Birthweight & Childhood Leukaemia:

Results from pooled analyses

Tracy Lightfoot Epidemiology & Cancer Statistics Unit

Department of Health Sciences University of York

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

Aetiology of childhood leukaemia

• Known risk factors– Age– Sex– Trisomy 21

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)

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

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)

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?

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)

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

    USA   UK   Germany    Controls Cases   Controls Cases   Controls Cases

    N (%) N (%)   N (%) N(%)   N (%) N (%)                             Total 1948 100 1775 100   7463 100 1405 100   2412 100 742 100

Gender                  Boys 1056 54.2 987 55.6   4199 56.3 784 55.8   1365 56.6 439 59.2  Girls 892 45.8 788 44.4   3264 43.7 621 44.2   1047 43.4 303 40.8

Age at diagnosis (years)  0 80 4.1 59 3.3   614 8.2 49 3.5   224 9.3 28 3.8  1-4 1029 52.8 942 53.1   3102 41.6 757 53.9   1012 42.0 403 54.3  5-9 569 29.2 518 29.2   2033 27.2 378 26.9   736 30.5 213 28.7  10-14 270 13.9 256 14.4   1714 23.0 221 15.7   440 18.2 98 13.2

Maternal age birth (years)  <20 114 5.9 158 8.9   463 6.2 113 8.0   66 2.7 30 4.0  20-29 1240 63.7 1086 61.2   4529 60.7 852 60.6   1558 64.6 494 66.6  30-39 581 29.8 516 29.1   2345 31.4 416 29.6   764 31.7 208 28.0  ≥ 40 13 0.7 15 0.9   91 1.2 15 1.1   23 1.0 8 1.1     Birth order  1 855 43.9 751 42.3   3306 44.3 644 45.8   1173 48.6 395 53.2  2 670 34.4 648 36.5   2585 34.6 470 33.5   867 36.0 240 32.4  3 291 14.9 235 13.2   1074 14.4 207 14.7   286 11.9 80 10.8  ≥4 132 6.8 141 7.9   498 6.7 84 6.0   85 3.5 26 3.5

    USA   UK   Germany    Controls Cases   Controls Cases   Controls Cases

    N (%) N (%)   N (%) N(%)   N (%) N (%)

                             

Total 1948 100 17755 100   7463 100 1405 100   2412 100 742 100

                 

Type of delivery  Vaginal 1515 77.8 1392 78.4   6594 88.4 1238 88.1   2097 86.9 642 86.5  Caesarian 433 22.2 383 21.6   867 11.6 164 11.7   313 13.0 98 13.2     

Gestational age (weeks)                          <37 107 5.5 84 4.7   440 5.9 92 6.6   92 3.8 42 5.7  37-40 1345 69.1 1246 70.2   4849 65.0 894 63.6   1686 69.9 502 67.7  >40 496 25.5 445 25.1   2123 28.5 405 28.8   605 25.1 187 25.2

     

Birth weight (kg)                          <2.5 94 4.8 69 4.0   428 5.7 65 4.7   68 2.8 23 3.1  2.5-3.4 932 47.8 827 46.6   3986 53.4 706 50.3   1248 51.7 360 48.5  3.5-4.4 869 44.7 826 46.6   2853 38.3 587 41.8   1041 43.2 331 44.6  > 4.5 52 2.7 50 2.8   129 1.7 32 2.3   48 2.0 22 3.0                                    

Individual countries and pooled birthweight distributions

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ALL cases and controlsUS birth weight

control ALL

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control ALL

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

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under36 36 37 38 39 40 41 42 over42

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ALL cases and controlsPooled birth weight by gestation

control ALL

   Birthweight

 

Number (%)  Adjusted OR†

(95% CI)Adjusted OR‡  

(95% CI)    Controls Cases

Grams                ≤1500 57 (0.5)  5 (0.1)    0.3 (0.1-0.7) 0.2 (0.1-0.7)    1500-1999 109 (0.9)  38 (1.0)   1.2 (0.8-1.6) 0.8 (0.4-1.4)    2000-2499 421 (3.6) 111 (2.9)   0.8 (0.7-1.0) 0.7 (0.6-1.0)    2500-2999 1732 (14.8)  494 (12.7)   0.9(0.8-1.0) 0.9 (0.8-1.0)    3000-3499 4410 (37.7) 1393 (35.9)   } 1.0  } 1.0     3500-3999 3664 (31.3) 1279 (32.9)      4500-4499 1086 (9.3) 460 (11.9)   1.2 (1.1-1.4) 1.2 (1.1-1.4)    ≥4500 227 (1.9) 103 (2.6)   1.2 (0.9-1.6) 1.2 (0.9-1.6)

             P<0.0001 P<0.0001 

Birthweight and ALL

    Birthweight 

Number (%)   Adjusted OR†

(95% CI)Adjusted OR‡  (95% CI)    Controls Cases

  Gestational age              <37 weeks              < 10 62 (9.8) 10 (4.6)   0.5 (0.2-1.0) 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 1.0    80-89 58 (9.1) 22 (10.1)   1.2 (0.7-2.1) 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) 1.4 (1.1-1.8)    37-40 weeks              < 10 778 (9.9) 184 (7.0)   0.8 (0.7-0.9) 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 1.0    80-89 778 (9.9) 281 (10.7)   1.0 (0.9-1.2) 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) 1.0 (0.8-1.3)    10-19 279 (8.7) 90 (8.7)   1.2 (0.9-1.6) 1.2 (0.9-1.6)    20-79 1966 (61.0) 580 (56.0)   1.0 1.0    80-89 320 (9.9) 120 (11.6)   1.2 (1.0-1.6) 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) 1.3 (1.1-1.5)

 Variable 

Birthweight  Number  (%)    Adjusted  OR‡  (95% CI) 

OR ‡ (95% CI) Per kg increase   Centile  Cases   Controls   

Gender               Boys  < 10  167 (7.6)  643 (9.8)    0.8 (0.6-1.0)       10-19  204  9.3  660  10.1    1.0 (0.8-1.2)       20-79  1281  58.6  3875  59.1    1.0  1.2(1.1-1.3)      80-89  245  11.2  713  10.9    1.0 (0.8-1.2)  P<0.001     ≥ 90  290  13.3  662  10.1    1.2 (1.1-1.5)                        Girls  < 10  123  7.3  496  9.6    0.7 (0.5-0.9)       10-19  145  8.6  522  10.1    0.9 (0.7-1.1)       20-79  1012  59.7  3104  60.2    1.0  1.2 (1.1-1.4)      80-89  169  10.0  514  10.0    1.0 (0.8-1.2)  P<0.001     ≥ 90  247  14.6  517  10.0    1.3 (1.1-1.6)   Age at diagnosis                   < 1 year  < 10  8  5.9  91  10.0    0.7 (0.3-1.6)       10-19  11  8.2  85  9.3    0.8 (0.4-1.6)       20-79  89  65.9  554  60.7    1.0  1.4 (1.0-2.1)      80-89  12  8.9  87  9.5    0.8 (0.4-1.7)  P>0.05     ≥ 90  15  11.1  96  10.5    1.2 (0.6-1.3)                        1-4  years  < 10  160  7.7  506  9.9    0.7 (0.6-0.9)       10-19  197  9.4  512  10.0    1.0 (0.8-1.2)       20-79  1235  59.1  3035  59.4    1.0  1.2 (1.1-1.3)      80-89  227  10.9  542  10.6    1.0 (0.8-1.2)  P<0.001     ≥ 90  271  13.0  512  10.0    1.2 (1.0-1.4)                        5-9 years  < 10  80  7.3  328  10.0    0.8 (0.6-1.1)       10-19  96  8.8  307  9.3    1.1 (0.8-1.4)       20-79  630  57.7  1984  60.2    1.0  1.2 (1.0-1.4)      80-89  142  13.0  346  10.5    1.2 (0.9-1.5)  P<0.05     ≥ 90  144  13.2  333  10.1    1.3 (1.1-1.7)                        10-14 years  < 10  49  8.7  232  9.7    0.8 (0.5-1.2)       10-19  49  8.7  202  8.5    1.0 (0.7-1.4)       20-79  316  55.8  1453  60.9    1.0  1.2 (1.0-1.5)     80-89  73  12.9  263  11.0    1.2 (0.8-1.6)  P<0.05     ≥ 90  79  14.0  238  10.0    1.4 (1.0-1.9)   

 Variable 

Birthweight  Number (%)    Adjusted  OR‡ (95% CI) 

OR ‡ (95% CI) Per kg increase   Centile  Cases   Controls   

Birth order                   1  < 10  142  8.0  525  10.0    0.7 (0.6-0.9)       10-19  157  8.9  486  9.2    1.0 (0.8-1.2)       20-79  1066  60.2  3199  60.7    1.0  1.2 (1.0-1.3)     80-89  152  8.6  522  9.9    0.8 (0.7-1.1)  P<0.01     ≥ 90  253  14.3  541  10.3    1.2 (1.0-1.5)                        > 1  < 10  155  7.3  636  9.9    0.8 (0.6-0.9)       10-19  167  7.9  606  9.4    0.9 (0.8-1.1)       20-79  1277  60.5  3903  60.7    1.0  1.2 (1.1-1.4)     80-89  245  11.6  645  10.0    1.1 (1.0-1.4)  P<0.001     ≥ 90  268  12.7  643  10.0    1.3 (1.1-1.5)   Caesarean Section                   No  < 10  248  7.7  1002  9.9    0.8 (0.7-1.0)       10-19  299  9.2  940  9.3    1.0 (0.9-1.2)       20-79  1904  58.8  6102  60.4    1.0  1.2 (1.1-1.3)     80-89  352  10.9  1045  10.3    1.1 (0.9-1.2)  P<0.001     ≥ 90  437  13.5  1016  10.1    1.3 (1.2-1.5)                        Yes  < 10  34  5.3  154  9.6    0.4 (0.2-0.8)       10-19  51  8.0  158  9.9    0.7 (0.5-1.0)       20-79  398  62.2  965  60.4    1.0  1.3 (1.0-1.6)     80-89  61  9.5  146  9.1    0.9 (0.6-1.2)  P<0.05     ≥ 90  96  15.0  176  11.0    1.2 (0.8-1.6)   

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

UK BWT interview versus birth certificates

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UKCCS gestational age relative frequencyobstetric & interview data

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UKCCS gestational age relative frequencyobstetric & interview data

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UKCCS gestational age relative frequencyobstetric & interview data

Obstetric Interview

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UKCCS gestational age relative frequencyobstetric & interview data

Obstetric Interview

UK control dataBirth

weight(grams)

E & W,1988   UKCCS   Unadjusted ORs (95% CI)

Live births 

Controls Cases   UKCCS cases versus UKCCS

Controls

UKCCS cases Versus

E & W Controls  N= 693,577 (%)

 N=6337 (%) N=1366 (%)  

<1500 6511 (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 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)

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

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?

Map of Childhood Leukemia Studies participating in CLIC

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Pooled analysis : California State, USA, COG, USA, Canada; Brazil; UK, France (x3), Germany; Greece, Australia, New Zealand.

Fetal growth and childhood acute lymphoblastic leukemia: LGA v AGA

OR 1.24 95% CI (1.13-1.36)

  Total N1

Cases/Controls

Cases N LGA/AGA

Controls N LGA/AGA

OR 95% CI

Overall 7,292/12,406 988/5,670 1,398/9,779

1.21 1.11, 1.32

Birth weight <4,000g

6,394/11,077 297/5,463 408/9,440 1.26 1.07, 1.48

Sex          Males 4,106/6,905 552/3,192 782/5,435 1.18 1.05, 1.33Females 3,186/5,501 436/2,478 616/4,344 1.25 1.09, 1.43

Age at diagnosis        0-1 636/1,447 76/521 154/1,149 1.04 0.75, 1.44>1-5 4,075/6,087 559/3,178 712/4,808 1.20 1.06, 1.35>5 2,581/4,872 353/1,971 532/3,822 1.26 1.08, 1.46

Ethnicity          White/European/Caucasian

6,042/10,858 812/4,747 1,232/8,618

1.18 1.07, 1.30

Other 1,250/1548 176/923 1,66/1,161 1.44 1.14, 1.83

Immunophenotype          B-lineage cases 5,735/12,406 771/4,456 1,398/9,77

91.20 1.09, 1.33

T-lineage cases 705/12,406 105/546 1,398/9,779

1.32 1.05, 1.64

Proportion of Optimal Birthweight

• Takes into account mothers height (cm), birthorder, sex, birthweight (g) and gestational age

Fetal growth and childhood acute lymphoblastic leukemia: POBW

OR 1.16 95% CI (1.09-1.24)

Subgroup N Cases/controls

Pooled OR2

95% CI

Overall 1,689/3,154 1.16 1.09, 1.24Birth weight <4,000g 1,467/2,771 1.21 1.12, 1.31Sex of child3      Males 954/1,746 1.11 1.02, 1.21Females 735/1,408 1.22 1.12, 1.34Age at diagnosis (years) 4

     

0-1 179/268 1.09 0.87, 1.37>1-5 971/1,769 1.17 1.08, 1.27>5 539/1,117 1.18 1.06, 1.31Ethnic Group5      White/European/Caucasian

1,281/2,583 1.14 1.06, 1.23

Other 408/571 1.22 1.08, 1.39Immunophenotype      B-lineage cases 1,400/3,154 1.17 1.09, 1.24T-lineage cases 161/3,154 1.22 1.04, 1.43

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.

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• ???????????????????

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