study involving preterm infants < 1500 gm in a single centre | ||
| Patient characteristics and setting | VLBW infants < 1500 gm | ||
| Index tests | NTpro BNP measured using VITROS NT‐ proBNP reagent pack using Intellicheck technology | ||
| Target condition and reference standard(s) | hsPDA defined as PDA > 1 mm diameter plus 2 additional clinical or echo criteria; cardiologist blinded to results of index test | ||
| Flow and timing | Index test and echo performed on same day | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | High risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Cambonie 2012.
| Study characteristics | |||
| Patient Sampling | Prospective study involving preterm infants < 32 weeks gestation in a single centre | ||
| Patient characteristics and setting | |||
| Index tests | NT‐proBNP assay performed using Rxl‐Dimension, Siemens, Newark, DE, USA. Assay performed within 1 hour of echo. Laboratory personnel blinded to echo and sonographers blinded to index test | ||
| Target condition and reference standard(s) | hsPDA defined as LA/Ao ratio > 1.48 and absent diastolic flow in aorta in addition to clinical criteria. All echos were reviewed by same observer who performed all measurements. | ||
| Flow and timing | Index test performed within 1 hour of reference standard. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | No | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Yes | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Low risk | ||
Chen 2010.
| Study characteristics | |||
| Patient Sampling | Retrospective study that included preterm infants with gestational ages between 24 and 32 weeks with at least one BNP‐echo measurement performed on the same day | ||
| Patient characteristics and setting | Retrospective study, infants who were > 5 days of age were excluded. | ||
| Index tests | BNP assay performed using Triage BNP assay after 5 days of age, BNp and echo were performed on same day, no blinding occurred. Assay performed in lab. | ||
| Target condition and reference standard(s) | Echo performed on the same day as BNP. A single cardiologist, blinded to clinical and BNP data re‐read all the original echos. The magnitude of the PDA measured as ductus diameter > 1.5 mm, LA/Ao ratio > 1.5, diastolic flow velocity in the LPA > 0.2 m/s and presence of holodiastolic reversal of flow in the descending aorta. |
||
| Flow and timing | Echo performed on the same day as BNP. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | No | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | No | ||
| Could the selection of patients have introduced bias? | Unclear risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | High risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Choi 2005.
| Study characteristics | |||
| Patient Sampling | Prospective single centre study involving preterm infants from 25 to 34 weeks gestation. Echo performed every other day from day 3 of life. | ||
| Patient characteristics and setting | |||
| Index tests | BNP measured using Triage BNP assay. Blood samples obtained at the time when echo was performed | ||
| Target condition and reference standard(s) | hsPDA as the presence of 2/5 clinical signs with a confirmation of a large left‐to‐right ductal flow by colour‐flow Doppler echocardiography. All echos were performed by one investigator to avoid interobserver variability; unknown if echocardiographer was blinded to BNP assay | ||
| Flow and timing | hsPDA as the presence of 2/5 clinical signs with a confirmation of a large left‐to‐right ductal flow by colour‐flow Doppler echocardiography. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | No | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | High risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Unclear | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Yes | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Low risk | ||
Czernik 2008.
| Study characteristics | |||
| Patient Sampling | Prospective single centre study involving preterm infants < 28 weeks. Aim was to determine if BNP levels on day 2 of life predict the need for PDA intervention. | ||
| Patient characteristics and setting | |||
| Index tests | BNP measured using ADVIA Centaur, Siemens. BNP measured at 24 to 48 hours of age | ||
| Target condition and reference standard(s) | Reference standard performed at 24 to 48 hours of age. Indication of PDA intervention (hsPDA) included ventilatory support, ductal diameter > 2 mm with left to right shunt. Echocardiographer blinded to BNP results. | ||
| Flow and timing | Both index test and reference standard were performed at 24 to 48 hours; however, the interval between tests was unclear. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Unclear | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Deorari 2011.
| Study characteristics | |||
| Patient Sampling | Prospective study involving preterm infants < 32 weeks in gestation of < 1500 gm birth weight. Aim was to determine the utility of NT‐proBNP at 72+/‐ 12 hrs of life in the diagnosis of hsPDA. | ||
| Patient characteristics and setting | |||
| Index tests | NT‐proBNP measured before and after PDA treatment using electrochemiluminescence kit | ||
| Target condition and reference standard(s) | Echocardiogram performed on day 1, 3 and 7 of life | ||
| Flow and timing | Details not available | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Unclear | ||
| Could the selection of patients have introduced bias? | Unclear risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Unclear | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | High risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Unclear | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Unclear | ||
| Were all patients included in the analysis? | Unclear | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
El‐Khuffash 2007.
| Study characteristics | |||
| Patient Sampling | Prospective study involving preterm infants < 29 weeks. Aim was to evaluate NT‐proBNP as a marker for hsPDA | ||
| Patient characteristics and setting | |||
| Index tests | NT‐proBNP measured at 12 hours and 3 days of life. Kit unknown | ||
| Target condition and reference standard(s) | hsPDA definition was not provided. Echo performed at 12 hours, day 3 and day 5 to 6 and after PDA treatment | ||
| Flow and timing | While both the index test and reference standard were performed at 12 and 48 hrs, the interval between the index test and reference standard is not explicitly stated. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Unclear | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Low risk | ||
Elsayed 2011.
| Study characteristics | |||
| Patient Sampling | Prospective single centre study | ||
| Patient characteristics and setting | Preterm infants < 31 weeks gestation. To determine whether serum BNP in addition to a PDA score between 48 to 72 hrs of life predicts hsPDA | ||
| Index tests | BNP at 48 to 72 hours. Test kit unknown | ||
| Target condition and reference standard(s) | hsPDA defined. In addition, a PDA score was used. Echo performed at 4 to 6 days of age | ||
| Flow and timing | Unclear as to the time interval between BNP and echo. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Unclear | ||
| Could the selection of patients have introduced bias? | High risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Unclear | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | High | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Unclear | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Elsayed 2012.
| Study characteristics | |||
| Patient Sampling | Prospective single centre study. To determine whether serum BNP at 48 to 72 hours of life predicts hsPDA | ||
| Patient characteristics and setting | Preterm infants < 31 weeks gestation | ||
| Index tests | BNP, test kit unknown | ||
| Target condition and reference standard(s) | hsPDA defined. Echo performed at 4 to 6 days of age | ||
| Flow and timing | Unclear as to the time interval between BNP and echo | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | |||
| Was a case‐control design avoided? | |||
| Did the study avoid inappropriate exclusions? | |||
| Could the selection of patients have introduced bias? | Unclear risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | |||
| If a threshold was used, was it pre‐specified? | |||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Low risk | ||
Farombi‐Oghuvbu 2008.
| Study characteristics | |||
| Patient Sampling | Prospective observational single centre study | ||
| Patient characteristics and setting | Preterm infants < 34 weeks gestation and < 2000 gm in birth weight | ||
| Index tests | NT‐proBNP measured using Roche assay, measured on days 1,3,5 and 10 of life | ||
| Target condition and reference standard(s) | HsPDA defined as large ductal flow with left to right shunt which measured at least 1.6 mm with retrograde flow in the descending aorta. Echo performed by a single investigator. | ||
| Flow and timing | Index test and reference standard were performed within 1 hour. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | |||
| If a threshold was used, was it pre‐specified? | |||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Yes | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Low risk | ||
Halil 2017.
| Study characteristics | |||
| Patient Sampling | Prospective single centre observational study | ||
| Patient characteristics and setting | Preterm infants < 32 weeks in gestation | ||
| Index tests | NTproBNP measured using Roche assay | ||
| Target condition and reference standard(s) | hsPDA defined as ductal diameter > 1.5 mm, LA/Ao ratio > 1.5 and end diastolic retrograde flow in aorta. The same cardiologist performed all the echos. | ||
| Flow and timing | Unclear as to time interval between index test and reference standard. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Low risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Harris 2018.
| Study characteristics | |||
| Patient Sampling | Prospective observational single centre study | ||
| Patient characteristics and setting | Preterm infants < 30 weeks gestation | ||
| Index tests | NT‐proBNP measured using Roche assay, index test performed on days 3,10 and 28 of life | ||
| Target condition and reference standard(s) | hs PDA defined as ductal diameter > 1.5 mm, LA/Ao ratio > 1.5 and reversed diastolic retrograde flow in aorta. Two clinicians performed all the echos, who were blinded to NT‐proBNP results. Clinicians were also blinded to index test results. | ||
| Flow and timing | Index test and reference standard were paired as closely as possible. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | |||
| If a threshold was used, was it pre‐specified? | |||
| Could the conduct or interpretation of the index test have introduced bias? | Low risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Low risk | ||
Kalra 2011.
| Study characteristics | |||
| Patient Sampling | Prospective single centre observational study | ||
| Patient characteristics and setting | All preterm infants < 1250 gm birth weight and infants < 34 weeks with clinical suspicion of PDA included | ||
| Index tests | BNP measured using Triage BNP kit, Clinicans were blinded to BNP levels. | ||
| Target condition and reference standard(s) | PDA was classified as small, moderate and large based on ductal diameter and absolute size of PDA in comparison to branch pulmonary arteries. Also considered were diastolic reversal of flow in aorta and LA/Ao ratio. Echo read by four cardiologists who were blinded to the BNP results | ||
| Flow and timing | BNP and echo were performed between day 3 and day 7 | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Unclear | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Khosroshahi 2014.
| Study characteristics | |||
| Patient Sampling | Prospective single centre study | ||
| Patient characteristics and setting | Preterm infants < 34 weeks gestation and birth weight < 2500 gm | ||
| Index tests | BNP measured using Triage BNP assay | ||
| Target condition and reference standard(s) | hsPDA defined as one of the following: LA/Ao ratio >1.3 or >1.5, retrograde diastolic flow in descending aorta exceeding 30% of anterograde flow, narrowest ductal diameter >1.4 mm. All echos were performed and interpreted by a single cardiologist, who was blinded to the BNP and clinical data. |
||
| Flow and timing | Index test and reference standard were performed within a time interval of 24 hours | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Low concern | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Low risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Kim 2012.
| Study characteristics | |||
| Patient Sampling | Prospective observational single centre study | ||
| Patient characteristics and setting | Preterm infants < 37 weeks | ||
| Index tests | BNP measured using Aggott architect BNP assay from Abbott, measured on days 1,4 and 7. | ||
| Target condition and reference standard(s) | hsPDA defined as one of the following echo criteria plus 3/6 clinical findings: echo criteria include: LA/Ao ratio > 1.4, ductal diameter > 1.4 mm or diastolic turbulence in pulmonary artery All echos were performed and interpreted by a single investigator. |
||
| Flow and timing | Index test test was performed on day 1,4 and 7 and the echo was performed by day 4. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Low concern | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Unclear | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | High risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | High risk | ||
Lee 2013.
| Study characteristics | |||
| Patient Sampling | Retrospective single centre study | ||
| Patient characteristics and setting | Birth weight < 1000 gm | ||
| Index tests | BNP measured using Triage BNP assay; measured at 24 hours of age | ||
| Target condition and reference standard(s) | hsPDA defined as symptomatic PDA with the presence of 2/5 clinical signs, and echocardiographic evidence of a large left to right ductal shunt | ||
| Flow and timing | Echo performed every day from day 1 of life, whereas BNp was performed at 24 hrs. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Unclear | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Unclear risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Unclear | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Unclear | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Letshwiti 2014.
| Study characteristics | |||
| Patient Sampling | Prospective single centre study | ||
| Patient characteristics and setting | Preterm infants < 1500gm birth weight | ||
| Index tests | NT‐proBNP measured using Roche assay; measured on day 7 of life | ||
| Target condition and reference standard(s) | hsPDA defined as ductal diameter > 2 mm. Echo performed by two operators | ||
| Flow and timing | Echos were paired with NT‐proBNP, which were collected at time of imaging | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Low risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Yes | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Low risk | ||
Letzner 2012.
| Study characteristics | |||
| Patient Sampling | Prospective single centre study | ||
| Patient characteristics and setting | Preterm infants < 32 weeks gestation | ||
| Index tests | NT‐proBNP measured using Brahms Kryptor kit on day 2 to 3 of life | ||
| Target condition and reference standard(s) | Echo performed on day 2 to 3 of life by a single sonographer. hsPDA defined using the following: LA/Ao ratio > 1.4, ductal diameter > 1.5 mm, diastolic retrograde flow in descending aorta and left to right shunting. Methods describe as 'blinded'. |
||
| Flow and timing | Nt‐proBNP and echo were performed within a 4‐hour window. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Yes | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Unclear | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Low risk | ||
Liu 2020.
| Study characteristics | |||
| Patient Sampling | Prospective single centre observational study | ||
| Patient characteristics and setting | Preterm infants measuring < 1500 gm birth weight | ||
| Index tests | NT‐proBNP measured using Roche assay; clinicians blinded to the results | ||
| Target condition and reference standard(s) | hsPDA defined as PDA diameter > 1.5 mm plus at least 2 clinical criteria. Echo performed by 2 investigators blinded to the NT‐proBNP results | ||
| Flow and timing | Interval between echo and NT‐proBNP not well defined | ||
| Comparative | |||
| Notes | Reference standard labelled as unclear risk of bias, and unclear applicability given that the study included additional clinical criteria. | ||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Low risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Lu 2015.
| Study characteristics | |||
| Patient Sampling | Retrospective cohort study | ||
| Patient characteristics and setting | Preterm infants | ||
| Index tests | NT‐proBNP measured using miniVidas analyzer, Biomerieux | ||
| Target condition and reference standard(s) | hsPDA defined as left to right shunt during diastole, ductal diameter > 1.5 mm and LA/Ao ratio > 1.3. Patient listed as hsPDA if meeting echo criteria and 2 of listed clinical/radiographic criteria, | ||
| Flow and timing | Echo was performed within 48 hrs followed by day 3 and day 5. NT‐proBNP performed on day 3 and day 5 of life | ||
| Comparative | |||
| Notes | This article is in Chinese. | ||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | High risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Low risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Unclear | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Martinovici 2011.
| Study characteristics | |||
| Patient Sampling | Prospective single centre observational study | ||
| Patient characteristics and setting | Preterm infants < 32 weeks gestation or < 1500 gm birth weight, clinicians blinded to NT‐proBNP and echo results | ||
| Index tests | NT‐proBNP measured using Roche assay. Measured on days 2, 4 and 7 of life. | ||
| Target condition and reference standard(s) | hsPDA defined as ratio of ductal diameter to birth weight > 1.4 and L/Ao ratio > 1.4. Echocardiogrpahers were blinded to NT‐proBNP results and all echos were reviewed by a single cardiologist. | ||
| Flow and timing | Echo and NT‐proBNp were performed on same day ‐ days 4 and 7 of life | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Yes | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Mine 2013.
| Study characteristics | |||
| Patient Sampling | Retrospective single centre cohort study | ||
| Patient characteristics and setting | Preterm infants < 33 weeks gestation and birth weight < 1500 gm | ||
| Index tests | BNP measured daily on days 1 to 5 using Shionospot test kit, Osaka, Japan | ||
| Target condition and reference standard(s) | Echo performed every 12 hrs. The echocardiographers were blinded to the BNP results. hsPDA defined as end diastolic blood flow velocity of left pulmonary artery > 30 to 40 cm/s or diastolic blood flow of the anterior cerebral artery interrupted | ||
| Flow and timing | Echo and BNP were timed anywhere from 0 to 12 hours apart. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | No | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Unclear risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | |||
| If a threshold was used, was it pre‐specified? | |||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Unclear | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Montaner 2017.
| Study characteristics | |||
| Patient Sampling | Retrospective cohort study | ||
| Patient characteristics and setting | Preterm infants < 28 weeks gestation and/or < 1000 gm birth weight | ||
| Index tests | NT‐proBNP measured using Roche assay kit, measured at 48 to 72 hours at the same time of echo | ||
| Target condition and reference standard(s) | hsPDA defined as ductal diameter > 1.5 mm, retrograde diastolic flow in descending aorta, LA/Ao ratio > 1.4 or ductal velocity < 2 m/s, all echos read by a single cardiologist blinded to NT‐proBNP results. | ||
| Flow and timing | |||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | No | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | No | ||
| Could the selection of patients have introduced bias? | High risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Unclear | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Yes | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Nuntnarumit 2009.
| Study characteristics | |||
| Patient Sampling | Prospective single centre observational study | ||
| Patient characteristics and setting | Preterm infants < 33 weeks gestation | ||
| Index tests | NT‐proBNP measured using Roche Elecsys assay kit, measured on day 2, 4 and 7 of life | ||
| Target condition and reference standard(s) | Echo performed on day 2, 4 and 7 of life, and whenever clinically suspected. hsPDA defined left to right shunt with > 1.5 mm ductal diameter plus two clinical criteria, unclear if echocardiographers were blinded to NT‐proBNP results. | ||
| Flow and timing | echo and NT‐proBNp were performed within 6 hours of each other | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | High risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Yes | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Low risk | ||
Occhipinti 2014.
| Study characteristics | |||
| Patient Sampling | Prospective single centre observational study | ||
| Patient characteristics and setting | Preterm infants < 32 weeks | ||
| Index tests | NT‐proBNP measured using Roche assay kit. NT‐proBNP measured at 6 to 24 hours of life. Clinicians blinded to index test results. | ||
| Target condition and reference standard(s) | Echo performed by a single cardiologist, who was blinded to the NT‐proBNP results. hsPDA defined as ductal diameter to weight ratio > 1.4 and LA/Ao ratio > 1.4 | ||
| Flow and timing | Echo and NT‐proBNP were performed within a window of 18 hrs | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Low risk | ||
Parra‐ Bravo 2021.
| Study characteristics | |||
| Patient Sampling | Retrospective single centre study | ||
| Patient characteristics and setting | Preterm infants < 32 weeks gestation and < 1500 gm birth weight | ||
| Index tests | BNP measured using Triage BNP assay, measured simultaneously with echo | ||
| Target condition and reference standard(s) | Echo performed by a single echocardiographer between day 3 and 5 of life. hsPDA defined as ductal diameter > 1.5 mm, left to right shunt, PDA diameter/weight > 1.4 mm/kg, retrograde flow > 30% of diastole in descending aorta, in addition to 3/6 clinical criteria; unclear if echocardiographer was blinded to NT‐proBNP results. | ||
| Flow and timing | BNP and echo were performed at the same time. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | No | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | High risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | |||
| If a threshold was used, was it pre‐specified? | |||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Unclear | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Yes | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Low risk | ||
Permyakova 2021.
| Study characteristics | |||
| Patient Sampling | Initially reported as a prospective single centre observational study; however, subsequently reported as retrospective study, hence high risk | ||
| Patient characteristics and setting | Preterm infants 25 to 32 weeks, less than 1500 gm birth weight | ||
| Index tests | NT‐proBNP measured using JSC Vector‐Best, Novosibirsk, Russia. Measured on day 3 of life. | ||
| Target condition and reference standard(s) | Echo performed on day 3 of life, hsPDA defined as ductal diameter > 1.5 mm, LA/Ao ratio > 1.4, retrograde descending aortic flow > 50%, unclear if echocardiographers were blinded and if performed by a single echocardiographer. | ||
| Flow and timing | Both Echo and NT‐proBNp performed on day 3 of life | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | High risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Unclear | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Unclear | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Ramakrishnan 2009.
| Study characteristics | |||
| Patient Sampling | Prospective single centre observational study | ||
| Patient characteristics and setting | Preterm infants 23 to 34 weeks gestation | ||
| Index tests | NT‐proBNP measured using Roche Elecsys assay kit. Measured on day 3 of life. | ||
| Target condition and reference standard(s) | Echo performed between day 5 and 7 by a single investigator and independently reviewed by a second investigator, both of whom were blinded to the NT‐proBNP results. hsPDA defined as ductal diameter > 1.5 and LA/Ao ratio > 1.5 mm | ||
| Flow and timing | Echo performed on day 5‐7 whereas NT‐proBNp performed on day 3 | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Unclear risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Low risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | No | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Rodriguez‐Blanco 2018.
| Study characteristics | |||
| Patient Sampling | Prospective single centre observational study. Preterm infants noted to have hsPDA after one week of life were excluded. | ||
| Patient characteristics and setting | Preterm infants < 32 weeks gestation | ||
| Index tests | NT‐proBNP measured at 48 to 96 hours of life. Measured using Roche Elecsys assay. | ||
| Target condition and reference standard(s) | Echo performed at 48 to 96 hours of life. hsPDA defined as left to right shunt with ductal diameter of > 1.4 mm. Echocardiographers were blinded to NT‐proBNP results. No mention of whether echo performed by single echocardiographer. | ||
| Flow and timing | Echo and NT‐proBNP were performed within a 12 hour window. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | No | ||
| Could the selection of patients have introduced bias? | Unclear risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Low risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Sanjeev 2005.
| Study characteristics | |||
| Patient Sampling | Prospective single centre observational study | ||
| Patient characteristics and setting | Preterm infant 500 to 1500 gm birth weight if echo was performed in first month of life. | ||
| Index tests | BNP measured using Triage BNP assay | ||
| Target condition and reference standard(s) | Echo performed at discretion of treatment team and subsequent echos 48 to 72 hours later. hsPDA defined as 2 of the following 3 criteria: LA/Ao ratio > 1.4, ductal diameter > 1.5, LV/Ao ratio > 2.1. A single cardiologist performed the echo and was blinded to clinical data and the BNP results. | ||
| Flow and timing | Echo and BNP were performed within a 3‐hour window. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | Unclear | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | High risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Yes | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Low risk | ||
Sellmer 2020.
| Study characteristics | |||
| Patient Sampling | Prospective single centre cohort study | ||
| Patient characteristics and setting | Preterm infants < 32 weeks gestation | ||
| Index tests | NTproBNP measured using Cobas e601 platform, Roche Diagnostics, measured on day 3 of life. | ||
| Target condition and reference standard(s) | Echo performed on day 3 and 6 of life. All echos performed by 2 echocardiographers who were not aware of the NTproBNP results as the blood samples were processed 2 years later. hsPDA defined as ductal diameter > 1.5 mm, LA/Ao ratio > 1.5 and retrograde diastolic flow in descending aorta | ||
| Flow and timing | Significant number of patients were not accounted for in the analysis. NT‐proBNP and echo were performed on day 3 of life | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Unclear | ||
| If a threshold was used, was it pre‐specified? | Yes | ||
| Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Unclear | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Low concern | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | No | ||
| Could the patient flow have introduced bias? | High risk | ||
Tauber 2016.
| Study characteristics | |||
| Patient Sampling | Prospective single centre observational study | ||
| Patient characteristics and setting | Preterm infants 24 to 31 6/7 weeks gestation | ||
| Index tests | BNP measured using Triage BNP assay on days 1, 5, 10 and 15 of life, in addition to BNP on the same day of echocardiogram. Clinical team were blinded to the results. | ||
| Target condition and reference standard(s) | All echos were reviewed by a single cardiologist who was blinded to clinical data and BNP results. While the study did categorise PDAs into hsPDA and non hsPDA using ductal diameter and LA/Ao ratio, definition for hsPDA was not explained in detail. | ||
| Flow and timing | BNP and echo were performed within 24‐hour window | ||
| Comparative | |||
| Notes | Haemodynamically significant patent ductus arteriosus (hsPDA) patent ductus arteriosus (PDA) brain natriuretic peptide (BNP) left atrium‐to‐aortic root (LA/Ao) |
||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Yes | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | Low risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Low concern | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Unclear | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
Wang 2021.
| Study characteristics | |||
| Patient Sampling | Prospective single centre observational study | ||
| Patient characteristics and setting | Preterm infants < 32 weeks gestation who had an echo performed within 48 hours after birth. | ||
| Index tests | NT‐proBNP measured using Minivoid analyzer, measured on days 3 and 5 of life | ||
| Target condition and reference standard(s) | Echo performed within 48 hours of life and days 3 and 5 of life. hsPDA defined as left to right shunt in diastole, ductal diameter > 1.5 mm, LA/Ao ratio > 1.3 in addition to 2 of the clinical/radiographic criteria. Unclear if echocardiographers were blinded to NT‐proBNP results. | ||
| Flow and timing | Echo and NT‐proBNP performed on same day. | ||
| Comparative | |||
| Notes | |||
| Methodological quality | |||
| Item | Authors' judgement | Risk of bias | Applicability concerns |
| DOMAIN 1: Patient Selection | |||
| Was a consecutive or random sample of patients enrolled? | Unclear | ||
| Was a case‐control design avoided? | Yes | ||
| Did the study avoid inappropriate exclusions? | Yes | ||
| Could the selection of patients have introduced bias? | Low risk | ||
| Are there concerns that the included patients and setting do not match the review question? | High | ||
| DOMAIN 2: Index Test (All tests) | |||
| Were the index test results interpreted without knowledge of the results of the reference standard? | Unclear | ||
| If a threshold was used, was it pre‐specified? | No | ||
| Could the conduct or interpretation of the index test have introduced bias? | High risk | ||
| Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Unclear | ||
| DOMAIN 3: Reference Standard | |||
| Is the reference standards likely to correctly classify the target condition? | Yes | ||
| Were the reference standard results interpreted without knowledge of the results of the index tests? | Unclear | ||
| Could the reference standard, its conduct, or its interpretation have introduced bias? | Unclear risk | ||
| Are there concerns that the target condition as defined by the reference standard does not match the question? | Unclear | ||
| DOMAIN 4: Flow and Timing | |||
| Was there an appropriate interval between index test and reference standard? | Unclear | ||
| Did all patients receive the same reference standard? | Yes | ||
| Were all patients included in the analysis? | Yes | ||
| Could the patient flow have introduced bias? | Unclear risk | ||
BNP: brain natriuretic peptide; hsPDA: haemodynamically significant patent ductus arteriosus; LA/Ao:left atrium‐to‐aortic root; NT‐proBNP: amino‐terminal pro‐B‐type natriuretic peptide; PDA: patent ductus arteriosus; VLBW: very low birth weight
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Ahmed 2012 | BNP was measured only in patients with PDA and no measurements related to hsPDA were reported. |
| Attridge 2009 | Used BNP to reduce the number of indocin doses |
| Bagnoli 2010 | No cut‐off threshold reported |
| Celik 2013 | Urine levels of natriuretic peptide, not serum |
| Czernik 2013 | Urine levels of the natriuretic peptide, not serum |
| da Graca 2006 | No cutoff threshold reported |
| Ding 2014 | Study measured the effects of ibuprofen treatment on NT‐proBNP levels. |
| Ding 2018 | NT‐proBNP was measured to observe treatment responses to ibuprofen. |
| El‐Khuffash 2008 | Outcomes of interest not reported |
| El‐Khuffash 2011 | Outcomes of interest not reported |
| Elsayed 2013a | Correlation of BNP and regional blood flow in PDA and for the diagnosis of PDA |
| Elsayed 2013b | Included patients with PDA only and used BNP to predict failure of medical therapy |
| Flynn 2005 | Insufficient data for 2 x 2 table |
| Gao 2015 | Review of studies |
| Hallioglu 2012 | Insufficient data for 2 x 2 table and no cut‐off threshold reported |
| Hammerman 2010 | Included patients with hsPDA only, used percentage drop in NT‐proBNP to predict response to treatment |
| Hollinger 2011 | No cut‐off threshold reported |
| Holmström 2001 | Not enough data for 2 x 2 table. Cut‐off = 25 pmol/L |
| Hsu 2010 | Included patients with PDA and used BNP to predict indomethacin responsiveness |
| Jeevananthan 2011 | Not enough data for 2 x 2 table. Babies on indocin prophylaxis, day 4 cut‐off 141 pg/ml and day 7 cut‐off 216 pg/ml |
| Kazanci 2012 | No cut‐off threshold reported |
| Khan 2017 | The study evaluated urinary levels of NT‐proBNP. |
| Makimura 2014 | The study population consisted of patients of 36 weeks' gestational age and older. |
| Mannarino 2010 | Compared BNP in term vs preterm infants |
| Nuntnarumit 2011 | Used a predefined cut‐off from previous study for early targeted treatment with indocin. |
| Perugu 2011 | BNP and other markers for ventricular function in ELBW |
| Perugu 2014 | Excluded as study objective was to measure ventricular function in VLBW infants and not hsPDA. No documentation of measurements of hsPDA |
| Potsiurko 2021 | Excluded because inclusion criteria included only infants with hsPDA > 1.5 mm and the objective of the study was to predict closure of PDA by 10 days of life. |
| Puddy 2002 | No cut‐off threshold reported |
| Rodríguez‐Blanco 2018 | Outcome of interest not reported; study assessed whether NT‐proBNP predicts the risk of BPD and/or death. |
| Rossetti 2012 | Excluded as the objective of the study was to predict closure of PDA rather than diagnose hsPDA. |
| Sellmer 2011 | No cut‐off threshold reported |
| Shin 2017 | Aim of study was to determine use of BNP as a tool to tailor therapy. No data reported to determine its use in diagnosis of hsPDA. |
| Tauber 2013 | No cut‐off threshold reported |
| Tauber 2016a | Outcome of interest not reported; this study determined BNP levels in preterm infants who did not have clinical or echocardiographic signs of PDA. |
| Tosse 2012 | Urine levels of the natriuretic peptide, not serum |
| Yildirim 2010 | No cut‐off threshold reported |
BNP: brain natriuretic peptide; BPD: bronchopulmonary dysplasia; ELBW: extremely low birth weight; hsPDA: haemodynamically significant patent ductus arteriosus; NT‐proBNP: amino‐terminal pro‐B‐type natriuretic peptide; PDA: patent ductus arteriosus; VLBW: very low birth weight
Characteristics of studies awaiting classification [ordered by study ID]
Alenazi 2016.
| Patient Sampling | Prospective single centre study |
| Patient characteristics and setting | A total of 33 preterm infants < 31 weeks in gestation and of < 1200 gm in weight were studied. |
| Index tests | NT‐proBNP measured using Roche assay |
| Target condition and reference standard(s) | hsPDA defined |
| Flow and timing | Unclear |
| Comparative | No |
| Notes | Awaiting further information from author regarding whether a cutoff threshold for NT‐proBNP was determined to calculate sensitivity and specificity for hsPDA. |
Dasraf 2017.
| Patient Sampling | Observational cross‐sectional study in a single centre |
| Patient characteristics and setting | Preterm infants < 37 weeks and weight < 2000 gm |
| Index tests | NT‐proBNP |
| Target condition and reference standard(s) | Defined hsPDA |
| Flow and timing | NT‐proBNP and echo were performed on same day |
| Comparative | No |
| Notes | Awaiting further information from author regarding whether a cut‐off threshold for NT‐proBNP was determined to calculate sensitivity and specificity. |
Elsayed 2016.
| Patient Sampling | Prospective study in single centre |
| Patient characteristics and setting | Preterm infants < 31 weeks |
| Index tests | BNP measured using Triage BNP assay |
| Target condition and reference standard(s) | PDA score developed based on PDA ductal diameter, LA/Ao ratio and descending aorta diastolic flow. However, no threshold cut‐off was determined. |
| Flow and timing | BNP was measured concurrently with echo, which was performed at 48 to 72 hours of age. |
| Comparative | No |
| Notes | Awaiting further information from author regarding whether a cut‐off threshold for BNP and NT‐proBNP were determined to calculate sensitivity and specificity. |
Jeong 2016.
| Patient Sampling | Retrospective single centre study |
| Patient characteristics and setting | Preterm infants 25 to 36 weeks gestation |
| Index tests | BNP measured using BNP Triage assay |
| Target condition and reference standard(s) | While BNP levels significantly correlated to the magnitude of the shunt, cut‐off thresholds not reported |
| Flow and timing | unclear |
| Comparative | no |
| Notes | Awaiting cut off values and data for 2x 2 table to calculate sensitivity and specificity |
König 2015.
| Patient Sampling | Propspective observational study in a single centre involving preterm infants < 32 weeks |
| Patient characteristics and setting | To determine whether BNP or NT‐proBNP was more closely correlated with PDA size. |
| Index tests | BNP assay: chemiluminescent microparticle immunoassay. NT‐proBNP: Elecys electrochemiluminescence immunoassay |
| Target condition and reference standard(s) | hsPDA defined as PDA > 3.2 mm, all echos performed by a single echocardiographer |
| Flow and timing | BNP and NT‐proBNP were simultaneously measured prior to echo. |
| Comparative | No |
| Notes | Awaiting further information from author regarding whether a cut‐off threshold for BNP and NT‐proBNP were determined to calculate sensitivity and specificity. |
Olsson 2019.
| Patient Sampling | Prospective observational single centre study |
| Patient characteristics and setting | A total of 47 preterm infants < 28 weeks in gestation |
| Index tests | BNP and NT‐proBNP measured using PEA technique using Proseek Multiplex |
| Target condition and reference standard(s) | hsPDA was defined and BNP and NT‐proBNP were associated with persistence of PDA. |
| Flow and timing | All echos were paired with serum |
| Comparative | No |
| Notes | Awaiting further information from author regarding whether a cut‐off threshold for BNP and NT‐proBNP were determined to calculate sensitivity and specificity. |
Shi 2021.
| Patient Sampling | Prospective observational single centre study |
| Patient characteristics and setting | A total of 90 preterm infants between 28 and 34 weeks and birth weight 1000 to 1500 gm included |
| Index tests | NT‐proBNP measured using Roche kit |
| Target condition and reference standard(s) | Authors defined target condition using ductal diameter, LA/Ao ratio and LVEF but did not define actual cut‐offs |
| Flow and timing | Unclear |
| Comparative | No |
| Notes | Awaiting further information from author regarding whether a cut‐off threshold for NT‐proBNP was determined to diagnose hsPDA, and 2 x 2 table data to calculate sensitivity and specificity. |
BNP: brain natriuretic peptide; hsPDA: haemodynamically significant patent ductus arteriosus; LA/Ao: left atrium‐to‐aortic root; LVEF: left ventricular ejection fraction; NT‐proBNP: amino‐terminal pro‐B‐type natriuretic peptide; PDA: patent ductus arteriosus
Differences between protocol and review
Use of STATA for statistical analysis instead of SAS
Modified subgroup analyses mentioned in the protocol
Our chosen arbitrary cutoff levels for BNP(< 250 pg/ml and ≥250 pg/ml) and for NT‐proBNP (< 6000 pg/ml and ≥ 6000 pg/ml) for subgroup analyses are different from those mentioned in the protocol.
We have modified our results based on reviewers' comments. We reported only summary curves not summary points because of a wide range of thresholds used among the included studies.
Contributions of authors
Ganga Gokulakrishnan participated in design, methodological assessment, revision of the protocol, and wrote the review
Madhulika Kulkarni participated in conception, design, and methodological assessment, wrote the protocol, and assisted in the review
Shan He participated in the methodological quality assessment.
Antonio Cabrera provided critical intellectual input for the review.
Caraciolo Fernandes provided critical intellectual input and participated in revision of the protocol and review.
Mariska Leeflang provided critical intellectual input and participated in revision of the protocol and review.
Mohan Pammi conceived the project and participated in protocol design and the analysis plan, guided and co‐ordinated the review. He revised the review to incorporate editorial review comments (23 July 2022).
Sources of support
Internal sources
No sources of support provided
External sources
-
Vermont Oxford Network, USA
Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence‐based care of the highest quality for newborn infants and their families.
Declarations of interest
Ganga Gokulakrishnan: has declared they have no financial or other conflicts of interest to disclose. Madhulika Kulkarni: has declared they have no financial or other conflicts of interest to disclose. Shan He: has declared they have no financial or other conflicts of interest to disclose. Mariska MG Leeflang: has declared they have no financial or other conflicts of interest to disclose. Antonio G Cabrera: has declared they have no financial or other conflicts of interest to disclose. Caraciolo J Fernandes: has declared they have no financial or other conflicts of interest to disclose. Mohan Pammi: MP is an Associate Editor with Cochrane neonatal and did not take part in the editorial assessment of this review.
New
References
References to studies included in this review
Asrani 2018 {published data only}
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El‐Khuffash 2007 {published data only}
- El-Khuffash AF, Amoruso M, Culliton M, Molloy EJ. N-terminal pro-B-type natriuretic peptide as a marker of ductal haemodynamic significance in preterm infants: a prospective observational study. Archives of Disease in Childhood Fetal Neonatal Edition 2007;92(5):F421-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Ahmed 2012 {published data only}
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Flynn 2005 {published data only}
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Holmström 2001 {published data only}
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Perugu 2014 {published data only}
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Tauber 2016a {published data only}
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References to studies awaiting assessment
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