Multifactorial pathophysiology: the “jigsaw” hypothesis

We also have to recognise that it is still not known, in spite of much research and speculation, how sleeping posture influences risk; indeed, one study from Victoria, Australia, examining ethnic variation and risk of SIDS, did not show sleeping position or cigarette smoking as having any influence on the risk of death.5 We remain ignorant of the pathophysiology of SIDS, although a defect in the neural control of breathing is viewed as an important possible mechanism. There is no reason that the cause of SIDS should not be multifactorial. I believe all infants are potentially vulnerable to sudden unexpected death, risk factors for this being as pieces of a jigsaw; only when the puzzle is complete will the baby die. According to this hypothesis, each baby has a different and unique jigsaw of risk factors and what we are doing by reducing the risk is to manipulate the pieces we know for the whole infant population, an approach that has met with remarkable success. Or, as Bergman has so eloquently put it: “SIDS is like a nuclear explosion where the critical mass must be obtained before the event is to occur.”6 Avoidance of risk factors prevents this critical mass being attained. To reduce the risk further, to try to shift the stubborn residuum of deaths, we need to identify other risk factors and, if possible, mechanisms of their action.

Prolongation of QT interval

It is against this background that the recently reported prospective study, by Schwartz et al from the University of Pavia, Italy, of the clinical association between prolongation of the QT interval in electrocardiographs (ECGs) of neonates and risk of later SIDS, is of particular interest.7 In this remarkable study, 33 034 ECGs taken on the 3rd or 4th day after birth from healthy babies born in 1976–94 were analysed to measure QT interval corrected for heart rate (QTc) and the babies followed for one year. During this period there were 34 deaths, 24 attributed to SIDS, an incidence of 0.7 per 1000 live births. Twelve of the 24 SIDS victims had a longer QTc interval (mean (SD) 435 (45) ms) than infants who were alive at 1 year (400 (20) ms) or who died from other causes (393 (24) ms). Half of the infants who died of SIDS had a prolonged QTc compared with none of the survivors or infants who died from other causes. The odds ratio for SIDS in infants with a prolonged QTc (> 440 ms) was about 41, significantly higher than the odds ratio for traditional factors such as prone posture and maternal smoking.

The QTc interval is a marker for ventricular repolarisation; prolongation of this interval, a developmental abnormality in cardiac sympathetic innervation, points to reduced cardiac stability favouring susceptibility to potentially lethal ventricular fibrillation. It is associated with death in some clinical conditions8 and in apparently healthy people.9 This is not the first time a cardiac arrhythmia has been postulated to explain SIDS10but, until now, substantial evidence has not been forthcoming. The QTc increases during the 2nd month of life, peaks between the 2nd and 3rd, and declines to birth values by about 6 months.11 Thus a tendency towards reduced cardiac stability closely parallels the known epidemiology of SIDS. Available evidence suggests that 30% to 35% of infants later to become victims of SIDS can be expected to have a prolonged QTc interval in the first week.7

What are the implications of these findings for paediatric practice, especially for the prevention of SIDS? There can surely be no justification to consider all newborn babies for routine ECGs on the 3rd or 4th day of life. The main drug treatment for prolonged QTc interval is β blockers and Schwartz et alpostulate that 100 infants would need to be treated to save the lives of two babies.7 Even if this were to be remotely successful, considering iatrogenic harm to the remaining 98 significantly weakens the case, let alone the enormous worry to families in revealing this diagnosis. But in babies with a family history of SIDS, prolonged QTc or other unexplained life threatening events, selective ECGs on days 3–4 of life could be taken with a view to treating those babies discovered to have a prolonged QTc for as long as it takes the QTc to return to normal. We will have to be guided by our cardiology colleagues for some of the answers to these difficult issues if effective preventive intervention is ever to be targeted for those particularly at risk.

QTc interval and stress

Let us make a lateral move and return to the increased risk of SIDS in families who live in a parlous state of serious social disadvantage containing the various elements of social adversity and personal stress I have previously alluded to. If we recognise that there will be babies born to these families who have a prolonged QTc, could it be that this vulnerability, under certain circumstances, might lead to a life threatening arrhythmia? Lethal arrhythmias associated with prolonged QTc interval are usually triggered by sudden increase in sympathetic activity.12 Does stress in a baby cause increased catecholamine release? We know infants undergoing heel stab blood tests cry, show facial grimacing, have an increase in baseline heart rate, and increased variability of heart and respiratory rate,13 14 features strongly suggesting increased catecholamine release associated with pain. Preterm infants receiving intensive care have been shown to have lower adrenaline concentrations when sedated with morphine.15 Studies in infant and adult rodents have apparently shown that the “innate fear paralysis reflex” produced by a range of frightening stimuli of the type that commonly occur in daily life transiently prolongs the QT interval and is associated with bradycardia and changes in the T wave.16 Visiting the homes of many SIDS victims often shows a picture of chaos, a smokey atmosphere, very poor housing, obvious social stresses, and a pre-existence of child abuse or drug abuse in the family (Davis P, personal communication, 1998). Expressions of this social dysfunction include irregular feeding, being left alone for long periods of time, infrequent changes of nappies, exposure to cold, poor hygiene, and haphazard sleeping routines. It is likely, therefore, that this type of home environment is a source of potential serious stress for the baby. Could it be that this stress is, on occasion, another piece of the jigsaw causing increased catecholamine release that increases the risks of cardiac arrhythmias where there is a prolonged QTc interval? We need to research how severe social adversity and its parenting consequences might stress the baby, along with its pathophysiological consequences. How encouraging, therefore, to discover that one of the new directions of research into SIDS, currently supported by the Foundation for the Study of Sudden Infant Death, is to look into wider issues of general infant care—especially in low income families at relatively high risk of SIDS.17 Ignorance of the influences of parenting on babies’ physiology should not prevent us from continuing to emphasise to parents the common sense of good, responsible, infant care. Babies must be fed regularly, changed frequently, sleep routines encouraged, not left alone for long periods, physical and emotional contact nurtured, as well as obvious issues of laying babies on their backs and avoiding smoking. They must be cherished, looked after with great care, and considered extremely vulnerable—a concept highlighted by Gantleyet al in their anthropological study of Bangladesh parents and infant caregiving practices in Cardiff, a population at particularly low risk for SIDS.18 A mismatch in a baby of a prolonged QTc with stress factors could increase Bergman’s critical mass, with its tragic outcome.

Is this stretching speculation too far? I believe no more so than many other hypotheses that have been proposed to explain sudden and unexplained infant death. No more than the empirical observations many years ago that simply putting babies to lie on their backs from the prone posture would significantly reduce risk. In 1984, in a study highlighting the rarity of SIDS in Hong Kong, I reflected that “influences of lifestyle and caretaking practices on risks of cot death were being underestimated in preference for more exotic and esoteric explanations”.19 I am still of this opinion and hope Schwartz et al’s studies will indirectly continue the momentum of researching the home environment in which young babies are nurtured at such a critical stage of their development. One consequence of this might be a continuing reduction in the risk of SIDS.