Screening of 1-Month-Old Infants With Prolonged QT Interval and Its Cutoff Value

Abstract

Background: The prevalence of congenital long QT syndrome (LQTS) (1 : 2,000) is based on genetic testing and ECG data, but the prevalence of electrocardiographically determined prolonged corrected QT interval (pQTc) in infants is unclear.

Methods and Results: Subjects were 10,282 1-month-old infants who participated in 2 prospective ECG screening studies performed in 2010–2011 and 2014–2016. Infants with a QTc ≥0.45 using Bazett’s formula [QTc(B)] at 1-month medical checks were re-examined. pQTc was defined as QTc ≥0.46 on 2 different ECGs in early infancy. Infants with QTc ≥0.50 or progressive prolongation of QTc to 0.50 were defined as at high risk. The prevalence of infants with a pQTc was 11/10,282 (1 : 935; 95% confidence interval, 1 : 588–1 : 2,283). Five infants were diagnosed as at high risk, and all infants had an abrupt increase in QTc(B) values in early infancy, mostly at 6–11 weeks after birth and when medication was started. No infants with a pQTc experienced LQTS-related symptoms. Statistical analysis showed that a cutoff QTc(B) ≥0.45 was optimal for screening infants with a pQTc.

Conclusions: The prevalence of ECG-determined pQTc is approximately 1 : 1,000. An abrupt increase in QTc(B) values occurs in infants at high risk, mostly at 6–11 weeks after birth. A cutoff QTc(B) value ≥0.45 may be appropriate for 1-month-old screening in this population.

Congenital long QT syndrome (LQTS) is a genetic disorder that is characterized by delayed repolarization and a long QT interval on 12-lead ECG.^1,2 The hallmark of LQTS is syncope or sudden death due to torsade de pointes.^1,2 Sudden infant death syndrome (SIDS) is one of the major causes of death in infancy, with the highest peak at 75 days of life.³ SIDS is multifactorial in origin, but a previous study showed that the odds ratio for SIDS in infants with a prolonged corrected QT interval by Bazett’s formula [QTc(B)] was 41.3.⁴ The period of the highest peak of SIDS³ and the highest prevalence of unexpected sudden infant death (1–3 months of age)⁵ correspond to the period of the highest QTc values (6–11 weeks after birth) in the healthy general population.⁶

Population-based neonatal screening remains controversial.^7–10 However, prospective studies on the prevalence of LQTS that were performed in Italy (44,596 infants),¹¹ Japan (4,319 infants),¹² Germany (2,251 infants),¹³ and Spain (685 infants)¹⁴ showed that no infants with congenital LQTS or with a prolonged corrected QT interval (pQTc) showed LQTS-related symptoms,^11–14 including sudden death with interventional medication. Those studies suggest that ECG screening can identify most infants with a pQTc and that it is an effective preventive measure for sudden infant death in those with a pQTc.

The prevalence of congenital LQTS is approximately 1 : 2,000 when the diagnosis is based on the combination of QT interval and genetic testing.¹¹ The prevalence of infants with a pQTc can differ according to the definition of pQTc. However, the prevalence of QT prolongation determined by ECG in infancy is not well known, and screening cutoff values for infant pQTc is still under investigation. In previous studies, ECG recordings were repeated when the initial QTc(B) was >450 ms (or ≥450 ms).^11,12 A recent study of 5,000 neonatal ECGs, including 17 infants with LQTS-causing pathogenic variants, showed that an appropriate cutoff value of QTc(B) for infants was 460 ms,¹⁵ although subsequent studies still used the cutoff value of 450 ms.^13,14 The cutoff value of 460 ms should be applied to other ethnic groups that include a relatively large number of participants.

The first study of ECG screening was performed in 4,319 1-month-old infants in Japan.¹² A second prospective study of ECG screening was performed in 6,006 1-month-old infants, and 10,325 infants were prospectively screened. The present study aimed to determine the prevalence of infants with a pQTc and identify those at high risk, as well as determining the cutoff QTc(B) values for screening infants with a pQTc in this population.

Methods

Subjects

Prospective ECG screenings were performed twice at 1-month medical checks. The first study was conducted in 16 maternity institutes in 8 areas in Japan between July 2010 and March 2011. Details of this study were described in a previous report.¹² The second study was performed in 14 maternity institutes in 8 areas (Kagoshima, Fukuoka, Nagoya, Toyoake, Ogaki, Tsukuba, Toyama, and Niigata) between September 2014 and February 2016. The parents were asked to participate in these studies at the time of discharge from the maternity institutes. A total of 10,325 infants, including 4,319 and 6,006 infants in the first and second studies, respectively, participated at the time of the 1-month medical check after obtaining written informed consent from the parents. The procedures in this study were performed in accordance with the Declaration of Helsinki. We obtained permission to use and analyze these data from the Ethics Committee of the NHO Kagoshima Medical Center (Approval nos. 22-3, 26-7, and 2020-45).

Analysis of ECGs and Measurement of the QT Interval

The 12-lead ECGs were recorded at a speed of 25 mm/s using a FCP-series recorder (FCP-4700, -7431, -7541, -8221, and -8800; Fukuda Denshi, Tokyo, Japan). The ECGs were initially read in each center, and a written report was sent to the parents of each participant. All QT/RR data for the present study were re-measured by 1 author (M.Y.). The QT intervals of 3 consecutive beats were manually measured using the tangent method from the onset of the Q wave to the end of the T wave in lead V₅ or lead II.

Correction of the QT Interval in Infants and School-Age Children

The exponent k in the formula of (QTc) = (QT interval) / (RR interval)^k that minimizes the effect of heart rate in infants was shown to be 0.43 in a Japanese population⁶ or 0.467 in an Italian population.¹⁵ The k value was also determined for the present population and calculated by simple regression analysis using the log-transformed QT interval as the dependent variable and the log-transformed RR interval as the independent variable. All 3 QT/RR data of the subjects were used in the calculation, which revealed that the k value was 0.449 for the present population. The k values for these 3 populations (0.430 for Japanese infants, 0.467 for Italian neonates, and 0.449 for infants at 1-month medical check in the present study) were closer to that calculated by Bazett’s formula (k=1/2 or 0.500) than that calculated by Fridericia’s formula (k=1/3 or 0.333). We used Bazett’s formula to correct the QT interval in the present study because the difference in k values between population studies and Bazett’s formula was smaller than that between those and Fridericia’s formula. We also wanted to compare the cutoff value of the present study with that of Stramba-Badiale et al. who used Bazett’s formula.¹⁵ In the follow-up ECGs of infants at school age, the QTc by Fridericia’s formula [QTc(F)] was also used.¹⁶

Screening and Follow-up Strategies

The algorithm for screening and follow-up strategies is shown in Supplementary Figure 1. Infants who showed a QTc(B) ≥0.45 were reexamined. Infants who showed a QTc ≥0.45 and <0.46 were reexamined 2–3 weeks later, and those who showed a QTc ≥0.46 were reexamined within 2 or 3 weeks. After that, they were reexamined based on the judgement of the doctors. Infants were diagnosed as having a pQTc when they showed a QTc(B) value ≥460 ms on 2 different standard 12-lead ECGs⁸ during the follow-up, because the QT interval lengthens physiologically and temporarily during early infancy, particularly within few weeks after birth.^9,13 Infants who were diagnosed as pQTc were followed for at least 1 year after birth, and subsequently followed based on the judgement of the doctors. Infants who fulfilled 1 of the following 3 criteria were diagnosed as at high risk and medication was initiated: (1) presence of symptoms; (2) presence of QT prolongation, with a QTc(B) ≥0.50¹⁷ or a progressive prolongation of QTc(B) to 0.50 including a QTc(B) on Holter recordings^17–20 during sleeping; and (3) presence of both QT prolongation and a family history of LQTS with symptoms. No infants fulfilled the criterion of (1) or (3). Therefore, we used the second criterion for at high risk in the present study.

In this study, a β-blocker alone or the co-administration of a β-blocker and mexiletine was used for treatment. The reason for this administration is that, in a nation-wide study in Japan, patients with LQTS who showed life-threatening arrhythmia in the perinatal period and whose mutations were determined were mostly those with LQTS type 2 (LQT2) or LQTS type 3 (LQT3).²¹ In this Japanese series, a β-blocker and mexiletine were co-administered to 7 of 11 infants with LQT2 and to all 7 infants with LQT3.²¹ The clinical course of these patients was favorable.

Familial Study and Genetic Testing

In the first and second studies, thorough familial ECG recording and/or genetic testing was not mandatory. Therefore, the conducting of familial ECG screening and/or genetic testing was based on the judgment of the doctors.

Genetic testing was performed after obtaining written informed consent. In the first study, screening of causative genes for LQTS type 1 (LQT1) to LQT3 and types 5–7 (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and KCNJ2) was performed by polymerase chain reaction and direct DNA sequencing.¹⁹ Genes that were related to inherited arrhythmia syndrome, including LQTS, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome, were retrospectively screened for in infants at high risk or those whose parents asked for it. The test was performed by a targeted gene sequencing method using the HaloPlex Target Enrichment System (Agilent Technology, Santa Clara, CA, USA) and the MiSeq system (Illumina, San Diego, CA, USA). Detected variants were confirmed using Sanger’s method.²²

Presence or Absence of Symptoms (e.g., Cardiac Arrest and Sudden Death) During Infancy

The maternity institutes that collaborated with the present study were asked to provide any information on the health condition of infants who participated in the study. Additionally, 1 year after screening, questionnaires were sent to parents to ask the following: infant’s present health condition, and the presence or absence of syncope, convulsion, diseases, aborted cardiac arrest, or death.²³

Statistical Analysis

Differences in mean values were examined using Student’s t-test. To determine the optimal cutoff QTc(B) value, Youden’s index and the distance between the point (0,1) and the receiver-operating characteristic curve plots were used.²⁴ For the analysis, QTc(B) values at 1-month medical check were used. Statistical analysis was performed using IBM^® SPSS^® Statistics Version 23.0 (IBM Japan, Ltd., Tokyo, Japan). A two-tailed probability value <0.05 was considered statistically significant.

Results

Participants

Of 10,325 participants, 34 and 9 infants’ ECGs in the first and second studies, respectively, were excluded (Figure 1). Finally, ECGs from 10,282 infants were analyzed. ECGs of 12 infants with few ventricular premature contractions, 16 with few supraventricular premature contractions, and 2 with a small ventricular septal defect were included. Among 5 infants with Wolf-Parkinson-White syndrome who were excluded from the analysis, 1 had left ventricular non-compaction and experienced supraventricular tachycardia.¹²

Figure 1.

Flow chart of the participants and final subjects in the present study.

There were significant differences in the QT interval, RR interval, heart rate, and QTc(B) values between the first and second studies (all P<0.05, Table 1). However, the differences were small, and may have been due to the large number of participants.

Table 1.

Characteristics of the Infant Subjects

	1st study	2nd study	P value	Total
No of participants	4,285	5,997		10,282
Male/female*	2,150/2,041	3,017/2,978	0.33	5,167/5,019
Gestational age (weeks)†	(1,547) 39.2±1.3	(5,980) 39.3±1.3	0.11	(7,527) 39.2±1.3
Birth weight (g)†	(1,549) 3,008±381	(5,982) 3,026±382	0.21	(7,531) 3,022±382
QT interval (ms)	254±17	253±17	0.26	254±17
RR interval (ms)	381±39	379±40	0.002	380±40
Heart rate (bpm)	159±16	160±17	<0.001	160±16
QTc(B) values (ms)	412±19	413±19	0.02	412±19

*Sex was not described in 96 infants (94 and 2 infants in the 1st and 2nd studies, respectively). ^†Data of gestational age and birth weight were not mandatory in the first study. QTc(B), QT interval corrected by Bazett’s formula.

The frequency distribution of the QTc(B) values of infants at a 1-month medical check is summarized in Supplementary Table 1 and Figure 2.

Figure 2.

Distribution of QTc(B) of infants at their 1-month medical check. QTc(B), QT interval corrected by Bazett’s formula.

Infants With QT Prolongation and Their ECG Findings

A total of 11 infants showed a QTc(B) value ≥460 ms on 2 different ECGs during early follow-up. The prevalence of a pQTc was 4/4,285 (1 : 1,080) and 7/5,997 (1 : 857) infants in the first and second studies, respectively. The total prevalence of a pQTc was 11/10,282 infants (1 : 935; 95% confidence interval, 1 : 588 to 1:2,283). The distribution of the QTc(B) intervals of the infants is shown in Supplementary Table 1. Of these infants, 5 were diagnosed as being at high risk and medication was started (Table 2). The prevalence of infants at high risk was 2/4,285 (1 : 2,143) and 3/5,997 (1 : 1,999) infants in the first and the second studies, respectively. The total prevalence of infants at high risk was 5/10,282 infants (1 : 2,056; 95% confidence interval, 1 : 1,095 to 1 : 16,666). No infants with a pQTc, including those at high risk, experienced LQTS-related symptoms. Genetic testing was performed for all 5 infants at high risk, and showed 1 KCNH2 mutation (c.3065 delT, p.L1022PfsTer35) in these 5 high-risk infants.

Table 2.

Characteristics of High-Risk Infants With Prolonged QT Interval

Case no.	Age at sequencing (days)	QTc(B) at screening (ms)	Age at 1st visit (days)	Start of medication (days)	Pharmacotherapy		Cessation of therapy (mg/kg/day)	Last visit (years) (days or months)	Genetic testing by a targeted gene method (refer to the text)
					Propranolol (mg/kg/day)	Mexiletine
1	34	474	46	52	0.71	3.6	92 daysa	1.1	Performed but not determined
2	31	492	37	65	0.94	3.1	14 months	13.2	KCNH2- L1022PfsTer35
3	29	469	51	53	1.90	4.5	16 months	8.8	Performed but not determined
4	32	450	57	98	1.59	(−)	21 months	2.0	Performed but not determined
5	32	456	62	175	1.86	(−)	18 months	8.3	Performed but not determined

^aIn case 1, mild liver dysfunction (AST/ALT=67/50) appeared after starting medication (before medication, AST/ALT=36/18). The infant was followed without medication at 1-month intervals till 6 months old and at a 3- or 4-month intervals till 1 year old. QTc(B), QT interval corrected by Bazett’s formula.

The resting ECGs of the 5 infants at high risk showed that the peak of the T waves was present in the latter half of the T wave (Figure 3A). Additionally, all 5 infants showed prolonged QTc(B) values that exceeded 500 ms, and 4 of them also showed notched T waves on their Holter ECGs (Figure 3B). The infants at high risk showed an abrupt increase in their QTc(B) between 6 and 11 weeks after birth, except for 1 who showed an abrupt increase at 5 months (Figure 4A). Case 5 was followed up repeatedly, although he sometimes showed normal QTc(B) values (<0.45) because he showed prominent notched T waves during the follow-up. Infants who were not at high risk showed a plateau or a decrease during infancy (Figure 4B).

Figure 3.

ECGs at 1 month of age (A) and Holter ECGs during follow-up (B) of 5 infants who were at high risk and who all showed prolonged QTc(B) values >500 ms’ 4 also showed notched T waves (arrows) (B). QT intervals of 3 consecutive beats (white circles) were measured. Timing of the ECG recorded is shown in the left upper corner of each Holter ECG. QTc(B), QT interval corrected by Bazett’s formula.

Figure 4.

Changes in QTc(B) values in infants who were (A) at high risk and (B) not at high risk. Four of five infants who were at high risk showed an abrupt increase in QTc(B) values between 6 and 11 weeks after birth, and one infant showed an increase in QTc(B) values at 5 months of age (A). Infants who were not at high risk showed a plateau or a decrease in QTc(B) values during infancy (B). QTc(B), QT interval corrected by Bazett’s formula.

Follow-up of 5 Infants at High Risk

All 5 infants at high risk showed a decrease in their QTc(B) values to <0.45 by 1–1.5 years of life (Figure 5) and medications were stopped (Table 2). Cases 1 and 2 dropped out of the study after stopping medication. Case 2 was screened again through a school-based screening program at 12 years of age owing to the presence of notched T waves from leads V2 through V6 and a QTc(B) of 0.465 (Supplementary Figure 2A). His Holter ECG on the day of the hospital visit showed extremely prolonged QTc(B) values and medication was restarted (Supplementary Figure 2B,C). He was not screened through the screening program at 6 years of age. Unfortunately, his ECG at this age was missing. Cases 3 and 5 were followed from 1 year through 8 years of age; their QTc(B) values did not increase on resting 12-lead ECGs (0.416 and 0.356, respectively, at 8 years of age). Case 4’s medication was stopped at 21 months old. Her family moved out of the study area when she was 24 months old and her present QTc(B) value is unclear.

Figure 5.

ECGs after 1 year of age of the 5 infants who were at high risk. All showed a decrease in QTc(B) values to <0.45. QT intervals of 3 consecutive beats (white circles) were measured. QTc(B), QT interval corrected by Bazett’s formula.

Out-of-Hospital Cardiac Arrest (OHCA) at <1 Year

Among all participants, 5 infants experienced OHCA. The participating researchers in the present study obtained information about these OHCAs from the collaborating maternity institutes. Of them, 4 infants died, 3 of unknown etiology, and 1 of suffocation (Supplementary Table 2). All 5 infants showed a QTc(B) value <0.43 at a 1-month medical check, suggesting that the cause of their OHCA was probably not due to prolonged QT intervals.

Cutoff QTc(B) Values for ECG Screening at 1 Month of Life

To assess the diagnostic performance of each QTc(B) value in identifying the 11 infants with a pQTc, sensitivity, specificity, predictive values, Youden’s index, and the distance between the point (0,1) and receiver-operating characteristic curve plot were determined (Table 3, Supplementary Figure 3). Youden’s index and the distance showed that a cutoff QTc(B) value ≥0.45 was appropriate for screening infants with a pQTc for this population.

Table 3.

Sensitivity, Specificity, Predictive Values, and Calculation for the Optimal Cutoff Point of QTc(B) Using Youden’s Index and the ROC Curve

QTc(B)	Sensitivity	Specificity	PPV	NPV	Youden’s index	Distancea
0.45	1.0000	0.9915	0.1122	1.0000	0.9915	0.0001
0.46	0.7273	0.9991	0.4706	0.9997	0.7264	0.2727
0.47	0.2727	0.9999	1.0000	0.9992	0.2726	0.7273
0.48	0.0909	1.0000	1.0000	0.9990	0.0909	0.9091

Youden’s index denotes (sensitivity + specificity − 1). The largest is the best value. ^aDistance denotes the shortest distance between the point (0,1) and ROC plot, calculated as {(1 − sensitivity)² + (1 − specificity)²}^0.5. The smallest is the best value. NPV, negative predictive value; PPV, positive predictive value; QTc(B), QT interval corrected by Bazett’s formula; ROC, receiver-operating characteristic.

Discussion

The present study showed that the prevalence of infants with a pQTc and that of infants at high risk were approximately 1 : 1,000 and 1 : 2,000, respectively. Importantly, all 5 infants at high risk in the present study showed an abrupt increase in QTc(B) during early infancy, mostly between 6 and 11 weeks after birth. This time corresponds to the period of the highest values of QTc in the healthy general population and to the highest peak of sudden unexpected infant death. The cutoff QTc(B) value for screening infants with a pQTc was 0.45.

The prevalence of congenital LQTS was 1 : 2,000 in a previous cohort study with a large number of infants, and the data were mainly based on genetic testing in addition to ECG findings.¹¹ The present study showed that the prevalence of a pQTc was 1:935 when infants with a pQTc were defined as those whose QTc(B) was ≥0.46 on 2 different ECGs in early infancy. This prevalence is not high. A previous study in Italy showed that the prevalence of a QTc(B) ≥0.46 at least once between 15 and 25 days of life was 1 : 730 (59/43,080).¹¹ Another study showed that the probability of diagnosing LQTS was 1 : 988 in subjects aged 12 years according to the criteria of the Expert Consensus Statement of the Heart Rhythm Society, the European Heart Rhythm Association, and the Asia Pacific Heart Rhythm Society.²⁵ These data indicate that the prevalence of a QTc(B) ≥0.46 at multiple times during early infancy may be approximately 1 : 1,000.

Well-known diagnostic criteria for LQTS were published in 1993.²⁶ Thereafter, a QTc(B) criterion ≥450 ms has been used in the clinical setting for many years with a minor change (a QTc(B) at 4 min of recovery from an exercise stress test) in 2013.¹ In 2018, Stramba-Badiale et al. reported that a cut-off QTc(B) value of 460 ms was best for neonatal screening¹⁵ using 5,000 ECGs from a cohort of 44,596 healthy neonates.¹¹ There were no neonates with congenital LQTS whose QTc(B) values were <460 ms in their cohort, and thus this cutoff point was suitable for their population. In the present study, 2 infants showed a QTc(B) between 450 and 460 at a 1-month medical check-up (Table 2), and they showed a QTc(B) ≥0.46 on 2 different ECGs during follow-up. We believe that the cutoff value of 450 ms should also be used for neonatal screening, at least in Japan, as a well-known diagnostic criterion for LQTS. Researchers who want to perform neonatal screening are unlikely to choose the criterion of a QTc(B) ≥440 ms because the criterion of a QTc(B) ≥450 ms has been used to diagnose LQTS for many years, and the criterion of a QTc(B) ≥440 ms would screen many infants (598/10,282, 5.82% in the present study). Therefore, the criterion of a QTc(B) ≥450 appears to be best for neonatal screening. All 4 studies that performed neonatal screenings used the screening criterion of a QTc(B) >450 ms or ≥450 ms.^11–14 Finally, it should be stated that the premise of the definition of pQTc was that a QTc(B) value should be ≥450 ms on initial screening, and that this was not a study that examined the validity of values <450 ms, but was a comparison with ≥460 ms.

A definition for infants at a high risk of aborted cardiac arrest or sudden death has not been established. Therefore, concluding that infant ECG screening contributes to the eventual prevention of sudden death is difficult. Regarding risk stratification of patients with LQTS, Priori et al. classified patients with LQTS on the basis of the probability of a first cardiac event (syncope, aborted cardiac arrest, or sudden cardiac death) before 40 years of age and before therapy, and defined a probability ≥50% as “the high risk group”.¹⁷ One of their criteria of “the high risk group” was a QTc(B) of ≥500 ms.¹⁷ Hobbs et al. determined risk factors for aborted cardiac arrest or sudden cardiac death during adolescence, and found that a QTc(B) ≥530 ms was associated with a higher risk (adjusted hazard ratio, 2.3; 95% confidence interval, 1.6–3.3; P<0.001) than those who had a shorter QTc(B).²⁷ We also used a QTc(B) ≥500 ms to represent a high risk. Of the 5 infants at high risk, in case 2 there was a QTc(B) ≥530 ms including on Holter ECG (Figure 3B). He was rescreened thorough a school-based screening program at 12 years of age. His Holter ECG on the day of revisiting hospital showed a QTc of 567 ms by both Bazett’s and Fridericia’s formulae (Supplementary Figure 2B). This infant might have had strong potential for aborted cardiac arrest or sudden death, and he might have had a lower risk of life-threatening events with medication. The number of infants in the present study was 10,282. Therefore, this study suggests that life-threatening events could be prevented in 1 of 10,000 infants.

All 5 infants at high risk in the present study showed an abrupt increase in QTc(B) during early infancy. Of them, 4 showed an increase in QTc(B) between 6 and 11 weeks of life, which corresponds to the period of the highest QTc values (6–11 weeks after birth) during infancy in the healthy general population.⁶ This finding indicates that infants with a pQTc should be followed carefully during this time. Another infant showed an abrupt increase in QTc(B) at 25 weeks (5 months) of age, which suggests that infants with a pQTc may have an abrupt increase in QTc(B) values during the early half of infancy.

To implement population-based ECG screening, several issues need to be solved. (1) The number of cardiologists who are familiar with infant ECGs. Accurate measurement of the QT interval, even by cardiologists, may be difficult.¹⁰ Consequently, the distribution of QT intervals from different groups of clinicians is dissimilar.¹⁰ (2) Another concern is insufficient time to perform any sort of intervention from the time of ECG screening to the peak of unexpected sudden infant death at 1 or 3 months.⁵ A system with artificial intelligence-assisted ECG analysis might improve accurate measurement of the QT interval,²⁸ and such as system might also help screen abnormal T wave morphologies, which are characteristic of LQTS, and were also shown in the present study. (3) Creation of follow-up systems, including authorized cardiovascular institutions and psychosocial assistance to follow-up, are also required.

Study Limitations

Genetic testing was not mandatory. We aimed to screen infants with a pQTc to prevent them from experiencing LQTS-related symptoms and identify the prevalence of an ECG-determined pQTc. However, currently, genetic testing using next-generation sequencing is becoming increasingly available. Thorough genetic testing for infants with a pQTc will help determine their precise background, although genetic variants determined by next-generation sequencing technologies should be carefully interpreted.^29,30

Conclusions

There should be awareness of the genetically determined prevalence of LQTS (1 : 2,000) and ECG-determined prevalence of a pQTc in infants (≈1 : 1,000). In this study, all 5 infants at high risk showed an abrupt increase in QTc(B) during early infancy, mostly between 6 and 11 weeks after birth, which corresponds to the period of the highest values of corrected QT interval in the healthy general population and to the highest peak of sudden unexpected infant death. The QTc(B) cutoff value for screening infants with a pQTc might be 0.45 in this population, and the 0.45 value in this study is for screening for the present definition of pQTc, but not for screening of high-risk infants.

Acknowledgments

We are grateful to the many physicians and nurses in the 16 maternity institutes who contributed to this study and to the parents of the 10,325 infants who agreed to participate in this study. We express our gratitude to the Ministry of Health, Labour and Welfare of Japan for their funding of this study. We thank Ellen Knapp, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Sources of Funding

This work was supported by a Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare of Japan (H22-032, H24-033, H26-002, and H29-055).

Disclosures

W.S. is a member of the Circulation Journal’s Editorial Team.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0148

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