The Sudden Infant Death Syndrome and the Long QT Syndrome - is there a link?Sudden Infant Death Syndrome (SIDS), also known as 'cot death', is the leading cause of mortality in the first year of life after the first month. The typical history is that of an apparently healthy baby who is found dead in the cot shortly after a meal or early in the morning. The autopsy does not reveal an adequate cause for death. These deaths have devastating psycho-social consequences on the affected families. The cause of SIDS remains unknown despite a huge amount of theories proposed and, currently there is no preventive strategy. The only agreement concerns the fact that SIDS is multifactorial, ie., several different abnormalities may result in the sudden death of an infant. The greatest credit goes to abnormalities in respiratory and in cardiac mechanisms.

In 1976 I proposed that some of the SIDS deaths might have been due to a lethal arrhythmia facilitated by a prolongation of the QT interval, possibly secondary to an alteration in the development of right and left cardiac sympathetic nerves. The only way to test this hypothesis was that of performing an extremely large prospective study recording the ecg during the 3rd - 4th day of life and then following all the infants for one year. As some would have unavoidably died of SIDS it would have been eventually possible to compare the ECGs of the victims and of the survivors and observe potential differences in their QT intervals.

The study was performed: it did last 19 years and was published in June this year. We studied 34,442 newborns. One year follow-up data were available for 33,034 infants. There were 34 deaths, of which 24 were due to SIDS. The infants who died of SIDS had a longer QT interval corrected for heart rate (QTc) than did the survivors (435 45 vs 400 20 msec.P<0.01> and the infant who died for other causes (393 24msec). Moreover, 12 of 24 SIDS victims, but none of the infants who died, had a prolonged QTc (defined a priori as a QTc greater than 440 msec). As the procedure to correct the QT interval for heart rate may result in some error when dealing with infants who have fast rates, we also determined the actual value of the QT interval for similar lengths of the cardiac cycle and found again that 12 of 24 SIDS victims had QT values exceeding the 97.5th percentile for the study group as a whole. This allowed us to calculate the risk of SIDS for infants with a prolonged QT interval. This was found to be 41, and increased to the striking number of 47 for male infants. This means that a baby boy with a prolonged QT interval in the first week of life has 47 times greater probability of dying of SIDS compared to an infant with a normal QT. On the other hand, the actual risk of SIDS is relatively low, about 1 per 1,000 live births.

The unavoidable conclusion of this large study is that prolongation of the QT interval is a major risk factor for SIDS. The major practical implication of this study, based on the hard data presented, is that it becomes now possible - by performing an ECG during the first week of life - to identify a significant percentage of infants destined to die of SIDS. There are however two further issues. One is the cost-benefit ratio of performing routine ECGs in infants. Admittedly, a very large number of infants would have to be screened in order to identify the few at risk for SIDS. On the other hand, the association between QT prolongation and sudden death raises the logical possibility of potential efficacy of preventative treatment, for 7-8 months, with beta-blockers. Even here, 100 infants would have to be treated to (hopefully) save two. These are complex and troublesome questions, where financial reasons, lack of actual evidence on the effective prevention of SIDS by beta-blockers, and the tragedies of the affected families should all be weighed carefully.

Finally, why should the QT interval prolong in infants and how could this relate to the Long QT Syndrome. The first, unproven possibility, is that this could indeed be the result of a development imbalance in the sympathetic innervation of the heart; this would fit well with the epidemiological data which shows that after the 6th month of life SIDS becomes quite rare. The second, unproven possibility, stemming from the knowledge that the parents of the victims have a normal QT interval is that these may actually be unusual cases of LQTS. They would occur either because of a de novo mutation (ie., a mutation on one of the LQTS genes taking place during pregnancy) or because of the new evidence that in certain families affected by LQTS the parents may be 'silent' gene carriers (they 'carry' the disease but show no signs nor symptoms of it) while one of the offsprings shows the full blown disease with QT prolongation and sudden death.

There are several lessons to be taken from this study. One is that there are no short cuts in science and that sometimes it may take a painstakingly long study to either confirm or dismiss a scientific hypothesis in contrast with current views.

Peter J Schwartz M.D. Sads Scientific Advisor - Professor and Chairman, Department of Cardiology, Policlinico S, Matteo IRCCS, Pavia and University of Pavia, Italy.