Major congenital heart defects are rarely diagnosed after newborns' hospital discharge with modern screening

Our aim was to assess undiagnosed congenital heart defects (CHD) after newborns' hospital discharge in patients with a murmur or CHD suspicion, to find out the signs that predict CHDs and to estimate the costs of the examinations.

Severe forms of CHDs, such as duct-dependent or cyanotic CHDs, must be diagnosed in their early phases before the deterioration of the condition.In a Czech study conducted before the era of the routine use of pulse oximetry screening, 12% of all major and 26% of postnatally diagnosed CHDs remained undiagnosed before discharge from the hospital.The majority of delayed diagnoses were VSDs and coarctations of the aorta (CoA).Symptoms leading to diagnoses were most commonly murmur (51%) and cyanosis (26%). 9 Finland, CHDs are currently screened effectively with foetal anomaly screening, with pulse oximetry screening directly after birth and with clinical examination before discharge from delivery hospital.The purpose of this study was to assess the amount and severity of undiagnosed CHDs in this highly pre-screened population after discharge from the delivery hospital.Our study material was based on the examinations conducted on the basis of elective referrals to the Paediatric Cardiac Outpatient Clinic due to heart murmur or CHD suspicion.In addition, we aimed to determine the signs and symptoms that most reliably predict CHDs.We also aimed to estimate the costs incurred by visits to the Paediatric Cardiac Outpatient Clinic due to benign murmurs.

| PATIENTS AND ME THODS
We retrospectively reviewed the patient charts of children with elective referrals to paediatric cardiologists at Tampere University Hospital (TAUH) due to CHD suspicion or heart murmur between 1 January 2017 and 31 December 2018.TAUH is a tertiary hospital in Tampere, Finland, that serves as a central hospital of Tampere, which has a population of about 530 000 inhabitants and 4500 live births per year.Patients were referred by local general practitioners in primary health care from child health centres, school health care or from other outpatient clinics in health centres; from private health care; or from other departments of TAUH after being discharged from the delivery hospital.All newborns in the study district undergo foetal anomaly screening, pulse oximetry screening and clinical examination before discharge including an echocardiography if a murmur is heard on the routine pre-discharge neonatal physical examination or if other abnormal screening results exist.
Elective referrals leading to echocardiography were included.
We included only those patients without a previous echocardiography.In addition, serious CHDs were searched from emergency room and intensive care unit consultations.Referrals due to chest pain, genetic disorders, arrhythmias, previously known CHD and hereditary heart diseases were excluded.
The clinical signs and symptoms that comprised a CHD suspicion included murmur, abnormal femoral pulses, abnormal blood pressure gradient between arms and legs, constant split of S2, tachypnoea and excessive sweating.Murmur was considered pathological if it had a harsh quality, grade ≥3, a certain location or diastolic or continuous timing. 8,10 Hypertension was defined by age-specific reference values. 11Gs were analysed according to age-specific reference values. 12fferent evaluation criteria were used for infants up to 1 week of age. 13iRBBB was defined as terminal R wave in V1, wide terminal S wave in leads I and V6 with normal QRS duration. 14atistical analyses were performed using IBM SPSS Statistics for Macintosh (version 28.0; IBM).Frequencies and percentages were used for categorical variables.The median and interquartile range

| RE SULTS
A total of 1243 elective referrals after discharge from the delivery hospital were received in the TAUH Paediatric Cardiac Outpatient Clinic during 2017 and 2018.The study inclusion criteria were met by 490 patients who underwent clinical examinations and echocardiography (Figure 1).The median age of the patients was 2.5 (IQR

Key notes
• Screening for congenital heart defects (CHD) is carried out well in Finland, and therefore, only a small number of significant heart defects are diagnosed after newborn's hospital discharge.
• The high number of benign murmurs in children, as well as the difficulty in recognising benign murmurs, leads to many referrals resulting in unnecessary healthcare costs.

| DISCUSS ION
In our data, only a few CHDs were found after newborn hospital discharge among the patients who had undergone foetal and The number of CHDs detected in previous studies should be related to the patient population studied and the diagnostic methods used.In a murmur study of children aged 2-18 years, 7% of 473 had a CHD.They performed echocardiography on less than half of the patients, so minor defects may have gone undetected. 15The CHD yield in our study was slightly higher due to the larger age distribution and because echocardiography was performed on all study patients.An English study revealed a CHD in 19% of 150 outpatient children evaluated by echocardiography due to asymptomatic murmur, with CHDs being more common among the youngest infants. 16In another study of 903 outpatients with a murmur under 21 years of age, a CHD was detected in 27% of infants under 6 weeks of age compared with 6% in older children. 17ither ductal-dependent nor cyanotic CHD was found in our study, which was based on elective referrals after discharge from the delivery hospital.The most probable contributor to the absence of delayed diagnoses of serious CHDs is the foetal and newborn screening system in Finland.If any suspicion of CHD arises in the screening, an echocardiography is routinely performed before the discharge of the newborn.Since our data were collected over only 2 years, the annual variation may affect the incidence of CHD in our study.Due to foetal and newborn screening, our study did not reveal a higher proportion of CHDs in infants than in other age groups, contrary to other studies. 16,17However, the screening system does not detect all heart defects. 18,19The physiologic changes in neonates' circulatory systems, such as the closure of PDA and the decline of pulmonary vascular resistance, cause some CHDs (e.g.CoA and VSD) to be diagnosed later, as was seen in our study in patients who came to the emergency room due to symptoms.ALCAPA is not detectable in newborn screening because the symptoms develop later as pulmonary resistance decreases.

Age groups and number of patients at intervention
Most of the study patients were under 2 years of age and most of the referrals were from primary health care and child health clinics.In child health clinics, clinical examinations, which also serve as a part of screening for CHDs, are made by a doctor for every child at the age points of 4-6 weeks, 4, 8 and 18 months, and 4 years.A murmur heard during examinations often seems to lead to a referral to a paediatric cardiologist even though most murmurs are benign.
Shunt lesions comprised the largest group of CHDs in our cohort, which is consistent with previous studies. 5,20A quarter of patients had physiologic findings such as PFO, PDA and MI in echocardiography.Physiologic findings were most common in the youngest subjects and were detected in 60% of infants under 3 months of age.
Knowledge of haemodynamics is crucial in the evaluation of the significance of physiologic findings.Guidelines concerning benign and physiologic findings are needed to avoid unnecessary follow-up visits, leading to waste of resources. 21rmur is the most common reason for referrals to the Paediatric Cardiac Outpatient Clinic, as was also noticeable in our research. 22,23Even though the characteristics of a benign murmur are well defined, recognition seems to be difficult, and one does not dare to assess the murmur as benign based solely on a clinical examination.However, the murmur was no longer audible at the paediatric cardiologist's office in 11% of our 459 murmur referrals.
This suggests that a murmur could have been diagnosed as benign with control auscultation and further examinations could have been avoided.Our results are in line with the finding of previous studies that CHD is more likely in children with harsh or loud murmurs. 8,16 addition, diastolic or continuous murmurs were associated with CHD.A few CHDs were found in children without a murmur, some of them being incidental findings, such as mild AI.In these cases, the family history, or symptoms such as tachypnoea raise concern about a possible underlying CHD.Limb blood pressure measurement is part of the murmur assessment, and a gradient over 10 mmHg was highly suggestive of CoA in our study.
ECG is not routinely used in diagnosing CHDs, unless arrhythmia disease is suspected.It rarely adds diagnostic value to the clinical examination but increases costs. 24,25Our results support previous findings of the low importance of ECG in the diagnosis of CHDs.However, an ECG can be helpful in assessing the urgency of cardiac examinations 26 or may be useful in older children in whom cardiomyopathy may cause abnormal ECG with zero or minimal murmurs, 27 as was found in our study.
According to the criteria for transthoracic echocardiography in outpatient paediatric cardiology, a presumptively innocent murmur without signs or findings of CHD rarely requires an echocardiography.
Instead, if the murmur sounds pathological or a symptomatic patient has a murmur, an echocardiography is needed. 28However, it is challenging to manage this common clinical problem in the most effective and cost-effective way so that all significant CHDs are diagnosed early. 3Local practices vary depending on the resources available.
During the study period, our practice was to perform echocardiography in all children with a murmur, regardless of whether the clinical findings indicated a benign murmur.However, this strategy increases Recognising a benign murmur requires both experience and feedback.Auscultation skills can be taught with the help of artificial intelligence (AI).AI could also be used to identify benign murmurs from pathological murmurs.In a virtual validation study assessing an AI algorithm in the identification of pathological murmurs, AI identified pathological murmurs with a sensitivity of 93% and a specificity of 81%. 29Another small (n = 34) clinical validation study using AI to assess pathological murmurs had a sensitivity of 87% and a specificity of 100%. 30In the future, an AI algorithm could be used in primary care to confirm the diagnosis of a benign murmur so that echocardiography would not be needed.An AI algorithm could identify the pathological murmur and help to refer these patients for further investigation.The AI algorithm could be cost-effective in identifying pathological murmurs from a large number of children's murmurs, which would reduce the number of referrals and echocardiography, as well as the healthcare costs.
The limitation of this retrospective study was that we could not estimate the total number of CHDs in our region during the study period.In addition to elective referrals, only major CHDs from the emergency room were included.No CHDs detected before the newborns' discharge were included.
In conclusion, CHD screening in Finland is carried out well; therefore, the number of significant CHDs diagnosed after discharge from delivery hospitals is low.However, the high number of benign murmurs in children leads to many referrals that incur unnecessary healthcare costs.Although the auscultatory finding of the murmur makes it possible to distinguish a benign murmur from a pathological one, additional tools are still needed in primary care to reduce unnecessary examinations.Additional training is needed to improve auscultation skills.Using AI as an additional diagnostic tool could help save healthcare costs.

FU N D I N G I N FO R M ATI O N
Ida Papunen received a 2500€ grant from The Finnish Medical Foundation in 10/2021.

ECG abnormality
The

CO N FLI C T O F I NTE R E S T S TATE M E NT
Tuija Poutanen and Kaisa YIänen do not have conflicts of interest.
Electrocardiography (ECG) findings considered to indicate CHDs were signs of atrial or ventricular hypertrophy, pathological Q-waves, ST-abnormalities, right bundle branch block (RBBB), incomplete RBBB (iRBBB) with R' >10 mm, T wave abnormalities, delta waves or superior frontal plane QRS axis.Data on referrals, symptoms, clinical examination findings, limb blood pressure measurements, ECG-and echocardiography findings were collected retrospectively from medical records.The follow-up visits, heart medications and cardiac surgical and catheter interventions after diagnosis were recorded.Echocardiography findings were classified as normal, abnormal or physiologic (patent foramen ovale [PFO], tiny patent ductus arteriosus [PDA] or tiny mitral insufficiency [MI] with no need for cardiac follow-up).

(
IQR) (Q1-Q3) were expressed for the non-normally distributed variables.The normal distribution of the continuous variables was assessed using histogram and normal distribution tests.Categorical variables were compared with chi-squared tests.p-values <0.05 were considered statistically significant.The cost estimate was calculated based on the year 2017 level of the Paediatric Cardiology Unit's visit fees charged by the hospital.The Research Director of the Pirkanmaa Hospital Districts gave permission for the study.According to Finnish legislation, register-based studies do not need Ethics Committee approval.

| 145 PAPUNEN
et al. 0.5-7.4)years and 265 (54%) were males.Forty-seven per cent (n = 230) of the study patients were under 2 years of age.Of the referrals, 172 (35%) were from other outpatient clinics in health centres, 152 (31%) from child health clinics, 80 (16%) from TAUH Paediatric Department, 36 (7%) from other TAUH departments, 30 (6%) from school health care, 13 (3%) from private health care and 7 (1%) from other institutes.The reason for the referral was murmur in 459 (94%) cases, abnormal ECG in 66 (14%), abnormal femoral pulses in 15 (3%), abnormal blood pressure gradient in 6 (1%) and other reasons in 11 (2%) of the cases.Altogether, 301 (61%) of the cases had normal and 126 (26%) physiologic findings in echocardiography with no need for cardiac control.An abnormal echocardiography was found in 63 of the 490 (13%) patients, with altogether 71 cardiac lesions (one patient could have more than one cardiac lesion).Thirty-five (49%) were shunt lesions, 29 (41%) valvular lesions and seven (10%) others.Neither ductal-dependent nor cyanotic CHDs were found.The CHD diagnoses in the age groups are shown in Table 1.There was no statistically significant difference in the number of CHDs between sexes (male 31/265 [12%] and female 32/225 [14%]) or age groups, respectively p = 0.406; p = 0.840.During the study period, four children with undiagnosed significant CHDs came to the emergency department due to symptoms.An 8-week-old infant had a critical CHD and an abnormal left coronary artery from the pulmonary artery (ALCAPA) and died.A 2-week-old infant with heart failure symptoms had a large VSD and needed medication but not operation.A 7-month-old infant with weak femoral pulses had CoA and was treated with angioplasty.The fourth symptomatic patient (1-year-old) had myocarditis.Until spring 2020, after a median (IQR) follow-up time of 2.3 (1.8-2.8)years, 14 surgical or catheter interventions were made for 14 of 63 (22%) patients with a CHD at the median (IQR) age of 6.0 (1.8-15.2) years (Table2).In addition to these interventions, one transesophageal electrophysiologic study was performed.Five of 63 (8%) patients with a CHD needed heart medication during the follow-up period.

F I G U R E 1
Flowchart of patient selection.TA B L E 1 ECG and echocardiography findings and heart defect diagnosis by age group.
costs and referrals, because it misguides local practitioners into believing that all children with murmurs need echocardiography.If all benign murmurs in our cohort had been diagnosed in primary health care without echocardiography, it would have saved an estimated 153 700 euros.Healthcare resources are not sufficient to perform echocardiography on all children with a murmur.Primary care would need more training and better diagnostic tools to identify benign murmurs so that echocardiography can be targeted to the children more likely to have a CHD.A diagnosis of a benign murmur by a paediatric cardiologist based on clinical findings can enhance the confidence of local physicians avoiding unnecessary referrals for echocardiography.

Table 3 .
The percentages of CHDs found in patients with a certain symptom or sign are shown in Table4.Five patients had an audible murmur at the back, but only one had an abnormal echocardiography (CoA).Eight patients without murmur had a CHD: one VSD, two PDAs, one cardiomyopathy, two bicuspid aortic valves and two aortic insufficiencies (AI).Of all the children included in this study, 83 (17%) had no murmur at the Paediatric Cardiac Outpatient Clinic.Two patients had a limb blood pressure gradient over 10 mmHg, and both had CoA.Table5shows abnormal ECG findings and their relation to echocardiography findings.ECG was obtained from 487 (99%) study patients.Altogether, 49 ECG abnormalities were found in 40 cases.
Note: A single patient can have multiple diagnoses.Only elective referrals included.Abbreviations: AI, aortic insufficiency; AS, aortic stenosis; ASD, atrial septal defect; CoA, coarctation of aorta; MI, mitral insufficiency; PDA, patent ductus arteriosus; PS, pulmonary stenosis; VSD, ventricular septal defect.tion:pathological heart murmur added with pulmonary area or abnormal femoral pulses or enlarged liver or abnormal breathing sounds) had a sensitivity of 59% and a specificity of 65% to find a CHD.When abnormal blood pressure and abnormal ECG were added to the abnormal clinical findings, sensitivity was 60% and specificity 63%.The fee for the Paediatric Cardiac Outpatient Clinic visit, including echocardiography, was 530€ in 2017.The cost of the first visits of this research population was a total of 259 700€.In our study group, 290 (59%) patients had normal clinical findings at this visit (including normal blood pressure and ECG, benign murmur or no murmur).The cost of the assessment of children with normal clinical findings was 59% (153700€) of the entire expense.A total of 426 (87%) patients had normal or physiologic findings on echocardiography.The cost of the visits of the patients without CHD was 225 780€ in total.
Symptoms and signs in relation to echocardiography findings (percentages by symptoms/signs).
TA B L E 4