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.
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.
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.
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).
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.
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).
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.
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.