Pulse Oximetry and Auscultation for Congenital Heart Disease Detection

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Xiao-jing Hu, PhD,a Xiao-jing Ma, MD,a, b Qu-ming Zhao, MD,a Wei-li Yan, PhD,a,b Xiao-ling Ge, MD,a Bing Jia, MD,a Fang Liu, MD,a LinPulse Wu, MD,a Ming Ye,Oximetry MD,a Xue-cun Liang, MD,a Jing and Zhang, MD, aAuscultation Yan Gao, MD,a Xiao-wen Zhai, MD,a Guo-ying for Huang, MDa,b Congenital Heart Disease Detection OBJECTIVES: abstract

Pulse oximetry (POX) has been confirmed as a specific screening modality for critical congenital heart disease (CCHD), with moderate sensitivity. However, POX is not able to detect most serious and critical cardiac lesions (major congenital heart disease [CHD]) without hypoxemia. In this study, we investigated the accuracy and feasibility of the METHODS: addition of cardiac auscultation to POX as a screening method for asymptomatic major CHD. A multicenter prospective observational screening study was conducted at 15 hospitals in Shanghai between July 1, 2012, and December 31, 2014. Newborns with either an abnormal POX or cardiac auscultation were defined as screen positive. All screen- ’ positive newborns underwent further echocardiography. False-negative results were identified by clinical follow-up, parents feedback, and telephone review. We assessed the RESULTS: accuracy of POX plus cardiac auscultation for the detection of major CHD.

CHD screening was completed in all 15 hospitals, with a screening rate of 94.0% to 99.8%. In total, 167190 consecutive asymptomatic newborn infants were screened, of – which 203 had major CHD (44 critical and 159 serious). The sensitivity of POX plus cardiac – auscultation was 95.5% (95% confidence interval 84.9% 98.7%) for CCHD and 92.1% (95% confidence interval 87.7% 95.1%) for major CHD. The false-positive rate was 1.2% for CONCLUSIONS: detecting CCHD and 1.1% for detecting major CHD. In our current study, we show that using POX plus cardiac auscultation significantly improved the detection rate of major CHD in the early neonatal stage, with high sensitivity and a reasonable false-positive rate. It provides strong evidence and a reliable method for neonatal CHD screening.

What’sw Kno n on This Subject: The accuracy of aChildren’s Hospital of Fudan University, Shanghai, China; and bShanghai Key Laboratory of Birth Defects, pulse oximetry (POX) as a screening tool for critical Shanghai, China congenital heart disease (CHD) has been extensively Dr Huang contributed to the study design and the establishment of the screening system, studied. However, POX detects only lesions with organized and conducted the project, and finalized the manuscript; Dr Hu organized and hypoxemia with moderate sensitivity. Most cases conducted the project, undertook data management and data analysis, and drafted the report; of serious CHD without hypoxemia cannot be Drs Ma, Zhao, and Ge undertook data management and data analysis; Dr Yan contributed to recognized early enough to avoid heart failure or the study design and data analysis; and all authors discussed, critically revised, and approved collapse. the final study protocol, discussed and approved the final strategy for analysis, and discussed, revised, and approved the final manuscript as submitted and agree to be accountable for all What This Study Adds: Many structural heart aspects of the work. defects present as a cardiac murmur. Using POX in The Shanghai Public Health 3-Year Action Plan, sponsored by the Shanghai Municipal Government, conjunction with cardiac auscultation significantly monitored study progress but had no role in study design, data collection, data interpretation, or improved the detection rate of both critical and writing of the report. The corresponding author had full access to all the data in the study and serious CHD in the early neonatal stage, with high had final responsibility for the decision to submit for publication. sensitivity and reasonable false-positive rate. DOI: https://doi.org/10.1542/peds.2017-1154 Accepted for publication Jun 30, 2017

To cite: Hu X-j, Ma X-j, Zhao Q-m, et al. Pulse Oximetry and Auscultation for Congenital Heart Disease Detection. Pediatrics. 2017;140(4):e20171154

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Congenital heart diseases (CHDs) with clinical assessment could (hospitals 14 and 15 in Fig 1) in are a leading cause of infant death be successfully implemented in Shanghai. Of the 15 hospitals, 8 were

worldwide1 and affect 8 in 1000 common hospital settings with few urban and 7 were suburban; 5 were live births. About 1 to 2 per 1000 barriers, and combining POX with tertiary and 10 were secondary

newborn infants have critical CHD clinical assessment resulted in a high9 hospitals. Ten hospitals (67.0%) had (CCHD), which is defined as CHD that detection rate of major and CCHD. echocardiography available on-site, Importantly, in a post hoc analysis, whereas the remaining hospitals causes death or needs intervention ’ in the neonatal period. Neonates we observed that POX combined referred neonates with positive

with CCHD2 benefit most from early with cardiac murmur had the same screening results to the Children s detection. Because of this, CCHDs sensitivity as did POX plus clinical Hospital of Fudan University (CHFU) have become the target for screening assessment in the detection of major for a diagnostic echocardiogram schemes in developed countries, CHD (90.0%) and CCHD (93.0%), free of charge. All consecutive and pulse oximetry (POX) has been whereas the false-positiveP rate (FPR) asymptomatic newborn infants were confirmed as an effective– screening was significantly lower (2.4%P vs included (irrespective of gestational modality, with moderate3 7 sensitivity 2.7% for major CHD, < .0001, and age), but newborn infants with and high specificity. ‍‍ However, 2.5% vs 2.9% for CCHD, < .0001), prenatally diagnosed CHD were POX detects only those lesions with suggesting that POX plus cardiac excluded from the analysis of the hypoxia. Most simple but serious auscultation may be a screening current study. cases of CHD, such as severe left strategy for major CHD. With this This study was approved by the heart obstructive lesions and large study, we aimed to investigate ethics committee of CHFU. Oral left-to-right shunt lesions, cannot be the accuracy and feasibility of the ’ informed consent was obtained from recognized early enough by POX to addition of cardiac auscultation the participants parents. avoid heart failure, collapse, or even to POX as a screening method for Procedures

irreversible pulmonary8 vascular asymptomatic major CHD, hoping disease at a later stage. Therefore, to provide a more comprehensive all major CHDs (those causing death reference for routine neonatal CHD Screening methodology, POX or requiring intervention during screening policy. measurement criteria, and the infancy, including CCHD and serious Methods definition of CHD severity were 9 defects) should be regarded as9 main the same as our previous study, targets of neonatal screening. Study Design and Participants but in this study, we only screened asymptomatic neonates, and In 2014, we reported the first screening modalities included large-scale prospective study on A multicenter prospective only POX and cardiac auscultation. neonatal CHD screening in China and observational screening study was Cardiac auscultation was performed – proposed that the benefits of POX conducted at 13 hospitals (hospitals and immediately followed by POX recorded in high-income countries 1 13 in Fig 1) between July 1, measurement by the same clinician. could be translated with success 2012, and December 31, 2014, and A positive screen result was defined to China as well; we also suggested at 2 hospitals between February as presence of any abnormality in the that POX used in conjunction 1, 2013, and December 31, 2014, 2 examinations as presented in Fig 2. Downloaded from www.aappublications.org/news by guest on September 26, 2021 2 Hu et al

Hu et al https://doi.org/10.1542/peds.2017-1154 October 2017 Pulse Oximetry and Auscultation for Congenital Heart Disease Detection 4 140 Pediatrics 2017 ROUGH GALLEY PROOF compare differences in sensitivity and specificity. A logistic regression model was performed to test the trend of FPRs across 7 time intervals χ during2 which screening occurred. decomposition analysis was further performed to identify the difference of the FPRs between time intervals. Results

The Complete Compliance of POX Plus Cardiac Auscultation Screening

All 15 hospitals that participated in the study were able to complete routine CHD screening and complete or refer for echocardiography in a timely and effective manner, with a screening rate of 94.0% to 99.8% as shown in Fig 1. There was no significant difference in positive screening – P results between these hospitals (1.1% 1.8%, > .05).

Among 172865 consecutive deliveries, 4108 infants with incomplete screening data, 90 infants with major CHD (28 infants with FIGURE 2 CCHD and 62 infants with serious CHD) identified prenatally, and CHD screening protocol. Spo2, pulse oxygen saturation. 1385 symptomatic newborns were transported to the NICU without screening at birth hospitals (92

Neonates who screened positive hospital. In addition, the first infants with major CHD, including for CHD were referred for consecutive 27201 neonates who 34 with CCHD and 58 with serious CHD among them) were excluded echocardiography within 24 hours screened negative were followed of screening. CHFU was responsible up via telephone at 1 year of age, for screening accuracy analysis for the confirmation of a diagnosis which was done to determine if the (Fig 3). In total, 167190 asymptomatic newborns were screened by using by echocardiography for neonates infant had cardiac symptoms or the standard screening protocol. with a positive screening result and was diagnosed with CHD in other hospitals. There were 88941 male (53.2%) follow-up of all infants with CHD. Statistical Analysis and 78249 female (46.8%) infants. False-negative cases of CHD were The median age at POX plus cardiac estimated by using the following – auscultation screening was 26 hours methods. For infants who had Sensitivity, specificity, positive and (range 6 72 hours). Of 167 190 negative screening results, clinical negative predictive values, and asymptomatic infants, 1170 with follow-up was done at 6 weeks of age, positive and negative likelihood CHD (including 42 with CCHD and in combination with feedback from ratios were calculated for POX alone 145 with serious defects) were parents about cardiac symptoms and in combination with cardiac identified before discharge. An such as cyanosis, tachypnea, and auscultation. 95% confidence interval additional 156 patients with CHD feeding difficulty or CHD diagnosis of sensitivity and specificity was (including 2 with CCHD and 14 ’ ’ by any hospitals after the infant computed by the Wilson method. with serious CHD) were diagnosed was discharged from the delivery McNemar s test was used to later by clinical follow-up, parents Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 140, number 4, October 2017 3

Hu et al https://doi.org/10.1542/peds.2017-1154 October 2017 Pulse Oximetry and Auscultation for Congenital Heart Disease Detection 4 140 Pediatrics 2017 ROUGH GALLEY PROOF The overall FPR for detection of major CHD was 0.1% for POX alone (Table 2). To evaluate if the rate varied according to the timing of screening, we classified the time of POX screening into 7 time intervals. The analysis showed the optimal and feasible time window for CHD screening by POX. As shown in ‍Table 4, the FPR for POX tendedP to decline with the age of the newborn infant at screening ( < .0001; overall odds ratio of false- – positives to true-negatives: 0.8; 95% χ confidence2 interval 0.7 0.8). Further decomposition analysis showed that the FPR in theP earliest 4 time intervals were significantly higher than the others ( < .0001); however, the FPR in the fifth, sixth, and seventh P – time intervals did not differ from P – P each other ( = .139 for 36 48 hours, – = .198 for 49 60 hours, and = .907 for 61 72 hours). Discussion Prevalence of Major CHDs

Although CHD prevalence demonstrated significant FIGURE 3 10,11 Profile of screening study. geographical differences, ‍ which may have environmental components The FPR of Screening for Major such as nutritional status and CHD by Using POX Plus Cardiac teratogen exposure in addition to feedback, and telephone review Auscultation genetic factors, in this study we did T(Fighe S3,ensitivity Table 1). of Screening for not show a significant difference in Major CHD by Using POX Plus Cardiac major CHD prevalence compared Auscultation The overall FPR was 1.2% for CCHD with our previous study. and 1.1% for major CHD. Among Major CHD includes CCHD and 1860 infants with false-positive serious defects as defined in both POX alone as a screening method screening results, 74 (4.3%) were of our studies. In the current study, detected 34 out of 44 (77.3%) CCHD referred to the NICU for further which was conducted in 15 hospitals cases but only 90 out of 203 (44.3%) treatment. Among them, 57 patients in Shanghai city, 44 infants with major CHD cases. POX plus cardiac screened positive with POX had CCHD and 159 infants with serious auscultation detected 42 out of 44 sepsis (32), pneumonia (18), CHD were detected from those (95.5%) cases of CCHD and 187 out hypoglycemia (4), jaundice (2), and asymptomatic neonates, whereas of 203 (92.1%) cases of major CHD. necrotizing enterocolitis (NEC) (1). another 34 infants with CCHD and The addition of cardiac auscultation Twelve patients screened positive 58 infants with serious CHD were to POX significantly improved the with cardiac murmur had pneumonia identified from those symptomatic sensitivity of screening for both (4), jaundice (2), sepsis (1), NEC neonates who were transported to CCHD and serious CHD (Table 2). (1), and diarrhea (1). Five patients the NICU of CHFU without screening The detection rate for individual screened positive with both POX and in the birth hospitals; there were CCHD in the asymptomatic cohort is cardiac murmur had pneumonia (3), 28 cases of CCHD and 62 cases of presented in Table 3. sepsis (1), and NEC (1). serious CHD identified prenatally. Downloaded from www.aappublications.org/news by guest on September 26, 2021 4 Hu et al

of major CHD among 172 865 prevalence of major CHD was 2.23 conducted in 18 hospitals from TABLEconsecutive 1 Spectrum newborn of the 1326 infants Cases inof CHD and Corresponding(385 out ofSeverity 172 865). 10 provinces in China, there were 357 cases of major CHD (157 critical Predominant Defect N (%)a Severityb and 173 serious from both Aortic stenosis 1 (0.1) A asymptomatic and symptomatic

Total anomalous pulmonary venous connection 2 (0.2) A infants and 27 prenatally diagnosed Interrupted aortic arch 2 (0.2) A Coarctation of the aorta 6 (0.5) A cases of major CHD) among 130282 consecutive newborn infants in the 3 (0.2) B ‰ 2 (0.2) D cohort, and the overall prevalence

Hypoplastic left heart syndrome 2 (0.2) A of major CHD was 2.7 (357 out of Transposition of the great arteries 7 (0.5) A 130282). The overall prevalence of Double outlet right ventricle 3 (0.2) A 1 (0.1) B major CHD in the current study looks Pulmonary atresia 8 (0.6) A a bit lower than that in the previous 1 (0.1) B study, but Pthe prevalence of CHD Single ventricle 5 (0.4) A in both studies was not statistically Tetralogy of Fallot 5 (0.4) A different ( = .05). 18 (1.4) B Pulmonary stenosis 3 (0.2) A One of our major concerns with this 15 (1.1) B study is the possibility that some 27 (2.0) C Atrioventricular septal defect 4 (0.3) B infants with CHD were missed on Ebstein 1 (0.1) C follow-up. In our study, clinical 2 (0.2) B follow-up was done at 6 weeks of age, Atrial septal defect 153 (11.5) C in combination with feedback from 87 (6.6) D parents about cardiac symptoms Ventricular septal defect 104 (7.8) B 320 (24.1) C or a CHD diagnosis by any hospitals 82 (6.2) D after an infant was discharged from Patent ductus arteriosus 11 (0.8) B the birth hospital. To investigate 377 (28.4) D the likelihood of missing major 74 (5.6) C CHD through clinical follow-up and Major CHD includes CCHD (A) and serious defects (B). feedback from parents of the infants a Based on the number of affected newborns (including those diagnosed before discharge and after discharge). b Classification of severity: A = critical, B = serious, C = significant, D = nonsignificant. who screened negative by POX plus cardiac auscultation screening, we made calls to the parents of the TABLE 2 Accuracy of Screening Methods for Detecting CCHD and Major CHD in Asymptomatic Newborns (N = 167 190) CCHD Major CHDa POX Alone Cardiac Auscultation POX Plus Cardiac POX Alone Cardiac Auscultation POX Plus Cardiac alone Auscultation Alone Auscultation True-positives 34 33 42 90 170 187 False-negatives 10 11 2 113 33 16 False-positives 292 1748 2005 236 1611 1860 True-negatives 166 854 165 398 165 141 166 751 165 376 165 127 FPR (%) 0.2 1.1 1.2 0.1 1.0 1.1 Sensitivity (%) 77.3 (63.0–87.2) 75.0 (60.6–85.4) 95.5 (84.9–98.7) 44.3 (37.7–51.2) 83.7 (78.1–88.2) 92.1 (87.6–95.1) Specificity (%) 99.8 (99.8–99.8) 99.0 (98.9–99) 98.8 (98.8–98.9) 99.9 (99.8–99.9) 99.0 (99.0–99.1) 98.9 (98.8–98.9) Positive predictive 10.4 (7.6–14.2) 1.9 (1.3–2.6) 2.1 (1.5–2.8) 27.6 (23.0–32.7) 9.5 (8.3–11.0) 9.1 (8.0–10.5) value (%) Negative predictive 100.0 (100.0– 100.0 (100.0–100.0) 100.0 (100.0–100.0) 99.9 (99.9–99.9) 100.0 (100.0–100.0) 100.0 (100.0–100.0) value (%) 100.0) Diagnostic 99.8 (99.8–99.8) 99.0 (98.9–99.0) 98.8 (98.8–98.9) 99.8 (99.8–99.8) 99.0(99.0–99.1) 98.9 (98.8–98.9) accuracy (%) Positive likelihood 442.3 (432.0– 71.7 (70.2–73.2) 79.6 (79.3–79.8) 313.7 (302.7– 86.8 (86.5–87.1) 82.7 (82.5–82.9) ration 452.9) 325.1) Negative likelihood 0.2 (0.2–0.3) 0.3 (0.2–0.3) 0.1 (0.0–0.1) 0.6 (0.6–0.6) 0.2 (0.2–0.2) 0.1 (0.1–0.1) ratio Data are number or percentage (95% confidence interval). a Major CHD includes CCHD and serious defects.

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Hu et al https://doi.org/10.1542/peds.2017-1154 October 2017 Pulse Oximetry and Auscultation for Congenital Heart Disease Detection 4 140 Pediatrics 2017 ROUGH GALLEY PROOF All Major CHDs Should Be Set as a Screening Target first consecutive 27201 infants emphasis placed on POX. It seemed as ‰ who screened negative and found 3 if there was little emphasis placed on serious defects (0.1 , 3/27201), With significant evidence from clinical assessment, such as cardiac indicating that few cases of major auscultation. previous –studies, screening for CHD would be missed on follow-up. CCHD 4,is12 now15 spreading across the ∼ Furthermore, CHFU was the globe. ‍ ‍ Whether to implement In previous studies, researchers referral center of the 15 participant an inexpensive, quick, painless showed that 1% of newborns hospitals in the current study. All screening for CCHD with the had a heart murmur, and 31.0% newborn infants who manifested to 86.0% of these infants had potential to save lives is no16, longer17 symptoms or severe conditions the question being asked. ‍ There structural heart disease (even were transported to our NICU. If the appears to be no need for further potentially life-threatening heart infant was diagnosed with major confirmation of the advantages of defects may not be associated with any initial signs or symptoms other CHD and needed intervention, the POX screening for CCHD. However, 18,19 majority of medical expenses would POX testing alone may lead to missed than a heart murmur). ‍ In our be covered by insurance and some diagnoses of those who have CHD previous study, we demonstrated charity funding. There were few without right-to-left shunt lesions that POX used in conjunction incentives for the family to seek and and the progression of some simple with clinical assessment could pay for care outside of our hospital, but serious lesions, such as large be successfully implemented in common hospital settings which ensured that almost all infants septal defects, to heart failure8 were on the track to follow-up. In the or Eisenmenger syndrome. It is with few barriers, and using current study, we indicate that the noteworthy that a large number POX in conjunction with clinical prevalence of major CHD was similar of previous studies were based assessment resulted in a high detection rate of major CHD and in different regions in China. in developed countries, with an 9 CCHD. This was further confirmed TABLE 3 Detection Rate for Individual CCHD in the Asymptomatic Cohort by our present study. Hence, we CCHD N Detection Rate (True-positives/False-negatives) would suggest that POX plus cardiac Cardiac Auscultation POX POX Plus Cardiac auscultation should be applied to Auscultation screen for all major CHDs, including Aortic stenosis 1 100.0% (1/0) 0.0% (0/1) 100.0% (1/0) CCHDThe Current and serious CHD S creeningdefects. Strategy Coarctation of the aorta 6 66.7% (4/2) 16.7% (1/5) 66.7% (4/2) Double outlet of right 3 67.0% (2/1) 100.0% (3/0) 100.0% (3/0) Has High Accuracy ventricle Interrupted aortic arch 2 100.0% (2/0) 100.0% (2/0) 100.0% (2/0) Pulmonary atresia 8 75.0% (6/2) 100.0% (8/0) 100.0% (8/0) Pulmonary stenosis 3 100.0% (3/0) 100.0% (3/0) 100.0% (3/0) In our current study, we have Single ventricle 5 80.0% (4/1) 100.0% (5/0) 100.0% (5/0) validated the high accuracy of POX Total anomalous pulmonary 2 50.0% (1/1) 100.0% (2/0) 100.0% (2/0) plus cardiac auscultation in screening venous connection for major CHD. The sensitivity of Transposition of great 7 57.1% (4/3) 100.0% (7/0) 100.0% (7/0) this screening method was 95.5% arteries Tetralogy of Fallot 5 100.0% (5/0) 20.0% (1/4) 100.0% (5/0) for CCHD and 92.1% for major CHD, Hypoplastic left heart 2 50.0% (1/2) 100.0% (2/0) 100.0% (2/0) which was similar9 to that of our syndrome published study. Moreover, the FPR Total 44 75.0% (33/11) 77.3% (34/10) 95.5% (42/2) in the current study had significant reduction, which was 1.2% for CCHD and 1.1% for major CHD compared TABLE 4 Accuracy of POX for Detection of Major CHD by Age in Asymptomatic Newborn Infants 6–12 h 13–18 h 19–24 h 25–36 h 37–48 h 49–60 h 61–72 h N = 167 190 14 933 20 737 42 382 32 669 28 237 14 164 14 068 True-positives 11 9 21 18 10 11 10 False-negatives 9 8 22 21 15 17 21 False-positives 39 44 66 46 23 11 7 True-negatives 14 874 20 676 42 273 32 584 28 188 14 125 14 030 FPR (%) 0.26 0.21 0.16 0.14 0.08 0.08 0.05 Sensitivity (95% CI) 55.0 (34.2–74.2) 52.9 (31.0–73.8) 48.8 (34.6–63.3) 46.2 (31.6–61.4) 40.0 (23.4– 59.3) 39.3 (23.6–57.6) 32.3 (18.6–49.9) Specificity (95% CI) 99.7 (99.6–99.8) 99.8 (99.7–99.8) 99.8 (99.8–99.9) 99.9 (99.8–99.9) 99.9 (99.9–100.0) 99.9 (99.9–100.0) 100.0 (99.9–100.0) Data are number or percentage (95% CI). Major CHD includes CCHD and serious defects. CI, confidence interval.

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Hu et al https://doi.org/10.1542/peds.2017-1154 October 2017 Pulse Oximetry and Auscultation for Congenital Heart Disease Detection 4 140 Pediatrics 2017 ROUGH GALLEY PROOF with 2.5% and 2.4% in our previous with China as a prime example. In and found that to lower the FPR of study. China, the number of pediatricians is POX screening, it would be better greatly outnumbered by births, with to perform the screening after Although the similar study protocol the average facility delivering 30 to 36 hours of life. However, in our and training course were applied for 50 infants per day. Whether there present cohort, 1385 symptomatic both studies, there were a couple of is sufficient manpower and time for newborns were transported to the reasons for the significant reduction each newborn screening and whether NICU without screening at birth of the FPRs. First, the current screening would greatly increase the hospitals. Among them, there were study started in July 2012, when workload of pediatricians are areas 34 infants with CCHD and 58 infants we had more experience based on of concern. The 15 facilities chosen with serious CHD who had symptoms the previous study in training and for this study are representative of within 12 hours after birth. This quality control for our screening the situation in Shanghai, and in our information should be emphasized protocol. Second, all clinicians who results, we showed that all facilities when we make decisions about would perform the auscultation in could successfully implement major the optimal time to conduct CHD the study were highly trained, but the CHD screening. The amount of time screening; we need to balance the current study was conducted in 15 spent screening was not a significant risk of false-positives against the hospitals in Shanghai area, whereas increase in the workload of doctors. likelihood of a timely diagnosis. the 2014 study was conducted in 18 This is reflected by satisfactory The fourth issue is how to meet hospitals in 10 provinces around the screening rates and diagnostic the need for timely cardiologic country. Obviously, it was easier to echocardiography rates. assessment after a positive supervise the quality of auscultation The second issue is economic burden. screening test result, especially for performance in the current study. Limited data from US studies suggest community hospitals. Advances in Furthermore, we emphasized the average cost per infant screened pediatric cardiology and cardiac that cardiac auscultation must be 21 ’ ranges from $5.10 to $14.20. surgery during the past 30 years performed in a quiet environment However, in Shanghai, one of China s in China have made possible in the current study, which might largest and most expensive cities, the diagnosis and treatment of make the auscultation more accurate. ∼ 23 the average cost per infant screened most cases of CCHD. Policies Given the close supervision of the was $2.50. Echocardiography that prioritize surgical treatment clinicians and the quiet environment ∼ is available in most hospitals for of neonatal CCHD have been in which auscultation was performed $30.00 per examination. Therefore, established in major pediatric in this study, we would believe that costs for screening and diagnostic cardiac centers. Furthermore, the reasonable FPRs of <2.5% for echocardiography are markedly through the work of our group, CCHD and <2.4% for major CHD can lower than in developed countries, CHFU has established a nationwide be reproducible and generalizable by with the cost acceptable for families neonatal CHD screening, diagnosis using POX plus cardiac auscultation not covered by government health and evaluation, and intervention in different birth hospitals. insurance plans. network, collaborating with 48 hospitals in 13 provinces, Moreover, among 1860 infants The third issue of note is false- providing timely teleconsultations who had positive test results for positive screen results. In particular, and referral services on detection of noncardiac conditions, 74 (4.3%) this includes the potential burden of major CHD. The network continues infants were referred to the NICU false-positives and the demand on to grow, with facilities joining across for further treatment. Most of them pediatric echocardiography services. the nation. had an infection such as sepsis or In a meta-analysis, researchers Limitations and Perspective pneumonia. The detection of these showed that the FPR of POX conditions could be considered an screening for CCHD was significantly addedThe Current value ofCH screening.D Screening Strategy lower when screening was done With a view to vast geographical Is Feasible after 24 hours of birth than when22 variability, if universal screening it was done before 24 hours. In is implemented, issues such as our present study, the overall FPR screening algorithms to account for Although the advantages of CCHD was 1.2% for CCHD and 1.1% for moderate- and high-altitude locations screening are well recognized, when major CHD as mentioned above, must be considered, with the compared with developed countries, which was reasonable in terms of possibility of establishment of cutoff

challenges to the implementation20 of the high sensitivity of screening. points for infants screened at higher screening certainly exist. The first Moreover, we grouped participants altitudes. In addition, further work issue of note is burden of resources, into more specific timing intervals on how to evaluate a low-saturation Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 140, number 4, October 2017 7

Hu et al https://doi.org/10.1542/peds.2017-1154 October 2017 Pulse Oximetry and Auscultation for Congenital Heart Disease Detection 4 140 Pediatrics 2017 ROUGH GALLEY PROOF Acknowledgments

screening needs to be done because University of Singapore, Singapore), 27.0% of false-positive findings We thank all the newborn infants and Andrew Ewer (University of were conditions that24,25 needed and their parents who participated in Birmingham, United Kingdom) for medical attention, ‍ such as this study. We thank all professionals their valuable comments and review respiratory diseases and infections, involved in the Neonatal Congenital of the report. Drs Niu, Cheung, which contributed to the highest Heart Disease Screening Project Quek and Ewer did not receive any mortality rate during the neonatal (Wei-fen Luo, Li-ping Xiao, Jun compensation for this contribution. Coperiod.nclusions Huang, Jin-xiang Ding, Ying Wang, Abbreviations Zhi-rong Fan, Zhi-hong Lu, Min-shu Yu, Qin Gu, Qiu-ling Xu, Gui-fang In our current study, we further Cai, Xiao-ming Wang, M. Jun Yu, Ye CCHD: critical congenital heart displayed that using POX plus cardiac Chen, Feng Zhao, Guo-zhen Xu, and disease auscultation significantly improved Chen-lan Guo). We thank Conway ’ CHD: congenital heart disease the detection rate of major CHD in Niu (Department of Pediatrics, CHFU: Children s Hospital of the early neonatal stage, with high Shanghai Medical College of Fudan Fudan University sensitivity and reasonable FPR. University) for his help in preparing FPR: false-positive rate It provides strong evidence and a the manuscript and Yiu-fai Cheung NEC: necrotizing enterocolitis reliable method for neonatal CHD (University of Hong Kong, Hong POX: pulse oximetry screening. Kong), Swee Chye Quek (National Address correspondence to Guo-ying Huang, MD, Pediatric Heart Center, Children’s Hospital of Fudan University, 399 Wan Yuan Rd, Shanghai 201102, People’s Republic of China. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2017 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Supported by the Shanghai Public Health 3-Year Action Plan, which is sponsored by the Shanghai Municipal Government (2011–55) and by the National Key Research and Development Project of China (2016YFC1000506). POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

References 1. van der Linde D, Konings EE, Slager MA, heart defects in newborn infants assessment to screen for congenital et al. Birth prevalence of congenital (PulseOx): a test accuracy study. heart disease in neonates in heart disease worldwide: a systematic Lancet. 2011;378(9793):785–794 China: a prospective study. Lancet. review and meta-analysis. J Am Coll 6. de-Wahl Granelli A, Wennergren M, 2014;384(9945):747–754 Cardiol. 2011;58(21):2241–2247 Sandberg K, et al. Impact of pulse 10. Hoffman JI. The global burden of 2. Chang RK, Gurvitz M, Rodriguez S. oximetry screening on the detection congenital heart disease. Cardiovasc Missed diagnosis of critical congenital of duct dependent congenital heart J Afr. 2013;24(4):141–145 heart disease. Arch Pediatr Adolesc disease: a Swedish prospective 11. Bolisetty S, Daftary A, Ewald D, Knight Med. 2008;162(10):969–974 screening study in 39,821 newborns. B, Wheaton G. Congenital heart defects 3. Ewer AK. Pulse oximetry screening: do BMJ. 2009;338:a3037 in Central Australia. Med J Aust. we have enough evidence now? Lancet. 7. Meber g A, Brügmann-Pieper S, Due R 2004;180(12):614–617 2014;384(9945):725–726 Jr, et al. First day of life pulse oximetry 12. de-Wahl Granelli A, Meberg A, Ojala T, 4. Mahle WT, Martin GR, Beekman RH III, screening to detect congenital heart Steensberg J, Oskarsson G, Mellander defects. J Pediatr. 2008;152(6):761 765 Morrow WR; Section on Cardiology and – M. Nordic pulse oximetry screening– Cardiac Surgery Executive Committee. 8. Ho TC, Ouyang H, Lu Y, Young AH, implementation status and proposal Endorsement of Health and Human Chintala K, Detrano RC. Postprocedural for uniform guidelines. Acta Paediatr. Services recommendation for pulse outcomes of rural children undergoing 2014;103(11):1136–1142 oximetry screening for critical correction of congenital heart lesions 13. Bhola K, Kluckow M, Evans N. Post- congenital heart disease. Pediatrics. in Yunnan Province, China. Pediatr implementation review of pulse 2012;129(1):190–192 Cardiol. 2011;32(6):811–814 oximetry screening of well newborns 5. Ewer AK, Middleton LJ, Furmston AT, 9. Zhao QM, Ma XJ, Ge XL, et al; Neonatal in an Australian tertiary maternity et al; PulseOx Study Group. Pulse Congenital Heart Disease Screening hospital. J Paediatr Child Health. oximetry screening for congenital Group. Pulse oximetry with clinical 2014;50(11):920–925

Downloaded from www.aappublications.org/news by guest on September 26, 2021 8 Hu et al

Hu et al https://doi.org/10.1542/peds.2017-1154 October 2017 Pulse Oximetry and Auscultation for Congenital Heart Disease Detection 4 140 Pediatrics 2017 ROUGH GALLEY PROOF 14. Singh A, Ewer AK. Pulse oximetry 18. Rein AJ, Omokhodion SI, Nir A. Defects Res A Clin Mol Teratol. screening for critical congenital heart Significance of a cardiac murmur as 2015;103(11):962–971 defects: a UK national survey. Lancet. the sole clinical sign in the newborn. 22. Thangaratinam S, Brown K, Zamora 2013;381(9866):535 Clin Pediatr (Phila). 2000;39(9): J, et al. Pulse oximetry screening 511 520 15. Saxena A, Mehta A, Ramakrishnan S, – for critical congenital heart defects et al. Pulse oximetry as a screening 19. Azhar AS, Habib HS. Accuracy of in asymptomatic newborn babies: a tool for detecting major congenital the initial evaluation of heart systematic review and meta-analysis. heart defects in Indian newborns. murmurs in neonates: do we need Lancet. 2012;379(9835):2459–2464 Arch Dis Child Fetal Neonatal Ed. an echocardiogram? Pediatr Cardiol. 23. Wu KH, Lü XD, Liu YL. Recent 2015;100(5):F416–F421 2006;27(2):234–237 progress of pediatric cardiac 16. Peterson C, Ailes E, Riehle-Colarusso 20. Amsbaugh S, Scott SD, Foss K. surgery in China. Chin Med J (Engl). T, et al. Late detection of critical Pulse oximetry screening for 2006;119(23):2005–2012 congenital heart disease among US critical congenital heart disease: 24. Singh A, Ewer AK. Newborn pulse infants: estimation of the potential bringing evidence into practice. oximetry screening. J Paediatr Child impact of proposed universal J Pediatr Nurs. 2015;30(4): Health. 2014;50(10):841–842 screening using pulse oximetry. 591 597 – 25. Jawin V, Ang HL, Omar A, Thong MK. JAMA Pediatr. 2014;168(4): 21. Reeder MR, Kim J, Nance A, et al. Beyond critical congenital heart 361 370 – Evaluating cost and resource use disease: newborn screening using 17. Ewer AK. Evidence for CCHD screening associated with pulse oximetry pulse oximetry for neonatal sepsis and its practical application using screening for critical congenital and respiratory diseases in a pulse oximetry. Early Hum Dev. heart disease: empiric estimates middle-income country. PLoS One. 2014;90(suppl 2):S19–S21 and sources of variation. Birth 2015;10(9):e0137580

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Hu et al https://doi.org/10.1542/peds.2017-1154 October 2017 Pulse Oximetry and Auscultation for Congenital Heart Disease Detection 4 140 Pediatrics 2017 ROUGH GALLEY PROOF Pulse Oximetry and Auscultation for Congenital Heart Disease Detection Xiao-jing Hu, Xiao-jing Ma, Qu-ming Zhao, Wei-li Yan, Xiao-ling Ge, Bing Jia, Fang Liu, Lin Wu, Ming Ye, Xue-cun Liang, Jing Zhang, Yan Gao, Xiao-wen Zhai and Guo-ying Huang Pediatrics 2017;140; DOI: 10.1542/peds.2017-1154 originally published online September 22, 2017;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/140/4/e20171154 References This article cites 25 articles, 4 of which you can access for free at: http://pediatrics.aappublications.org/content/140/4/e20171154#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Fetus/Newborn Infant http://www.aappublications.org/cgi/collection/fetus:newborn_infant_ sub Birth Defects http://www.aappublications.org/cgi/collection/birth_defects_sub Cardiology http://www.aappublications.org/cgi/collection/cardiology_sub Cardiovascular Disorders http://www.aappublications.org/cgi/collection/cardiovascular_disord ers_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 26, 2021 Pulse Oximetry and Auscultation for Congenital Heart Disease Detection Xiao-jing Hu, Xiao-jing Ma, Qu-ming Zhao, Wei-li Yan, Xiao-ling Ge, Bing Jia, Fang Liu, Lin Wu, Ming Ye, Xue-cun Liang, Jing Zhang, Yan Gao, Xiao-wen Zhai and Guo-ying Huang Pediatrics 2017;140; DOI: 10.1542/peds.2017-1154 originally published online September 22, 2017;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/140/4/e20171154

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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