Sudden Infant Death Syndrome A Review of Literature

J. Forens. Sci. Soc. (1977), 17, 223.

Sudden Infant Death Syndrome A Review of ~iterature S. R. M. KENDEEL, and J. A. J. FERRIS* University Department of Pathology, Royal Victoria Injirmaty, Queen Victoria Road, Newcastle upon Tyne, England, NEl 4LP

A detailed review of current literature on the Sudden Infant Death Syndrome is given. Following an historical introduction, the epidemiology of SIDS and its aetiology and pathogenesis are comprehensively discussed. "And this woman's child died in the night; because she overlaid it" (1 Kings, Chapter 3 : 19). Although this first reference to sudden death in infants appeared many thousands of years ago, overlaying by an a d ' It remained the usual explanation for such deaths throughout the centuries ( are, 1841). I n 1892 Templeman reviewed 258 cases of alleged asphyxiated infants and concluded that overlaying was the main cause of death in these children. During the 19th Century, Paltauf (1889) observed that sudden death in infants was usually associated with an enlarged thymus gland. He argued that certain cases of sudden death in infants might be the result of abnormalities in the enlarged thymus and accordingly he published his theory of status thymicolymphaticus. This theory remained popular for several decades until Hammar (1906, 1926) and Boyd (1927, 1932) showed that the large thymus found in cases of sudden infant death was probably a normal gland. As a result, between 1910 and 1930, there was a gradual return to the view that external mechanical suffocation was the possible cause for cot death. The evidence for such a mechanism for death was almost entirely circumstantial and only rarely was an autopsy performed in such instances (Froggatt et al., 1968). Then late in the 1920's there was a shift in opinion regarding the aetiology of such deaths from external mechanical suffocation to pneumonia and other natural causes of death. This shift appears to have been the result of a change in the Coroner's law which made it the rule rather than the exception to perform a n autopsy in cases of unexplained infant deaths (Davison, 1945; Froggatt et al., 1968; Froggatt, 1970). This change was followed during the next two decades by a n exaggeration of the role of "pneumonia" and other infections. Pathologists often reported the cause of death in cases of sudden infant death as pulmonary infection even though they found only minimal respiratory changes. There may be many reasons for such an exaggeration. There are often no sure pathological grounds for diagnosing suffocation, and in order to avoid self reproach and further distress of an inquest, it has been convenient to report a natural cause for death in such cases (Barrett, 1954; Froggatt et al., 1968). As a result of this common practice, credibility was given to the theory of respiratory infection and this was further supported by earlier investigators who had isolated bacterial pathogens from the blood and the tissues of sudden infant death cases (Farber, 1934; Werne, 1942). The significance of these

b

*Present Address: Department of Forensic Pathology, Hamilton General Hospital, Hamilton, Ontario, Canada.

223

isolations of pathogenic bacteria was questioned, and by the mid 1940's, the theory of infection had been challenged from two directions. First by Abramson (1944) who disputed respiratory infection as the main cause for cot deaths. He called attention to what he referred to as the excessive number of infants under 1 year of age who were dying from accidental mechanical suffocation. The second challenge came from Carr (1945) who strongly supported the hypothesis of status thymic0 lymphaticus. Nevertheless, the infective theory received renewed support late in the 1940's and early 1950's when many investigators suggested that the histological changes indicated respiratory infection, possibly viral, although no significant viral or bacterial pathogens had been isolated (Adams, 1943; Werne and Garrow, 1947, 1953; Arey and Sotos, 1956). Only in the past few years have significant viral isolations been made, after considerable improvement in laboratory techniques (Ray, 1970; Ferris et al., 1973). After 1960, other aetiological theories for sudden infant death became popular. Prominent among them was the theory of "allergy to milk protein". The basic principle had been put forward by Barrett in 1954. He had reported that the majority of cases of sudden infant death were due to inhalation of regurgitated milk into the lungs and had suggested that death might result from shock rather than asphyxia. Parish et al. (1960a), following up Barrett's idea, introduced the hypothesis of anaphylactic shock due to inhalation of cow's milk proteins in hypersensitised infants leading to sudden collapse and death. This theory was based on experimental work on guinea-pigs carried out by Parish and his colleagues and their studies of serum antibodies to cow's milk proteins (Parish et al., 1960b). The theory has continued to receive relatively little support from other workers, as most have failed to find scientific evidence of a n allergy to cow's milk proteins, and many of the epidemiological observations cannot be explained by this hypothesis. Although in any sudden death, a lethal disturbance of cardiac conduction is a vital consideration (James, 1968), until recently, very few had pointed to the heart as a possible explanation for SIDS. James (1968) was the first to suggest that lethal dysrhythmias could be due to the consequences of developmental histological changes in the conducting tissue of the heart and that this might be the final common pathway in sudden and unexpected death in infancv. During the last 15 years, many international conferences and symposia have been held to discuss the problem of sudden deaths in infants. The first conference was in September 1963 at Seattle (Washington, U.S.A.). Many aetiological theories were discussed at this conference including that of milk allergy. The most significant conclusions were the international recognition of cot death as a separate syndrome and the stimulation of more comprehensive and detailed epidemiological and virological studies on the condition. Following that conference a t Seattle in 1963, a brief symposium was held at the American College of Cardiology in 1968. Three aspects of sudden infant death were discussed. The first paper was presented by Froggatt and he reported his initial results of the epidemiology of cot deaths in Northern Ireland. T h e second paper was that of Dawes on the cardio-pulmonary physiology of young mammals in which he discussed some possible cardio-respiratory mechanisms for sudden death in infancy. Finally, James presented his findinqs on the conducting system of human infant hearts and suggested how these might explain a terminal cardiac episode as the final common pathway for the sudden infant death syndrome. I n 1969, the second international conference on causes of sudden death in infants was held a t Seattle. Detailed discussion of the epidemiology, virology and some physiological considerations took place and among the results of the conference was the decision to use "Sudden Infant Death Syndrome" as a standard international terminology. The first British International Symposium was the "Sir Samuel Bedson

Symposium" held at Cambridge in April 1970. The participants of this symposium discussed various aspects of the epidemiology, the immunology, inborn errors of metabolism and the possibility of airway obstruction in respect of the aetiology of sudden infant death syndrome. I t was concluded that more research was needed in the areas of virology, immunology and the physiological development of the normal infant especially of the nasopharynx and the respiratory tract. At this symposium, the British Foundation for the Study of Infant Death was founded. As part of a post graduate course in paediatric forensic medicine, a small symposium was held a t Newcastle upon Tyne (England) in July 1971. The purpose of the symposium was to bring together people interested in different aspects of sudden infant death and attempt to put the "cot death syndrome" in a proper perspective within the wider field of infant mortality. The most recent international conference on this subject was held in May 1974 at Toronto (Canada) in memory of Francis E. Camps. Many new ideas were presented and discussed a t this symposium in the field of pathology and epidemiology as well as in the field of developmental physiology. Consideration was given to the problem of the deceased's family, of humanvalues and possible new directions for future research. This symposium saw the inception of the Canadian Foundation for the Study of Infant Death. Undoubtedly, a great deal of research into the sudden infant death syndrome was stimulated as a result of these conferences and symposia. Nevertheless, the question of SIDS remains unanswered. I n the summing up at the Toronto symposium, Professor Bain said "We have not solved the dilemma of the sudden infant death syndrome and we must keep an open mind as to the possibilities as well as the probabilities". EPIDEMIOLOGY Introduction Most of the comprehensive epidemiological research concerning sudden infant death syndrome has been carried out during the past 15 years. I t seems that such studies resulted from the recognition of the existence of the syndrome as an entity following the first International Conference on the cause of sudden death in infants held at Seattle in 1963. Very few detailed epidemiological studies are reported in the literature before that date. Nowadays, the scope of epidemiological studies has been enlarged to such a n extent that a prediction of' "infant at high risk" is being made a t certain centres (Prostestos et al., 1973; Carpenter and Emery, 1974). Incidence Before the first international conference on sudden infant death held in Seattle in 1963 it was very difficult to obtain an accurate estimation of the incidence of the sudden infant death syndrome. Almost all SIDS cases were recorded as infant dying as a result of accidental suffocation or respiratory infection, and in many centres these causes of death continued to be used for several years after the Seattle conference in 1963. As a result, any retrospective analysis of the causes of sudden infant death in different centres will produce a wide variety of results. For example, in Newcastle upon Tyne, there was no case of sudden infant death syndrome recorded as such before 1969. Different causes of death were given often depending on the practice of the individual pathologist. After 1969, with a steady increase in recorded cases of SIDS or cot death, it is interesting to note that there was a commensurate decrease in the number of infants reported to be dying as a result of other causes such as accidental suffocation or respiratory infection as, for example, acute bronchiolitis (Table 1). However, between 1963 and 1974 most of the centres studying the sudden infant death syndrome adopted a more or less similar

TABLE 1 RECORDED CAUSES O F DEATH I N INFANTS DYING SUDDENLY IN NEWCASTLE UPON TYNE Years Studied (inclusiue)

SZDS

Accidental Suffocation

Aspiration

Acute Pneumonia Bronchiolitis

Others

definition far the syndrome and as a result, the identification of the SIDS cases became more accurate. Riley (1970) reported that the syndrome accounted for approximately 10 per cent of total infant mortality and 37 per cent of total post neonatal mortality between 4-52 weeks of age in England and Wales. Similar figures were recorded by Froggatt et al. (1971) for Northern Ireland (Table 2). However, higher figures have been reported from Canada and Sweden probably due to a comparatively lower infant mortality in these countries. The incidence of this syndrome in England and Wales has recently been estimated at 1.4 per thousand live births (Gardner and Carpenter, 1974). A comparison of incidence between different centres is shown in Table 3. It can be shown that there is little variation throughout the United States of America and the figures are similar to those reported in Great Britain. The highest reported incidence comes from Canada (Steele, 1974) and from the USA among the non-white population (Bergman et al., 1972; Valdes Dapena, 1974) (Table 4). A possible explanation for the relatively low incidence in the TABLE 2 INCIDENCE O F SIDS I N RELATION T O INFANT MORTALITY IN GENERAL Author Riley (1970) Froggatt et al. (1971) Steele (1974) Fohlin (1974)

Place England and Wales Northern Ireland Canada Sweden

SZDS % of total infant mortality 10 11

20

SZDS % of post neonatal mortali[y 37 33 50

-

TABLE 3 INCIDENCE O F SIDS REPORTED FROM DIFFERENT CENTRES Year of Author publication Gardner and Carpenter 1974 Froggatt et al. 1971 1974 Fohlin Baak and Huber 1974a Fitzgibbon et al. 1969 Bergman et al. 1972 Valdes Dapena 1974 1974 Steele 1974 Tonkin

Incidence per 1000 live births Place England and Wales 1.4 Northern Ireland 2.8 Stockholm, Sweden 0.6 Netherlands 0.42 Minneapolis, USA. 1.2 King County, USA. 2.32 Philadelphia, USA. 1.92 Canada 3.00 Auckland. New Zealand 1.9

TABLE 4 INCIDENCE O F SIDS I N WHITE AND NON-WHITE AMERICANS Incidence per 1000 live births Author Bergman et al. Valdes Dapena

Year of publication 1972 1974

All infants 2.32 1.92

Whites 2.03 0.6

Non- Whites 5.64 3.64

Netherlands and in Sweden might be a significantly higher standard of preand post-natal care associated with low post-natal mortality as compared with other countries.

Sex Most published series show that males are more often involved than females (Froggatt et al., 1972; Bergman et al., 1972; Carpenter, 1972; Fohlin, 1974; Tonkin, 1974). Table 5 shows the comparative results from these studies. One of the exceptions to these reports is the work of Banks (1965) in which more females were affected than males. However, Banks concluded that the difference was not statistically significant. This male predominance may be partly explained by the larger number of male infants at risk (Froggatt et al., 1968; Marshall, 1972) and by the higher overall male mortality which is part of the general decrement of the male compared with female from the time of conception (Froggatt et al., 1968). A true sex factor may exist, but if so it is slight (Froggatt et al., 1968). Age Distribution The syndrome has a characteristic age distribution regardless of sex. I t is basically limited to the first year of life (Riley, 1970; Froggatt et al., 1971; Bergrnan et al., 1972; Tonkin, 1974). Table 6 shows that more than 78 per cent TABLE 5 MALEIFEMALE RATIO IN SUDDEN INFANT DEATH SYNDROME Author Place Froggatt et al. (1971) Northern Ireland King County, USA Bergrnan et al. (1972) Carpenter (1972) England and Wales Fohlin (1974) Sweden Tonkin (1974) New Zealand *excluding negroes and indians.

-

Male 95 3* 127 34 58

Female 67 2* 100 19 28

TABLE 6 NUMBER AND PER CENT OF SIDS LESS THAN 6 MONTHS OF AGE REPORTED IN DIFFERENT CENTRES.

Author Riley (1970) Froggatt et al. (1971) &rgman et al. (1972) Tonkin (1974)

Total Number of SIDS Place studied England and Wales 250 Northern Ireland 162 170 USA 86 New Zealand

Number of SIDS % of SIDS less than 6 less than 6 months of age months of age 198 79 127 78.4 160 93 80 93

of the cases occurs during the first 6 months of life. The age distribution of SIDS cases has a clearly defined peak at 2 to 4 months (Figure 1) and rarely affects infants of less than 4 weeks of age (Froggatt et al;, 1971). Physiological developmental changes, probably cardio-respiratory, have been incriminated as the possible cause of such striking age distribution in sudden infant death syndrome (Dawes, 1968; Wedgewood, 1972). However, there is no satisfactory explanation for the apparent protection of infants in the first 4 weeks of life and this cannot be completely explained by masking by other perinatal problems or congenital abnormalities (Ferris, 1975).

Seasonal variation Banks (1965) reported a peak incidence of SIDS in England and Wales 227

4

8

16

24

32

40

48

52

AGE (WEEKS)

Figure 1.

Comparison of age distribution of Sudden Infant Death Syndrome in different areas of study.

during winter months. This observation was supported by Froggatt et al. (1971) who found that SIDS cases were commonest in colder months and rarest in warmer months. Bergrnan et al. (1972) observed more cases in winter than in summer when the data for several years of the study were pooled. However, great variations were observed from year to year with respect to any given month. A similar observation was recorded by Steele (1974) and Tonkin (1974). This seasonal variation of the incidence is very similar to that of respiratory viral infection (Froggatt et al., 1968; Houstek, ,1970; Carpenter, 1972).

Time of Day Valdes Dapena, in her review of the literature in 1967, pointed out that all investigators who have studied the hour of the day at which these deaths would seem to have occurred, agreed that a great majority of these infants died between midnight and 6 a.m. Froggatt et al. (1971) reported that 50 per cent of their cases died between midnight and 8 a.m., 36.4 per cent between 8 a.m. and 4 p.m. and only 13.6 per cent between 4 p.m. and midnight. Houstek (1970) divided the day into 6 hour periods and from midnight reported a time 228

distribution of 43 per cent, 29 per cent, 13 per cent and 15 per cent respectively (Figure 2). O n the other hand, Bergman (1970a) who compared the times at which the infants were found dead reported that 74 per cent of SIDS were discovered between 6 a.m. and 12 noon, mostly between 7 a.m. and 9 a.m. which corresponds to the usual time of parental awakening. He also recorded that 16 per cent were found dead between noon and 6 p.m., 6 per cent between 6 p.m. and midnight and only 4 per cent between midnight and 6 a.m. Bergman pointed out that the striking feature of his study was that not one SIDS was observed to die. I n other words, every single case was discovered lifeless, implicating sleep as a necessary. component of the syndrome. This observation was supported by Tonkin (1974) in her study of sudden infant death syndrome in New Zealand. Bergman (1970b) concluded that sleep could alter the "set" of automatic control centres. Probably many sleeping infants come close to the trigger all the time, but such a process must be reversible up to a certain point. Socio-economic and Maternal Factors Carpenter and Shaddick (1965) stressed the importance of a poor home background in cases of sudden infant death syndrome. They found 18 per cent of their cases illegitimate as compared with 8 per cent of control children. There was evidence of overcrowding and in 14 per cent of cases the mother was under the age of 20 years compared with two per cent of the controls. Carpenter and Shaddick also noted that the general standard of mothering was poor. Similarly, Froggatt et al. (1971) reported a high incidence of SIDS cases among underprivileged children, while Bergman (1970a) noted a predominance of SIDS among lower socio-economic class families as measured by income, occupation, status of housing and class of neighbourhood. This apparent

Midnight

Figure 2. The time of death in cases of SIDS (Froggatt and Houstek) and the time of discovery of death (Bergmanl.

229

significance of low socio-economic status was supported by Steele (1974) who reported a higher incidence of SIDS among illegitimates, lower socio-economic class families, non-whites regardless of the socio-economic level and in poor living conditions in general. However, babies living under ideal conditions are not immune from the sudden and unexpected death syndrome (Riley, 1970). Good homes and homes where the standard of mothering was described as excellent were also involved (Carpenter, 1972). Steele and Langworth (1966) observed that mothers of the affected infants had several significant differences from mothers of control infams. They described the former as younger at the time of marriage, younger a t the time of the first pregnancy and younger at the time of delivery of the infant under study. SIDS families were noted to be associated with a n increased rejection of health visitors and a reduced use of community welfare services (Emery and Carpenter, 1974). I t was reported by Prostestos et al. (1973) that the single most powerful criterion for identifying high risk children was whether or not, having been given a clinic appointment on discharge from the maternity hospital, the appointment was kept. Only 44 per cent of the cases kept the appointment compared with 85 per cent of controls. This factor probably represents a n accumulation of several other factors.

Birth Weight and Period of Gestation A higher incidence of sudden infant death syndrome have been reported among the prematures as identified by their birth weight or by their period of gestation (Steele, 1974). Many other workers in this field have expressed the view that prematurity was a general risk factor in SIDS (Wedgewood, 1972; Emery and Carpenter, 1974). The term "prematurity" used in this paper refers to birth weight of less than 5 lb or to a gestational period of less than 37 weeks. Recently, different terms have been used to describe such conditions, i.e., "short gestation" for infants whose weights are normal for their gestational age but who are born a significant period before term. The other term in use nowadays is "low birth weight" for infants who are small for their gestational age. Bergman et al. (1972) found a marked preponderance of low birth weight babies in their series, the incidence of SIDS in infants weighing 3.5-4 pounds at birth was 10 times more than those weighing 7.5-8 pounds. However Bergrnan and his colleagues found that premature infants tended to succumb at the same age as the full term infant, thus excluding any significant difference in post-natal maturation and development. Coe (1963) reported that 15 per cent of his cases were premature compared with an 8.4 per cent incidence of prematurity in the community as a whole, and these figures were supported by Steele and Langworth (1966) who found that 16.2 per cent of his cases were premature compared with 6.4 per cent of his controls. O n the other hand, although Cameron and Asher (1965) reported that 16 per cent of their cases of SIDS were premature, they pointed out that their figure was not significant as the incidence of prematurity in total infant mortality was 22 per cent. Similarly, Houstek (1970) reported 14.5 per cent prematurity in his SIDS and an incidence of 4-7 per cent prematurity in the community as a whole. He found also that 21 per cent of total infant mortality involved premature babies. It is interesting to note that while Froggatt et al. (1971) concluded from their series that birth weight may correlate with sudden infant death syndrome, but that this was not an importadt determinant factor, Prostestos et al. (1973) concluded that SIDS babies were significantly. lighter than controls and on average, they were born a few days earlier. Type of Feeding Banks, in his report in 1965, reported that only 5 per cent of SIDS were 230

completely breast fed a t the time of death compared with 9 per cent of controls. However, Carpenter and Shaddick (1965) reported that 56 per cent of the affected infants were fully breast fed during the first 2 weeks of life compared with 70 per cent of the controls during the same period of their life. Similar studies in other countries have yielded more or less similar results. Houstek (1970) reported that 6-37 per cent of his cases were fully breast fed at the time of death. Tonkin (1974) mentioned that only 4 per cent of her SIDS were breast fed a t the time of death while 45 per cent of her controls were breast fed at the age of 2 weeks and 25 per cent at the age of 3 months. Bergman et al. (1972) noted that in 61 per cent of their cases, cow's milk was the sole source of milk from birth and 26 per cent of the cases received predominantly breast milk with some supplement of cow's milk, while 8 per cent of the cases were given mostly cow's milk with occasional breast milk. While Bergman et al. concluded that the feeding patterns of affected infants were parallel to those of other children in the community, Steele (1974) and Tonkin (1974) concluded that there is a significant association between artificial feeding and the sudden infant death syndrome.

Sleeping Position There is no significant difference between the usual sleeping position of SIDS cases and the sleeping position noted at the time of discovery of their death (Froggatt et al., 1968). Bergman (1970a) found that most of affected babies were put to bed and found dead on their abdomen, which was the usual sleeping position of most control children. Carpenter and Shaddick (1965) concluded that the syndrome was significantly associated with soft pillows. However, Bergman et al. (1972) found that 95 per cent of the cases had no pillow on their bed. Multiple Births Sudden infant death syndrome is frequent among twins, equally so for males and females and in uniovular and binovular pairs. When both twins have been victims of the syndrome, their deaths have usually been contemporaneous (Geertinger, 1968; Froggatt et al., 1971). The incidence of the syndrome among multiple birth babies is usually higher than among singletons (Carpenter and Shaddick, 1965; Kraus and Borhani, 1972). For England and Wales, this incidence is 2.2 per 1000 live multiple births compared with 1.4 per 1000 live births for all infants (Carpenter and Shaddick, 1965; Gardner and Carpenter, 1974). This higher incidence among twins may be explained by their relatively low birth weight. Twins may also succumb as a result of cross transference of some common bacterial or viral infection. History of Illness Prior to Death Many of the affected infants had a history of mild illness, especially of the respiratory tract, and to a lesser degree of the gastrointestinal tract during the last week or two of their life (Adelson and Kinney, 1956; Carpenter and Shaddick, 1965; Froggatt et al., 1971). I n 63 per cent of the cases reported by Adelson and Kinney (1956) a history of mild illness during the last 48 hours pribr to death was obtained. Furthermore, 68 per cent of the cases of Carpenter a ~ Shaddick d (1965) had a history of respiratory illness during the last two weeks of their life compared with 32 per cent of controls. I n the Froggatt et al. series, during the week prior to death, 40 per cent were allegedly symptom free, 29 per cent had some minor symptoms not requiring a doctor, and in 31 per cent medical advice was sought. Comparable figures for controls were respectively 85 per cent, 3 per cent and 12 per cent (Froggatt, 1970; Froggatt et al., 1971).

Summary of Principal Epidemiological Factors The sudden infant death syndrome is a disease characteristically affecting male and female infants of less than 1 year of age, with a peak incidence occurring between the ages of 2 and 4 months. The syndrome has an incidence rate of 0.42-3.0 per 1000 live births world wide. A high incidence is reported among twins, non-whites, premature babies and in illegitimacy. There is also a higher incidence during the colder months of the year, among families with a low socio-economic status, and in poor living conditions in general. The syndrome appears to be associated with sleep and with artificial feeding. The mothers of affected infants are usually young with poor prenatal health, diet and unsatisfactory post natal care. Finally, the syndrome is usually preceded by a history of an apparently mild illness during the 2 weeks prior to death. AETIOLOGY AND PATHOGENESIS Introduction Sudden Infant Death Syndrome is a disease remarkable for its lack of pathological findings (Wedgewood, 1972). I t is generally agreed that a satisfactory explanation can be found a t autopsy for only 15 per cent of the sudden unexpected deaths in infancy and that 85 per cent remain unexplained (ValdesDapena, 1967) and this group comprises the true SIDS cases. However there are recent studies on SIDS reporting the presence of microscopical pathology sufficient to cause death in the majority of cases investigated (Cameron and Watson, 1975). McWeeny and Emery (1975) recorded that a t least a quarter of the babies dying unexpectedly at home (cot deaths) do so from recognisable diseases. This difference in the number of the explained sudden and unexpected deaths in infancy might be due to the difference in the definition and the criteria for the selection of the SIDS cases adopted by different scientific workers. As a result, many theories have been put forward to explain the aetiology and pathogenesis of the sudden infant death syndrome. Some investigators believed that one single mechanism was responsible for the syndrome, while others attributed the syndrome to multiple causes which were still unrecognised (Valdes-Dapena, 1967; Raak and Huber, 1974b; Valdes-Dapena et al., 1976). Unfortunately, none of theye theories has gained a world wide acceptance, as most of them are based on the study of single or small groups of cases and they also lack conclusive evidence concerning the fundamental processes underlying the conditi~n(Ferris et al., 1973). The following review covers most of the important hypothese.; in respect to the pathogenesis of SIDS whlch appear in the literature.

Asphyxia There are several ways in which asphyxia might cause sudden death in a healthy infant as, for example, in cases of mechanical obstruction of the air passages whether externally by any object or internally by inhalation of regurgitated food. Mechanical Suffocation Accidental si~focation b y pillows and bed clothes. Barrett (1954) described the possible sequence of events for this mechanism of death in SIDS. He reported "Newborn infants are usually unable to turn over unaided, but as they grow in strength, they become more adventurous. As a result of an ambitious excursion, an infant may end up with its face buried in the pillow. If the pillow is soft, and the obstruction to respiration is partial, the baby might not become alarmed immediately, then, as in carbon monoxide poisoning, anoxaemia

might develop insidiously; sleep might pass into anoxaemic coma, and anoxaemic coma into death". I n support of this theory, Banks (1965) concluded that the sudden infant death syndrome was significantly associated with the use of soft pillows. However, in 1968, Emery and Thornton observed that there was a wide variation in the obstruction to air flow in pillows of different designs. They found that a firm pillow which allows air and fluid to pass through, was the best. Although this theory could account for the rarity of the cases during the first months of life and the association with sleep, other epidemiological observations can not be so explained. For example, the increased incidence during winter, the rareness of the condition after 1 year of age and its strict age distribution with its peak at 2 to 4 months, the higher incidence among twins etc. Besides, there was no significant difference between normal sleeping position and the sleeping positions in which these infants were found dead (Froggatt et al., 1968). I n addition to that, 95 per cent of the cases reported by Bergman et al. (1972) had no pillow on their bed. Woolley, in 1945, did experimental work in this field. He analysed the atmosphere breathed by infants covered in various ways by different types of bedding. He was only able to demonstrate a reduction in oxygen or increase in carbon dioxide afier the addition of a rubber sheet, secured tightly a t each border. The infants under ordinary bedding showed no discomfort until sufficient time had elapsed for heat and humidity to build up. The author also attempted to induce anoxaemia by having the subjects sleep with nose and mouth closely approximated to their mattresses and pillows, but here again he was unsuccessful since the smallest child was capable of rolling to obtain an airway and the larger children were generally out of accord with position. I n 1950, Bowden concluded that to a certain extent a healthy baby can take care of himself and if ordinary care is taken in putting the baby to bed there is, in his opinion, virtually no risk of accidental suffocation from bed clothes. This conclusion is supported by the author's own observations. Similarly, Adelson and Kinney (1956) pointed out that in their opinion, an ordinary child can not be smothered by ordinary bed clothes. Lastly, during the last 3 decades there has been an increasing number of reports showing series of cases from different parts of the world in which no evidence to support the theory of mechanical suffocation by pillows and bed clothes has been found (Davison, 1945; Bowden, 1950; Adelson and Kinney, 1956; Arey and Sotos, 1956). Accidental suffocation b y overlaying. Abramson (1944) recorded the possible mechanism of accidental sufocation and death in infants by overlaying, he reported, "Accidental death was brought about by occlusion of infant's nose and mouth either by the breast or by one of the upper extren..ities of the mother who had fallen asleep. Occasionally, the infant was wedged in between both sleeping parents". Many forensic pathologists nowadays believe that a normal sleeping adult will be aroused by the struggles of an "overlain" infant before suffocation occurs unless the adult be inebriated 01 under the influence of drugs (ValdesDapena, 1967; Ferris, 1975). So, if overlaying results in accidental suffocation of an infant, it cel tainly accounts for a very small proportion of infants who sleep with their parents. Also an infant may die suddenly and unexpectedly from natural causes or disease when he is in bed with his parents (Bowden, 1952; Ferris, 1975). Sufocation by inhalatio+z of regurgitated food. I n the published series of SIDS by Cameron and Asher in 1965, the authors reported that aspiration of vomit was found at autopsy in 48 out of 97 cases. Like any other material, the authors concluded, aspirated vomit may cause fatal respiratory obstruction hy occludinq the respiratory passages or by causing obstruction spasm of the bronchi. Nowadays, most pathologists think that the mere presence of regurgitated

gaterial in the trachea and bronchi plays no part in causing death and may have entered the airways during the agonal period or after death (ValdesDapena, 1967; Marshall, 1970; Ferris, 1975). Nasal infection and obstruction. Shaw (1968, 1972) suggested that nasal obstruction in an infant less than 6 months of age who is unable to establish respiration through its mouth, may be a cause of the sudden infant death syndrome. In 1972, Cross reported more details about the role of nasal infection in respect to the pathogenesis of SIDS. The important points recorded by Cross in favour of this hypothesis can be summarised as follows: 1. There should be evidence of a sudden nasal infection 2. Babies are obligatory nasal breathers 3. The reaction of babies in upper respiratory tract obstruction is physiologically different from adults (with increasing respiratory obstruction, respiratory rate remains unchanged, but the tidal volume decreasesthe reverse of what h a ~ ~ e in n san adult) I 4. A cool environment increases the oxygen requirement of a baby 5 . In a cool environment the hyperventilatory response for hypoxia is not maintained 6. Consequently, with increased metabolic demand and diminished ventilation, lethal asphyxia might well arise without crying or actual obstruction (Cross, 1972). As a matter of fact, neither Shaw nor Cross have reported finding any objective evidence at post mortem of SIDS cases to support this theory of nasal infection with or without obstruction. Most of the evidence which Cross (1972) put forward to support his hypothesis was actually derived from experimental work (respiratory function tests) carried out on neonates. Since it is recognised that the peak incidence of S I D S occurs between 2 to 4 months of age and that the syndrome is rare during the neonatal period, respiratory function tests may produce different results if they are done in different infant age groups as, for example, in the neonatal period and the 2-4 months age group. Also, not all infants are unable to breath orally, obligatory nasal breathing appears to exist in about 30 per cent at 3 months of age (Shaw, 1972), so unless obligatory nasal breathing has been recognised before death, it is not possible to be sure that any particular infant who died suddenly and unexpectedly was unable to breath through his mouth when his nose became obstructed. On the other hand. one should exDect a higher incidence of the syndrome as a result of the high percentage of infants who get minor respiratory infection and nasal obstruction especially during cold months. Atresia of posterior nares. This theory of asphyxia due to atresia of the posterior nares was put forward by Beinfield (1959) who reported, "If a bilateral obstruction of the posterior nares will cause suffocation, a un~lateralobstruction due to atresia will produce the same result, when under favourable conditions it is converted into a bilateral obstruction". Although this theory was supported by Canby (1962), in the many published series in which a thorouph t examination of the cases was Der" ~ o s mortem formed, no single case was encountered with this anomaly (Valdes-Dapena, 1967). I t is very unlikely that sudden total nasal obstruction in a child in the age group of 2-3 months would within a matter of hours cause death (Evans, 1972). Choanal atresia if it accounts for sudden death, would be expected to cause asphyxia early in life and not a t the age of 2-3 months when sudden infant death syndrome occurs (Shaw, 1968). Lacyngospasm. At the second Seattle conference in 1969 on causes of sudden infant death, Bergman and his colleagues proposed their theory of la~yngospasm as a possible terminal event in respect of the pathogenesis of sudden infant death syndrome. They stated, "The strict intrathoracic distribution of petechiae in sudden infant death syndrome argues most compellingly for the concept that at least agonally intra-thoracic negative pressure is markedly I

1

elevated, and this provides strong evidence of high airway obstruction as the dgonal episode in most such cases. There are certain factors which make the infant more or less eligible, such as prematurity or the presence of respiratory infection. A chain of events, each possessing its own probability factor m a t occur a t the same instant to trip the switch and throw the infant into the final common pathway which terminates with laryngeal spasm. I n other words, if all the factors such as autonomic instability, sleep respiratory inflammation and head position come together a t the same instant, the threshold is reached and laryngospasm occurs and results in asphyxia and death" (Bergman, 1970b). As a matter of fact, 10 years before this conference Handforth (1959) had suggested that respiratory arrest produced by temporary laryngospasm or bronchospasm due to infection may cause sudden death in infancy. This suggestion was based on experimental work on rats. I t had been shown that it is- possible to produce fatal respiratory arrest in rats by temporarily blocking the airway. Again there is no actual evidence suggesting that spasm of the larynx or bronchi has occurred in the victims of the syndrome. As regards the intrathoracic petechiae, the question is whether or no-c intrathoracic distribution of petechiae occur only in elevated intrathoracic negative pressure as a result of upper respiratory tract obstruction? Recent experiments on rats showed, contrary to Handforth's experimental rewlts in 1959, that with abrupt and uninterrupted occlusion of the upper respiratory tract, intrathoracic petechial haemorrhages appeared only in 7 per cent of the animals used in the experiment, while hypoxia without obstruction (breathing in 100 per cent nitrogen) resulted in the appearance of intrathoracic petechiae in 80 per cent of the animals (Guntheroth et al., 1973). Sleep Apnoea Steinschneider (1972, 1974) suggested that prolonged sleep apnoea, which is a formal physiological process, results in sudden infant death syndrome. He concluded that infants with prolonged sleep apnoea can die suddenly and the autopsy findings in such infants might allow for the diagnosis of SIDS. He argued that the fundamental issue is not whether prolonged sleep apnoea is the mechanism of death in some infants who die of SIDS, but rather whether or not this mechanism is responsible for the majority, or all of the deaths due to SIDS (Steinschneider, 1974). Steinschneider's hypothesis was based on 2 sets of studies. The first one involved 5 infants who were referred to him a t the age of 1 month because of their cyanosis of undetermined aetiology. The laboratory sleeping studies on these infants revealed frequent periods of a p o e a (less than 2 seconds) which decreased in amount after a certain age and were most frequent during REM (Rapid Eye Movement) sleep. All the infants had a number of prolonged apnoeic and cyanotic episodes (more than 15 seconds) during sleep, mostly in conjunction with upper respiratory tract infection. Subsequently, two infants died and no cause of death was found at autopsy. Steinschneider (1972) concluded from these results that prolonged sleep apnoea is part of the final pathway resulting in sudden death. The number of infants involved in these studies is too small on which to build any firm conclusions. Also, the two infants who died, had a history of cyanosis which is rarely obtained from cases of sudden infant death syndrome. The second set of sleep studies performed by Steinschneider involved a larger number of apparently normal infants including some prematures (birth weight less than 4 lb). These infants were observed up to six months of age. The results of the previous laboratory sleep studies were confirmed and it was found that the frequency of apnoeic episodes reached its peak at the age of 3 weeks and then it decreased gradually with age (Steinschneider, 1974). If one assumes that apnoeic episodes are "near misses" and could result in SIDS (Steinschneider, 1974) one should expect the peak of SIDS incidence to occur

at the age of 3 weeks, while, in fact, the peak of SIDS incidence occurs at the age .of 2-4 months and it is very rare for SIDS to happen during the first 4 weeks of life. Finally, although most of the infants observed in these studies had prolonged sleep apnoeic episodes and many of them had upper respiratory tract infection which could have prolonged the apnoeic episodes, nevertheless, none of them died. This means that there are other factors irtvolved besides the prolonged sleep apnoea and the upper respiratory tract infection in order to result in sudden infant death syndrome.

The Infection Theory General Since 1934 many articles have appeared in the literature suggesting that infection miqht be the cause of death in cases of sudden infant death syndrome. The first published study in this respect was that of Farber (1934) who investigated 2 case$ of SIDS and was able to isolate Streptococcus haemobticu~ bacteria from heart blood. He concluded that at least some cases of SIDS were the result of overwhelming streptococcal infection. Then in 1942, Werne published his study of 50 case5 of unexpected death in infancy. He reported the presence of what he described as bronchitis, peribronchitis and peribronchial pneumonitis in the majority of cases. These pulmonary findings in conjunction with positive post mortem bacteriological results of doubtful pathogeneity and significance led Werne to conclude that acute infection was the cause of death in these cases (Werne, 1942). Similarly, Adams (1943) reported a study of 3 cases of sudden death in infants on whom autopsies revealed marked interstitial mononuclear pneumonia associated with diffuse pulmonary oedema and haemorrhage~.He concluded that these pulmonary changes might result from viral infection although no viral agent was isolated. He further suggested that this kind of infection might be responsible for other cases of sudden death in infants. Two years later, in 1945, Davison of Birmingham reviewed 318 cases of sudden unexpected death in infancy. He found that acute infection, whether respiratory or not, was the cause of death in 270 cases of his series. As a result, he suggested that acute infection might be the principal cause for sudden and unexpected death in infants. Werne and Garrow (1947, 1953) provided further support for the infection hypothesis when they published their studies on infants alleged to be suffocated while they were in apparent good health. In many cases, histological examination revealed the presence of focal bronchopneumonia or focal interstitial pneumonitis with widespread vascular engorgement, vascular thrombosis, mural vascular and tissue oedema, perivascular haemorrhages and focal tissue reactions mainly in the form of mononuclear cellular infiltration. Werne and Garrow concluded that these microscopic changes could be regarded as evidence in support of the view that these infants died as a result of fulminating respiratory disease. Similarly, Bowden and French (1951) reported that a combination of methods of assessment including macroscopical, microscopical and systemic cultural studies adequately established a cause of death of an infective nature in their series of 43 cases of sudden death in infants. O n the other hand, Coe and Hartman (1960) divided the cases in their ~eriesinto 3 groups on the basis of acute inflammatory changes in the respiratory tracts. Those with definite acute laryngotracheo-bronchitis or pneumonia had an average age of 3.8 months; those with questionable pneumonia an average age of 2.3 months; and those with no acute inflammatory changes an average age of 1.5 months. As a result of these observations, the authors believed that most of these infarts died as a result of respiratory infection and the age at the time of death determined in large part the anatomical pathological finding? a t autopsy.

I n most of the foregoing studies, the investigators depended on the histopathological appearances and the clinical history to support the infective hypothesis as the main cause of SIDS. Only rarely were significant pathogenic organisms isolated. Knowing that different pathologists give different interpretation for similar histopathological findings regarding their fatal outcome, the conclusions and the suggestions of these studies remain speculative. Banks in 1965 sho-wed that although respiratory symptoms were common among SIDS cases, there was nothing to suggest that they heralded an overwhelming infection. Similarly Cooke and Welsh (1964) reported "it is difficult to believe that so many children could die of an overwhelming infection and yet have no preceding history of illness, histological signs of infection and in whom no pathogenic organisms, viruses or bacteria were grown".

Bacteriology Many investigators have vigorously attempted to isolate pathogenic bacteria from cases of sudden infant death syndrome. Table 7 shows examples of such efforts. In addition to the studies shown in Table 7, Sutton and Emery (1966) carried out bacterial and viral studies on the contacts of 10 infants dying suddenly and unexpectedly. They found that the proportion of these contacts harbouring pathogenic bacteria was significantly higher than that in a control population. As a result of the bacteriological studies shown in Table 7 most of the authors considered their results as evidence in favour of the infective theory in respect to the aetiology of SIDS (Farber, 1934; Werne, 1942; Coe and Hartman, 1960;Johnston and Lawy, 1966). However, although Gormsen (1957) isolated potentially pathogenic bacteria in many of his 50 cases of SIDS, he pointed out that in none of the cases could it be definitely established that bacteria was the cause of death. He concluded that bacteriological examination afforded no definite guidance. Similarly, Werne and Garrow (1953) who isolated potentially pathogenic bacteria from 11 out cf 24 SIDS had questioned their significance except as a secondary invader, as similar bacteria have been recovered occasionally from infants dying immediately after violence. The significance of post mortem isolation of bacteria even if they are potentially pathogenic in the absence of organic pathologic lesions, is in most instances questionable. 1t is difficult, therefore, to seriously consider any of the above apparent positive results as of aetiological importance in sudden infant death syndrome. Virology Although viral infection was first suggested as a possible cause of sudden infant death syndrome several decades ago (Adams, 1943) significant viral isolations from cases of SIDS were not reported until about 15 years ago. After 1966, with major changes ir, the techniques in viral isolations, and the use of fresh non freezing method of culture, significant changes in the number and TABLE 7 EXAMPLES OF BACTERIOLOGICAL INVESTIGATION IN SIDS

Authors Farber Werne Werne and Garrow Coe and Hartman Cooke and Welsh Johnstone and Lawy Brandt et al.

Year 1934 1942 1953 1960 1964 1966 1974

Total Number of cases studied bacteriologically

2 50 24 19 85 55

96

Number of cases with post-bacterial isolation 2 28 11 3 30 37 20

the type of viruses isolated in SIDS were achieved. Table 8 shows some examples of different attempts to isolate viruses from sudden infant death syndrome reported in the literature between 1961 and 1974. Gold et al. (196 1) recovered viruses from specimens obtained from 12 SIDS cases out of 48 studied, no virus was isolated from 2 controls who died after trauma. All viruses recovered in this study were members of the Entero virus family. Then, Moore et al. (1964) investigated 10 SIDS and iecovered 12 viruses from 7 case?. Most of the viruses recovered were ECHO 7, the remaining were Polio 1, Polio 2 and ECHO 22 v i r u ~ .However, Gardner C. E. (1970) isolated viruses from 27 cases out of 40 SIDS. The main viral groups recovered were adenovirus, para influenza virus and rhinov~rus.And in only one case was respiratory syncytial virus recovered. Balduzzi et al. (1966) investigated the relationship between sudden infant death syndrome and Enteric virus. A total of 97 SIDS cases and 33 controls were studied. One viral strain was found in the stools of a control case and 14 viral agents were isolated from the SIDS group. Nine strains were found in the stools and 5 strains, all Coxsackie B, were isolated from organ tissues obtained at autopsy. The authors concluded "while the last finding suggests that Enteric virus may cause sudden death, the frequency of isolation is too low to be significant in a sample of the size investigated here" (Balduzzi et al. 1966). I n all the viral studies previously mentioned, the post-mortem materials were frozen before inoculation in tissue culture. The fresh non freezing method of viral isolation was started after the discovery of respiratory syncytial virus which is a very delicate virus destroyed by freezing (Chanock et al. 1961). As recent researchers have shown that respiratory syncytial (R.S.) virus causes the majority of viral respiratory diseases in children under 1 year of age (Gardner, P. S., 1968) and as both respiratory syncytial virus disease and SIDS have very similar age and seasonal distribution, it is essential to include a search for R.S. virus in any attempt to isolate viruses from sudden infant death syndrome. This adoption of the new methods of viral isolation in sudden infant death syndrome began in 1966 (Ray, 1970). The author reported that since January 1965 a study of sudden infant death syndrome in King County (Washington) had been conducted and that between August 1966 and January 1968, major changes in the protocol were made including the study of SIDS cases and controls as soon as possible after death. Extensive respiratory sampling and strict avoidance of freezing of specimens before inoculation into tissue culture was introduced. With the use of this new system, significant "non-polio virus" isolates were made in 37.5 per cent of SIDS cases and in only 16.2 per cent of the controls and a considerable diversity of serotypes was found. No respiratory syncytial virus was recovered from the SIDS group but it was isolated from 3 control cases (Ray, 1970). Gardner (P. S.) who carried out the virological investigation published in

TABLE 8 SOME EXAMPLES OF VIROLOGICAL INVESTIGATION IN SIDS Authors Gold et al. Moore et al. Balduzzi et al. Gardner, C . E. Ray Ferris et al. Brandt et al. Urquhart

Year 1961 1964 1966 1970 1970 1973 1974 1974

Total Number of Number of cases with post-viral isolation cases studied 12 48 7 10 14 97 27 40 58 171 13 51 39 96 32 72

the paper by Ferris et al. (1973) succeeded in isolating viral agents in 13 cases of SIDS studied. By the use of non freezing methods, Gardner was able to recover R.S. virus in 6 SIDS out of 13 cases with positive viral isolation. However, Brandt et al. (1974) were able to isolate viruses from 40-63 per cent of their SIDS series (the absolute number in Table 8), but in only 3.13 per cent (3 cases) was R.S. virus recovered. Urquhart (1974) recovered viral agents from 47 per cent of his SIDS and the viruses isolated were of enterovirus, adenovirus and rhinovirus families. However, a similar range and frequency of viruses was isolated from controls. No R.S. virus way isolated from any case whether SIDS or control. No R.S. virus antigen was seen in lung smears of SIDS cases and heart sections were negative for Coxsackie B antigen. These viral results have introduced a new aetiological parameter to the SIDS problem. Generally speaking, if one is faced with a case of sudden infant death syndrome with minimal pathologic findings but with a positive viral isolation, does this mean that the virus recovered has played a part in the pathogenesis of the syndrome or could the presence of such a virus be an incidental finding or even post mortem contamination? If the virus recovered does have a role in the pathogenesis of the syndrome, then by what mechanism does this virus kill its victim? Many investigators currently believe that viruses have a significant role in the pathogenesis of SIDS (Gardner, 1970; Ray, 1970; Ferris et al., 1973; Downham et al., 1975). Some serotypes may have relatively greater importance than others (Ray, 1970). The mechanism by which viruses cause death in SIDS is in most instances speculation. The viruses which have been isolated tend to reflect those circulating and causing diseases in the community a t a particular time and such viral isolations do not necessarily suggest that overwhelming virus infection is a common feature of sudden infant death syndrome (Urquhart et al., 1972; Urquhart, 1974). If the recovery of a pathogenic virus is an indication of viral infection, such infection could make the infant more susceptible to sudden death and yet not be the main underlying or necessarily the principle cause of the sudden infant death syndrome (James, 1968; Bergman, 1970b). Another view held by some is that the syndrome might be the result of a hypersensitivity reaction induced by viral infection (Gunther, 1966; Aherne et al., 1970; Urquhart, 1974). Unfortunately, there is no objective evidence supporting such a theory and so the role played by the virus in SIDS remains speculation. Lastly, a final comment regarding the infective hypothesis. Froggatt et al. (1968) reported that the presence of minimal but typical changes in the respiratory tract, the prevalence of cases in winter and in the socially and biologically underprivileged, the association with respiratory virus epidemics, the susceptibility of twins, the frequent symptoms of respiratory tract in the affected infant prior to death and sometimes concurrently in his sibs, all supported the respiratory infection theory for sudden infant death syndrome. Against this view, however, is the failure to consistently isolate bacterial pathogens, and more crucially to demonstrate a viral infection in every case of SIDS. (Froggatt et al., 1968).

Immunology One of the earlier investigations into the serum gammaglobulins levels in infancy and childhood is that of Orlandini et al. (1955). They reported that serum gammaglobulins levels usually fall soon after birth reaching about one third of its birth level at about 1 month of age. These authors observed very little changes between 1-3 months of age after which the levels started to rise and adult levels closely approximated by the age of 2 years. They found, however, that a rapid decrease in serum gammaglobulin was present in both

breast fed as well as in artificially fed newborn infants. Fulginiti et al. (1966) studied the different classes of immunoglobulins at birth and during the first year of life. They recorded that IgG was present in cord sera and its level declined during the first 6 months of life. It then increased to almost 314 of the normal adult level during the next 6 months. The authors found no IgA in the cord sera, but its level progressively increased reaching a level approximately 115 of that of adult by the age of one year. IgM was found in most cord sera studied, the level of which steadily rose to 112 of the adult level by 52 weeks of age (Fulginiti et al., 1966). Allansmith et al., (1968) investigated the development and synthesis of IgG, IgA and IgM from birth through the neonatal period, infancy, childhood and into adulthood. They reported that a rapid synthesis of IgM started in the first week of post natal life. The IgM system expanded to adult levels by the age of about 1 year in boys and 2 year5 in girls. IgA synthesis begins by 2-3 weeks of age, increases slowly and attains adult levels by about the age of 12 years. Rapid IgG synthesis probably begins by the first 4-6 weeks of life and adult levels are reached a t about the age of 8 years (Allansmith et al., 1968). Finally, a normal infant can form antibodies from birth and the ability to form antibodies improves during early life and this ability depends upon the antigenic stimulation, for example, diphtheria and tetanic antitoxins, the antibody response for these antitoxins is rapid during the first two months and then it is much slower later on (Osborn et al., 1952). Hypogamrnaglobulinaemia and SIDS Spain et al. (1954) found that the post mortem serum gammaglobulin levels were exceptionally low in 3 infants who died suddenly and unexpectedly as compared with 2 controls of the same age group who showed normal levels. They suggested that a lowered antibody level or gammaglobulin level or both may be an important factor in many sudden and unexpected deaths occurring during infancy. This suggestion was supported by Janeway et al. (1957) who noted that the period cf physiological transient hypogammaglobulinaemia between 1 and 6 months of age, was the time of greatest incidence of severe and overwhelming septic infection, such as purulent meningitis. They suggested that a connection might exist between the low gammaglobulin level in this period and the sudden infant death syndrome. Oppe (1964) recorded the results of protein fractionation performed by paper electrophoresis on the sera of 114 infants who died suddenly and unexpectedly and 33 healthy living controls of comparable age. The values for the test group were not lower than those of the controls, Oppe concluded that abnormally low levels of gammaglobulin did not appear to play a part in the mechanism responsible for these unexplained deaths. At the same time, when infants of less than 8 months in the test group (1 12 cases) and controls (24 cases) group are considered alone, the levels of gammaglobulin in gram per cent were significantly highel in the test group than in the control group. The same statistically significant elevation was observed in the value of albumin and beta globulin. Oppe suggested that such elevations might be the result of agonal dehydration or some post mortem alteration. Stiehm and Gold (1968) determined the serum levels of IgM, IgG and IgA and the total immunoglobulins in 88 SIDS and compared these levels with those obtained from 16 infants who died from known causes and 177 normal age matched living controls. The immunoglobulin levels in all groups were similar except that SIDS infants aged 4-6 months had higher mean levels of total gammaglobulin than controls. Three SIDS infants (3.5 per cent) had hypogammaglobulinaemia and 13 SIDS (15 per cent) had eithcr elevated IgM (9 cases) or diffuse hypergammaglobulinaemia (4 cases). As a result, Stiehm and Gold concluded that primary derangement of antibody proteins was not a frequent and important factor in SIDS. Similarly, Balduzzi et al. (1968) reported that the immunoglobulin level of 35 infants who died suddenly and 240

unexpectedly were measured and compared with values obtained from a control group of 33 cases and with the values reported in the literature for children of the same age. These authors observed no significant difference in the value of IgG, IgM and IgA between the SIDS, controls and the previously reported normal values for 2-5 month old infants. In addition to the previous studies, infants with hypogammaglobulinaemia usually give a history of repeated infections and do not die suddenly and unexpectedly in apparent good health as is the case in sudden infant death syndrome. SIDS and the hypersensitivity reactions SIDS and hypersensitivity to cow's milk proteins. Barrett (1954) expressed the view that if inhaled food or vomit causes death, it may not be so by directly obstructing the air passages, death might not be due purely to asphyxia, but due to shock resulting from the absorption of undue amounts of milk derivatives into the blood stream. Parish et al. (1960a) followed up Barrett's idea and introduced the hypothesis that SIDS might result from a hypersensitivity reaction to cow's milk proteins in sensitised infants. Many studies have been presented by the authors to support their theory. I n their first publication in this respect, Parish et al. (1960a) reported that the introduction of 1 ml of cow's milk proteins, in soluble or insoluble form into the respiratory tract of conscious normal guinea pigs produced negligible clinical effects. I n animals sensitised to milk proteins, similar treatment produced severe typical anaphylactic reaction, and in some animals caused rapid death. I n unsensitised guinea pigs, lightly anaesthetised simulate sleep, similar administration of milk was without significant effects, but the inhalation of cow's milk by lightly anaesthetised sensitised guinea pigs results in a n arrest of respiration and many of the animals died quietly without any struggle or excitement. The lungs of these animals did not show the acute emphysema characteristic of anaphylactic shock. Parish et al. concluded that these experimental results supported the hypothesis that SIDS may be caused by a hypersensitivity reaction consequent upon the inhalation of cow's milk proteins regurgitated from the stomach during sleep. In the same year, Parish et al., published more details about the experimental materials and techniques used In challenging the sensitised animals. They reported that experiments on anaesthetised guinea pigs sensitised to the cow's milk proteins, showed that many such animals died rapidly and without struggle when small quantities (0.25 ml) of cow's milk, stomach contents of SIDS cases, 1 per cent solution of casein, or 1 per cent solution of betalactoglobulin were introduced into the air passages. The histopathological changes in the lungs of the animals experimented upon was found to be similar to those changes found in SIDS lungs (Parish et al., 1960b). As to the question of the effect of anaesthesia on the anaphylaxis induced in these experiments, it was later found that the majority of the anaesthetics used did not prevent the fatal outcome, but might modify the anaphylactic reaction itself (Parish et al., 1963). I n addition to these experimental results, Parish et al. (1964) presented other evidence in support of their theory of hypersensitivity to cow's milk protein. 1. The antibody titres to cow's milk proteins measured by the coated tanned cell agglutination test in a serie~of 38 SIDS were found to be higher than the average titres in a sera of normal infants of the same age. 2. The bera of some SIDS cases may have incomplete antibodies to cow's milk undetected by the antigen coated tanned cell technique. 3. Cow's milk protein has been demonstrated (by double diffusion agar gel test) in a high proportion of SIDS lungs and in the sera of some SIDS cases. 4. Casein has not been demonstrated in the lungs, but only in low concentrations in the sera of 3 SIDS cases. 5. Tests were made to demonstrate bronchial constriction in the lungs of guinea pigs and at the post mortem of some SIDS cases in order to provide

evidence of death by anaphylaxis. Evidence for anaphylactic death could be shown in guinea pigs up to 30 minutes after death but in SIDS no definite evidence of bronchial constrictions could be shown though some obstruction of the airway was present in 2 cases 6. In 8 SIDS, especially chosen for the freshness of the post mortem material, no evidence of viral infection, including respiratory syncytia, could be found. 7. Attempts to detect the presence of an eosinophil stimulating substance in the lungs of SIDS, as an indication of an anaphylactic death were unsuccessful and the examination of the mast cells of SIDS lungs revealed no widespread changes associated with anaphylaxis (Parish et al., 1964). The introduction of Parish's theory of hypersensitivity in 1960 stimulated a world wide interest in this field. I n the United Kingdom, in a confidential enquiry into post neonatal deaths (Riley, 1970), it was recorded that although no cow's milk sensitisation was detected in a number of SIDS investigated from this point of view, nevertheless the work of Parish and his colleagues could not be disregarded and as a result it was advised to encourage bieast feeding especially in the early weeks of life (Report on public health and med. subjects No. 125). However, the theory received very little support from other investigators. For example, Gold et al. (1961) who used the coated tanned cell method in their serologica! investigations reported that 50 per cent of infants fed on cow's milk developed antibodies to cow's milk within the first 3-8 months of life, while very rarely breast fed infants developed measurable amounts of circulating cow's milk antibodies. There was no significant difference between a group of SIDS and the normal living children in the frequency and the amount of circulating cow's milk antibodies. A similar study was done by Coe and Peterson (1963) who used the capillary tube precipitin and haemagglutination methods in their serological study. They found that there was no significant difference between a group of 28 SIDS and a control group of 67 infants in respect of serum antibodies to cow's milk proteins. Then in 1964, Gold et al. published another study in which the titres of antibodies to cow's milk proteins were measured in 4 groups of children. (a) Infants died from known causes (bl Infants died from sudden infant death syndrome (c) Living and well babies fed cow's milk formulas exclusively (d) Living and well babies fed both cow's milk and human milk The authors found no significant difference between the 4 groups in the mean antibody titres to cow's milk proteins. Gold et al. (1964) reported that no evidence was obtained to support the hypothesis that hypersensitivity to milk was causally related to the sudden infant death syndrome. Similarly, Johnstone and Lawy (1966) measured the titre of serum milk antibodies by the sensitised tanned red cell agglutination technique in 37 SIDS, 9 infants observed tc die and another group of normally living control infants. Antibodies to cow's milk protein were found in only a small proportion of both SIDS and control groups and in low titres. The percentage and the distribution of cases harbouring such antibodies was virtually the same in SIDS and control groups, and such results cannot be considered to suggest that the SIDS died from hypersensitivity to cow's milk proteins. As to the question of the presence of cow's milk proteins in the lungs of victims of the sudden infant death syndrome. its mere plesence is of doubtful significance and much will depend on the way in which the affected infant's body is handled after death. Also, the presence of cow's milk proteins in the lungs may be part of the agonal event and not its cause (Ferris, 1975). No one except Parish et al. (1964) has found cow's milk protein in the serum of SIDS cases (Coe and Peterson, 1963). Valdes Dapena and Felipe (1971) employed the new technique of immunofluorescent staining of frozen sections of a variety of tissues to explore the theory that SIDS might be due to hyper-

sensitivity to cow's milk. Blocks of tissue from the lungs, larynx, trachea, spleen, thymus and lymph nodes were taken at autopsy from 89 SIDS and 76 control infants who died of recognisable causes. Three of the major proteins of cow's milk conjugated with fluoreseine were used to identify and count cells producing or containing antibodies to these antigens. There was no significant increase in the number of such cells in infants who had died from sudden infant death syndrome when compared with control infants. The authors concluded that tnis observation could not support the hypothesis that SIDS results from anaphylaxis secondary to sensitisation to cow's milk proteins (Valdes Dapena and Felipe, 1971). These apparently conflicting views mean that one should interpret the experimental results of Parish and his colleagues with caution as it is very easy to induce anaphylactic reaction in guinea pigs. Also, the negative virological results in the Parish et al. (1964) study does not mean that SIDS results from hypersensitivity to cow's milk proteins especially when it is noted that they tried to isolate respiratory syncytial virus, a notoriously difficult virus to identify. Anaphylactic shock after intrauterine injection. Gunther (1966) suggested that while some cases of SIDS might result from anaphylactic shock to cow's milk proteins, others might be the result of anaphylactic shock to infective antigens. He drew attention to what he referred to as the unusual immune state of a baby in the first months of life after intrauterine infection. The author added "Studies reported a persistent rubella virus and changing antibody pattern, these were taken as evidence that during the first 6 months after birth some babies have unrecognised viral infection and active allergic response to it." (Gunther, 1966). The difficulty facing this theory is that neither rubella nor any other virus was isolated by the author and his hypothesis has failed to get any support from other investigators in this field. Hypersensitivity reaction induced by viral agents during infancy. Aherne et al. (1970) reported that because of the rarity of respiratory syncytial virus in uninfected children, their recovery of the R.S. virus from 3 out of 5 SIDS was intriguing. There was no histological evidence of established tissue response in these cases, but the possibility of hypersensitivity suggests a hypothesis which might be tested. The normal antibody response to mucosal replication is probably IgA. The authors shared the view expressed by Chanock et al. (1968) that circulating IgG may form cytotoxic antigen complexes bound to mucosa cells. A phenomenon of this kind might provide a mechanism for a rapid and severe hypersensitivity reaction (Aherne et al., 1970). This hypothesis was supported by Urquhart et al. ( 1971, 1972); Urquhart (1974) who succeeded in isolating viral agents in 47 per cent of their SIDS. They also reported a raised IgM level in 67 per cent of the cases which is consistent with prolonged antigenic stimulation. Urquhart (1974) suggested that viruses might be important in SIDS as antigenic 3timuli rather than as infective agents and Urquhart et al. (1972) argued that when antigen persists, it is possible for antigen and antibody to coexist as an immune complex. One of the reactions to the presence of immune complexes is the formation of antiglobulin antibody. Serum studies showed that these antiglobulin antibodies were present in 56 per cent of SIDS compared with 5 per cent of the controls which is indirect evidence that immune complexes may be present in SIDS cases (Urquhart et al., 1972). Urquhart (1974) thought that consideration of SIDS as an immune complex disease was compatible with the gross pathology, the known epidemiology and specific viral and immunological studies. So far there are no other scientific results to support this theory. However, much of the current work in the pulmonary field would be consistent with Urquhart's results and there is no doubt that much more research is needed in this direction.

Anaphylaxis secondary to inhalation of house dust mite. Nelson in 1971 suggested that there might be correlation between SIDS and the presence of house dust mites, their cast skin and faecal pellets. This suggestion was supported by Mulvey (1972) who recorded that SIDS could be caused by anaphylaxis secondary to inhalation of Dermatophagoidcs pteronyssinus (house dust mite). This theory was questioned by Mobbs (1973). No other studies in this field have been reported elsewhere.

The Heart in Sudden Infant Death Syndrome As most instantaneous or sudden deaths are cardiogenic in origin, lethal dysrhythmias deserve particular considerations in the sudden infant death syndrome. Nevertheless, such a mechanism of death has received little attention in SIDS investigations before 1968 and only modest consideration after that date (Froggatt and James, 1973). James (1968, 1970) was the first to study the specialised tissues of the heart in SIDS. He observed a n unusual histological process involving the atrioventricular node and His bundle. This consisted of resorptive degeneration and replacement fibrosis of the left portion of the His bundle and the left margin of the atrioventricular node. Since this phenomenon was not present in still births and in adult hearts, James suggested that it was probably part of a normal post-natal remodelling process. He proposed that during this period of remodelling, infants might be vulnerable to temporary dysfunction of the conducting system and that such a n episode might lead to sudden death. Then, in 1970, Anderson and his colleagues reported the presence of inflammatory, degenerative and vascular lesions in components of the conduction system in 6 out of 14 SIDS. The authors stressed the importance of lethal arrhythmias in the pathogenesis of sudden infant death syndrome. James' findings were later supported by Ferris (1972a, 1972b) who studied the conducting tissue of the heart in 47 infants dying suddenly as a result of natural and unnatural causes. He was unable to confirm the inflammatory and the vascular lesions reported by Anderson et al. 1970). Ferris suggested that these changes may interfere with cardiac impulse conduction. Fatal dysrhythmia might follow stimulation of the conducting tissue by an abnormal reaction to virus infection or some allergic phenomenon. Such a sequence of events would explain the rapidity of death and the relative absence of pathological changes in sudden infant death syndrome. However, Valdes Dapena et al. (1973) were unable to demonstrate any degeneration in any part of the conducting tissue of the heart examined in SIDS cases. They found no evidence to support the theory of lethal arrhythmias as the mechanism of death in SIDS. Recently, Ferris (1973) reported the presence of petechial haemorrhages in the region of the sinus node and internodal conducting tissue tracts in 11 out of 50 SIDS. He suggested that these findings indicated myocardial hypoxia and that such disturbance of the conducting system may well account for the failure to survive in cases of sudden infant death syndrome. Abnormal Calcium Metabolism and Parathyroid Inadequacy Maresch (1962, 1968) found that the myocardial content of calcium in SIDS cases was significantly lower than that of control case5. He suggested that the abnormal metabolism which led to rickets and tetany may be responsible for sudden infant death syndrome. Geertinger (1967, 1968, 1969) modified this theory as follows 'Sudden unexpected death in infancy is due to a congenital disorder involving calcium metabolism. This congenital disorder is acquired during fetal life, probably about the second month as indicated by the post mortem morphological features of the parathyroids'. Geertinger found parathyroids in only 66 per cent of his SIDS cases. He demonstrated masses of thymic tissues within the parathyroid capsule in 60 per cent of the cases with

parathyroid glands. Complete fusion of parathyroid tissue and thymic tissue was found in 31 per cent of the cases with parathyroids. The theory seems to be unlikely for many reasons, firstly the infant who dies suddenly and unexpectedly has usually been in relative good health before death and bv definition. SIDS have no historv of serious illness or r e ~ e a t e d convulsions such as might be expected with parathyroid insufficiency. Secondly, in SIDS, the thymus is relatively large, well preserved and plump, and since the thymus and parathyroids are derived from the same embryonic analgen one would expect that if the parathyroids had not developed adequately, the thymus in many instances at least, might also be hypoplastic (Valdes Dapena and Weinstein, 1971). Besides, many parathyroid studies have failed to confirm the findings of Geertinger. Parathyroid glands, two or more, were present in every case of SIDS (Valdes Dapena and Weinstein, 1971) and fusion of parathyroid glands and the thymus was found in infants regardless of the nature of their death (Ellis and Knight, 1969; Valdes Dapena and Weinstein, 1971).

Adrenal Insufficiency, Acidosis and Electrolyte Imbalance Finlayson (1964) found that the adrenal glands in the sudden infant death syndrome were small and flat. He investigated the serum cortisol level of 18 cases of the syndrome, he found that the mean level of post-mortem cortisol level was significantly lower than that of the controls. He concluded that adrenal insufficiency may be responsible for the sudden infant death syndrome. As the small, flat adrenals found at autopsy of the cases of the syndrome are within normal limits, and as the post-mortem analysis of serum cortisol level is not reliable, this theory is a very remote possibility. I t received no support from any other investigator except McGaffey (1968) who reported that postmortem electrolytes and p H studies suggest that a severe imbalance of electrolyte and p H with an acidosis preceded death in cases of sudden unexpected death in infants. A possible relationship to hypoadrenalism secondary to the natural adrenal involution during the first year of life is suggested by the finding of hyponatremia and metabolic acidosis found in these cases. Acidosis of sleep, upper respiratory infection, or perhaps some unknown acidosis from metabolism may be the final factor that pushes the p H below the limits of life in these infants. Electrolyte levels and the p H estimations on post-mortem blood are unreliable and most of the remaining points mentioned in this theory are speculative. Inborn Error of Metabolism Porter (1966, 1972, 1974) proposed a theory that some SIDS might occur in infants made vulnerable to an adverse environment by an inborn error of metabolism, probably as heterozygous recessive form, and the mode of death is hypoglycaemia. Porter summarises the a d v e r ~ eenvironments mentioned in his theory as follows : Reconstituted milk feed. Reconstituted cow's milk contains up to 3 time, more proteins than human milk contains. A bottle fed infant is thus fed on unnatural protein loaded food and this must aggravate any tendency to hyperaminoacidaemia. Milk supplement. These are commonly used by mothers to thicken the feeds. Though they are derived from cereals, they are rich in proteins. Their use can only aggravate the protein excess received by the bottle fed infants. Prwaturity. Low birth weight infants may continue to have low blood sugar value for a long time. Nocturnal fasting. Most mothers try to drop night feed. The longest time between feeds is likely to be 12 midnight to 6 a.m. This i~ when hypoglycaemia is likely to occur.

Anorexia. An infant with a n upper respiratory infection or an infant who has become chilled. is most likelv to be anorexic. A tendency to hypoglycaemia might be anticipated. The author presented only 2 SIDS cases affecting one family. He claimed that they fit his hypothesis. He offered no genetic or biochemical studies in his SIDS cases or their relatives to support his theory. Besides, this theory failed to get any support from other investigators.

Nutrition Magnesium Dejciency Caddell in 1972 suggested that SIDS might result from magnesium deprivation which leads to the liberation of histamine without exogenous histamine liberators. This will initiate autonomic reflex activity through vagus nerve and subsequently the victim dies from histamine shock. As a result of the introduction of this hypothesis, Swift and Emery (1972) investigated the level of magnesium in the vitreous humor of SIDS group and compared the results with a control non SIDS infants. They reported that the magnesium concentration of vitreous humor of the SIDS was within the range of that of the control infants. These results were supported later by Sturner and Dempsey (1973) and Peterson and Beckwith (1973) which makes Caddell's hypothesis less likely to explain the majority of SIDS cases. Dejciency of Vitamin E and/or Selenium Money (1970, 1971) recorded his observations on Vitamin E and/or Selenium deficiency on pigs. He reported that such deficiency caused sudden death in pigs and accordingly he suggested their SIDS might result from deficiency of Vitamin E and/or Selenium. This suggestion stimulated Rhead et al. (1972, 1973) to investigate the plasma level of Vitamin E and/or Selenium in a SIDS group and to compare the results with normal living control infants. They reported that Vitamin E and Selenium were essentially identical in both SIDS and normal control groups. So, Vitamin E and/or Selenium deficiency i a remote possibility in respect of the aetiology of sudden infant death syndrome

Mechanical Spinal Injury The finding of spinal epidural haemorrhages in some cases of sudden infant death syndrome led Towbin (1967, 1968) to suggest that mechanical injury to the upper cervical spinal structure is the cause of sudden infant death syndrome. This theory has received no support from any other investigators, Harris and Adelson (1969) published a study which ruled out such a possibility. Their series included a study of 19 consecutive SIDS which revealed no mechanical injury to the cervico-thoracic vertebral column in any child. Spinal epidural venous congestion, frequently accompanied by foci of epidural haemorrhages, was present in nearly every child. Such findings were observed in infants dying of acute inflammatory disease as well as in children who are victims of the classic SIDS. The authors concluded that physical trauma did not play any significant role in the pathogenesis of the sudden infant death syndrome. Neurological Mechanisms and Diving Reflex Adelson (1953, 1954) reported that in a n autopsy with no anatomical cause of death in a case who died suddenly, neurologic mechanisms may be responsible for this death by causing sudden cardiac syncope and cardiac arrest. The death resulted from primary shock or syncope with instantaneous exitus. This syncope is characterised by suddenly developing circulatory failure on the basis of either reflex vago cardiac inhibition with slowing or stoppage of the heart, reflex systemic vasodilatation with profound fall in blood pressure,

or a combination of these two mechanisms. Wolf in 1968 recorded that many bizarre sudden deaths including crib death "SIDS" may be attributed to an overexuberant oxygen conserving reflex (Diving reflex). I n fact it is very difficult to obtain objective evidence to support such mechanisms of death. Such possibilities are usually diagnosed by exclusion. I n SIDS there are pathological findings although they are minimal, viruses were recovered from about one third of SIDS cases and there are also some epidemiological observations which can not be explained by the neurologic or diving reflex theories. So, such possibilities are very remote in the majority of cases of sudden infant death syndrome.

The Thymus General During the 19th Century many attempts were made to relate the sudden and unexpected death to enlarged thymus glands often reported at the autopsy in such cases (Baak and Huber, 1974b). This led to the introduction of the concept of Status thymico lymphaticus which was thought to offer an explanation for some cases of the sudden infant death syndrome (Paltauf, 1889; Carr, 1945; Boyd, 1970). This theory remained popular for many years until Hammar (1906, 1926) showed that the large thymus found in SIDS was probably a normal gland. Thymic studies have been revived during the past 10 years, but no direct causal connection between the thymus and SIDS has yet been found (Geertinger, 1967; Beckwith, 1970; Baak and Huber, 1974b). Status Thymico Lymphaticus In 1889 Paltauf published his concept of status thymico lymphaticus (or status lymphaticus). He proposed that enlargement of the thymus together with hyperplastic lymphoid tissue often found in sudden death was a basic anomaly which in certain cases might have a causal relationship to the occurrence of sudden, clinically unexpected death as, for example, SIDS. He argued that such deaths were not due to an "obstructive effect" of the enlarged thymus, but due to lowered resistance to various injuries as a result of a specific constitutional anomaly, lymphatic-chloritic in type. This concept remained popular among pathologists for some time as a possible cause for SIDS and any other unexpected death (Greenwood and Woods, 1927; Marine, 1928). As a result, in 1911 the heading 'status lymphaticus" was accepted by the Registrar General in England and Wales (Greenwood and Woods, 1927). However, its popularity gradually declined especially after the publication of Hammar's (1906, 1926) detailed thymic studies which showed that the large thymus found in cases of sudden and unexpected death was probably a normal gland. This view was supported by Greenwood and Woods (1927), Boyd (1927, 1932, 1936) and many other investigators who campaigned to have the term status thymico lymphaticus omitted from medical writings (Arey and Sotos, 1956). Nevertheless, despite these views, Boyd (1970) recorded that status thymico-lymphaticus was a real entity and might be responsible for some cases of sudden infant death syndrome. Another concept of status thymico lymphaticus was suggested by Carr (1945). He proposed that death could be asphyxia1 in type caused by compression and distortion of the trachea and cardiac atria by an enlarged thymus gland. Accordingly Carr (1945) concluded that status thymico lymphaticus might be one of the causes of sudden infant death syndrome since asphyxia was considered the commonest cause for death in infants less than 2 years of age. This concept of status thymico lymphaticus has been disregarded by most pathologists as the large thymus usually found in cases of sudden unexpected death has been shown to be within normal limits, and Valdes Dapena in 1967

has stated that if enlargement of the thymus gland has any relation to SIDS, it is certainly not an obstructive one. Even in 1927, Greenwood and Woods described status thymico lymphaticus as a good example of the growth of medical mythology in which a nucleus of truth is buried beneath a pile of intellectual rubbish, conjecture, bad observations and rash generalisation and it is as accurate to attribute the cause of death as 'a visit from God' as to the status thymico lymphaticus ! Other Thymic Investigations in SIDS I n addition to the previously mentioned studies in connection with status thymico-lymphaticus, other thymic investigations in SIDS cases have appeared recently in the literature but without suggestion of any direct aetiological role in SIDS. Among the investigations was that of Geertinger (1967) in which he suggested that parathyroid insufficiency caused partially by parathyroid thymic fusion was a primary cause for SIDS. No evidence was found to support this hypothesis by Ellis and Knight (1969) or by Valdes Dapena and Weinstein (1971) who carried out similar studies on parathyroids and thymus glands and found the parathyroids were normal in number, size and position. Another thymic study in SIDS was that of Beckwith (1970) who reported more petechial haemorrhages in the thoracic portion of the thymus than in the cervical portion. Beckwith concluded that this distribution of petechial haemorrhages might be the result of elevated intrathoracic negative pressure which could be a feature of the terminal event in SIDS. Finally, a more comprehensive study of the thymus gland in childhood and in SIDS was performed by Baak and Huber (197413). They described the normal thymus gland in childhood and found that there were differences between the thymus of normal children and that of SIDS victims. They found that in SIDS the percentage volume of the thymic cortex was higher and that of' the medulla and connective tissue was lower than in normal children. Also, the number of lymphocytes per cubic mm. of cortex and medulla and the percentage volume of the first stage of Hassall bodies were lower in SIDS than in normal children and the blood vessel surface cubic millimetre of cortex was higher. Baak and Huber (1974b) have expressed the view that stress and hypoxia could be among several possible mechanisms leading to these thymic changes in the sudden infant death syndrome.

Conclusions In spite of intensive research in many fields of paediatric medicine the problem of the sudden infant death syndrome and its aetiology is still unsolved. Many theories have been offered to explain the cause and mechanism of death in SIDS. Each theory explains the mode of death in single or certain defined groups of cases. The presence of scanty pathological findings in such cases adds to the difficulties facing the pathologist in proposing a mechanism of death in such instances. Most of the pathological findings are characteristic but in no way pathognomonic. These findings have been described as non specific although they might indicate terminal hypoxia. Such a terminal hypoxic event might be the end result of many other processes probably involving the lung and/or the heart. As a result, most of the current theories have considered the respiratory system as the primary mechanism for death. I t had been suggested that the death in SIDS might be due to laryngospasm, prolonged sleep apnoea, respiratory infection or due to respiratory failure secondary to a hypersensitivity reaction probably involving viral or other antigens. Other theories have been suggested which involve the heart as the primary mechanism for death. Many workers have suggested fatal dysrhythmias due to either electrical instability of the heart as a consequence of developmental

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