1. Birthweight & Childhood Leukaemia: Results from pooled analyses Tracy Lightfoot Epidemiology & Cancer Statistics Unit Department of Health Sciences University of York

2. In utero origins of leukaemia Evidence childhood leukaemia originates in utero. Chromosomal translocations such as t(12;21), t(4;11), or t(8;21) are found at birth in children who later develop leukaemia. Indicative that prenatal exposures may be important in leukaemogenesis

3. Aetiology of childhood leukaemia Known risk factors –Age –Sex –Trisomy 21

4. Aetiology of childhood leukaemia Known risk factors –Age –Sex –Trisomy 21 Consistent observations –Genetic variants IKZF1(7p12.2), CDKN2A/CDKN2B(9p21), ARID5B(10q21.2), CEBPE(14q11.2) –Heavy birthweight (> 3500, 4000 or 4500g)

5. Previous meta-analysis 18 studies conducted between 1962-2002 10282 children - 5281 ALL cases OR 1.26 (95% CI 1.17-1.37) (≥4,000 g vs. <4,000 g) 14% increase in risk of ALL per 1000g increase in birthweight

6. Additional observations Findings similar for B-cell ALL and T-cell ALL and individuals subtypes (Hjalgrim et al., 2004; O’Neil et al., 2012) –Suggest determinants are not risk factors for a specific type of ALL Children with ALL have the same birthweight as their siblings ( Hjalgrim et al., 2004 and Smith et al., 2010 )

7. Questions still to answer? What’s the relationship between ALL and fetal growth across the gestational age spectrum? What’s the relative importance of a baby’s absolute weight/size at birth versus the rate of fetal growth?

8. Potential issues….. Rare events: ALL accounts for less than 0.5% of all incident cancers Less than 1% of live births weighing < 1500g, and only 1- 3% weight above 4500g. Most investigations concentrate on high birthweight, either dichotomizing their data (e.g. <4000g versus ≥ 4000g) or using relatively conservative cut-points (e.g. <2500g, 2500-3999g, ≥ 4000g). Self-reported data: Many of the case-control studies on this topic have relied on birth characteristics reported by mothers at interview, (potential for maternal recall bias)

9. Recent studies Pooled analyses from Germany, UK and USA – started 2001 – published 2013 –4075 cases and 12065 controls Pooled analyses from CLIC –Started 2009 – published 2013 –7348 cases and 12489 controls (12 studies) 1680 cases and 3139 controls POBW

10. USA UK Germany ControlsCases ControlsCases ControlsCases N (%) Total19481001775100 74631001405100 2412100742100 Gender Boys105654.298755.6 419956.378455.8 136556.643959.2 Girls89245.878844.4 326443.762144.2 104743.430340.8 Age at diagnosis (years) 0804.1593.3 6148.2493.5 2249.3283.8 1-4102952.894253.1 310241.675753.9 101242.040354.3 5-956929.251829.2 203327.237826.9 73630.521328.7 10-1427013.925614.4 171423.022115.7 44018.29813.2 Maternal age birth (years) <201145.91588.9 4636.21138.0 662.7304.0 20-29124063.7108661.2 452960.785260.6 155864.649466.6 30-3958129.851629.1 234531.441629.6 76431.720828.0 ≥ 40130.7150.9 911.2151.1 231.081.1 Birth order 185543.975142.3 330644.364445.8 117348.639553.2 267034.464836.5 258534.647033.5 86736.024032.4 329114.923513.2 107414.420714.7 28611.98010.8 ≥41326.81417.9 4986.7846.0 853.5263.5

11. USA UK Germany ControlsCases ControlsCases ControlsCases N (%) Total194810017755100 74631001405100 2412100742100 Type of delivery Vaginal151577.8139278.4 659488.4123888.1 209786.964286.5 Caesarian43322.238321.6 86711.616411.7 31313.09813.2 Gestational age (weeks) <371075.5844.7 4405.9926.6 923.8425.7 37-40134569.1124670.2 484965.089463.6 168669.950267.7 >4049625.544525.1 212328.540528.8 60525.118725.2 Birth weight (kg) <2.5944.8694.0 4285.7654.7 682.8233.1 2.5-3.493247.882746.6 398653.470650.3 124851.736048.5 3.5-4.486944.782646.6 285338.358741.8 104143.233144.6 > 4.5522.7502.8 1291.7322.3 482.0223.0

12. Individual countries and pooled birthweight distributions

13. US, UK and Germany pooled birth weight distribution by gestational age

14. Birthweight Number (%) Adjusted OR † (95% CI) Adjusted OR ‡ (95% CI) ControlsCases Grams ≤150057 (0.5) 5 (0.1) 0.3 (0.1-0.7)0.2 (0.1-0.7) 1500-1999109 (0.9) 38 (1.0) 1.2 (0.8-1.6)0.8 (0.4-1.4) 2000-2499421 (3.6) 111 (2.9) 0.8 (0.7-1.0)0.7 (0.6-1.0) 2500-29991732 (14.8) 494 (12.7) 0.9(0.8-1.0) 3000-34994410 (37.7) 1393 (35.9) } 1.0 3500-39993664 (31.3) 1279 (32.9) 4500-44991086 (9.3) 460 (11.9) 1.2 (1.1-1.4) ≥4500227 (1.9) 103 (2.6) 1.2 (0.9-1.6) P<0.0001 Birthweight and ALL

15. Birthweight Number (%) Adjusted OR † (95% CI) Adjusted OR ‡ (95% CI) ControlsCases Gestational age <37 weeks < 10 62 (9.8) 10 (4.6) 0.5 (0.2-1.0) 10-19 65 (10.2)24 (11.1) 1.0 (0.6-1.7)1.0 (0.6-1.8) 20-79 382 (60.1)131 (60.4) 1.0 80-89 58 (9.1)22 (10.1) 1.2 (0.7-2.1) ≥ 90 69 (10.9)30 (13.8) 1.6 (0.9-2.6)1.6 (0.9-2.7) Per kg increase 1.4 (1.1-1.8) 37-40 weeks < 10 778 (9.9)184 (7.0) 0.8 (0.7-0.9) 10-19 781 (10.0)234 (8.9) 0.9 (0.8-1.1)0.9 (0.9-1.2) 20-79 4691 (59.8)1573 (59.8) 1.0 80-89 778 (9.9)281 (10.7) 1.0 (0.9-1.2) ≥ 90 820 (10.5)358 (13.6) 1.2 (1.0-1.4)1.2 (1.0-1.3) Per kg increase 1.2 (1.1-1.3)1.2 (1.0-1.3) >40 weeks < 10 308 (9.6)88 (8.5) 1.0 (0.8-1.3) 10-19 279 (8.7)90 (8.7) 1.2 (0.9-1.6) 20-79 1966 (61.0)580 (56.0) 1.0 80-89 320 (9.9)120 (11.6) 1.2 (1.0-1.6) ≥ 90 349 (10.8)158 (15.3) 1.5 (1.2-1.9)1.5 (1.2-1.8) Per kg increase 1.3 (1.1-1.5)

18. Study population  Children (≤ 15 years) registered for primary care with a General Practitioner (GP) Cases - ascertained from multiple sources  Treating/referring hospitals  Cross-checks with cancer registries Controls – 2 per case from primary care population registers, individually matched on:-  date of birth  sex  UKCCS region of residence Linked to primary care and maternity records, registration and census data, birth and death certificates for all cases and controls irrespective of participation in the study

19. UK BWT interview versus birth certificates

20. Gestational Age

21. Gestational age

22. UK control data Birth weight (grams) E & W,1988 UKCCS Unadjusted ORs (95% CI) Live births ControlsCases UKCCS cases versus UKCCS Controls UKCCS cases Versus E & W Controls N= 693,577 (%) N=6337 (%)N=1366 (%) <15006511 (0.9) 29 (0.5)0 } 0.6 (0.3-1.1) } 0.5 (0.3-0.9) 1500-1999 8989 (1.3) 88 (1.4) 16 (1.2) 2000-2499 30181 (4.4) 285 (4.5) 59 (4.3) 1.0 (0.7-1.3) 1.0 (0.8-1.4) 2500-2999 118808 (17.2) 1049 (16.6) 210 (15.4) 1.0 (0.8-1.1) 0.9 (0.8-1.1) 3000-3499 260932 (37.7) 2380 (37.6) 497 (36.4) 1.0 3500-3999 198593 (28.7) 1838 (29.0) 415 (30.4) 1.1 (0.9-1.2) 1.1 (1.0-1.2) 4000-4499 59299 (8.6) 583 (9.2) 135 (9.9) 1.1(0.9-1.4) 1.2 (1.0-1.4) ≥4500 9433 (1.4) 85 (1.3) 34 (2.5) 1.9(1.3-2.9) 1.9 (1.3-2.7)

23. Summary Children with ALL were, on average, heavier than controls at all gestations Overall, a 1.2 (95% CI 1.1-1.3) increase in ALL risk per kg increase in birthweight was observed –driven by a deficit of low-birthweight at all gestations and an excess of high-birthweight at ≥ 40 weeks. Stable relationship within age strata (< 1, 1-4, 5-9 and 10-14 years) is noteworthy and is in accord with other studies that have presented age-specific data. –Confirms association with size at birth is not restricted to infants, as had originally been suggested

24. Conclusions Importance of looking across full birthweight spectrum when examining associations with disease risk. For the first time identified marked paucity of very low-birthweight babies (< 1500g) among ALL cases at all gestational ages; –given in-utero origins of ALL presence of disease at birth could act to increase perinatal mortality in this immature and vulnerable group?

26. Map of Childhood Leukemia Studies participating in CLIC 26 4 13 12 14 15 9,10,11 16 17 18 6,7 8 5 1 2 3 Pooled analysis : California State, USA, COG, USA, Canada; Brazil; UK, France (x3), Germany; Greece, Australia, New Zealand.

27. Fetal growth and childhood acute lymphoblastic leukemia: LGA v AGA OR 1.24 95% CI (1.13-1.36)

28. Total N 1 Cases/Controls Cases N LGA/AGA Controls N LGA/AGA OR95% CI Overall 7,292/12,406988/5,6701,398/9,7791.211.11, 1.32 Birth weight <4,000g 6,394/11,077297/5,463408/9,4401.261.07, 1.48 Sex Males4,106/6,905552/3,192782/5,4351.181.05, 1.33 Females3,186/5,501436/2,478616/4,3441.251.09, 1.43 Age at diagnosis 0-1636/1,44776/521154/1,1491.040.75, 1.44 >1-54,075/6,087559/3,178712/4,8081.201.06, 1.35 >52,581/4,872353/1,971532/3,8221.261.08, 1.46 Ethnicity White/European/Caucasian6,042/10,858812/4,7471,232/8,6181.181.07, 1.30 Other1,250/1548176/9231,66/1,1611.441.14, 1.83 Immunophenotype B-lineage cases5,735/12,406771/4,4561,398/9,7791.201.09, 1.33 T-lineage cases705/12,406105/5461,398/9,7791.321.05, 1.64

29. Proportion of Optimal Birthweight Takes into account mothers height (cm), birthorder, sex, birthweight (g) and gestational age

30. Fetal growth and childhood acute lymphoblastic leukemia: POBW OR 1.16 95% CI (1.09-1.24)

31. SubgroupN Cases/controlsPooled OR 2 95% CI Overall1,689/3,1541.161.09, 1.24 Birth weight <4,000g1,467/2,7711.211.12, 1.31 Sex of child 3 Males954/1,7461.111.02, 1.21 Females735/1,4081.221.12, 1.34 Age at diagnosis (years) 4 0-1179/2681.090.87, 1.37 >1-5971/1,7691.171.08, 1.27 >5539/1,1171.181.06, 1.31 Ethnic Group 5 White/European/Caucasian1,281/2,5831.141.06, 1.23 Other408/5711.221.08, 1.39 Immunophenotype B-lineage cases1,400/3,1541.171.09, 1.24 T-lineage cases161/3,1541.221.04, 1.43

32. Summary Accelerated fetal growth associated with increased risk of ALL irrespective of high birth weight. Effect consistent whether using categorical or continuous measure of growth.

33. Mechanisms??????? Links with other childhood/adults cancers ↑ IGF1 levels –Drives pre-leukaemic cells towards leukemogenesis –Pre-leukaemic cells have higher IGF-1 levels leading to higher birthweight Not supported by sibling birthweight observations Factors governing IGF levels e.g. PAPP-A In utero levels of estrogens Increased numbers of stem cells ???????????????????

34. Acknowledgements Eve Roman Alex Smith Michele R Forman Martha S Linet Les Robison Jill Simpson Peter Kaatsch Kathrine Grell Kirsten Frederiksen Joachim Schüz Clinicians/Health Professionals Funders Families… Elizabeth Milne Kathryn R. Greenop Catherine Metayer Eleni Petridou Maria S. Pombo-de-Oliveira Claire Infante-Rivard John D. Dockerty Logan Spector Sérgio Koifman Laurent Orsi Jérémie Rudant Nick Dessypris Margarita Baka Alessandra Faro Bruce K. Armstrong Jacqueline Clavel Patricia A. Buffler