Abstract
Objective
To compare, through a systematic review and meta-analysis of observational accuracy studies, the main existing neonatal death prediction scores.
Method
Systematic review and meta-analysis of observational accuracy studies. The databases accessed were MEDLINE, ELSEVIER, LILACS, SciELO, OpenGrey, Open Access Thesis and Dissertations, EMBASE, Web of Science, SCOPUS and Cochrane Library. For qualitative analysis, Quality Assessment of Diagnostic Accuracy Studies 2 was used. For the quantitative analysis, the area under the curve and the SE were used, as well as the inverse of the variance as a weight measure, DerSimonian and Laird as a measure of random effects, Higgins’ I² as an estimate of heterogeneity, Z as a final measure with a 95% confidence level.
Results
55 studies were analysed, 8 scores were compared in a total of 193 849 newborns included. The most accurate neonatal death prediction score was Score for Neonatal Acute Physiology Perinatal Extension II (SNAPPE II) (0.89 (95% CI 0.86 to 0.92)) and the least accurate was gestational age (0.75 (95% CI 0.71 to 0.79)).
Conclusion
SNAPPE II was the most accurate score found in this study. Despite this, the choice of score depends on the situation and setting in which the newborn is inserted, and it is up to the researcher to analyse and decide which one to use based on practicality and the possibility of local implementation. Given this, it is interesting to carry out new prospective studies to improve the prediction of neonatal deaths around the world.
PROSPERO registration number
CRD42023462425.
Keywords: Mortality, Neonatology, Epidemiology
WHAT IS ALREADY KNOWN ON THIS TOPIC
There are eight main neonatal death prediction scores. There are several studies showing the advantages and disadvantages of each one, as well as comparisons between scores, but using restricted groups of newborns. As neonatal death does not only affect premature or low birth weight newborns, a comparison of the main scores in a broader population is needed.
WHAT THIS STUDY ADDS
The most accurate score was the Score for Neonatal Acute Physiology Perinatal Extension II, but it has some difficult criteria to follow in many settings.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Identifying the most accurate score can help health professionals, as well as institutions, to reduce the high numbers of neonatal deaths.
Introduction
Neonatal death corresponds to the death of a newborn between birth and the 28th day of life.1 2 Although it is a short period of time, it contains most deaths in childhood, with the highest risk of death occurring in the first week of the newborn’s life.3 The outcome of this period, early neonatal death, represents approximately 73% of all postnatal deaths recorded worldwide.4 This is why early neonatal death is a public health problem that is still far from being resolved.5
The main reason for neonatal death is the low birth weight (BW), followed by prematurity, inadequate prenatal care, the presence of congenital anomalies, the presence of neonatal asphyxia and the type of delivery.5 6 Given the various causes and rising numbers, there was a need to create systems to identify early neonatal deaths, such as the Clinical Risk Index for Babies (CRIB), Score for Neonatal Acute Physiology (SNAP) and Score for Neonatal Acute Physiology Perinatal Extension (SNAPPE).7
Despite the existence of a systematic review and meta-analysis comparing the main scores in premature babies,8 there is a need to expand the population studied, not being restricted only to premature babies or low BW newborns, to better understand the global impact of different neonatal death prediction scores in all situations. Therefore, this study aims, through a systematic review and meta-analysis of observational accuracy studies, to compare the main neonatal death prediction scores.
Methods
The PROSPERO protocol (https://www.crd.york.ac.uk/prospero/) has been published under number CRD42023462425.
Study selection, data extraction, risk of bias analysis, data analysis and quality of evidence analysis were carried out by two authors independently. Disagreements were resolved through an agreement between the parties. If there was no consensus, a third author decided the impasse.
Eligibility criteria
The eligibility criteria were made up of the following items: observational studies on neonatal death, studies that involved the main prediction scores (BW, CRIB, CRIB II, gestational age (GA), SNAP, SNAP II, SNAPPE), studies that used the area under the curve (AUC) and their respective CIs (95% CI) and/or SE, studies that had neonatal death as the main outcome. There were no restrictions on language, period or location.
Databases
The databases were MEDLINE via PubMed, ELSEVIER via ScienceDirect, LILACS via BVS, SciELO, OpenGrey, Open Access Thesis and Dissertations, EMBASE, Web of Science, SCOPUS and Cochrane Library.
The searches were carried out between November 2023 and February 2024. In June 2024, before submission, the searches were repeated to ensure that all possible studies were included.
Search strategy
The search strategy was defined based on the PECOS structure (Population, Exposure, Comparison, Outcome, Type of study). With this, a search strategy was constructed using MeSH terms (https://www.ncbi.nlm.nih.gov/mesh) and free terms.
Study selection
The selection of studies was divided into four stages: titles, abstracts, full articles and references. Furthermore, the selection of studies was complemented by seeking help from experts in the field to find studies relevant to the topic.
The removal of duplicates was carried out with the help of the Rayyan application (Qatar Foundation, Doha, Qatar) (https://rayyan.ai/).
Data extraction
Data extraction was organised in a spreadsheet using Microsoft Excel V.16.0 software (Microsoft, Redmond, USA) based on the following elements: name of authors, year of publication, prediction score used, AUC, 95% CI and SE.
Neonatal death prediction scores
The neonatal death prediction scores included were BW, CRIB, CRIB II, GA, SNAP, SNAP II, SNAPPE and SNAPPE II.
Risk of bias analysis
The risk of bias analysis was performed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool to evaluate accuracy studies. QUADAS-2 analyses four domains (patient selection, index test, reference standard, flow and time) and is applied in four phases: summary of the research question, adaptation of the tool and production of specific analyses, construction of a flow chart and judgement of bias and applicability.9
Data analysis
Data analysis was performed using RStudio software version 2023.12.1+402 (Posit Software, Boston, USA). The data analysed were AUC and SE. For studies that did not have SE, but rather 95% CI, the conversion form (SE=(upper limit of the CI−lower limit of the CI)/3.92)) was used.
Using the Meta package and Metagen documentation, the pooled AUC and its CI were found. Furthermore, the inverse of the variance was used as a weight measure, DerSimonian and Laird as a measure of random effects, Higgins’ I² as an estimate of heterogeneity and Z as a final measure. A confidence level of 95% was considered.
Heterogeneity was explored when Higgins’ I² was greater than 50%.10 The analysis was performed in subgroups. The evaluation of publication bias was carried out using the funnel scatterplot, in addition to the Egger test, only when the analysis had ten or more studies. Finally, if there was an asymmetry in the funnel scatterplot, the Trim-and-Fill method was used to nullify the asymmetry found.
Quality of evidence analysis
The quality of evidence analysis was carried out using the Grading of Recommendations, Assessment, Development and Evaluations, a tool composed of four levels of evidence to recommend a clinical decision.11
Patient and public involvement
No patient is involved.
Results
Study selection
The database search identified 3087 articles, of which 346 were duplicates. After the eligibility phase, 2686 studies were excluded, leaving 55 articles12,65 to be included in our study (figure 1).
Figure 1. Study selection flow chart. AUC, area under the curve.
The characteristics of the 55 included studies are available in table 1 and those relevant to the quantitative analysis are shown in table 2.
Table 1. General characteristics of the included studies.
Author | Year | Country | Type of study | Number of neonates analysed | Score |
Alshafei et al12 | 2024 | United Arab Emirates | Retrospective cohort | 404 | CRIB II, BW, GA |
Bastos13 | 1997 | Portugal | Retrospective cohort | 186 | CRIB, SNAP, SNAPPE, BW |
Bayen et al14 | 2023 | India | Prospective cohort | 57 | CRIB II, SNAPPE II |
Beltempo et al | 2018 | Canada | Retrospective cohort | 9240 | SNAP II |
Bhandekar et al16 | 2024 | India | Prospective cohort | 44 | CRIB II |
Brito et al17 | 2003 | Brazil | Prospective cohort | 284 | CRIB, BW, GA |
Bührer et al18 | 2008 | Germany | Retrospective cohort | 1358 | CRIB, CRIB II, BW, GA |
Bührer et al19 | 2000 | Germany | Retrospective cohort | 430 | CRIB, BW, GA |
Eriksson et al20 | 2002 | Sweden | Retrospective cohort | 240 | CRIB, SNAP, SNAPPE, BW, GA |
Escobar et al21 | 1995 | USA | Prospective cohort | 1251 | SNAPPE, BW |
Ezz-Ezdin et al22 | 2015 | Egypt | Prospective cohort | 113 | CRIB II, BW, GA |
De Felice et al23 | 2005 | Italy | Retrospective cohort | 147 | CRIB, CRIB II, BW, GA |
Fontenele et al24 | 2020 | Brazil | Prospective cohort | 247 | SNAPPE II |
Gagliardi et al25 | 2004 | Italy | Prospective cohort | 720 | CRIB, CRIB II, SNAPPE II |
Gooden et al26 | 2014 | Jamaica | Retrospective cohort | 109 | CRIB II, BW, GA |
Guenther et al27 | 2015 | Germany | Retrospective cohort | 5340 | CRIB, BW, GA |
Guzmán Cabañas et al28 | 2009 | Spain | Prospective cohort | 10 608 | CRIB, BW, GA |
Harsha nd Archana29 | 2015 | Bangalore | Prospective cohort | 248 | SNAPPE II |
Heidarzadeh30 | 2016 | Iran | Prospective cohort | 215 | CRIB II |
International Neonatal Network31 | 1993 | UK | Retrospective cohort | 735 | CRIB, BW |
Jasic32 | 2016 | Croatia | Prospective cohort | 153 | CRIB II, BW, GA |
Lago et al33 | 1999 | Italy | Prospective cohort | 81 | CRIB, BW, GA |
Lee et al | 2019 | South Korea | Prospective cohort | 636 | CRIB II |
Lokraj35 | 2023 | Nepal | Prospective cohort | 260 | SNAP II, SNAPPE II |
Medvedev et al7 | 2020 | UK and Gambia | Retrospective cohort | 110 726 | CRIB II |
Menéndez36 | 2018 | Ecuador | Retrospective cohort | 227 | CRIB, CRIB II, SNAP II, SNAPPE II |
Mesquita37 | 2011 | Paraguay | Retrospective cohort | 288 | SNAP II, SNAPPE II |
Moreira et al38 | 2022 | Sweden | Prospective cohort | 3752 | CRIB II, BW, GA |
Muktan et al39 | 2019 | Nepal | Prospective cohort | 255 | SNAPPE II |
Muñoz-Garcia et al40 | 2014 | Spain | Retrospective cohort | 81 | CRIB II, SNAP II, SNAPPE II |
Park et al41 | 2018 | South Korea | Retrospective cohort | 564 | CRIB II, BW, GA |
Patra and Karmakar42 | 2019 | India | Prospective cohort | 143 | CRIB II |
Phillips et al | 2010 | UK | Retrospective cohort | 408 | CRIB |
Radfar et al44 | 2018 | Iran | Prospective cohort | 191 | SNAP II, SNAPPE II |
Rastogi et al45 | 2010 | India | Prospective cohort | 86 | CRIB II |
Rautonen et al46 | 1994 | Finland | Prospective cohort | 222 | CRIB, SNAP, SNAPPE, GA |
Ray et al47 | 2019 | India | Prospective cohort | 961 | SNAPPE II |
Reid et al | 2014 | Australia | Prospective cohort | 1607 | CRIB II, SNAPPE II |
Richardson et al49 | 1993 | USA | Retrospective cohort | 1621 | SNAP, SNAPPE, BW |
Richardson et al50 | 2001 | Canada | Prospective cohort | 14 610 | SNAPPE II, BW |
Rosenberg et al51 | 2008 | Bangladesh, Egypt and Nepal | Retrospective cohort | 467 | CRIB II |
Ruiz et al52 | 2007 | Spain | Prospective cohort | 163 | CRIB, BW, GA |
Sarquis et al53 | 2002 | Brazil | Prospective cohort | 100 | CRIB, BW, GA |
Shrestha et al54 | 2017 | Nepal | Prospective cohort | 126 | SNAP II, SNAPPE II |
Silveira et al55 | 2001 | Brazil | Retrospective cohort | 553 | SNAP, SNAPPE |
Singh56 | 2018 | Nepal | Prospective cohort | 255 | SNAPPE II |
Sotodate et al | 2020 | Japan | Retrospective cohort | 171 | CRIB II, SNAP II, SNAPPE II, BW, GA |
Thimoty et al58 | 2009 | Indonesia | Prospective cohort | 40 | SNAPPE II |
Tyagi et al59 | 2022 | India | Prospective cohort | 100 | SNAPPE II |
Vardhelli et al60 | 2022 | India | Prospective cohort | 419 | CRIB II, SNAPPE II |
Vardhelli et al | 2023 | India | Prospective cohort | 669 | SNAPPE II |
Vasudevan et al62 | 2006 | India | Retrospective cohort | 97 | SNAP |
Weirich et al63 | 2005 | Brazil | Retrospective cohort | 20 286 | BW |
Yang et al64 | 2002 | China | Prospective cohort | 192 | CRIB, CRIB II, SNAP II, SNAPPE II |
Zhang et al65 | 2023 | China | Prospective cohort | 1363 | CRIB II |
BWbirth weightCRIB IIClinical Risk Index for Babies IIGAgestational ageSNAPScore for Neonatal Acute PhysiologySNAPPE IIScore for Neonatal Acute Physiology Perinatal Extension II
Table 2. Characteristics relevant to the quantitative analysis of the included studies.
Scale | Studies included | Pooled AUC | SE |
BW | 22 | 0.76 | 0.015 |
CRIB | 17 | 0.87 | 0.010 |
CRIB II | 25 | 0.82 | 0.020 |
GA | 17 | 0.75 | 0.020 |
SNAP | 6 | 0.82 | 0.020 |
SNAP II | 9 | 0.83 | 0.035 |
SNAPPE | 6 | 0.88 | 0.025 |
SNAPPE II | 21 | 0.89 | 0.015 |
AUCarea under the curveBWbirth weightCRIB IIClinical Risk Index for Babies IIGAgestational ageSNAP IIScore for Neonatal Acute Physiology IISNAPPE IIScore for Neonatal Acute Physiology Perinatal Extension II
Risk of bias analysis
The studies were analysed using the QUADAS-2 tool. In the ‘patient selection’ domain, 14 studies12 13 15 18 20 23 31 36 43 49 55 57 62 63 were classified as having a high risk of bias. In the ‘index test’ and ‘flow and time’ domains, 281213 15 19,21 23 7 26 27 31 33 34 36 37 40 41 43 4647 51 55,57 62 63 and 14 studies718 19 31 34 37 38 41 45,47 49 had the same classification, respectively. Finally, in the ‘reference standard’ domain, all studies were classified as low risk of bias. Likewise, in relation to applicability, all studies were classified as not worrying. The graphs relating to the risk of bias and concerns about applicability are illustrated in figure 2.
Figure 2. Risk of bias analysis of the included studies. QUADAS-2, Quality Assessment of Diagnostic Accuracy Studies 2.
Data analysis
Figure 3 illustrates the relationship between neonatal death prediction scores represented by pooled AUC and their 95% CI. Below, separately, the results of the neonatal death prediction scores analysed. The figures for each of the scores analysed are available in online supplemental material.
Figure 3. Summary of neonatal death prediction scores. AUC, area under the curve; BW, birth weight; CRIB II, Clinical Risk Index for Babies II; GA, gestational age; SNAP II, Score for Neonatal Acute Physiology II; SNAPPE II, Score for Neonatal Acute Physiology Perinatal Extension II.
Birth weight
BW was highly accurate in predicting neonatal death (pooled AUC=0.76; 95% CI (0.73 to 0.79); p=0.000; I² = 93% (p<0.01)).1213 18,23 26 When exploring heterogeneity, it was noticed that heterogeneity was maintained in four of the subgroups analysed (Germany18 19 27: I²=77% (p=0.01); Italy23 33: I²=92% (p<0.01); South Korea41: I²=90% (p<0.01); Canada21 50: I²=99% (p<0.01)).
Regarding publication bias, there was symmetry in the funnel graph (Egger’s test: t=−1.53; p=0.13).
Clinical Risk Index for Babies
CRIB showed high accuracy in predicting neonatal death (pooled AUC=0.87; 95% CI (0.85 to 0.89); p=0.00; I²=87% (p<0.01)).1317,20 23 25 27 28 31 33 36 43 46 52 53 64 When exploring heterogeneity, it was noticed that heterogeneity was maintained in two of the subgroups analysed (Germany18 19 27: I²=88% (p<0.01) (Spain)13 28 52: I²=73% (p=0.03)).
Regarding publication bias, there was symmetry in the funnel plot (Egger’s test: t=0.52; p=0.60).
Clinical Risk Index for Babies II
CRIB II showed high accuracy in predicting neonatal death (pooled AUC=0.82; 95% CI (0.78 to 0.86); p<0.01; I²=99% (p=0.00)).7 12 14 16 18 20 23 25 26 30 32 34 36 38 40,4345 48 51 57 60 64 65 When exploring heterogeneity, it was noticed that heterogeneity was maintained in three of the subgroups analysed (India14 16 42 45 60: I²=93% (p<0.01); South Korea34 41: I²=98% (p<0.01); China64 65: I²=96% (p<0.01)).
Regarding publication bias, there was asymmetry in the funnel graph (Egger’s test: t=−4.46; p=0.001). To adjust the graph, it was necessary to impute 15 studies to eliminate the asymmetry (Egger’s test: t=−0.61; p=0.54).
Gestational age
GA showed good accuracy in predicting neonatal death (pooled AUC=0.75; 95% CI (0.71 to 0.79); p<0.01; I²=94% (p<0.01)).1217 18 26,28 32 33 38 41 46 52 53 When exploring heterogeneity, it was noticed that there was a decrease in heterogeneity in two of the subgroups analysed (Germany18 19 27: I²=92% (p<0.01); Spain28 52: I²=75% (p=0.05); South Korea41: I²=78% (p=0.03)).
Regarding publication bias, there was symmetry in the funnel graph (Egger’s test: t=−1.53; p=0.14).
Score for Neonatal Acute Physiology
SNAP showed high accuracy in predicting neonatal death (pooled AUC=0.82; 95% CI (0.78 to 0.86); p=0.00; I²=44% (p=0.11)).13 20 46 49 55 62
Score for Neonatal Acute Physiology II
SNAP II showed good accuracy in predicting neonatal death (pooled AUC=0.83; 95% CI (0.76 to 0.90); p<0.01; I²=99% (p<0.01)).1535,37 40 44 54 57 64 When exploring heterogeneity, it was noticed that heterogeneity was maintained in one of the subgroups analysed (Nepal35 54: I²=80% (p=0.03)).
Score for Neonatal Acute Physiology Perinatal Extension
SNAPPE showed high accuracy in predicting neonatal death (pooled AUC=0.88; 95% CI (0.83 to 0.93); p<0.01; I²=87% (p<0.01)).13 20 21 46 49 55 It was not possible to analyse heterogeneity due to the unitary nature of each subgroup analysed.
Score for Neonatal Acute Physiology Perinatal Extension II
SNAPPE II showed high accuracy in predicting neonatal death (Pooled AUC=0.89; 95% CI (0.86 to 0.92); p=0.00; I²=94% (p<0.01)).1424 25 29 35,37 39 40 44 47 48 50 54 56 When exploring heterogeneity, it was noticed that heterogeneity was maintained in two of the subgroups analysed (India1447 59,61: I²=84% (p<0.01); Nepal35 39 54 56: I²=75% (p<0.01)).
Regarding publication bias, there was asymmetry in the funnel plot (Egger’s test: t=−3.01; p=0.006). To adjust the graph, it was necessary to impute nine studies to eliminate the asymmetry (Egger’s test: t=−0.37; p=0.71).
Table 3 illustrates the compilation of results obtained in the qualitative and quantitative analysis.
Table 3. Summary of results obtained in the qualitative and quantitative analysis.
Scores | Studies included | Number of participants analysed | Pooled AUC | 95% CI | I² | Publication bias |
BW | 22 | 62 706 | 0.76 | (0.73 to 0.79) | 93% | p=0.13 |
CRIB | 17 | 21 441 | 0.87 | (0.85 to 0.89) | 87% | p=0.60 |
CRIB II | 25 | 123 754 | 0.82 | (0.78 to 0.86) | 99% | p=0.001 |
GA | 17 | 24 239 | 0.75 | (0.71 to 0.79) | 94% | p=0.14 |
SNAP | 6 | 2919 | 0.82 | (0.78 to 0.86) | 44% | – |
SNAP II | 9 | 10 776 | 0.83 | (0.76 to 0.90) | 99% | – |
SNAPPE | 6 | 4073 | 0.88 | (0.83 to 0.89) | 87% | – |
SNAPPE II | 21 | 21 724 | 0.89 | (0.86 to 0.92) | 94% | p=0.006 |
AUCarea under the curveBWbirth weightCRIBEClinical Risk Index for BabiesGAgestational ageSNAPScore for Neonatal Acute PhysiologySNAPPE IIScore for Neonatal Acute Physiology Perinatal Extension II
Quality of evidence analysis
The studies were analysed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool. Only one of the five domains was identified as high risk. Therefore, the certainty of the study’s evidence was classified as moderate. The graphs relating to the risk of bias and concerns about applicability are illustrated in table 4.
Table 4. Quality of evidence analysis.
GRADE domains | Judgement |
Risk of bias | Low |
Imprecision | Low |
Inconsistency | High |
Indirectness | Low |
Publication bias | Low |
Overall | Moderate |
GRADEGrading of Recommendations, Assessment, Development and Evaluations
Discussion
The study showed that the most accurate neonatal death prediction score was SNAPPE II (0.89 (95% CI 0.86 to 0.92)),1424 25 29 35,37 39 40 44 47 48 50 54 56 and GA was the score with the lowest accuracy (0.75 (95% CI 0.71 to 0.79)).1217,20 22 23 26 There were 55 studies analysed, 8 scores being compared in a total of 193 849 newborns included.
As the most up to date of the main scores, SNAPPE II would tend to be the most accurate. Built on the positive and negative points of its predecessors, SNAPPE II is an extension of SNAP II.66 In addition to measurements of blood pressure, temperature, PO2/FiO2 ratio, serum pH, amount of fainting and urinary output, there are three data points that aggregate SNAPPE II: BW≤749 g, Apgar<7 in the 5th minute and small for GA.50 It is because of these refined data that SNAPPE II was probably the most accurate score in this study.
In our study, SNAPPE (0.88 (95% CI 0.83 to 0.93))13 20 21 46 49 55 and CRIB (0.87 (95% CI 0.85 to 0.89))1317,20 23 25 27 28 31 33 36 43 46 52 53 64 were the second and third most accurate scores. This fact was different from the recently published systematic review and meta-analysis that compared the main scores in premature infants. In the study in question, CRIB was the most accurate score (0.98), followed by SNAPPE (0.71), the reason being that it is a simple-to-apply score.8 In fact, the CRIB has only six parameters to be collected in a hospital environment in the first 12 hours of a newborn’s life.31 66 SNAPPE, an extension of SNAP, has 31 parameters to be collected, becoming a barrier to effective collection.49 This difficulty, years later, led to the emergence of the SNAP II and SNAPPE II updates, the most accurate score in our study.
BW (0.76 (95% CI 0.73 to 0.79))1213 17,23 26 50 52 53 63 was expected e o GA (0.75 (95% CI 0.71 to 0.79))1217,20 22 23 26 38 41 46 52 53 were the worst scores, as they only analysed one parameter in isolation. Furthermore, such parameters are present in all other scores.12 The inclusion of BW and GA was necessary to provide a base standard for the other scores in our study.
Given the existence of so many neonatal death prediction scores for the most diverse situations,8 66 choosing the best score becomes a herculean task. However, the guiding factor for this choice is precisely the situation in which the newborn is inserted.66 Although SNAPPE II is the most accurate score in this study, if the newborn is in a hospital environment where the parameters necessary to predict death are only sufficient to compose the CRIB,31 the researcher can use this score without prejudice. Likewise, if it is necessary to collect data for more than 12 hours, as requested by the CRIB, the researcher can use SNAP,49 for example, which also has high accuracy.
Despite the complexity of these scores, they are widely used in Neonatal Intensive Care Units (NICUs), mainly due to their degree of accuracy.66 With data collection starting at birth and ending in the first 12 or 24 hours, the data to be collected involves components of prenatal, delivery and postpartum care, more precisely, the hospital environment, especially the NICU environment.66 The elements collected from blood gas analysis and ventilation parameters make these scores almost impractical in places where access to healthcare is difficult.7
The closest solution would be a less complex score, with single or combined elements, such as GA and BW, however, as seen in this study, the accuracy is low, and it is not the best score to predict death. However, in the absence of access to quality healthcare, these scores become an alternative in the attempt to reduce neonatal deaths.
Heterogeneity was observed in 7 of the 8 scores analysed. The score with the greatest heterogeneity was CRIB II. When exploring it, it was seen that the countries with the greatest contribution were India, South Korea and China. Regarding the Indian studies,14 16 42 45 60 despite having similar eligibility criteria, there was a sample variation between the studies, which is the possible reason for the heterogeneity between these studies. As for the Korean studies,34 41 the possible factor of heterogeneity was the methodological difference of the studies, one being prospective and the other retrospective. Finally, the Chinese studies64 65 differ both in the eligibility criteria, one being more restrictive than the other, and in the size of the sample collected.
Regarding the lowest and highest accuracy scores, respectively, GA and SNAPPE II, both had the same heterogeneity value (I²=94%). The first was influenced by German studies and the latter by Indian studies. The German studies18 19 27 were prospective, with similar eligibility criteria, but the collection time differed between them, with 5 years being the shortest collection time and 15 years being the longest. In the Indian studies,1447 59,61 not all were multicentre, despite the prospective nature of all of them. In addition, the collection time varied from 1 to 2 years.
In general, one of the main reasons for this difference between the studies, in addition to the characteristics of each country, was the longitudinal design of the studies, since many were prospective, and others were retrospective. Another point to be highlighted was the publication bias found in 2 of the 8 scores. An interesting detail to be highlighted was that these two scores are the most current (CRIB II and SNAPPE II). Despite the facts mentioned above, the heterogeneity of our study does not invalidate the individual clinical results of the included studies, since, individually, the studies maintained the expected methodological accuracy, given the complexity of the main scores.
In the analysis of the risk of bias, high-risk studies were found in three of the four domains. The main reasons for this occurrence were the retrospective nature of the studies, the knowledge of the reference standard, which was neonatal death, and the absence of all participants in the final analysis. Despite the finding of risk in the individual analysis, when using GRADE, we classified the degree of evidence of the study as moderate since heterogeneity was found in most of the scores analysed in the meta-analysis.
There are some limitations in our study. The first, inherent to review studies, arises from the fact that secondary data were collected to compose our qualitative and quantitative analysis. Another limitation is the use of retrospective cohorts which, despite being good accuracy studies, cannot completely nullify the fact of knowledge of the participant’s outcome. Finally, when using the AUC instead of data referring to true positives and negatives and false positives and negatives, there is a risk of overvaluation or undervaluation of the analysed data, but the largest evaluated sample reduces these bias’s chances to be significant.
Given the data presented and the limitations outlined, steps should be taken to verify and apply the data, as well as to eliminate the limitations presented. Prospective studies using the main available scores are interesting for analysing the impact of these scores on the same population and even on different populations. Furthermore, selecting the most appropriate scores, aiming to create a new score for the most diverse economic and social situations, to ensure simple and practical application, is an innovative and bold proposal that deserves the attention of both the academic community and public authorities, highlighting the issue of neonatal death as an important public health problem to be solved.
Conclusion
SNAPPE II was the most accurate score found in this study. Despite this, the choice of score depends on the newborn’s situation, and it is up to the researcher to analyse and decide which one to use. In view of this, it is interesting to conduct prospective studies, using the main available scores, in the same population and even in different populations, aiming to find the most appropriate score, as well as the creation of a new simple, practical and comprehensive score to improve the prediction of neonatal deaths around the world.
supplementary material
Footnotes
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Ethics approval: As a systematic review study with meta-analysis, approval by the research ethics committee was not necessary.
Contributor Information
Felipe C S Veloso, Email: fcamilo.veloso@gmail.com.
Carine R A Barros, Email: carine.accioly91@gmail.com.
Samir B Kassar, Email: samirbrk@uol.com.br.
Ricardo Q Gurgel, Email: ricardoqgurgel@gmail.com.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
References
- 1.United Nations Inter-agency Group for Child Mortality Estimation . UNICEF; 2024. Levels and trends in child mortality report 2024. [Google Scholar]
- 2.Tamir TT. Neonatal mortality rate and determinants among births of mothers at extreme ages of reproductive life in low and middle income countries. Sci Rep. 2024;14:12596. doi: 10.1038/s41598-024-61867-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Malka ES, Solomon T, Kassa DH, et al. Time to death and predictors of mortality among early neonates admitted to neonatal intensive care unit of Addis Ababa public Hospitals, Ethiopia: Institutional-based prospective cohort study. PLoS One. 2024;19:e0302665. doi: 10.1371/journal.pone.0302665. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Lehtonen L, Gimeno A, Parra-Llorca A, et al. Early neonatal death: A challenge worldwide. Semin Fetal Neonatal Med. 2017;22:153–60. doi: 10.1016/j.siny.2017.02.006. [DOI] [PubMed] [Google Scholar]
- 5.Veloso FCS, Kassar L de ML, Oliveira MJC, et al. Analysis of neonatal mortality risk factors in Brazil: a systematic review and meta-analysis of observational studies. J Pediatr (Rio J) 2019;95:519–30. doi: 10.1016/j.jped.2018.12.014. [DOI] [PubMed] [Google Scholar]
- 6.Karami B, Abbasi M, Tajvar M. Determinants of Neonatal, Infant and Child Mortalities in Iran: A Systematic Review. Iran J Public Health. 2024;53:104–15. doi: 10.18502/ijph.v53i1.14687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Medvedev MM, Brotherton H, Gai A, et al. Development and validation of a simplified score to predict neonatal mortality risk among neonates weighing 2000 g or less (NMR-2000): an analysis using data from the UK and The Gambia. Lancet Child Adolesc Health. 2020;4:299–311. doi: 10.1016/S2352-4642(20)30021-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Zeng Z, Shi Z, Li X. Comparing different scoring systems for predicting mortality risk in preterm infants: a systematic review and network meta-analysis. Front Pediatr. 2023;11:1287774. doi: 10.3389/fped.2023.1287774. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Whiting PF, Rutjes AWS, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529–36. doi: 10.7326/0003-4819-155-8-201110180-00009. [DOI] [PubMed] [Google Scholar]
- 10.Higgins JPT, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–6. doi: 10.1136/bmj.39489.470347.AD. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Alshafei A, Zawam E, Galal M, et al. Validity of the Mean Platelet Volume and Revised Clinical Risk Index for Babies (CRIB-II) Score to Assess Mortality Risk in Preterm Infants. NEMJ. 2024;05:e040923220679. doi: 10.2174/0250688205666230904104508. [DOI] [Google Scholar]
- 13.Bastos G. Comparação de quatro escalas de avaliação da gravidade clínica (CRIB, SNAP, SNAP-PE, NTISS) em recém-nascidos prematuros. Acta Med Port. 1997;10:161–5. [PubMed] [Google Scholar]
- 14.Bayen A, Sk MH, Chaudhuri S, et al. Comparison of crib-ii with snappe-ii as predictor of mortality and neurodevelopmental outcome at 12 months of age for newborns ≤ 32 weeks of gestational age. In Review. 2023 doi: 10.21203/rs.3.rs-3458785/v1. Preprint. [DOI]
- 15.Beltempo M, Shah PS, Ye XY, et al. SNAP-II for prediction of mortality and morbidity in extremely preterm infants. J Matern Fetal Neonatal Med. 2018;32:2694–701. doi: 10.1080/14767058.2018.1446079. [DOI] [PubMed] [Google Scholar]
- 16.Bhandekar H, Bansode Bangartale S, Arora I. Evaluating the Clinical Risk Index for Babies (CRIB) II Score for Mortality Prediction in Preterm Newborns: A Prospective Observational Study at a Tertiary Care Hospital. Cureus. 2024;16:e58672. doi: 10.7759/cureus.58672. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Brito ASJ de, Matsuo T, Gonzalez MRC, et al. CRIB score, birth weight and gestational age in neonatal mortality risk evaluation. Rev Saude Publica . 2003;37:597–602. doi: 10.1590/s0034-89102003000500008. [DOI] [PubMed] [Google Scholar]
- 18.Bührer C, Metze B, Obladen M. CRIB, CRIB-II, birth weight or gestational age to assess mortality risk in very low birth weight infants? Acta Paediatr. 2008;97:899–903. doi: 10.1111/j.1651-2227.2008.00793.x. [DOI] [PubMed] [Google Scholar]
- 19.Bührer C, Grimmer I, Metze B, et al. The CRIB (Clinical Risk Index for Babies) score and neurodevelopmental impairment at one year corrected age in very low birth weight infants. Intensive Care Med. 2000;26:325–9. doi: 10.1007/s001340051157. [DOI] [PubMed] [Google Scholar]
- 20.Eriksson M, Bodin L, Finnström O, et al. Can severity-of-illness indices for neonatal intensive care predict outcome at 4 years of age? Acta Paediatr. 2002;91:1093–100. doi: 10.1080/080352502760311601. [DOI] [PubMed] [Google Scholar]
- 21.Escobar GJ, Fischer A, Li DK, et al. Score for neonatal acute physiology: validation in three Kaiser Permanente neonatal intensive care units. Pediatrics. 1995;96:918–22. doi: 10.1542/peds.96.5.918. [DOI] [PubMed] [Google Scholar]
- 22.Ezz-Ezdin ZM, Abdel Hamid TA, Labib Youssef MR, et al. Clinical Risk Index for Babies (CRIB II) Scoring System in Prediction of Mortality in Premature Babies. J Clin Diagn Res. 2015;9:SC08–SC11. doi: 10.7860/JCDR/2015/12248.6012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.De Felice C, Del Vecchio A, Latini G. Evaluating illness severity for very low birth weight infants: CRIB or CRIB-II? J Matern Fetal Neonatal Med. 2005;17:257–60. doi: 10.1080/14767050500072557. [DOI] [PubMed] [Google Scholar]
- 24.Fontenele MMFT, Silva CF, Leite ÁJM, et al. SNAPPE II: ANALYSIS OF ACCURACY AND DETERMINATION OF THE CUTOFF POINT AS A DEATH PREDICTOR IN A BRAZILIAN NEONATAL INTENSIVE CARE UNIT. Rev Paul Pediatr. 2020;38:e2019029. doi: 10.1590/1984-0462/2020/38/2019029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Gagliardi L, Cavazza A, Brunelli A, et al. Assessing mortality risk in very low birthweight infants: a comparison of CRIB, CRIB-II, and SNAPPE-II. Arch Dis Child Fetal Neonatal Ed. 2004;89:F419–22. doi: 10.1136/adc.2003.031286. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Gooden M, Younger N, Trotman H. What is the best predictor of mortality in a very low birth weight infant population with a high mortality rate in a medical setting with limited resources? Am J Perinatol. 2014;31:441–6. doi: 10.1055/s-0033-1351658. [DOI] [PubMed] [Google Scholar]
- 27.Guenther K, Vach W, Kachel W, et al. Auditing Neonatal Intensive Care: Is PREM a Good Alternative to CRIB for Mortality Risk Adjustment in Premature Infants? Neonatology. 2015;108:172–8. doi: 10.1159/000433414. [DOI] [PubMed] [Google Scholar]
- 28.Guzmán Cabañas JM, Párraga Quiles MJ, del Prado N, et al. Análisis de la utilidad del Clinical Risk Index for Babies por estratos de peso como predictor de muerte hospitalaria y de hemorragia intraventricular grave en la Red Neonatal Española SEN 1500. Anales Pediatr. 2009;71:117–27. doi: 10.1016/j.anpedi.2009.04.007. [DOI] [PubMed] [Google Scholar]
- 29.Harsha SS, Archana BR. SNAPPE-II (Score for Neonatal Acute Physiology with Perinatal Extension-II) in Predicting Mortality and Morbidity in NICU. J Clin Diagn Res. 2015;9:SC10–2. doi: 10.7860/JCDR/2015/14848.6677. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Heidarzadeh M, Ghorbani F, Dastgiri S. Prediction value of crib-ii in outcome of preterm and low birth weight infants: a prospective cohort study. Int J Pediatr. 2016;327:1583–9. doi: 10.22038/ijp.2016.6656. [DOI] [Google Scholar]
- 31.International Neonatal Network The CRIB (clinical risk index for babies) score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units. The Lancet. 1993;342:193–8. doi: 10.1016/0140-6736(93)92296-6. [DOI] [PubMed] [Google Scholar]
- 32.Jasic M. CRIB II score versus gestational age and birth weight in preterm infant mortality prediction: who will win the bet? SV. 2016;11:172. doi: 10.22514/SV111.052016.12. [DOI] [Google Scholar]
- 33.Lago P, Freato F, Bettiol T, et al. Is the CRIB score (clinical risk index for babies) a valid tool in predicting neurodevelopmental outcome inExtremely low birth weight infants? Biol Neonate. 1999;76:220–7. doi: 10.1159/000014162. [DOI] [PubMed] [Google Scholar]
- 34.Lee SM, Lee MH, Chang YS, et al. The Clinical Risk Index for Babies II for Prediction of Time-Dependent Mortality and Short-Term Morbidities in Very Low Birth Weight Infants. Neonatology. 2019;116:244–51. doi: 10.1159/000500270. [DOI] [PubMed] [Google Scholar]
- 35.Lokraj S. Evaluate and compare SNAP II and SNAPPE II as predictors of neonatal mortality in a neonatal intensive care unit at B. P. Koirala Institute of Health Sciences. Int J Acad Med Pharm. 2023;5:593–8. doi: 10.47009/jamp.2023.5.1.122. [DOI] [Google Scholar]
- 36.Menéndez P. Comparación de escalas de predicción mortalidad neonatal (CRIB, CRIB II, SNAP II, SNAPPE II) entre recién nacidos prematuros y a término.Rev ecuat pediatr. 2018;19:29–33. [Google Scholar]
- 37.Mesquita M. SNAP II and SNAPPE II severity scoring for determining the risk of neonatal mortality in a polyvalent intensive care unit. Pediatr (Asunción) 2011;38:93–100. [Google Scholar]
- 38.Moreira A, Benvenuto D, Fox-Good C, et al. Development and Validation of a Mortality Prediction Model in Extremely Low Gestational Age Neonates. Neonatology. 2022;119:418–27. doi: 10.1159/000524729. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Muktan D, Singh RR, Bhatta NK, et al. Neonatal mortality risk assessment using SNAPPE- II score in a neonatal intensive care unit. BMC Pediatr. 2019;19:279. doi: 10.1186/s12887-019-1660-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Muñoz-Garcia M, Martínez-Padilla M, Millán-Miralles L, et al. PO-0638 Usefulness Of Clinical Risk Index For Babies, Score For Neonatal Acute Physiology And Snappe Ii In Predicting Hospital Mortality In Preterm With Low Birth Weight. Arch Dis Child. 2014;99:A462. doi: 10.1136/archdischild-2014-307384.1279. [DOI] [Google Scholar]
- 41.Park JH, Chang YS, Ahn SY, et al. Predicting mortality in extremely low birth weight infants: Comparison between gestational age, birth weight, Apgar score, CRIB II score, initial and lowest serum albumin levels. PLoS ONE. 2018;13:e0192232. doi: 10.1371/journal.pone.0192232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Patra K, Karmakar BC. NEONATAL MORTALITY AND NEURODEVELOPMENTAL OUTCOME OF VERY LOW BIRTH WEIGHT (VLBW) NEWBORNS ATTENDING A RURAL TERTIARY CARE HOSPITAL, PREDICTED BY CLINICAL RISK INDEX FOR BABIES SCORE II (CRIBS II) J Evolution Med Dent Sci. 2019;8:1521–7. doi: 10.14260/jemds/2019/338. [DOI] [Google Scholar]
- 43.Phillips LA, Dewhurst CJ, Yoxall CW. The prognostic value of initial blood lactate concentration measurements in very low birthweight infants and their use in development of a new disease severity scoring system. Arch Dis Child Fetal Neonatal Ed. 2010;96:F275–80. doi: 10.1136/adc.2010.185793. [DOI] [PubMed] [Google Scholar]
- 44.Radfar M, Hashemieh M, Fallahi M, et al. Utilization of SNAP II and SNAPPE II Scores for Predicting the Mortality Rate Among a Cohort of Iranian Newborns. Arch Iran Med. 2018;21:153–7. [PubMed] [Google Scholar]
- 45.Rastogi PK, Sreenivas V, Kumar N. Validation of CRIB II for prediction of mortality in premature babies. Indian Pediatr. 2010;47:145–7. doi: 10.1007/s13312-010-0022-5. [DOI] [PubMed] [Google Scholar]
- 46.Rautonen J, Mäkelä A, Boyd H, et al. CRIB and SNAP: assessing the risk of death for preterm neonates. The Lancet. 1994;343:1272–3. doi: 10.1016/S0140-6736(94)92158-X. [DOI] [PubMed] [Google Scholar]
- 47.Ray S, Mondal R, Chatterjee K, et al. Extended Sick Neonate Score (ESNS) for Clinical Assessment and Mortality Prediction in Sick Newborns referred to Tertiary Care. Indian Pediatr. 2019;56:130–3. doi: 10.1007/s13312-019-1486-6. [DOI] [PubMed] [Google Scholar]
- 48.Reid S, Bajuk B, Lui K, et al. Comparing CRIB-II and SNAPPE-II as mortality predictors for very preterm infants. J Paediatr Child Health. 2014;51:524–8. doi: 10.1111/jpc.12742. [DOI] [PubMed] [Google Scholar]
- 49.Richardson DK, Phibbs CS, Gray JE, et al. Birth Weight and Illness Severity: Independent Predictors of Neonatal Mortality. Pediatrics. 1993;91:969–75. doi: 10.1542/peds.91.5.969. [DOI] [PubMed] [Google Scholar]
- 50.Richardson DK, Corcoran JD, Escobar GJ, et al. SNAP-II and SNAPPE-II: Simplified newborn illness severity and mortality risk scores. J Pediatr. 2001;138:92–100. doi: 10.1067/mpd.2001.109608. [DOI] [PubMed] [Google Scholar]
- 51.Rosenberg RE, Ahmed S, Saha SK, et al. Simplified age-weight mortality risk classification for very low birth weight infants in low-resource settings. J Pediatr. 2008;153:519–24. doi: 10.1016/j.jpeds.2008.04.051. [DOI] [PubMed] [Google Scholar]
- 52.Ruiz RR, Guzmán Cabañas JM, Párraga Quiles MJ, et al. Utilidad del CRIB para predecir la muerte hospitalaria y la hemorragia intraventricular en los prematuros de muy bajo peso y extremado bajo peso al nacer. Anales Pediatr. 2007;66:140–5. doi: 10.1157/13098931. [DOI] [PubMed] [Google Scholar]
- 53.Sarquis ALF, Miyaki M, Cat MNL. CRIB score for predicting neonatal mortality risk. J Pediatr (Rio J) 2002;78:225–9. doi: 10.2223/JPED.835. [DOI] [PubMed] [Google Scholar]
- 54.Shrestha D, Dhoubhadel BG, Parry CM, et al. Predicting deaths in a resource-limited neonatal intensive care unit in Nepal. Trans R Soc Trop Med Hyg. 2017;111:287–93. doi: 10.1093/trstmh/trx053. [DOI] [PubMed] [Google Scholar]
- 55.Silveira R de C, Schlabendorff M, Procianoy RS. Predictive value of SNAP and SNAP-PE for neonatal mortality. J Pediatr (Rio J) 2001;77:455–60. doi: 10.2223/JPED.343. [DOI] [PubMed] [Google Scholar]
- 56.Singh R. Abstract P-566: NEONATAL MORTALITY RISK ASSESSMENT USING SCORING SYSTEM IN A NICU OF EASTERN REGION NEPAL. Pediatr Crit Care Med. 2018;19:224–5. doi: 10.1097/01.pcc.0000538023.30754.19. [DOI] [Google Scholar]
- 57.Sotodate G, Oyama K, Matsumoto A, et al. Predictive ability of neonatal illness severity scores for early death in extremely premature infants. J Matern Fetal Neonatal Med. 2020;35:846–51. doi: 10.1080/14767058.2020.1731794. [DOI] [PubMed] [Google Scholar]
- 58.Thimoty J, Hilmanto D, Yuniati T. Score for Neonatal Acute Physiology Perinatal Extension II (SNAPPE II) as the predictor of neonatal mortality hospitalized in neonatal intensive care unit. PI. 2009;49:155. doi: 10.14238/pi49.3.2009.155-9. [DOI] [Google Scholar]
- 59.Tyagi MK, Daga G, Pandey M. PRISM-III and SNAPPE-II to Predict Outcome in Neonates undergoing Surgery under General AnaesthesiaA Prospective Cohort Study. JCDR. 2022;16:UC61–4. doi: 10.7860/JCDR/2022/58084.16955. [DOI] [Google Scholar]
- 60.Vardhelli V, Murki S, Tandur B, et al. Comparison of CRIB-II with SNAPPE-II for predicting survival and morbidities before hospital discharge in neonates with gestation ≤ 32 weeks: a prospective multicentric observational study. Eur J Pediatr. 2022;181:2831–8. doi: 10.1007/s00431-022-04463-2. [DOI] [PubMed] [Google Scholar]
- 61.Vardhelli V, Seth S, Mohammed YA, et al. Comparison of STOPS and SNAPPE-II in Predicting Neonatal Survival at Hospital Discharge: A Prospective, Multicentric, Observational Study. Indian J Pediatr. 2023;90:781–6. doi: 10.1007/s12098-022-04330-w. [DOI] [PubMed] [Google Scholar]
- 62.Vasudevan A, Malhotra A, Lodha R, et al. Profile of neonates admitted in pediatric ICU and validation of Score for Neonatal Acute Physiology (SNAP) Indian Pediatr. 2006;43:344–8. [PubMed] [Google Scholar]
- 63.Weirich CF, Andrade ALSS, Turchi MD, et al. Neonatal mortality in intensive care units of Central Brazil. Rev Saude Publica. 2005;39:775–81. doi: 10.1590/s0034-89102005000500012. [DOI] [PubMed] [Google Scholar]
- 64.Yang Y, Chi X, Tong M, et al. Comparison of different neonatal illness severity scores in predicting mortality risk of extremely low birth weight infants. J Zhejiang Univ (Med Sci) 2002;51:73–8. doi: 10.3724/zdxbyxb-2021-0217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Zhang W-W, Wang S, Li Y, et al. Development and validation of a model to predict mortality risk among extremely preterm infants during the early postnatal period: a multicentre prospective cohort study. BMJ Open. 2023;13:e074309. doi: 10.1136/bmjopen-2023-074309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Dorling JS, Field DJ, Manktelow B. Neonatal disease severity scoring systems. Arch Dis Child Fetal Neonatal Ed. 2005;90:F11–6. doi: 10.1136/adc.2003.048488. [DOI] [PMC free article] [PubMed] [Google Scholar]