OBJECTIVES: 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 addition of cardiac auscultation to POX as a screening method for asymptomatic major CHD.
METHODS: 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 accuracy of POX plus cardiac auscultation for the detection of major CHD.
RESULTS: CHD screening was completed in all 15 hospitals, with a screening rate of 94.0% to 99.8%. In total, 167 190 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 detecting CCHD and 1.1% for detecting major CHD.
CONCLUSIONS: 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.
- CCHD —
- critical congenital heart disease
- CHD —
- congenital heart disease
- CHFU —
- Children’s Hospital of Fudan University
- FPR —
- false-positive rate
- NEC —
- necrotizing enterocolitis
- POX —
- pulse oximetry
What’s Known on This Subject:
The accuracy of pulse oximetry (POX) as a screening tool for critical congenital heart disease (CHD) has been extensively studied. However, POX detects only lesions with hypoxemia with moderate sensitivity. Most cases of serious CHD without hypoxemia cannot be recognized early enough to avoid heart failure or collapse.
What This Study Adds:
Many structural heart defects present as a cardiac murmur. Using POX in conjunction with cardiac auscultation significantly improved the detection rate of both critical and serious CHD in the early neonatal stage, with high sensitivity and reasonable false-positive rate.
Congenital heart diseases (CHDs) are a leading cause of infant death worldwide and affect 8 in 1000 live births.1 About 1 to 2 per 1000 newborn infants have critical CHD (CCHD), which is defined as CHD that causes death or needs intervention in the neonatal period. Neonates with CCHD benefit most from early detection.2 Because of this, CCHDs have become the target for screening schemes in developed countries, and pulse oximetry (POX) has been confirmed as an effective screening modality, with moderate sensitivity and high specificity.3–7 However, POX detects only those lesions with hypoxia. Most simple but serious cases of CHD, such as severe left heart obstructive lesions and large left-to-right shunt lesions, cannot be recognized early enough by POX to avoid heart failure, collapse, or even irreversible pulmonary vascular disease at a later stage.8 Therefore, all major CHDs (those causing death or requiring intervention during infancy, including CCHD and serious defects) should be regarded as main targets of neonatal screening.9
In 2014, we reported the first large-scale prospective study on neonatal CHD screening in China and proposed that the benefits of POX recorded in high-income countries could be translated with success to China as well; we also suggested that POX used in conjunction with clinical assessment could be successfully implemented in common hospital settings with few barriers, and combining POX with clinical assessment resulted in a high detection rate of major and CCHD.9 Importantly, in a post hoc analysis, we observed that POX combined with cardiac murmur had the same sensitivity as did POX plus clinical assessment in the detection of major CHD (90.0%) and CCHD (93.0%), whereas the false-positive rate (FPR) was significantly lower (2.4% vs 2.7% for major CHD, P < .0001, and 2.5% vs 2.9% for CCHD, P < .0001), suggesting that POX plus cardiac auscultation may be a screening strategy for major CHD. With this study, we aimed to investigate the accuracy and feasibility of the addition of cardiac auscultation to POX as a screening method for asymptomatic major CHD, hoping to provide a more comprehensive reference for routine neonatal CHD screening policy.
Study Design and Participants
A multicenter prospective observational screening study was conducted at 13 hospitals (hospitals 1–13 in Fig 1) between July 1, 2012, and December 31, 2014, and at 2 hospitals between February 1, 2013, and December 31, 2014, (hospitals 14 and 15 in Fig 1) in Shanghai. Of the 15 hospitals, 8 were urban and 7 were suburban; 5 were tertiary and 10 were secondary hospitals. Ten hospitals (67.0%) had echocardiography available on-site, whereas the remaining hospitals referred neonates with positive screening results to the Children’s Hospital of Fudan University (CHFU) for a diagnostic echocardiogram free of charge. All consecutive asymptomatic newborn infants were included (irrespective of gestational age), but newborn infants with prenatally diagnosed CHD were excluded from the analysis of the current study.
This study was approved by the ethics committee of CHFU. Oral informed consent was obtained from the participants’ parents.
Screening methodology, POX measurement criteria, and the definition of CHD severity were the same as our previous study,9 but in this study, we only screened asymptomatic neonates, and screening modalities included only POX and cardiac auscultation. Cardiac auscultation was performed and immediately followed by POX measurement by the same clinician. A positive screen result was defined as presence of any abnormality in the 2 examinations as presented in Fig 2.
Neonates who screened positive for CHD were referred for echocardiography within 24 hours of screening. CHFU was responsible for the confirmation of a diagnosis by echocardiography for neonates with a positive screening result and follow-up of all infants with CHD. False-negative cases of CHD were estimated by using the following methods. For infants who had negative screening results, clinical follow-up was done at 6 weeks of age, in combination with feedback from parents about cardiac symptoms such as cyanosis, tachypnea, and feeding difficulty or CHD diagnosis by any hospitals after the infant was discharged from the delivery hospital. In addition, the first consecutive 27 201 neonates who screened negative were followed up via telephone at 1 year of age, which was done to determine if the infant had cardiac symptoms or was diagnosed with CHD in other hospitals.
Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were calculated for POX alone and in combination with cardiac auscultation. 95% confidence interval of sensitivity and specificity was computed by the Wilson method. McNemar’s test was used to compare differences in sensitivity and specificity. A logistic regression model was performed to test the trend of FPRs across 7 time intervals during which screening occurred. χ2 decomposition analysis was further performed to identify the difference of the FPRs between time intervals.
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 results between these hospitals (1.1%–1.8%, P > .05).
Among 172 865 consecutive deliveries, 4108 infants with incomplete screening data, 90 infants with major CHD (28 infants with CCHD and 62 infants with serious CHD) identified prenatally, and 1385 symptomatic newborns were transported to the NICU without screening at birth hospitals (92 infants with major CHD, including 34 with CCHD and 58 with serious CHD among them) were excluded for screening accuracy analysis (Fig 3). In total, 167 190 asymptomatic newborns were screened by using the standard screening protocol. There were 88 941 male (53.2%) and 78 249 female (46.8%) infants. The median age at POX plus cardiac auscultation screening was 26 hours (range 6–72 hours). Of 167 190 asymptomatic infants, 1170 with CHD (including 42 with CCHD and 145 with serious defects) were identified before discharge. An additional 156 patients with CHD (including 2 with CCHD and 14 with serious CHD) were diagnosed later by clinical follow-up, parents’ feedback, and telephone review (Fig 3, Table 1).
The Sensitivity of Screening for Major CHD by Using POX Plus Cardiac Auscultation
POX alone as a screening method detected 34 out of 44 (77.3%) CCHD cases but only 90 out of 203 (44.3%) major CHD cases. POX plus cardiac auscultation detected 42 out of 44 (95.5%) cases of CCHD and 187 out of 203 (92.1%) cases of major CHD. The addition of cardiac auscultation to POX significantly improved the sensitivity of screening for both CCHD and serious CHD (Table 2). The detection rate for individual CCHD in the asymptomatic cohort is presented in Table 3.
The FPR of Screening for Major CHD by Using POX Plus Cardiac Auscultation
The overall FPR was 1.2% for CCHD and 1.1% for major CHD. Among 1860 infants with false-positive screening results, 74 (4.3%) were referred to the NICU for further treatment. Among them, 57 patients screened positive with POX had sepsis (32), pneumonia (18), hypoglycemia (4), jaundice (2), and necrotizing enterocolitis (NEC) (1). Twelve patients screened positive with cardiac murmur had pneumonia (4), jaundice (2), sepsis (1), NEC (1), and diarrhea (1). Five patients screened positive with both POX and cardiac murmur had pneumonia (3), sepsis (1), and NEC (1).
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 tended to decline with the age of the newborn infant at screening (P < .0001; overall odds ratio of false-positives to true-negatives: 0.8; 95% confidence interval 0.7–0.8). Further χ2 decomposition analysis showed that the FPR in the earliest 4 time intervals were significantly higher than the others (P < .0001); however, the FPR in the fifth, sixth, and seventh time intervals did not differ from each other (P = .139 for 36–48 hours, P = .198 for 49–60 hours, and P = .907 for 61–72 hours).
Prevalence of Major CHDs
Although CHD prevalence demonstrated significant geographical differences,10,11 which may have environmental components such as nutritional status and teratogen exposure in addition to genetic factors, in this study we did not show a significant difference in major CHD prevalence compared with our previous study.
Major CHD includes CCHD and serious defects as defined in both of our studies. In the current study, which was conducted in 15 hospitals in Shanghai city, 44 infants with CCHD and 159 infants with serious CHD were detected from those asymptomatic neonates, whereas another 34 infants with CCHD and 58 infants with serious CHD were identified from those symptomatic neonates who were transported to the NICU of CHFU without screening in the birth hospitals; there were 28 cases of CCHD and 62 cases of serious CHD identified prenatally. In total, there were 385 cases of major CHD among 172 865 consecutive newborn infants in the present cohort, and the overall prevalence of major CHD was 2.23‰ (385 out of 172 865).
In our previous study, which was conducted in 18 hospitals from 10 provinces in China, there were 357 cases of major CHD (157 critical and 173 serious from both asymptomatic and symptomatic infants and 27 prenatally diagnosed cases of major CHD) among 130 282 consecutive newborn infants in the cohort, and the overall prevalence of major CHD was 2.7‰ (357 out of 130 282). The overall prevalence of major CHD in the current study looks a bit lower than that in the previous study, but the prevalence of CHD in both studies was not statistically different (P = .05).
One of our major concerns with this study is the possibility that some infants with CHD were missed on follow-up. In our study, clinical follow-up was done at 6 weeks of age, in combination with feedback from parents about cardiac symptoms or a CHD diagnosis by any hospitals after an infant was discharged from the birth hospital. To investigate the likelihood of missing major CHD through clinical follow-up and feedback from parents of the infants who screened negative by POX plus cardiac auscultation screening, we made calls to the parents of the first consecutive 27 201 infants who screened negative and found 3 serious defects (0.1‰, 3/27 201), indicating that few cases of major CHD would be missed on follow-up. Furthermore, CHFU was the referral center of the 15 participant hospitals in the current study. All newborn infants who manifested symptoms or severe conditions were transported to our NICU. If the infant was diagnosed with major CHD and needed intervention, the majority of medical expenses would be covered by insurance and some charity funding. There were few incentives for the family to seek and pay for care outside of our hospital, which ensured that almost all infants were on the track to follow-up. In the current study, we indicate that the prevalence of major CHD was similar in different regions in China.
All Major CHDs Should Be Set as a Screening Target
With significant evidence from previous studies, screening for CCHD is now spreading across the globe.4,12–15 Whether to implement an inexpensive, quick, painless screening for CCHD with the potential to save lives is no longer the question being asked.16,17 There appears to be no need for further confirmation of the advantages of POX screening for CCHD. However, POX testing alone may lead to missed diagnoses of those who have CHD without right-to-left shunt lesions and the progression of some simple but serious lesions, such as large septal defects, to heart failure or Eisenmenger syndrome.8 It is noteworthy that a large number of previous studies were based in developed countries, with an emphasis placed on POX. It seemed as if there was little emphasis placed on clinical assessment, such as cardiac auscultation.
In previous studies, researchers showed that ∼1% of newborns had a heart murmur, and 31.0% to 86.0% of these infants had structural heart disease (even potentially life-threatening heart defects may not be associated with any initial signs or symptoms other than a heart murmur).18,19 In our previous study, we demonstrated that POX used in conjunction with clinical assessment could be successfully implemented in common hospital settings with few barriers, and using POX in conjunction with clinical assessment resulted in a high detection rate of major CHD and CCHD.9 This was further confirmed by our present study. Hence, we would suggest that POX plus cardiac auscultation should be applied to screen for all major CHDs, including CCHD and serious defects.
The Current CHD Screening Strategy Has High Accuracy
In our current study, we have validated the high accuracy of POX plus cardiac auscultation in screening for major CHD. The sensitivity of this screening method was 95.5% for CCHD and 92.1% for major CHD, which was similar to that of our published study.9 Moreover, the FPR in the current study had significant reduction, which was 1.2% for CCHD and 1.1% for major CHD compared with 2.5% and 2.4% in our previous study.
Although the similar study protocol and training course were applied for both studies, there were a couple of reasons for the significant reduction of the FPRs. First, the current study started in July 2012, when we had more experience based on the previous study in training and quality control for our screening protocol. Second, all clinicians who would perform the auscultation in the study were highly trained, but the current study was conducted in 15 hospitals in Shanghai area, whereas the 2014 study was conducted in 18 hospitals in 10 provinces around the country. Obviously, it was easier to supervise the quality of auscultation performance in the current study. Furthermore, we emphasized that cardiac auscultation must be performed in a quiet environment in the current study, which might make the auscultation more accurate. Given the close supervision of the clinicians and the quiet environment in which auscultation was performed in this study, we would believe that the reasonable FPRs of <2.5% for CCHD and <2.4% for major CHD can be reproducible and generalizable by using POX plus cardiac auscultation in different birth hospitals.
Moreover, among 1860 infants who had positive test results for noncardiac conditions, 74 (4.3%) infants were referred to the NICU for further treatment. Most of them had an infection such as sepsis or pneumonia. The detection of these conditions could be considered an added value of screening.
The Current CHD Screening Strategy Is Feasible
Although the advantages of CCHD screening are well recognized, when compared with developed countries, challenges to the implementation of screening certainly exist.20 The first issue of note is burden of resources, with China as a prime example. In China, the number of pediatricians is greatly outnumbered by births, with the average facility delivering 30 to 50 infants per day. Whether there is sufficient manpower and time for each newborn screening and whether screening would greatly increase the workload of pediatricians are areas of concern. The 15 facilities chosen for this study are representative of the situation in Shanghai, and in our results, we showed that all facilities could successfully implement major CHD screening. The amount of time spent screening was not a significant increase in the workload of doctors. This is reflected by satisfactory screening rates and diagnostic echocardiography rates.
The second issue is economic burden. Limited data from US studies suggest the average cost per infant screened ranges from $5.10 to $14.20.21 However, in Shanghai, one of China’s largest and most expensive cities, the average cost per infant screened was ∼$2.50. Echocardiography is available in most hospitals for ∼$30.00 per examination. Therefore, costs for screening and diagnostic echocardiography are markedly lower than in developed countries, with the cost acceptable for families not covered by government health insurance plans.
The third issue of note is false-positive screen results. In particular, this includes the potential burden of false-positives and the demand on pediatric echocardiography services. In a meta-analysis, researchers showed that the FPR of POX screening for CCHD was significantly lower when screening was done after 24 hours of birth than when it was done before 24 hours.22 In our present study, the overall FPR was 1.2% for CCHD and 1.1% for major CHD as mentioned above, which was reasonable in terms of the high sensitivity of screening. Moreover, we grouped participants into more specific timing intervals and found that to lower the FPR of POX screening, it would be better to perform the screening after 36 hours of life. However, in our present cohort, 1385 symptomatic newborns were transported to the NICU without screening at birth hospitals. Among them, there were 34 infants with CCHD and 58 infants with serious CHD who had symptoms within 12 hours after birth. This information should be emphasized when we make decisions about the optimal time to conduct CHD screening; we need to balance the risk of false-positives against the likelihood of a timely diagnosis.
The fourth issue is how to meet the need for timely cardiologic assessment after a positive screening test result, especially for community hospitals. Advances in pediatric cardiology and cardiac surgery during the past 30 years in China have made possible the diagnosis and treatment of most cases of CCHD.23 Policies that prioritize surgical treatment of neonatal CCHD have been established in major pediatric cardiac centers. Furthermore, through the work of our group, CHFU has established a nationwide neonatal CHD screening, diagnosis and evaluation, and intervention network, collaborating with 48 hospitals in 13 provinces, providing timely teleconsultations and referral services on detection of major CHD. The network continues to grow, with facilities joining across the nation.
Limitations and Perspective
With a view to vast geographical variability, if universal screening is implemented, issues such as screening algorithms to account for moderate- and high-altitude locations must be considered, with the possibility of establishment of cutoff points for infants screened at higher altitudes. In addition, further work on how to evaluate a low-saturation screening needs to be done because 27.0% of false-positive findings were conditions that needed medical attention,24,25 such as respiratory diseases and infections, which contributed to the highest mortality rate during the neonatal period.
In our current study, we further displayed that using POX plus cardiac auscultation significantly improved the detection rate of major CHD in the early neonatal stage, with high sensitivity and reasonable FPR. It provides strong evidence and a reliable method for neonatal CHD screening.
We thank all the newborn infants and their parents who participated in this study. We thank all professionals involved in the Neonatal Congenital Heart Disease Screening Project (Wei-fen Luo, Li-ping Xiao, Jun Huang, Jin-xiang Ding, Ying Wang, Zhi-rong Fan, Zhi-hong Lu, Min-shu Yu, Qin Gu, Qiu-ling Xu, Gui-fang Cai, Xiao-ming Wang, M. Jun Yu, Ye Chen, Feng Zhao, Guo-zhen Xu, and Chen-lan Guo). We thank Conway Niu (Department of Pediatrics, Shanghai Medical College of Fudan University) for his help in preparing the manuscript and Yiu-fai Cheung (University of Hong Kong, Hong Kong), Swee Chye Quek (National University of Singapore, Singapore), and Andrew Ewer (University of Birmingham, United Kingdom) for their valuable comments and review of the report. Drs Niu, Cheung, Quek and Ewer did not receive any compensation for this contribution.
- Accepted June 30, 2017.
- 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:
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.
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- Copyright © 2017 by the American Academy of Pediatrics