Introduction
The QRS complex reflects the depolarisation of the ventricular myocardium and is an important diagnostic and prognostic parameter in many clinical settings [
1‐
3]. The duration and amplitudes of the QRS complex may be markers of altered conduction or structural/functional abnormalities of the left ventricle, including left ventricular hypertrophy (LVH) or dilatation [
1]. The electrocardiogram (ECG) is a diagnostic cornerstone in cardiology and a valuable tool in screening for numerous cardiac diseases, including LVH in adults [
4], and has predictive power for cardiovascular outcomes such as stroke, myocardial infarction, and death [
5‐
8].
Numerous processes may lead to LVH, including adaptation to increased hemodynamic stress [
9], alterations secondary to congenital heart disease (CHD), maternal diabetes mellitus [
10], metabolic- and neuromuscular diseases, as well as hypertrophic cardiomyopathy [
11]. Hypertrophic cardiomyopathy has been found to be one of the most common causes of sudden cardiac death in young people [
11] underlining the importance of an early diagnosis of LVH. Echocardiography is a non–invasive tool useful for determining left ventricular structure/function and can reliably detect LVH in adults [
12]. However, the ECG is widely available and ECG-LVH is an established prognostic marker [
13]. Previous studies have investigated the usefulness of standard ECG for detecting LVH in children and have found conflicting results [
9,
14‐
17]. Several ECG features including QRS area, maximum precordial amplitudes, voltage product, etc., have been investigated in relation to left ventricular mass (LVM) with variable sensitivity and specificity. However, previous studies were performed in smaller, selected cohorts, with a large variation in age (0–18 years) spectrums [
9,
15].
Definite evidence on whether ECG features are reliable predictors of left ventricular mass index (LVMI) outliers in neonates requires data from a large, population-based cohort with systematic, concurrent electro- and echocardiographic evaluation. We assessed QRS complex features during the first month of life and investigated the association between electrocardiographic features and echocardiographic measurements of LVMI in a large cohort of asymptomatic, consecutively enrolled neonates.
Discussion
In the present large, population-based cohort study of 17,450 neonates, we assessed QRS complex features and LVMI during the first month of life. Updated standard reference values for both electro- and echocardiographic parameters are presented. Our study showed that most investigated QRS features evolved during the first month of life. However, we found no to low correlation between QRS features and LVMI resulting in low sensitivity, but high specificity of these parameters to identify LVMI outliers in neonates.
There are a limited number of published smaller, reference studies [
27‐
30] (
n = 44–668) investigating QRS features in neonates. Rijnbeek et al. [
27] (
n = 44) investigated the QRS duration in neonates and found a median value of 67 ms, while Davignon et al. [
30] (
n = 668) found a value of ~ 50 ms in V5; relatively similar to our findings of 56 ms. Saarel et al. [
31] (
n = 257) found a median QRS duration of 60 ms for boys and 58 ms for girls; quite similar to our findings of 56 ms for boys and 54 ms for girls. Investigating precordial amplitudes during the first month of life, Davignon et al. reported a decrease in S-V1 (from ~ 800 to ~ 400 µV) very similar to our findings (from 825 to 517 µV), as well as an increase in R-V6 (from ~ 370 to ~ 700 µV). We also found an increase in R-V6, but the absolute values differed to some extent (from 859 to 1113 µV). Investigating the influence of sex on R-V6 in neonates, Saarel et al. found no effect of sex and median values of 665 µV for boys and 773 µV for girls. We have also previously documented no effect of sex on R-V6, as well as a large variation in absolute values for neonatal precordial amplitudes [
23]. Furthermore, these differences most likely reflect variation in applied methodologies, including use of manual vs. automated measurements, one lead vs. all leads, differences in neonatal characteristics and cohort sizes, etc. Taken together, the current study is the first to provide thorough reference values for a wide range of neonatal QRS features during the first month of life.
Previous pediatric studies [
9,
15,
17,
32‐
34] (
n = 12–3209) investigating the association between LVM/LVMI and QRS features have produced mixed results, and only few of these studies have focused on neonates. One of our main findings is no—to low—correlation between LVMI and QRS features resulting in low sensitivities (range 0–9%), generally high specificities (range 97.2–98.0%), and AUC values close to the identity line (range 0.494–0.607). Comparable to our results, Rivenes et al. [
15] (
n = 1688; 0–14 years) found a low sensitivity (< 20%), but a high specificity (range 76–99%) for a range of ECG criteria for detecting echocardiographic LVH, regardless of HIV status which was the study’s main aim. Similarly, Rijnbeek et al. [
9] (
n = 832; age 0–15 years) found low sensitivity (< 25%) for ECG criteria to identify high LVMI and reported that factors such as the applied LVH definitions, combination of several ECG criteria, and consideration of clinical indexes of volume and/or pressure overload, affected sensitivity. Contrary, Tauge et al. [
17] (
n = 3209; age 0–18 years) found a high sensitivity (≥ 90%), and a low specificity (43%); however this cohort had a very high prevalence of ECG-LVH, but low prevalence of echocardiographic-LVH, likely explaining the findings. Overall, limitations of the mentioned studies include the often small sample sizes, large variation in the age of the included children, and heterogenous cohort compositions (including children with CHD and/or other comorbidities). In our study, we did not find a noticeable effect on sensitivity after adjustment of the definition of LVMI outliers, but adjustment of the thresholds for QRS features had a minor effect.
Based on data from 17,450 unselected neonates from the general population, our study is to date the largest study presenting reference values for QRS complex features and their association with LVMI. Our findings show that QRS features are not reliable predictors of LVMI, consistent with most previous studies. However, we investigated LVMI outliers, as defined by ≥ 98th percentile, but all these neonates may not have true pathological left ventricular hypertrophy and greater sensitivity for ECG features in identifying LVH has been reported in smaller, selected cohorts enriched for CHD [
32,
33]. Sensitivity for children with VSDs (
n = 12) has been found to be 60%, with aortic stenosis (
n = 19) up to 67%, and up to 71% in children with rheumatic heart disease (
n = 84). ECG is a non-invasive, cost-effective, and easily obtainable diagnostic tool and continues to have diagnostic significance in neonates presenting with symptoms consistent with arrhythmia, suspicion of genetic channelopathy, drug side effect, etc., but is an insensitive screening tool for identifying LVMI outliers in unselected/asymptomatic neonates.
There are limitations to the present study. The sensitivity and specificity of a given diagnostic modality is dependent on the prevalence of the condition it is used to diagnose, i.e. had we investigated selected groups of hospitalized neonates with, e.g. hypertrophic cardiomyopathy, congenital aortic stenosis, or another major CHD, the sensitivity and specificity of QRS complex features to diagnose LVMI would likely have been higher. The ECGs were recorded with eight leads instead of twelve due to logistical reasons and considerations of participant discomfort, some inter-observational variation in measurements cannot be ruled out [
35], and external validation was not performed. Furthermore, ethnic differences may exist, and the results may not be generalizable to populations with different ethnic distributions. Previous studies have shown that non-ethnicity-specific LVH criteria result in overestimations for African-Americans and may underestimate LVH in white populations [
36]. Lastly, the use of the “cube” formula to calculate LVM has certain prerequisites and may be vulnerable to measurement inaccuracies explaining some of the differences in absolute values seen when comparing to previous studies. Other formulas for LVM calculation, such as, e.g. the 5/6 AL method, may be more precise and should be investigated in future projects.
In conclusion, the study presents updated reference values for QRS complex features and their association with LVMI in neonates from a large, unselected, population-based cohort. The QRS complex gradually evolved during the first month of life but had low correlation with LVMI. ECG features were associated with low sensitivity, but high specificity, and are therefore not reliable indicators of LVMI outliers. Taken together, our results do not support the use of QRS features as a diagnostic tool for identifying LVMI outliers in asymptomatic neonates.
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