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Risk of hepatoblastoma is strongly increased among children with very low birth weight (VLBW: <1,500 grams). Because data on VLBW and other childhood cancers is sparse, we examined the risk of malignancy following VLBW in a large dataset.
We combined case-control datasets created by linking the cancer and birth registries of California, Minnesota, New York, Texas, and Washington states, which comprised 17,672 children diagnosed with cancer at 0-14 years of age and 57,966 randomly selected controls. Unconditional logistic regression was used to examine the association of cancer with VLBW and moderately low birth weights (1,500-1,999g and 2,000-2,499g) compared to moderate/high birth weight (≥2,500) adjusting for sex, gestational age, birth order, plurality, maternal age, maternal race, state, and year of birth.
Most childhood cancers were not associated with low birth weights. However, retinoblastoma and gliomas other than astrocytomas and ependymomas were possibly associated with VLBW, with respective odds ratios (OR) of 2.43 (95% Confidence Interval (CI): 1.00-5.89) and 2.13 (95% CI: 0.71-6.39). Risk of other gliomas was also increased among children weighing 1,500-1,999g at birth (OR = 3.58; 95% CI: 1.98-6.47). For hepatoblastoma the ORs associated with birth weights of 2,000-2,499g, 1,500-1999g, and 350-1,499g were 1.56 (95% CI: 0.81-2.98), 3.37 (95% CI: 1.44-7.88), and 17.18 (95% CI: 7.46-39.54), respectively
These data suggest no association between most cancers and VLBW with the exception of the known association with hepatoblastoma and possible moderately increased risks of other gliomas and retinoblastoma, which may warrant confirmation.
As survival of very low birth weight (VLBW, usually defined as <1,500 grams) infants has improved markedly in recent decades (1), the long-term health of these children requires increasing attention, with much research focusing on neurocognitive outcomes(2, 3), growth and development (4, 5), and the metabolic syndrome (6, 7). Childhood cancer has not often been studied, but it has been demonstrated that incidence of a rare embryonal liver tumor, hepatoblastoma, is at least a magnitude greater among VLBW children than among children with moderate birth weights (8-12). As VLBW infants are exposed to multiple medical interventions in neonatal intensive care units (NICUs) (13, 14) at a time in development when antioxidant capacity is diminished (15, 16) and xenobiotic-metabolizing enzyme expression is variable(17, 18), an iatrogenic etiology is plausible.
Other childhood cancers might also be associated with VLBW for similar reasons, although no similar-sized associations have been noted to date. While birth weight has been examined frequently in relation to various childhood cancers (19-21), small or moderately increased risks associated with VLBW may not have been detected. Nearly all studies have grouped all infants <2,500 grams, possibly obscuring differences in biology and medical exposures between moderately and very low birth weight infants. Moreover, as the prevalence of VLBW is low, presently about 1% of births in the United States (1), the large sample sizes required to detect small-to-moderate relative risks are not generally available in studies of childhood cancers.
Our objective was to fill a gap in the literature by examining whether specific childhood cancers, in addition to hepatoblastoma, demonstrate associations with VLBW. Although high birth weight is a risk factor for several pediatric malignancies (20-23), we report here on VLBW alone, because the putative mechanism to explain increased cancer risk in large infants, growth factor excess (22, 24), differs from mechanisms we hypothesize for small infants. Our analysis constitutes the first comprehensive examination of cancer risk among children born at the lowest end of the birth weight distribution.
We pooled data from population-based case-control studies conducted in California, Minnesota, New York (excluding New York City), Texas and Washington states (8, 10, 12, 25, 26). Institutional Review Board approvals were obtained from each participating institution for the conduct of this analysis. Table 1 provides information about each component study. Cases of childhood cancer meeting eligibility criteria were identified in each population-based cancer registry and matched to birth records using sequential deterministic or probabilistic record linkage (27). Cases were classified according to the International Classification of Childhood Cancer 3rd edition (ICCC-3) (28).
Controls were selected at random from birth records in ratios to cases ranging from 1 to 10, with frequency matching used in four states and individual matching in one (California). All states matched on year of birth and two also matched on sex (6, 16-19). Cases selected as controls in Minnesota and New York were excluded from analysis, as were subjects with reported Down syndrome. However, this condition was not recorded in Texas before 1984 and Washington before 1989. Cases diagnosed before 28 days of life and controls that died prior to then were also excluded from analysis. The final pooled dataset consisted of 17,672 cases and 57,966 controls.
Birth weight, gestational age, plurality, sex, birth order, year of birth, and maternal age and race were obtained from birth records. Maternal education was not recorded by all states until 1992 and so was used only in secondary analyses. Gestational ages calculated from last menstrual period (LMP) and a clinical estimate were provided by four states, whereas California recorded only the former. A combined gestational age variable was developed that gave preference to the calculated estimate when available and used the clinical estimate otherwise.
Birth weights of <350g and gestational lengths <20 or >45 weeks were considered implausible and treated as missing. For the purposes of sensitivity analysis, we also identified subjects with implausible birth weights for gestational age using guidelines derived from expert clinical opinion(29).
Continuous and discrete variables were grouped using cut points determined a priori. Categories of birth weight were 350-1,499 grams (g), 1,500-1,999g, and 2,000-2,499g with a referent of ≥2,500g, thereby delineating groups with decreasing NICU utilization (30, 31). Separating high (>4,000g) from normal (2,500-3,999g) birth weight and using the latter as referent only minimally affected results for low birth weights (data not shown). High birth weight was therefore included in the referent category of >2,500g to simplify presentation. Categories of gestational age were <32 weeks, 32-36 weeks, and ≥37 weeks. Because methods for gestational age estimation shifted over the wide study period, adding to common concerns about the accuracy of early gestational ages(32), we did not pursue any finer discrimination of preterm weeks of gestation. Categorizations of other variables are shown in Table 3 and the footnotes to tables tables44 and and55.
Analyses were performed using SAS 9.1 (SAS Institute, Cary, NC). Odds ratios (OR) and two-sided 95% confidence intervals (CI) were obtained using unconditional logistic regression, with individual matching in the California dataset broken to allow use of this method. Risk estimates were adjusted for the matching variables state, year of delivery (1970-1985, 1986-1989, 1990-1993, 1994-2004), and infant sex (matched in 2 states only). We decided a priori to adjust all risk estimates for maternal age (<20, 20-24, 25-29, 30-34, 35-39, 40+ years), plurality (singleton/multiple delivery), birth order (1,2,3,4,5+), and maternal race/ethnicity as well, since these variables are associated with birth weight(33) and are established or suspected risk factors for several childhood cancers (34). Analyses of birth weight (<1500, 1500-1999, 2000-2499, 2500+ g) were additionally adjusted for gestational age (<32, 32-36, 37+ weeks), and vise versa.
ORs for birth weight and gestational age are presented for all cancers combined and for the 17 ICCC-3 cancer types with >200 cases in the dataset (excluding heterogeneous “other” and unspecified tumor categories). Several secondary analyses were also conducted, including: exclusion of subjects with implausible birth weight for gestational age, adjustment for maternal education during the years data were available, restriction to subjects with birth years coextensive with registry operation, and use of the alternate gestational age variable that gave preference to the clinical estimate.
Diagnoses were distributed approximately as would be expected based on national surveillance data (Table 2) (35). Male sex and white race were somewhat more frequent among cases compared to controls, while there were no appreciable differences regarding other variables (Table 3). Values for all variables (except maternal education) were available for 93.7% of cases and 92.7% of controls.
Childhood cancer overall and most cancer types, including those not shown in the table, did not have increased ORs for the associations of moderately or VLBW (Table 4). Having a birth weight of 350-1499g was associated with a greatly increased risk of hepatoblastoma (OR = 17.18; 95% CI: 7.46-39.54) relative to weighing > 2,500g at birth. Less marked, but still increased ORs were observed for birth weights of 1,500-1,999g (OR = 3.37; 95% CI: 1.44-7.88) and 2,000-2,499g (OR = 1.56; 95% CI: 0.81-2.98). The large number of hepatoblastoma cases with birth weights <1,500g allowed further division of VLBW into categories of 350-749g and 750-1,499g, with respective ORs of 46.78 (95% CI: 16.36-133.74) and 13.73 (95% CI: 5.63-33.48).
VLBW was associated with greater than two-fold increased ORs for two other tumor types, including gliomas other than astrocytomas and ependymomas (i.e. “other gliomas”) (OR = 2.13, 95% CI: 0.71-6.39 for birth weight <1500g; OR = 3.58, 95% CI: 1.98-6.47 for birth weight 1,500-1,999g) and retinoblastoma (OR = 2.43, 95% CI: 1.00-5.89 for birth weight <1500g). There was a significant OR of 1.42 (95% CI: 1.01-1.99) for intracranial embryonal tumors associated with birth weights of 2,000-2,499g group alone.
Excluding the 308 subjects with implausible birth weight for gestational age did not substantially alter most ORs or suggest associations of VLBW with cancers not apparent in the main analyses. However, the association of retinoblastoma with VLBW became markedly stronger (OR = 3.95; 95% CI: 1.55-10.07) and the OR for other gliomas increased slightly (OR = 2.60; 95% CI: 0.82-8.22). Hepatoblastoma remained strongly associated with VLBW but the OR was somewhat attenuated (11.55; 95% CI: 4.52-29.55). Results of the other sensitivity analyses, including adjustment of birth weight for maternal education and use of the alternate gestational age variable giving preference to the clinical estimate, were not materially different from those in the main analysis (data not shown).
Although there were modestly increased ORs for several tumors associated with very preterm delivery (<32 weeks), all confidence intervals included one (Table 5). Wilms tumor (OR = 1.51; 95% CI: 1.21-1.88) and Ewing sarcoma (OR = 1.68; 95% CI: 1.03-2.76) were associated with moderately preterm delivery (32-36 weeks). Using the alternate gestational age variable that gave preference to the calculated estimate produced similar results (data not shown), with the exception that Ewing sarcoma displayed somewhat stronger ORs for both moderately (OR = 2.14; 95% CI: 1.32-3.47) and very preterm delivery (OR = 3.11; 95% CI: 0.89-10.88).
As the risk of most cancers among children with the lowest birth weights has not been adequately assessed we undertook to examine this issue in a large population-based dataset. The strong inverse association between hepatoblastoma and birth weight was confirmed, with relative risks estimated more precisely here than in most previous studies (8-12). Most other cancers were not associated with moderately or very low birth weight, although retinoblastoma and other gliomas displayed possibly increased risks.
The size of association with VLBW that we were able to detect is an important consideration. Analysis of confidence limits is the preferred method for determining the size of association compatible with the data (36). Table 4 shows upper confidence limits of 1.50 and 1.13 for all childhood cancers and acute lymphoid leukemia, respectively, while upper confidence limits ranging from about 2 to 4 were found for most other cancers; ORs larger than the upper confidence limits are unlikely to have been missed. Thus our results indicate that no moderate to strong associations of VLBW with most types of childhood cancer were present in this dataset, notwithstanding possible biases and other limitations to interpretation.
The association of VLBW with hepatoblastoma is unlikely to be due to chance or bias, having been observed in the United Kingdom (11) and Japan (9) as well as in the current United States study (which included data reported in three prior publications (8, 10, 12)). Our findings regarding other gliomas and retinoblastomas may however be due to random error, given the number of comparisons made, and less weight may also be attributed to the observations since there was a lack of clear evidence of dose-response between lower birth weights and these cancers. However, if real these associations warrant some explanation, though necessarily speculative.
We posited that the increased risk of hepatoblastoma among VLBW infants may be attributable to exposures in the NICU, and sought to determine if similar, but weaker, associations existed with other childhood cancers. The list of possible iatrogenic hazards in NICUs, recently reviewed by Lai and Bearer,(14) includes light, oxygen, irradiation, electromagnetic fields, plasticizers, medications, and total parenteral nutrition. Among these exposures, irradiation and oxidative stress, through high fraction oxygenation or lipid peroxidation, stand out for their known carcinogencity (37, 38). The plasticizer di-(2-ethylhexyl)phthalate (DEHP) is also considered a “probable human carcinogen” (39). The possible role of NICU exposures in causing hepatoblastoma has been examined in three small Japanese studies with 5 to 15 cases; greater lengths of oxygen therapy, furosemide use, and hospitalization were observed among VLBW cases compared to weight-matched controls (40-42). Larger studies may provide more definitive answers.
One limitation of our record-linkage study is that we did not have access to NICU exposure information. The use of birth weight as a proxy for medical exposures also requires caution for several reasons. First, even among VLBW infants, almost all of whom spend some time in a NICU, there is variation in treatment. For instance, among infants with birth weights of 501-1,500g tracked by the NICHD Neonatal Research Network during 1999-2000, 57% received surfactant, 27% received oxygen therapy at 28 days of life, and 20% received postnatal steroids (43). Moreover, as medical practice has changed over time (e.g. no infants in the aforementioned series received surfactant in 1987-1988), VLBW may have acted as proxy for differing exposures during the long period of this study.
VLBW may also signal the underlying pathologic processes that produced small size rather than (or in addition to) postnatal treatments, although the effect of such confounding is difficult to predict and may differ by cancer type. Congenital anomalies are both overrepresented among VLBW infants compared to those with normal birth weights (44) and among children with cancer (45); the net effect of these tendencies would be to exaggerate associations of VLBW with malignancies. Conversely, high birth weight was associated with risk of acute lymphoid leukemia, Wilms tumor, and astrocytoma in our data (not shown) as in others (20-23), which would tend to countervail any increase in risk due to medical exposures among VLBW infants. In this context we note that the OR of 1.48 relating VLBW to astrocytomas was possibly inconsistent with the overall significant linear trend in risk of this tumor with increasing birth weight. The ORs relating VLBW to acute lymphoid leukemia and Wilms tumor, by contrast, supported the overall linear trends. Absent additional information about the causes of VLBW our data could not address these concerns.
We controlled for gestational age in analysis of birth weight and observed few associations of childhood cancers with preterm birth itself. However, we cannot dismiss the possibility that our results for VLBW were actually due to residual confounding by length of gestation, since the limitations of measurement of gestational age in vital records necessitated using broad categories of preterm birth (32).
The use of population-based cancer surveillance data and prospectively collected birth records were major strengths of this study. Birth weight is considered generally accurate in vital records, as are the other variables we used, apart from gestational age (46). Several limitations must also be noted. We may have missed cancer diagnoses among controls who were sampled from birth years prior to the inception of their respective cancer registries or who moved out of state, but estimate based on U.S. surveillance data (35) that only about 125 cancers would be expected among controls if all were lost to follow-up. Thus even under the most extreme assumption disease misclassification would be unlikely to bias our results. Mortality among VLBW infants is also many times greater than at higher birth weights (1). Limiting subjects to those who survived to 28 days of life minimized this issue since most deaths among VLBW infants occur before then (47). However, person-time at risk among VLBW controls was probably still overestimated relative to children with normal birth weight since later mortality was not accounted for in these data. This would result in underestimation of the ORs for VLBW, although it is not possible for us to gauge the extent of any such bias. Lastly, we could not control completely for socioeconomic status, which is associated with both VLBW(48) and some childhood cancers(49) However, subanalyses adjusting for maternal education as a marker for socioeconomic status were concordant with the main analysis
Medical exposures in the NICU, combined with the immature defenses of premature infants, may plausibly affect future cancer risk. Apart from hepatoblastoma, associations with most childhood cancers were not increased, although possible moderate increases in risks of other gliomas and retinoblastoma were noted and may warrant confirmation. These results may be reassuring to practitioners and families concerned with the long-term health of VLBW infants.