Textbooks of all sorts should never be taken literally and with too much faith. A good example comes from the a respected American textbook of electrocardiography very much in use 50 years ago for the training of medical doctors1 in which one could read the following sentence: “The measurement of the QT interval has little usefulness.” Today, such a statement would not go by unchallenged.
The clinical prognostic importance of a prolongation of ventricular repolarization, ie, of the QT interval on the surface electrocardiogram (ECG), has been demonstrated in conditions quite different from infancy. A good example is represented by postmyocardial infarction patients and, more generally, by patients with ischemic heart disease.2,3 It is true, however, that one of the earliest evidences for the relationship between QT prolongation and risk for sudden death was indeed obtained in a newborn, a 44-day-old infant4 affected by the long QT syndrome (LQTS).
LQTS is a familial disease characterized by syncopal episodes or cardiac arrest triggered most commonly by physical or emotional stress, but sometimes occurring also during sleep and often culminating in sudden cardiac death. This grim natural history, with 50% to 60% of symptomatic and untreated patients dying suddenly within 12 to 15 years from the first syncope,5 has been radically modified by the introduction of antiadrenergic therapies, beta-blockers, and left cardiac sympathetic denervation.6,7 Twelve LQTS genes have been identified, and most encode cardiac ion channels.7 Diagnostic criteria have been proposed, modified, and are in current use.8,9 More about LQTS can be found in a recent review.7
We focus primarily on practical aspects related to the presence of QT interval prolongation in newborns, on why it is important to recognize these alterations early on, on what can be the consequences of this early identification or, conversely, the implication of not recognizing them in time. Finally, we discuss some socioeconomic implications related to the still controversial concept of widespread neonatal ECG screening. As to the apparently, and probably, very rare short QT syndrome,7 we do not discuss it here because it is very difficult to recognize in infants because of the already very short QT interval and because of the major uncertainty surrounding its management in asymptomatic infants.
Assessment of Ventricular Repolarization in the Newborn
Ventricular repolarization can be evaluated on the surface ECG by measuring the QT interval duration and by analyzing the morphology of the ST segment and of the T wave. Measurements should be done manually because, at the present time, the software for automatic measurement is not adequately accurate in the newborn. As a result of the fast heart rate of infants, the P wave may be superimposed on the T wave, particularly when the QT interval is prolonged, and in this case, the end of the T wave should be extrapolated by drawing a tangent to the downslope of the T wave and considering its intersection with the isoelectric line, although this procedure is not entirely accurate. The QT interval duration changes with rate and it is usually corrected (QTc) by the time-honored Bazett's formula. As recommended by guidelines for the interpretation of neonatal electrocardiogram of the European Society of Cardiology,10 for a reliable measurement of QT interval and heart rate correction in the newborn, heart rate should not be too slow (lower than 80 beats/min) or too fast (greater than 180 beats/min), because Bazett's formula loses accuracy outside this range. The upper normal limit of QTc is 440 ms, which represents 2 standard deviations above the mean of a large population of newborns.11 The measurement of the QT interval in an infant is never easy given the fast heart rate. We recommend performing it by using the mean of four to six measurement in Leads II, V5, and V6. We advise some training with verification of the values obtained and to follow the published Guidelines.8
Ventricular Repolarization Abnormalities in the Newborn
QT interval prolongation in the newborn may be acquired and some causes are similar to those responsible for ventricular abnormalities in children and in adults. Electrolyte disturbances such as hypocalcaemia, hypokalemia, and hypomagnesaemia, often encountered in infants who have had vomiting or diarrhea, and central nervous system abnormalities can produce QT prolongation. Several drugs commonly used in the neonatal period and during infancy such as macrolide antibiotics12 and trimethoprim may induce QT interval prolongation because they block IKr, one of the most important ionic currents involved in the control of ventricular repolarization. Neonates born from mothers with autoimmune diseases and positive for the anti-Ro/SSA antibodies may also show QT interval prolongation, sometimes with QTc values exceeding 500 ms, which tends to be transient and to disappear by the sixth month of life, concomitantly with the disappearance of the anti-Ro/SSA antibodies.13 Finally, and of special clinical relevance, some of the neonates with QT interval prolongation may be affected by congenital LQTS.
The Congenital Long QT Syndrome in the Newborn
LQTS, one of the leading causes of death in those younger than 20 years of age in developed countries, is a disease resulting from mutations of genes that encode for ion channels responsible for the control of action potential duration.7 LQTS is a familial disease, but more than 35% of cases are the result of de novo mutations, ie, the parents are not mutation carriers. Current therapies are very effective and have reduced the mortality from 50% to 60% to less than 2%.7,14 Of the patients who die, approximately 70% do so during their first arrhythmic episode; when this happens during the first year of life, in the absence of a family history of LQTS, the diagnosis is often sudden infant death syndrome (SIDS). In 1976,15 we hypothesized that some SIDS cases might be the result of lethal arrhythmias favored by QT interval prolongation. In a large prospective study on 34,000 neonates11 in which an ECG was performed on the third to fourth day of life, we demonstrated that 50% of infants who died with a diagnosis of SIDS had a prolonged QT interval. This did not imply the presence of LQTS but demonstrated that the risk of SIDS was increased by 41 times (P < 0.0001) in infants with prolonged QT interval.
Subsequently, we identified LQTS disease-causing mutations in a few anecdotal cases of SIDS and they represented “proof of principle.”16,17 More recently, in a case-control study18 on 201 cases of SIDS, we found a prevalence of LQTS disease-causing mutations of 9.5%. Because 20% to 25% of the patients with typical LQTS are genotype-negative, we currently estimate the likely probability of SIDS cases explained by LQTS to be close to 12% to 15%.
On the basis of these results, the Italian Ministry of Health considered the possibility of introducing, as part of the National Health Service, an electrocardiographic screening program in the first month of life with the objective of identifying infants affected by the LQTS to treat these babies and prevent sudden death in the first months of life and during childhood. For a careful evaluation of this program, the Ministry of Health asked for (and funded as a research grant) a large prospective study with the objective of assessing the feasibility and the results of this program. This study has been recently completed with the enrolment of 44,596 neonates.19
Prevalence of Congenital Long QT Syndrome
LQTS, like all other arrhythmogenic diseases of genetic origin, is considered rare, but its real prevalence has remained unknown until a few months ago. Rates ranging from one in 20,000 to one in 5000 have been reported, but these numbers are unfortunately not supported by actual data. Our large prospective ECG study in 3- to 4-week-old infants provided the first opportunity for a data-driven assessment of the prevalence of LQTS.19
The population under study included 44,596 neonates (43,080 whites), 22,967 males (51%) and 21,629 females (49%), consecutively enrolled by 18 Italian maternity hospitals from 2001 to 2006 in whom an ECG was recorded between the 15th and the 25th day of life. Whenever a QTc greater than 450 ms was found, the ECG was repeated within 1 to 2 weeks to confirm the initial finding. If QT prolongation was confirmed or any other ECG abnormality was identified, the infants were managed and treated according to the guidelines,10 and in the case of a QTc greater than 470 ms, a blood sample was taken from the neonate and from his or her parents for genetic analysis. Molecular screening was performed on KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, CAV3, and SCN4B genes. Toward the end of the study, it was decided to extend the genetic analysis to the infants with a QTc between 461 and 470 ms.
The 97.5th and the 2.5th percentiles, defining the upper and lower normal values, were 443 and 364 ms, respectively. The QT interval was considered prolonged according to the guidelines for the interpretation of neonatal ECG of the European Society of Cardiology.10 In 1094 neonates (2.5%), the QTc was greater than 440 ms, and in 858 (2.0%), it was between 441 and 450 ms. There were 177 infants with a QTc between 451 and 460 ms, 28 between 461 and 470 ms, and 31 with a QTc greater than 470 ms. Among these 31 neonates (one in 1438 [0.07%]; 23 females and eight males), four had a QTc greater than 500 ms (Fig. 1).
Molecular analysis was performed in 28 neonates with a QTc greater than 470 ms available during follow up. LQTS mutations were identified in 12 of 28 neonates (43%); eight were carrying heterozygous mutations on the KCNQ1 gene (LQT1) and four on KCNH2 (LQT2), thus confirming the higher prevalence of LQT1. Among the 14 neonates with a QTc between 461 and 470 ms for whom a blood sample was available, LQTS mutations were identified in four (29%); one infant carried a mutation on KCNH2, one carried two independent mutations on KCNH2 and KCNQ1, and the remaining two cases, a mutation on KCNE1 and KCNE2, respectively. Thus, overall, 16 of 42 (38%) newborns with a QTc greater than 460 ms carried disease-causing mutations of LQTS. Of note, of the seven neonates who had a QTc greater than 485 ms on the ECG, six were disease-causing mutation carriers.
QTc normalization at 1 year of life occurred in three of 16 genotype-positive (19%) and in 24 of 25 genotype-negative infants (96%) Importantly, the only genotype-negative child in whom QTc remained prolonged was one whose father also had marked QT prolongation and who was considered affected by LQTS on clinical criteria. Among the 14 infants whose QT interval remained prolonged at 1 year of life, a disease-causing mutation was identified in 13 (92%).
In all 16 cases with LQTS mutations, genetic analysis was extended to the parents and, whenever appropriate and possible, to other family members, and it allowed the identification of 42 of 82 mutation carriers (51%).
This prospective study clearly indicates that at least 17 infants (16 because of disease-causing mutations and one because of a clearcut clinical diagnosis) among this cohort of 44,596 neonates are affected by LQTS. All of them are white. This indicates a prevalence among whites of one in 2534 (95% confidence intervals, 1:1583-1:4350). Considering the possibility that among the nongenotyped infants with a QTc between 450 and 470 ms, there might be some LQTS mutation carriers, we suggest that the prevalence of LQTS may be closer to one in 2000, much higher than that suggested previously.
Implications for Management
These findings have important implications for the early detection and management of LQTS in the neonatal period and during infancy, but also in childhood and later life. Infants with a QTc greater than 460 ms in the first month of life and whose QT interval remains prolonged at 1 year have a greater than 90% probability of carrying a LQTS-causing mutation. In addition, whereas genetic screening should be performed immediately in all infants with a QTc greater than 485 ms, the normalization within 1 year for 75% of the infants with an initial QTc between 460 and 485 ms suggests, unless one of the parents shows QT prologation, postponement of the genetic screening for this group until the end of the first year of life. This simple measure will reduce both costs and unnecessary anxiety. Another important clinical implication is that the ECG screening would identify most of the neonates affected by LQTS and guide genetic screening, which would be essential for the diagnosis of many affected relatives, thus allowing effective preventive measures.
What should be done once an infant is identified as having an abnormally prolonged QT interval on at least two different ECG tracings? Our current policy, based on our own data and experience, is to initiate preventive treatment with beta-blockers in all those with a QTc exceeding 470 ms. Of note, this is a small number, approximately seven per 10,000 newborns. Because we are fully aware that 40% to 50% of them may have a normalization of the QT interval during the first year of life, and that more than 90% of these will be genotype-negative, at age 1 year, we reassess the situation and, with QTc normalization and in the absence of any suggestion for LQTS in the family, we progressively withdraw medical therapy. The rationale for treating these infants is obviously that of reducing the probability of a life-threatening event in the first year of life. It goes without saying that in case of persistence of QT prolongation or of identification of a disease-causing mutation, therapy will continue.
As to the type of beta-blockers to be used, we do not believe that beta-blockers are “all Indians of the same tribe.” Although we do not have a controlled study on which to base rigorous conclusions, we use exclusively propranolol and nadolol because, over the years, we have observed too many failures occur in patients receiving other beta-blockers, particularly metoprolol and atenolol. It is not always possible to practice “evidence-based medicine” and in this case we can only say, with adequate personal experience, that we would not treat our grandchildren, were they affected by LQTS, with beta-blockers different from propranolol or nadolol. The reasonable exception might be that of an infant with a diagnosis of asthma, in whom a more cardioselective beta-blocker might be considered.
This review is not aimed at the management of infants or children with LQTS who have already had cardiac events. These issues have been dealt with in recent studies.20-22 We just want to stress that infants who have sustained cardiac arrest in the first year of life are at a very high risk of recurrence and do not always respond well to therapy.20-22
Some of the data reported here are not without practical consequences. We have shown the following: 1) between 10% and 15% of the infants labeled as SIDS victims carry LQTS disease-causing mutations; 2) beta-blocker therapy is highly effective in LQTS and there are no data suggesting a lesser efficacy in still asymptomatic newborns; and 3) LQTS is relatively common with a prevalence of approximately one in 2000 live births. It happens more and more frequently17 that tissue from a “SIDS victim” is sent to a genetic laboratory for molecular screening. It also happens that the result from the laboratory is that the infant was actually affected by LQTS. Unavoidably, soon or later, the parents of these unfortunate infants will begin to ask “Why was I not informed about this possibility?” It seems fairly obvious that the same question could, and probably will, be asked also by the parents of a child or teenager who drops dead at school or playing ball or swimming and who is later found-through a molecular autopsy23,24-to have been affected by LQTS.
It is our view that the parents of any newborn have the right to be informed that: 1) there is a disease, present in approximately one infant every 2000 births, which can kill at any time in life, including the first year; 2) there are medical treatments that are extremely effective; and 3) that the disease can be diagnosed by a simple ECG. Failure to provide this information might be regarded as a guilty omission.
Cost-Effectiveness of Neonatal Electrocardiographic Screening for the Long QT Syndrome
One of the arguments against the introduction of neonatal ECG as a screening test for the identification of LQTS has been the possible excessive cost of performing such a program. Accordingly, a cost-effectiveness study with the primary analysis focused on the impact of identifying early the infants affected by LQTS has been performed.25 The study used Markov process analysis to forecast natural and clinical histories of subjects with or without screening. Monte Carlo simulations were used to simultaneously alter all the uncertain parameters (process-related probabilities and costs) by ± 30% to cover for any potential error and for intercountry variability. The main findings of this analysis are that by screening with the ECG for LQTS, the cost per year of life saved is 11,740 Euros. This study demonstrated that neonatal ECG screening is highly cost-effective and that a significant number of lives can be saved for an objectively small cost.
Recently, an estimate of costs related to the actual organization of a mass neonatal ECG screening in Italy has been performed. Taking into account all the expenses, including implementation of the screening program, equipment, and personnel, genetic tests in neonates with a prolonged QT interval and in their family members if positive, additional tests and therapies in affected neonates and family members, the cost per infant is 12 Euros. Thus, the introduction of a program for the early identification of LQTS to prevent sudden cardiac death in infancy, but also in childhood, based on the ECG as a screening test and genetic analysis in selected cases, would cost less than 6 million Euros per year, which corresponds to one part in 17,500 of the national healthcare expenditure of a large European country such as Italy.
It seems fair to quote an important statement by Bob Myerburg26 “… whether the cost of saving a young life exceeds the economic inefficiency of the screening tool will need to be determined by the people.” These same views were very cogently expressed in a recent editorial by Myerburg and Vetter.27
Times have changed and the evidence is compelling. To perform a widespread ECG screening in newborns can save many lives and avoid many unnecessary tragedies. Someone will have to take responsibility.
We are grateful to Ms. Pinuccia De Tomasi for expert editorial support.
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