Childhood cancers and competing causes of death

Leukemia Research Vol. 19, No. 2, pp. 103-111, 1995. Copyright 0 1995 Ekvier Science Ltd Printed in Great Britain. AU rights reserved 0145-2126/95 $9.50 + 0.W

Pergamon 01452126(94)00122-7

CHILDHOOD

CANCERS

AND COMPETING

CAUSES OF DEATH

Alice Stewart Department of Public Health and Epidemiology, University of Birmingham, Birmingham B15 2TI’, U.K. (Received 10 August 1994.Accepted 28 August 1994) Abstract-From the survey that first identified cancer effects of foetal irradiation and related sources has come support for the following hypotheses: (I) competing causes of death for childhood cancers include abortions (solid turnours) and infections VIES neoplasms); (2) the forms taken by RES neoplasms vary with the nature and intensity of indigenous infections; (3) ideal conditions for developing diffuse RES neoplasms (leukaemia) include the gross immunological incompetence caused by trisomy 21; (4) the unusually localised RES neoplasms found in children who have survived repeated attacks of malaria (Burkitt lymphoma and chloroma) are probably the result of these children having exceptionally high levels of passive as well as active immunity; and (5) when teratogenic effects of in utero mutations include faulty erythropoiesis as well as faulty leucopoiesis, infections are not the only rival causes of death. Key words: Epidemiology,

childhood

cancers,

rival causes of death.

result of lymphatic leukaemia and the extra deaths were concentrated between 2 and 4 years of age. These observations were followed by a survey which finally came to the conclusion that all childhood cancers have in utero origins (Oxford Survey of Childhood Cancers or OSCC data).

Introduction Fifty years ago very little was known about childhood cancers apart from pathologists’ descriptions of rare tumours [l]. Obstetricians were in a position to realise that foetal tumours might be large enough to cause an obstructed delivery. But among compilers of vital statistics, cancer was not a recognised cause of stillbirths, and leukaemia was classified either among general diseases other than infections (1921-1930), or among diseases of blood and blood forming organs (1931-1949) [2]. By the time it was officially recognised that leukaemia and lymphoma were cancers of the reticula-endothelial system (1950 onwards), countries with falling death rates were experiencing a noticeable increase in these previously rare RES neoplasms. In 1955 a detailed analysis of leukaemia mortality statistics, by Hewitt, showed that the rising death rate in Britain and elsewhere was largely the result of extra deaths of children and old persons [3]. In the older age group, deaths from all types of leukaemia were increasing but, in children, the increase was solely the

Oxford Survey of Childhood Cancers OSCC data The Oxford survey began by obtaining death certificate data for all children (O-9 years) who died in England and Wales from any form of cancer in a 3-year period (1953-1955). These deaths numbered 1694 and included 934 RES neoplasms and 760 solid tumours. Live controls for these cases were obtained from birth registers of regional health departments, and eventually each dead child was matched for sex, date of birth and region with a live child to form a series of 1694 ‘case/ control pairs’. The same regional health departments also supplied the doctors and nurses needed for paired interviewing of case and control mothers. Four years after the original starting date, the Oxford survey was converted into an ‘ongoing case/control study’, and eventually included a continuous series of early cancer deaths from 1953 to 1979. The decision to prolong the survey was a direct consequence of finding that the children who had died (either from leukaemia or from other forms of cancer), had been more often X-

Abbreviations: RES, reticula-endothelial system; OSCC, Oxford Survey of Childhood Cancers;JLL, juvenile lymphatic leukaemia; JML, juvenile myeloid leukaemia; HbF, foetal haemoglobin. Correspondence to: Alice Stewart, Department of Public Health and Epidemiology, University of Birmingham, Birmingham B15 2lT, U.K. (Tel: 021 414 3367; Fax: 021 414 3630). 103

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A. Stewart

rayed before birth than their live controls [4]. This finding showed that it was important not to be totally dependent upon interview data (since a case mother’s recollection of antenatal events might be influenced by the subsequent death). It also revealed a need to compare children who were born before the X-ray finding with later births, and to confirm or refute certain early impressions. For example, it was possible that the nonX-rayed cases had a younger age distribution than the extra radiogenic cancers [S], and possible that the children who eventually developed leukaemia had been more at risk of dying from pneumonia than the children who eventually developed solid tumours [4,6]. After publication of the 1958 report, the boundaries of the Oxford survey were enlarged by adding Scotland to England and Wales; adding deaths between 10 and 16 years to younger deaths, and including deaths from nonmalignant as well as malignant neoplasms. Systematic checking of mothers’ claims for prenatal X-rays was extended to other antenatal events (e.g. illnesses, drugs and occupations) and there were two additions to the interview data in the form of: (a) three sets of official statistics for early deaths from leukaemia and pneumonia during the period 1911-1965 [7]; and (b) three sets of survey data relating to cot deaths [8]. These additions were the result of suspecting that, as a result of antibiotic intervention, competing causes of death were no longer masking the true frequency of leukaemia [6]. In 1984, after nearly 30 years of continuous data collection, there were two further additions to OSCC data in the form of: (a) regional statistics for stillbirths, live births, infant mortality and levels of population density; and (b) terrestrial gamma ray doses for each 1Okm square of the national grid. The background dose measurements came from the National Radiological Protection Board of Britain, and were part of a recent ‘programme of measurements in relation to natural radiation’ [9]. Together with the original death certificates, the interview data and the regional statistics, they made it possible to supplement comparisons between traced cases and matched controls with comparisons between all children born in a given region and year, and the children who experienced an early cancer death (regional birth cohort analysis) [lo, 111. OSCC Findings Comparisons between traced cases and matched controls An excess of prenatal X-rays among the OSCC cases (compared with their matched controls) was detected as early as September 1956 [12]. Only 547 of the 1684 deaths for 1953-1955 had so far been traced, but 2 years later, essentially the same findings were obtained for 1299 case/control pairs (Table 1) [4]. Following

publication of the preliminary (1956) report there were several attempts by other epidemiologists to discover whether children who had survived in utero exposure to A-bomb radiation or been involved in an obstetric X-ray examination were more leukaemia-prone than normal children [13]. A run of negative findings for these ‘prospective surveys’ began by casting doubt on the one ‘retrospective survey’, but eventually a 10 year followup of children from several U.S. maternity hospitals found that the number of cancer deaths among the children with records of prenatal X-rays was significantly greater than the expected number [14], and a second retrospective survey (with the doctors who had delivered the children as the source of the X-ray data) also confirmed the OSCC findings [15]. By this time the decision to prolong the collection of OSCC data had been made, and the survey was partway towards completing interviews with mothers of 14759 case/control pairs representing 22 351 cancer deaths during the period 1953-1979 (Table 2). From this uniquely large data base have come the following observations: 1. A significant excess of prenatal X-rays among the cancer cases compared with their matched controls was a constant finding of OSCC data, and repeated checking found no evidence of different reporting standards for mothers of cases and controls [16-241. 2. The strength of the association between prenatal Xrays and the cancer deaths was the same for leukaemia and solid turnours, but for first trimester exposures (which were rare) the estimated cancer risk was much greater than the estimate for third trimester exposures (which were common) [23]. 3. Though the association between prenatal X-rays and cancer deaths was stronger for children who were born before 1958 than for later births, even for children who were exposed in the 1970s there was still evidence of a cancer risk [24]. 4. An early impression of younger death ages for the non-X-rayed cases than the extra, radiogenic cases [5] was confirmed in larger samples of OSCC data [18-221. This difference, together with the findings for first trimester exposures, showed that the usual time for initiating a childhood cancer might be early enough for the mutations to have teratogenic as well as carcinogenic effects. But although the number of children with Down’s syndrome (trisomy 21) among the leukaemia cases was 40 times greater than the expected number, for other congenital anomalies there was no evidence of any cancer associations and, for trisomy 21, there was no evidence of any association with solid tumours or lymphomas [25,26]. 5. A raised incidence of pneumonia and other serious infections among the children who later developed leukaemia was confirmed in larger samples of interview

105

Childhood cancers

Table 1. Prenatal X-rays of 1299 case/control pairs included in the 1958 analysis of OSCC data Prenatal X-rays Specifications

1299 cases

1299 controls

Death age* in years

04 5-9

123 55

71 22

Birth rank

First born Other ranks

85 93

36 57

Over 4 months Under 4 months No record

18 148 12

2 83 8

X-ray reasons

Routine ? Twins ? Breach Other

35 53 61 29

20 29 29 15

No. of films

One 2+ No record

37 115 26

27 54 12

Exposure age (months before birth)

Total Types of cancer casest:Lymphatic leukaemia (292) Myeloid leukaemia (124) Other leukaemias (203) Lymphomas (109) Brain tumours (212) Wilms tumour (120) Neuroblastomas (87) Other solid turnouts (152)

RES Neoplasms (728)

Solid tumours (571)

178

93

Obs. 42 9 28 8

Exp.S 40.3 16.2 27.9 14.2

27 19 16 29

28.8 16.7 12.7 21.2

* Or corresponding age for live controls. t ( ) Numbers of cases. $ Assuming no differences between the different types of cancer.

data [27,28]. In this respect children with lymphomas had more in common with the leukaemia cases than the other cancers, but even for the solid tumours there was some evidence of mounting sensitivity to infections during the latent phase of the cancer process. 6. Routine immunisations of the children were reported less often by mothers of cases than by mothers of matched controls [29]. This unexpected difference owed more to solid tumours than leukaemia, and more to immunisations of school children than earlier immunisations, but it was finally estimated that a non-specific effect of the immunisations had achieved the equivalent of a 20 per cent reduction in the risk of an early cancer death. 7. Finally, from OSCC data relating to twins has come evidence that a major determinant of childhood leukaemia may be operating as early as the cleavage date for monozygotic pairs [30]; also evidence that the twins who had been most at risk of dying from anoxia during the second stage of labour (second deliveries of

non-X-rayed twins) had a much reduced risk of an early leukaemia death [31]. Regiona 1 birth cohort analysis The 1984 additions to OSCC data made it possible for a continuous series of 22351 childhood cancers (1953-1979 deaths) to be classified both by date of birth (36 years) and place of birth (911 regions). For the population at risk (i.e. the population described by the regional statistics and interview data) this classification produced 32796 subgroups, but only in 9943 of these ‘regional birth cohorts’ were there any cancer cases [lo]. The question of whether this represented a random or non-random distribution of the cases in two dimensions (space and time), was settled by, first, ascertaining the total period of follow-up (this amounted to 347 567 826 person years) and then giving the 22351 cancer cases their regional birth cohort positions before applying a Poisson heterogeneity test with 911 space units and 36 time units. This statistical test firmly rejected the

A. Stewart

106

Table 2. OSCC data. Distribution by years of birth and years of death of 14759 traced caseswith matchedcontrols Year of birth 1939 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78

Year of death 1953 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 1 1 4 19 27 30 40 60 66 71 59 71 52 30

16 28 36 44 55 61 72 62 58 49 21

9 4 9 6 13 41 48 46 54 51 81 79 80 51 21

6 12 15 15 9 19 32 38 54 53 50 65 59 68 41 25

2 10 12 21 15 15 27 38 23 36 45 39 68 65 43 49 24

14 10 13 10 13 21 42 47 41 54 56 58 75 58 42 27

8 9 19 17 20 28 33 40 42 50 57 64 73 57 54 23

1 12 25 17 10 14 30 43 43 43 51 63 62 64 70 55 19

17 45 35 33 43 28 27 27 32 34 53 55 58 88 73 49 21

20 36 40 35 29 33 28 30 33 28 46 55 58 78 79 55 24

13 45 25 48 17 26 40 40 40 49 45 73 69 68 57 56 33

21 24 40 26 23 24 30 34 37 40 48 69 60 59 55 52 29

16 31 30 25 32 31 29 33 31 48 62 62 79 58 56 48 19

15 38 26 34 25 38 29 32 39 31 51 70 61 78 62 49 29

16 35 34 35 31 32 32 34 43 48 37 62 71 54 68 56 35

12 28 32 24 26 32 28 32 39 29 43 70 67 57 63 38 17

20 30 29 28 23 22 25 28 29 37 38 54 45 58 53 36 17

10 24 27 26 23 28 32 27 25 37 56 35 53 51 35 20 25

8 11 25 30 17 34 28 27 37 39 31 41 44 39 38 33 20

8 23 22 15 18 19 21 26 32 45 39 42 38 52 45 37 19

12 21 15 23 23 23 16 20 16 25 35 35 35 34 29 20 19

14 22 17 19 27 23 14 17 21 39 39 43 36 30 33 26 11

7 21 29 21 16 18 21 30 24 26 27 30 39 24 22 19 21

6 18 21 18 26 18 17 17 22 24 32 33 27 23 25 17 13

7 28 12 16 13 21 25 20 18 25 19 33 19 21 19 18 8

10 21 19 21 15 19 17 17 18 30 22 33 22 17 20 20 6

Percentageascertainment 83

83 83 75 76 76 79 80 78 78 78 77 75 73 73 65 63 63 62 61 53 56 53 57 52 59

random distribution hypothesis in favour of there being an uneven or clustered distribution of the OSCC cases. The Poisson heterogeneity test was followed by a series of regression analyses of all the cancer and radiationrelated factors recorded either in the interview data (i.e. age, sex, social class, sibship position, maternal age, prenatal X-rays, pregnancy illness and postnatal infections) or in the 1984 additions to OSCC data (i.e. annual levels of population density, stillbirth rates and infant mortality rates, and TGR doses) [lo, 111. According to these analyses: (a) the causes of childhood cancers probably include in utero exposures to background radiation as well as prenatal X-rays; and

(b) sensitivity to carcinogenic effects of radiation is probably greater towards the beginning than the end of foetal life. Other factors with cancer associations included social class, pregnancy illnesses, postnatal infections, population density, stillbirths and infant death. For example, compared with all children from the same regions and birth cohorts, the cancer cases were biased in favour of children from well-to-do families, and children who had survived prenatal or postnatal illnesses. In addition, the cancer deaths were concentrated in regions with relatively low levels of population density (rural areas), low stillbirth rates and low rates of infant mortality.

107

Childhood cancers

Fig. 1. Secular trends of leukaemia and pneumonia deaths (O-9 years) (England and Wales, 1911-1966).

Additional Observations Following a run of exceptionally high death rates during World War I (1914-1918) there was, in Britain, both a steadily falling trend of pneumonia mortality and a steadily rising trend of leukaemia mortality. How these changes affected children is shown in Fig. 1, and how they affected age-specific death rates for leukaemia is shown in Fig. 2. After 15 years of age, all types of leukaemia were increasing, but for children, there was no increase in the frequency of juvenile myeloid leukaemia (JML), and even for juvenile lymphatic leukaemia (JLL) there was no increase in the age group most affected by the falling death rate (O-11 months) (Figs 3 and 4). The anomalous findings for infants and slightly older children prompted an inspection of the secular trends of pneumonia and leukaemia mortality in three countries with falling death rates of infant mortality (Britain, U.S.A. and Japan). This inspection was followed by an analysis of deaths before 5 years of age to discover Table 3. Excess risk for a child who is incubating leukaemia to die from pneumonia during the latent phase of the cancer process. From Kneale, 1971 [7]

Country

Age in years

Excess relative risk*

England and Wales (1911-1962)

O-l 1-2 2-3 3-4

83 138t 4137 481t

U.S.A. (1914-1967)

O-l l-2 2-3 3-4

-24 31 186t 193t

(1949-1967)

O-2 l-3 2-4

-199 481t 6334t

* The risk of dying from pneumonia shortly before an actual leukaemia death, compared with a normal risk of 1.0. t Significantly different from the normal risk.

whether there was any evidence of pre-empting of leukaemia deaths by the pneumonia deaths [6]. For deaths after 1 year of age there was strong support for this hypothesis, but for earlier deaths there was no evidence of any associations between the two diseases (Table 3). Though the statistical analysis found no evidence of any masking of infant leukaemias by infection deaths, inspection of the death certificate data for OSCC cases showed that during the period most affected by the switch from passive to active immunity (l-6 months of age) deaths from leukaemia, though rare, were a special risk of infants whose seasons of birth made it unlikely that there had been any exposure to winter conditions during the critical period [8]. The death certificates also showed that it was only among children who were over 2 months of age when they died that JLL was commoner than JML. Meanwhile, work by haematologists was making it increasingly certain that, in cases of JML, there are both raised levels of foetal haemoglobin (HbF) and other signs of faulty erythropoiesis [32]. Since 1975 there have been two reports of raised levels of HbF in infants who experienced sudden, unexplained deaths [33,34]. So far there has been no attempt to confirm this association (by relating HbF levels at the end of the neonatal period to all causes of death between 1 and 12 months of age), but there remains a suspicion that competing causes of death are different for JML and JLL. Discussion As isolated observations, neither the clustered distribution of childhood cancers in Britain, nor the much higher proportion of RES neoplasms among childhood than adult cancers, would mean very much. But together with other findings of the Oxford survey, they make it reasonable to assume that competing causes of death are different for cancers with in utero and later origins. According to this hypothesis, although a non-lethal mutation followed by clone formation may be sufficient to set a cancer process in motion (and thus allow even a small dose of radiation to carry a cancer risk), the mutant cells are in constant danger of being recognised and destroyed by the immune system. By lying dormant, a small clone of slightly abnormal cells may avoid detection until loss of immunological competence creates the conditions necessary for unleashing of a critical potentiality, namely, an abnormal growth potential. This release of a harmful potentiality, previously held in check by immune system constraints, would set in motion the second (promotion) phase of the cancer process and encourage further mutations. But as a result of the new conditions also

108

A. Stewart Acute/chronic i %I80 70 6050 40 30 -

20- Acute to-1

-

, ‘Chronic

o- -_----1920 s 2o-

\

, 10

30

50

I 70

90

I

I

I

I

I

IO

30

50

70

90

Age at death in years

Fig. 2. Age distribution of different types of leukaemia during different periods (England and Wales, 1968-1969).

favouring foreign organisms, there would still remain the possibility of infection death to pre-empting tumour formation. Since the body’s best defence against infections is the immune system, the risk of an infection death would necessarily be greater for RES neoplasms than for solid tumours. Under the influence of antibiotics this difference might disappear, but there would still be differences between cancers with in utero and later

origins. These differences would be largely the result of near-conception mutations having teratogenic effects which caused in utero as well as later deaths. In addition, the in utero environment (with low levels of immunological competence) would favour the second, promotion phase of the cancer process, and the sudden switch to a totally different (and infection-ridden) environment would have special consequences for cancers whose associated effects included faulty

Childhood cancers

60-

Lymphuic

109

Mslu Female: 0- -0

50-

i 40b 4 3020 -

IO -

Age in years

Fig. 4. Mortality from leukaemia children under 5 years of age (England and Wales, 1931-1953). Age in years

Fig. 3. Age and sex distribution of leukaemia by cell types (England and Wales, 1953-1955). maturation of immunoglobulins and haemoglobin. With teratogenic as well as carcinogenic effects of the original mutation there would be an infection risk from faulty maturation of the reticula-endothelial system and an abortion risk from faulty maturation of other cell systems. For tissues of little importance for post embryonic survival, such as the autonomic nervous system, the abortion risk might be small. But given the possibility of antibiotic intervention, RES neoplasms would rapidly become the dominant type of childhood cancer. In countries which have achieved low rates of infant mortality, children are five times as likely to develop leukaemia as more localised forms of RES neoplasms, and juvenile lymphatic leukaemia (JLL) is twice as common as juvenile myeloid leukaemia (JML). JLL has a better prognosis and an older age distribution than JML, and only in cases of JML is there any evidence of faulty maturation of red blood corpuscles [32]. For children with congenital anomalies which have prevented normal development of the immune system (such as trisomy 21, Blooms syndrome, Fanconi’s anaemia, ataxia-telangiectasia, congenital agammaglobulinaemia and familial lymphoedema) there has been a remarkable change from no risk of any leukaemia deaths to an exceptionally high risk [35]. But prevalence rates for JML are no higher today than they were 30 or 40 years ago. A high proportion of lymphatic leukaemias among childhood cancers is only typical of countries which have low rates of infant mortality and nothing unusual in the way of indigenous infections [36,37]. In Uganda, where repeated attacks of malaria are the norm, the

place of JLL has been taken by unusually localised forms of RES neoplasms known as giant lymphomas or Burkitt turnours, and even in cases of JML there are often localised collections of malignant cells or chloromas [38,39]. Burkitt tumours, which have an older age distribution and a better prognosis than JLL, have been ascribed to the Epstein-Barr virus [40]. But they could equally well be the result of constant bombardment by the malarial parasite and other live pathogens both creating exceptionally high levels of passive immunity (maternal effect) and making it possible for this temporary defence against neonatal infections to be immediately replaced by exceptionally high levels of active immunity (direct effect). This hypothesis assumes that immune system constraints are needed for tumour formation, and that relaxation of an excessive constraint was the reason why recent resolution of a malarial problem was followed both by a decreased incidence of Burkitt lymphoma and an increased incidence of JLL [41]. Immune system control of neoplastic as well as infective processes would account for the OSCC findings for immunisations [29], and would also explain why, in adults, localised forms of RES neoplasms (lymphoma and myeloma) are commoner than diffuse forms (leukaemia). But still left unexplained would be (i) the differences between myeloid and lymphatic leukaemia in Fig. 3; (ii) the differences between infants and slightly older children in Fig. 4; and (iii) the different trends of myeloid and lymphatic leukaemia mortality in children and adults (Figs 2 and 3). These outstanding problems are the reason why more than one epidemiologist has rejected the notion that the worldwide increase in leukaemia mortality was merely the result of fewer latency period deaths [35,42]. There are,

110

A. Stewart

however, several reasons why competing causes of death might be different not only for childhood and adult cancers, but also for JLL and JML. During embryogenesis, separation of the reticuloendothelial system into precursors of lymph nodes and red marrow occurs earlier than separation of erythrocytes from myelocytes. Therefore, mutations in embryonic equivalents of lymph nodes, whose only teratogenic effect was faulty maturation of immunoglobulins, might be occurring at the same time as mutations in embryonic equivalents of red marrow, whose effects also included faulty maturation of haemoglobin. With erythrocytic as well as leucocytic abnormalities there might be difficulty in replacing foetal haemoglobin with adult haemoglobin as well as difficulty in replacing passive with active immunity, and the two effects combined might be sufficient to cause a sudden death as soon as passive immunity was exhausted [43]. In short, there is clearly a need to discover how levels of HbF, at birth and at 4 weeks of age, are related to deaths in the next 6 months, since the commonest causes of these deaths are pneumonia and the sudden infant death syndrome, and the latter might be the result of malfunctioning of red as well as white blood corpuscles. References 1. Willis R. A. (1948) Pathology of Turnouts. Butterworths, London. 2. Stewart A. M. (1972) Epidemiology of acute (and chronic) leukemias. In Clinics in Huematology (Roath S., Ed.), Vol. 2, p. 3. W. B. Saunders, London. 3. Hewitt D. (1955) Some features of leukemia mortality. Br. J. Prev. Sot. Med. 9, 81. 4. Stewart A. M., Webb J. & Hewitt D. (1958) A survey of childhood malignancies. Br. Med. J. 1, 1495. 5. Wise M. E. (1961) Irradiation and leukemia. Br. Med. J. 2, 48. 6. Stewart A. M. (1961) Aetiology of childhood malignancies. Br. Med. J. 1, 452. 7. Kneale G. W. (1971) The excess sensitivity of preleukaemics to pneumonia: a model situation for studying the interaction of an infectious disease with cancer. Br. J. Prev. Sot. Med. 25, 152. 8. Stewart A. M. (1975) Infant leukemias and cot deaths. Br. Med. J. 2, 605. 9. Fry F. A. (1987) Doses from environmental radioactivity. In Radiation and Health (Russell, Jones and Southwood, Eds), Vol. 1, p. 9. John Wiley, Chichester, U.K. 10. Kneale G. W. & Stewart A. M. (1987) Childhood cancers in the UK and their relations to background radiation. In Radiation and Health (Russell, Jones and Southwood, Eds), Vol. 16, p. 203. John Wiley, Chichester, U.K. 11. Knox E. G., Stewart A. M., Gilman E. A. & Kneale G. W. (1988) Background radiation and childhood cancers. J. Sot. Radiol. Prot. 8(l), 9. 12. Stewart A. M., Webb J., Giles D. & Hewitt D. (1956) Malignant diseases in childhood and diagnostic irradiation in utero. Lancer 2, 447. 13. Rose K. S. B. (1990) Epidemiological surveys on the

effects of low level radiation dose. In AEA Environment and Energy B74. 14. MacMahon B. (1982) Prenatal X-ray exposure and childhood cancer. J. Nat1 Cancer Inst. 28, 1173. 15. Ford D. D., Paterson J. C. S. & Trueting W. (1959) Fetal exposure to diagnostic X-rays, and leukaemia and other malignant diseases in childhood. J. Nat1 Cancer Inst. 22, 1093. 16. Hewitt D., Lashof J. C. & Stewart A. M. (1966) Oxford survey of childhood cancer progress report IV: reliability of data reported by case and control mothers. Bull. Minist. Hlth. Lab. Serv. 25, 80. 17. Stewart A. M. & Kneale G. W. (1970) Radiation dose effects in relation to obstetric X-rays and childhood cancers. Lancet 1, 1185. 18. Stewart A. M. & Kneale G. W. (1970) The age distributions of cancers caused by obstetric X-rays and their relevance to cancer latent periods. Lancet 2, 4. 19. Bithell J. F. & Stewart A. M. (1975) Pre-natal irradiation and childhood malignancy: a review of British data from the Oxford survey. Br. J. Cancer 31, 271. 20. Kneale G. W. & Stewart A. M. (1976) M-H Analysis of Oxford data: I. Independent effects of several birth factors including fetal irradiation. J. Nat1 Cancer Inst. 56, 879. 21. Kneale G. W. & Stewart A. M. (1976) M-H Analysis of Oxford data: II. Independent effects of fetal irradiation subfactors. J. Nat1 Cancer Inst. 57, 1009. 22. Kneale G. W. & Stewart A. M. (1977) Age variation in the cancer risks from fetal irradiation. Br. J. Cancer 35, 501. 23. Gilman E. A., Kneale G. W., Knox E. G. & Stewart A. M. (1988) Pregnancy X-rays and childhood cancers: effects of exposure age and radiation dose. J. Sot. Radiol. Prot. 8(l), 3. 24. Knox E. G., Stewart A. M., Kneale G. W. & Gilman E. G. (1987) Prenatal irradiation and childhood cancer. J. Radiol. Prot. l(4), 3. 25. Lashof J. C. & Stewart A. M. (1965) Oxford Survey of Childhood Cancers progress report III: Leukaemia and Down’s syndrome. Bull. Minist. Hlth Lab. Serv. 24, 136. 26. Stewart A. M. & Hewitt D. (1965) Leukaemia incidence in children in relation to radiation exposure in early life. In Current Topics in Radiation Research (Egbert M. & Howard A., Eds), Vol. 1, p. 223. North-Holland Publ. Co., Amsterdam. 27. Kneale G. W. & Stewart A. M. (1978) Pre-cancers and liability to other diseases. Br. J. Cancer 37, 448. 28. Stewart A. M. & Kneale G. W. (1982) The immune system and cancers of fetal origin. Cancer Immunol. & Immunother. 14, 110. 29. Kneale G. W., Stewart A. M. & Kinnier Wilson L. M. (1986) Immunizations against infectious diseases and childhood cancers. Cancer Immunol. & Immunother. 21, 129. 30. Knox E. G., Marshall T. & Barling R. T. (1984) Leukaemia and childhood cancer in twins. J. Epid. & Comm. Health 38(l), 12. 31. Hewitt D., Lashof J. C. & Stewart A. M. (1966) Childhood cancer in twins. Cancer 19(2), 157. 32. Wintrobe M. M. (1981) Clinical Haematology, 8th edn. Lea & Febigh, Philadelphia. 33. Giulian G. G., Gilbert E. F. & Moss R. L. (1987) Elevated fetal hemoglobin levels in sudden infant death syndrome. New Engl. J. Med. 316, 1122. 34. Fagan D. G. & Walker A. (1992) Haemoglobin F levels in sudden infant deaths. Br. J. Haemat. 82, 422.

Childhood cancers 35. Doll R. (1989) The epidemiology of childhood leukemia. J. R. Statist. Sot. 152(3), 341. 36. Stewart A. M. (1980) Childhood cancers and the immune system. Cancer Immunol. & Immunother. 9, 11. 37. Stewart A. M. & Kneale G. W. (1969) The role of local infections in the recognition of haemopoietic neoplasms. Nature 223, 741. 38. Burkitt D. P. & Wright D. H. (1970) Burkitt’s Lymphoma. E. & S. Livingstone, Edinburgh & London. 39. Davies J. N. P. & Gwor R. Chloromatous tumours in African children in Uganda. Br. Med. J. 2, 405. 40. de The, Gesen A., Day N. E., et al. (1978) Epidemiological evidence of causal relationship between Epstein-Barr virus

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and Burkitt’s lymphoma from Uganda prospective study. Nature 274, 756. 41. Ramot B., Ben-Bassat I. & Modan M. (1984) Observations on lymphatic malignancies in Israel. In Pathogenesis of Leukaemias and Lymphomas: Environmental Influences (Magrath I. T., O’Connor G. T. & Ramot B., Eds). Raven Press, New York. 42. Greaves M. F. (1990) Etiology of childhood leukemia. In Acute Lymphoblastic Leukemia (Gale R. P., Ed.). Alan R. Liss, New York. 43. Stewart A. M. (1990) Etiology of childhood leukemia: a possible alternative to the Greaves hypothesis. Leukemia Res. 14, 937.