Background
A recent study, reported by Steliarova-Foucher et al. [
1], revealed that the incidence of childhood cancer from 2001 to 2010 has increased since the 1980s in most parts of the world. The most common cancers among children are leukemia and central nervous system (CNS) tumors. According to a recent study conducted in the US, a significant upward trend in the incidence rate of acute lymphocytic leukemia (ALL) was noticed in children aged 5 to 9 years between 2000 and 2010; however, the incidence rates of CNS tumors remained stable [
2]. For children aged 10 to 14 years, however, the incidence rates of both ALL and CNS tumors increased significantly [
2]. A few genetic syndromes and ionizing radiation are established risk factors for both childhood leukemia and CNS tumors [
3,
4]. High birth weight (BW), 4000 g or larger, is also known to be a risk factor for childhood leukemia, especially ALL [
5‐
8]. However, its association with childhood CNS tumor risk is yet unclear [
5,
6,
9,
10].
In a large case-control study of children younger than 5 years of age, conducted in Texas, the US, the leukemia risk was elevated among those with high BWs (Odds ratio [OR]) = 1.36; 95% confidence interval [CI] = 1.10, 1.69). However, the CNS tumor risk was not evidently increased among them (OR = 1.14; 95%CI = 0.83, 1.56) [
6]. Similar results were obtained by a German study. High-BW children had ORs of 1.41 (95%CI = 1.08, 1.84), 1.56 (95%CI = 0.88, 2.79) and 1.34 (95%CI = 0.97, 1.85), respectively, for ALL, acute myeloid leukemia (AML) and CNS tumors when compared to normal-BW children [
11]. However, it should be noted that gestational age (GA) was not adjusted in those studies. Another large case-control study, conducted in California, which focused on CNS tumors reported a GA-adjusted OR of 1.12 (95%CI = 0.91, 1.38) [
9]. In a population-based case-control study conducted in four Nordic countries, the ORs of ALL, AML and CNS tumors were 1.3 (95%CI = 1.1, 1.5), 1.5 (95%CI = 1.3, 1.8) and 1.3 (95%CI = 0.85–2.0), respectively, when children with BWs of 4500 g or larger were compared to those with 3000–3500 g, adjusting for GA [
12]. Taken together, the leukemia risk was increased by 30% to 50% even after the adjustment for GA. In the case of CNS tumor risk, the association appears to be weaker.
Regarding the effect of BW itself, several studies have investigated its effect on the risks of childhood leukemia and CNS tumors. Previous studies in Texas [
6] and California [
13] consistently found that an each 1000-g increase in BW was associated with leukemia risk: the ORs (95%CI) were 1.28 (1.12–1.44) and 1.11 (1.01, 1.21), respectively. On the other hand, the association of BW with CNS tumor risk in those states was not statistically significant: ORs were 1.17 (95%CI = 0.98, 1.40) [
6], and 1.11 (95%CI = 0.99, 1.24) [
9], respectively.
Longer GAs are also suspected to be a risk factor for CNS tumors. A French study [
14] reported that children with longer GAs (41 weeks or longer) were at an increased CNS tumor risk (OR = 1.4; 95%CI = 0.6, 3.3) when compared to those with the GA of 37–40 weeks, although there was no statistical significance. A Swedish study observed a similar trend in which children with the GA of 43 weeks or longer had a 1.2-fold increase of brain tumor risk (OR = 1.2; 95%CI = 0.4, 3.8) when compared to those with the GA of 38–42 weeks [
15]. Only a slight increase in the CNS tumor risk was observed in the Texas study (OR = 1.07; 95%CI = 0.78, 1.47) [
6]. However, the findings on the association of leukemia risk with GA were inconsistent. The Texas study reported that children with the GA of 41 weeks or longer had a slightly decreased leukemia risk (OR = 0.91; 95%CI = 0.71, 1.15) when compared to those with the GA of 37–40 weeks [
6]. A contrary result was reported in a study conducted in Denmark, Sweden, Norway and Iceland, which pointed to an OR of 1.08 (95%CI = 0.90, 1.29) for longer GAs (42 weeks or longer) compared to the GA of 40–41 weeks [
16].
BW is strongly related to GA [
17]. Based on GA, BW can be divided into three categories: small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA). In the Texas study, the LGA was significantly associated with an increased ALL risk (OR = 1.66; 95%CI = 1.32, 2.10), but not for CNS tumor risk (OR = 1.14; 95%CI = 0.82, 1.58) [
6]. A study in California also showed no significant association between LGA and the risk of CNS tumors (OR = 1.09; 95%CI = 0.89, 1.27) [
9]. In the German study, the OR of ALL was 1.45 (95%CI = 1.07, 1.97) in LGA children compared to AGA children. However, the OR for CNS tumor was not statistically significant: 1.18 (95%CI = 0.80, 1.72) [
11]. In the Nordic study, LGA was related neither ALL risk (OR = 1.2; 95%CI = 0.91, 1.5) nor CNS tumor risk (OR = 1.1; 95%CI = 0.85, 1.4) [
12]. Taken together, those studies suggested that LGA children may be at an elevated ALL risk. The association with the risk of CNS tumors is unlikely.
The studies described above showed no association between CNS tumor risk and SGA. The ORs in the studies of California [
9], Texas [
6], West Germany [
11], and the Nordic countries [
12] were 0.96 (95%CI = 0.75, 1.23), 0.98 (95%CI = 0.70, 1.38), 0.96 (95%CI = 0.67, 1.37) and 0.95 (95%CI = 0.77, 1.20), respectively. However, the findings on the association between leukemia risk and SGA are inconsistent. The ORs for all types of leukemia and ALL were 0.88 (95%CI = 0.68, 1.13) and 0.78 (95%CI = 0.57, 1.05), respectively, in the Texas study [
6]. The ORs for ALL and AML were 1.00 (95%CI = 0.74, 1.35) and 0.89 (95%CI = 0.43, 1.83), respectively, in the German study [
11], and 1.2 (95%CI = 0.96, 1.50) and 1.8 (95%CI = 1.1, 3.1), respectively, in the Nordic study [
12].
We analyzed data from a case-control study which was originally conducted in the US to examine the association between paternal preconception exposure to ionizing radiation and the risk of childhood cancer, and this study found no association between them [
18]. Using this dataset, we examined the association between BW and childhood cancer risk.
Results
The characteristics of the CNS tumor and leukemia cases and the controls, according to the factors matched (or surrogate factors) in the original study, are presented in Table
1. Cases and controls showed similar distributions regarding those factors. One exception was the year of birth. CNS tumor cases did not have those born before 1952. The proportion of children with CNS tumors born in later years, especially after 1970, was higher compared to that of children with leukemia. In this table, DOE sites are a surrogate factor for the county of residence, which was matched in the original study, but was unavailable in the database. Regarding the DOE sites’ distribution, the control group had more subjects in Hanford and less in Oak Ridge. In order to control those potential confounders, we included those variables in the conventional logistic models in the risk analysis.
Table 1
Characteristics of cases and controls by factors matched (or surrogate factors) in the original study
Year of birth | 1946–1989 | 1952–1989 | 1949–1989 |
1946–1959 | 120 (14.6%) | 11 (15.3%) | 22 (17.7%) |
1960–1969 | 240 (29.2%) | 16 (22.2%) | 44 (35.5%) |
1970–1979 | 294 (35.8%) | 28 (38.9%) | 35 (28.2%) |
1980–1989 | 168 (20.4%) | 17 (23.6%) | 23 (18.6%) |
Age at diagnosis (years)a
|
Mean (SD) | 6.1 (4.4) | 5.6 (4.3) | 5.3 (4.1) |
Min-Max | 0–15 | 0–14 | 0–14 |
Sex |
Male | 493 (60.0%) | 45 (62.5%) | 71 (57.3%) |
Female | 329 (40.0%) | 27 (37.5%) | 53 (42.7%) |
Ethnicity |
Black | 18 (2.2%) | 3 (4.2%) | 2 (1.6%) |
White | 804 (97.8%) | 69 (95.8%) | 122 (98.4%) |
Maternal age (years) |
Mean (SD) | 25.5 (5.4) | 25.2 (5.2) | 25.5 (5.8) |
Min-Max | 14–44 | 15–37 | 16–42 |
DOE sitesb
|
Hanford | 271 (32.9%) | 19 (26.4%) | 28 (22.6%) |
INEL | 183 (22.3%) | 15 (20.8%) | 33 (26.6%) |
Oak Ridge | 363 (44.2%) | 37 (51.4%) | 61 (49.2%) |
Unknown | 5 (0.6%) | 1 (1.4%) | 2 (1.6%) |
Gestational age (weeks)c
|
Mean (SD) | 39.3 (1.9) | 38.5 (2.4) | 39.4 (1.8) |
Min-Max | 28–45 | 27–43 | 34–44 |
In the following tables, the results of the logistic analysis are summarized. The analysis for leukemia risk was also conducted and their results are included in those tables for comparison. As shown in Table
2, CNS tumor risk increased with BW (
p value for trend =0.010). When those with BW less than 2500 g were excluded, the association became stronger (
p for trend <0.001). Even among those in the normal-BW range (2500–4000 g), the p for trend was significant (
p = 0.012). The increasing trend was mainly from those larger than 4000 g. The OR for this high BW adjusted for GA was 2.5 (95%CI = 1.2, 5.2) when compared to normal BW (2500–4000 g). The GA-unadjusted OR was 2.0 (95%CI = 1.0, 4.1) (Additional file
1: Table S1). In this table, we also made a comparison between low-BW and normal-BW children. The CNS tumor risk was also increased among low-BW children, and the OR was 2.0 (95%CI = 0.7–5.9); however, the increase was not statistically significant (
p = 0.241).
Table 2
The association between birth weight and the risk of CNS tumors
Total subjects |
< 2500 g | 24 | 7 | 1.8 | 0.5 | 5.8 | 0.363 |
2500- < 3000 g | 137 | 7 | 0.6 | 0.2 | 1.4 | 0.214 |
3000- < 3500 g | 305 | 21 | 1 | Reference | |
3500–4000 g | 276 | 25 | 1.5 | 0.8 | 2.8 | 0.205 |
> 4000 g | 80 | 12 | 2.9 | 1.3 | 6.6 | 0.012 |
| | |
P for homogeneity = 0.017
For all: P for trend = 0.010 (beta = 0.0007)
For birth weight ≥ 2500 g:P for trend < 0.001 (beta = 0.0011)
For birth weight 2500–4000 g: P for trend = 0.012 (beta = 0.0011)
|
< 2500 g | 24 | 7 | 2.0 | 0.7 | 5.9 | 0.241 |
2500–4000 g | 718 | 53 | 1 | Reference | |
> 4000 g | 80 | 12 | 2.5 | 1.2 | 5.2 | 0.018 |
| | |
P for homogeneity = 0.028
|
The risk of high-birth-weight and LGA children compared to normal-birth-weight childrena
|
2500–4000 g | 718 | 53 | 1 | Reference | | |
> 4000 g and LGA | 48 | 8 | 2.7 | 1.1 | 6.2 | 0.035 |
The risk of high-birth-weight and SGA/AGA children compared to normal-birth-weight childrena
|
2500–4000 g | 718 | 53 | 1 | Reference | | |
> 4000 g and SGA/AGA | 32 | 4 | 2.2 | 0.7 | 6.7 | 0.209 |
Among the high-BW children, SGA, AGA and LGA accounted for 2, 33 and 51 children, respectively. When high-BW children were restricted to LGA, the OR for CNS tumors was 2.7 (95%CI = 1.1, 6.2;
p = 0.035) as shown in the middle panel of Table
2. When high-BW children were restricted to SGA/AGA (the lower panel of Table
2), the OR for CNS tumors became smaller (OR = 2.2; 95%CI = 0.7, 6.7;
p = 0.209).
Leukemia risk was not associated with BW (Table
3). In the lower panel of Table
3, among high-BW children, the risk was increased by 40%, but the increase was not statistically significant.
Table 3
The association between birth weight and the risk of leukemia
Total subjects |
< 2500 g | 24 | 3 | 0.7 | 0.2 | 2.6 | 0.564 |
2500- < 3000 g | 137 | 20 | 0.7 | 0.4 | 1.3 | 0.300 |
3000- < 3500 g | 305 | 54 | 1 | Reference | |
3500–4000 g | 276 | 33 | 0.7 | 0.4 | 1.1 | 0.092 |
> 4000 g | 80 | 14 | 1.1 | 0.6 | 2.2 | 0.752 |
| | |
P for homogeneity = 0.396
For all: P for trend = 0.778 (beta = 0.00006)
For birth weight ≥ 2500 g: P for trend = 0833 (beta = 0.00005)
For birth weight 2500–4000 g: P for trend = 0.475 (beta = −0.00022)
|
< 2500 g | 24 | 3 | 0.8 | 0.2 | 3.0 | 0.765 |
2500–4000 g | 718 | 107 | 1 | Reference | |
> 4000 g | 80 | 14 | 1.4 | 0.7 | 2.6 | 0.343 |
| | |
P for homogeneity = 0.611
|
The risk of high-birth-weight and LGA children compared to normal-birth-weight childrena
|
2500–4000 g | 718 | 107 | 1 | Reference | | |
> 4000 g and LGA | 48 | 10 | 1.7 | 0.8 | 3.7 | 0.166 |
The risk of high-birth-weight and SGA/AGA children compared to normal-birth-weight childrena
|
2500–4000 g | 718 | 107 |
1
|
Reference
| | |
> 4000 g and SGA/AGA | 32 | 4 |
0.9
|
0.3
|
2.7
|
0.865
|
We examined the association of GA with the risks of CNS tumor and leukemia (Table
4). The CNS tumor risk was inversely associated with longer GA (42 weeks or longer) after adjustment for BW (p for trend = 0.001). However, the leukemia risk was elevated among children with longer GA.
Table 4
The association between gestational age and the risks of CNS tumors and leukemia
For the analysis of CNS tumor risk | |
< 37 weeks | 54 | 9 | 1.5 | 0.6 | 3.9 | 0.405 |
37–39 weeks | 331 | 38 | 1 | Reference | |
40–41 weeks | 366 | 20 | 0.3 | 0.2 | 0.6 | <0.001 |
> 41 weeks | 71 | 5 | 0.4 | 0.1 | 1.0 | 0.048 |
| | | | | |
P for trend = 0.001
|
For the analysis of Leukemia risk |
< 37 weeks | 54 | 6 | 0.9 | 0.3 | 2.4 | 0.842 |
37–39 weeks | 331 | 51 | 1 | Reference | | |
40–41 weeks | 366 | 52 | 0.7 | 0.5 | 1.2 | 0.175 |
> 41 weeks | 71 | 15 | 1.2 | 0.6 | 2.3 | 0.659 |
| | | | | |
P for trend = 0.930
|
We examined the association of LGA and SGA with the risks of CNS tumors and leukemia (Tables
5 and
6). LGA children were at higher risks of CNS tumors and leukemia, but neither increase was statistically significant. Even when the subjects were limited to those with BWs 2500 g or larger, or those with BWs 3000 g or larger, the results did not change sizably. The risk of CNS tumors or leukemia was not statistically significantly associated with SGA.
Table 5
CNS tumor risk among small-for-gestational-age and large-for-gestational-age children
Total subjects |
SGA | 189 | 15 | 0.9 | 0.4 | 1.7 | 0.643 |
AGA | 566 | 48 | 1 | Reference | |
LGA | 63 | 9 | 1.8 | 0.8 | 3.9 | 0.163 |
| | | | | |
P for homogeneity = 0.307
|
Birth weight 2500 g or larger |
SGA | 177 | 12 | 0.8 | 0.4 | 1.6 |
0.494
|
AGA | 544 | 44 | 1 | Reference | |
LGA | 63 | 9 | 2.0 | 0.9 | 4.5 |
0.101
|
| | | | | |
P for homogeneity = 0.173
|
Birth weight 3000 g or larger |
SGA | 97 | 9 | 1.2 | 0.5 | 3.1 |
0.672
|
AGA | 497 | 40 | 1 | Reference | |
LGA | 63 | 9 | 2.0 | 0.9 | 4.4 |
0.113
|
| | | | | |
P for homogeneity = 0.279
|
Table 6
Leukemia risk among small-for-gestational-age and large-for-gestational-age children
Total subjects |
SGA | 189 | 30 | 0.9 | 0.6 | 1.5 | 0.696 |
AGA | 566 | 83 | 1 | Reference | |
LGA | 63 | 11 | 1.4 | 0.7 | 2.9 | 0.342 |
| | | | | |
P for homogeneity = 0.555
|
Birth weight 2500 g or larger |
SGA | 177 | 29 | 0.9 | 0.5 | 1.5 | 0.714 |
AGA | 554 | 81 | 1 | Reference | |
LGA | 63 | 11 | 1.4 | 0.7 | 2.9 | 0.340 |
| | | | | |
P for homogeneity = 0.561
|
Birth weight 3000 g or larger |
SGA | 97 | 18 | 0.9 | 0.5 | 1.8 | 0.841 |
AGA | 497 | 72 | 1 | Reference | |
LGA | 63 | 11 | 1.5 | 0.7 | 3.1 | 0.298 |
| | | | | |
P for homogeneity = 0.547
|
The American Congress of Obstetricians and Gynecologists has redefined “term pregnancy” and replaced it with four new definitions of “term” deliveries: early term (37 weeks 0 day - 38 weeks 6 days), full term (39 weeks 0 day - 40 weeks 6 days), late term (41 weeks 0 day - 41 weeks 6 days) and post term (42 weeks 0 day and beyond). We relaxed the definition for normal GA to avoid losing the number of cases, and used children with GA of 37–42 weeks. This decision increased the number of CNS tumor and leukemia cases, and the controls by 5, 11 and 51, respectively. However, the associations of BW or LGA/SGA with the risk of CNS tumors or leukemia did not change appreciably (Additional file
2: Table S2, Additional file
3: Table S3 and Additional file
4: Table S4).
Discussion
The present study showed that higher BW was positively associated with childhood CNS tumor risk with or without adjustment for GA. This observed association was mainly from those larger than 4000 g. The OR among the high-BW children was 2.5 (95%CI = 1.2, 5.2) with adjustment for GA, and 2.0 (95%CI = 1.0, 4.1) without adjustment. Those values are higher than those reported by the previously conducted studies [
6,
9,
11,
12].
Leukemia risk was increased (OR = 1.4; 95%CI = 0.7, 2.6;
p = 0.343) among the high-BW children. A meta-analysis reported a similar OR (OR = 1.35; 95%CI = 1.24, 1.48) on the basis of 32 studies [
7]. The fact that this study was unable to establish a significant association between high BW and leukemia risk could be attributed to the fact that the effect estimate of high BW might be too small, relative to the sample size.
Even in the normal-BW range (2500–4000 g), higher BW was still positively associated with childhood CNS tumor risk (p for trend = 0.012), but not with leukemia risk (p for trend = 0.475). To date, no study has found that BW is related to CNS tumor risk in the normal-BW range. However, several studies examined the association of BW itself with CNS tumor risk. The magnitude of the OR change per 1000-g BW obtained from the present study was similar to those reported by other studies [
5,
6,
9,
13].
In the present study, GA was inversely associated with CNS tumor risk (p for trend = 0.001). This finding is at variance with those obtained from the other studies, which reported a weak positive association between BW and CNS tumor risk [
6,
14,
15]. The association between leukemia risk and GA was not found in our study (p for trend = 0.930) as was the case with the other studies [
6,
16].
BW and GA are known to be closely related to each other [
17]. When the high-BW children were restricted to those who were LGA, the OR was 2.7 (95%CI = 1.1, 6.2). When high-BW children were restricted to those without LGA, the OR was 2.2 (95%CI = 0.7, 6.7), which is smaller than the OR for high-BW and LGA children. In the present study, SGA was not statistically related to the risk of CNS tumors or leukemia.
Our study found an increased risk of CNS tumors among LGA children, but the increase was not statistically significant. The OR obtained in our study (OR = 1.8; 95%CI = 0.8, 3.9), which was larger than those reported by the other studies (in which the ORs were in the range of 1.09–1.18) [
6,
9,
11,
12]. In the case of leukemia, our study obtained an OR of 1.4 (95%CI = 0.7, 2.9), which is similar to those reported by other studies (in which the ORs were in the range of 1.45–1.66) [
6,
11].
In the present study, CNS tumor risk was not associated with SGA (OR = 0.9; 95%CI = 0.4, 1.7) as was the case with the other studies [
6,
9,
11,
12]. The OR for leukemia was 0.9 (95%CI = 0.6, 1.5). The association between leukemia risk and SGA on the literature is inconsistent. The ORs obtained from the US and German studies were in the range of 0.78 to 1.00 [
6,
11], and were 1.2 to 1.8 in Nordic study [
12]. Our result is similar to the values reported by the Texan and German studies [
6,
11].
CNS tumors have various histological types which may have different etiological backgrounds. The three most common types of childhood CNS tumors include medulloblastomas, astrocytomas and malignant gliomas, which accounted for 50% of those tumors in a US study [
24]. A meta-analysis of eight studies reported in 2008 showed that high-BW children had slightly elevated risks of astrocytoma (OR = 1.38, 95%CI = 1.07, 1.79) and medulloblastoma (OR = 1.27, 95%CI = 1.02, 1.60) [
10]. Among the eight studies, only California study considered the GA as a potential confounder [
15,
25‐
31]. In the present study, we did not have information on the pathological types of the tumors.
Several mechanisms which stimulate prenatal weight gain and act simultaneously as long-term carcinogens might explain the association between high BW and the increased risk of CNS tumors. First, high BW could be an indicator of a greater number of cells, leading to more cell divisions. It is strongly suspected that such a condition could make them more vulnerable to carcinogenic agents and therefore, the cancer risk increases after birth [
32]. BW is known to be positively correlated with insulin-like growth factor-1, which is strongly suggested to be involved in brain ontogenesis and carcinogenesis [
33,
34]. Second, Heuch et al. [
27] proposed the involvement of excess prenatal nutrition in medulloblastoma development, and suspected that high BW is an important indicator of excess nutrition in the last gestational trimester. They suspected that ample nutrition may interfere with the migration of granular neuronal cells, which starts at approximately 30 gestational weeks. If the cells migrate incompletely, they may remain immature. As a result, neoplastic potential of the cell may increase.
In the present study, childhood cancer patients were diagnosed from 1957 to 1991. As shown in Table
1, the proportion of CNS tumor patients seems to have increased with calendar year, though this upward trend was not observed in the case of childhood leukemia. The improvement in diagnostic technologies could have led to artifactual increases in the rate CNS tumor occurrence [
35]. It is to be noted that computed tomography and magnetic resonance imaging scans were widely used in the 1970s and 1980s, respectively.
Our study has several limitations. First, the results should be treated with considerable caution because of the limited number of cases. Regarding the leukemia risk, we failed to find a significant association. The effect estimate of high BW might be too small compared to the sample size. Second, cases were ascertained mainly from hospitals. Although the original study described “cancer registry” as a source of case ascertainment, we assumed that this might have been a hospital-based registry, as population-based cancer registries were unavailable in the 1957–1991 period. Thus, we could deny the possibility that cases without consultation at the hospitals or diagnosed outside of the study areas could be missed. Third, we lacked information on the subtypes of CNS tumors and leukemia. Typically, tumor registries did not cover those years. Death certificates did not provide identification of a hospital where diagnostic information might be located. The data in hospital records were insufficient for those years. Fourth, the study encountered problems in obtaining the birth records of the cases and controls. While Sever et al. received high level of cooperation from many hospitals that provided them with access to records, the medical records themselves were often missing and the data were incomplete [
18]. Since these problems were mainly with newborn records, that they did not affect the cases and controls differently. Fifth, the study did not collect sufficient information on the socio-economic status (SES) of the subjects. Unlike in the case of the relationship between SES and low BW, the association between SES and high BW risk is not consistent [
36]. Many studies have been conducted to examine the association between SES and leukemia risk. On reviewing studies published until 1982, higher SES was suspected to be related to childhood leukemia risk [
37]. A review by Poole et al. [
38], however, noted that most later studies consistently reported inverse associations of childhood leukemia with SES; it was concluded, therefore, that associations between SES measures and childhood leukemia likely vary with the time and place. A study based on 5240 leukemia cases from the Canadian cancer registries, that covered at least 95% of all the cases, reported a slightly lower relative risk of leukemia in the poorest group (RR = 0.87; 95%CI = 0.80, 0.95) [
39]. A similar finding was also reported in a large case-control study from the UK (OR = 0.99, 95%CI = 0.96, 1.01) [
40]. Thus, the effect of SES on the association between BW and leukemia risk may be considerably small even if SES is a potential confounding factor. The association between SES and CNS tumor risk was still inclusive [
41‐
44]. Sixth, information on maternal comorbidities was not available in this data set. Although gestational diabetes mellitus is the most important risk factor for high BW and LGA, we could not examine the effect of gestational diabetes mellitus on childhood cancer risk. Finally, SGA was not a risk factor for childhood cancers in our study. The Barker hypothesis shows that low BW is associated to the risk of developing chronic diseases in later life [
45‐
47]. However, the association of low BW and childhood cancer risk has not been clarified.