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. Author manuscript; available in PMC: 2014 Aug 1.
Published in final edited form as: Cancer Epidemiol. 2013 Apr 1;37(4):390–395. doi: 10.1016/j.canep.2013.03.004

Case-control study of birth characteristics and the risk of hepatoblastoma

Julia E Heck a, Travis J Meyers a, Christina Lombardi a, Andrew S Park a, Myles Cockburn b, Peggy Reynolds c, Beate Ritz a
PMCID: PMC3679264  NIHMSID: NIHMS458562  PMID: 23558166

Abstract

Background

Hepatoblastoma is a malignant embryonal tumor typically diagnosed in children younger than five years of age. Little is known on hepatoblastoma etiology.

Methods

We matched California Cancer Registry records of hepatoblastomas diagnosed in children younger than age 6 from 1988–2007 to birth records using a probabilistic record linkage program, yielding 261 cases. Controls (n=218,277), frequency matched by birth year to all cancer cases in California for the same time period, were randomly selected from California birth records. We examined demographic and socioeconomic information, birth characteristics, pregnancy history, complications in pregnancy, labor and delivery, and abnormal conditions and clinical procedures relating to the newborn, with study data taken from birth certificates.

Results

We observed increased risks for hepatoblastoma among children with low [1500–2499 g, Odds Ratio (OR)=2.02, 95% confidence interval (CI) 1.29–3.15] and very low birthweight (<1500 g, OR=15.4, 95% CI 10.7–22.3), preterm birth <33 weeks (OR=7.27, 95% CI 5.00, 10.6), small size for gestational age (OR=1.75, 95% CI 1.25–2.45), and with multiple birth pregnancies (OR=2.52, 95% CI 1.54–4.14). We observed a number of pregnancy and labor complications to be related to hepatoblastoma, including preeclampsia, premature labor, fetal distress, and congenital anomalies.

Conclusions

These findings confirm previously reported associations with low birthweight and preeclampsia. The relation with multiple birth pregnancies has been previously reported and may indicate a relation to infertility treatments.

Keywords: hepatoblastoma, birth weight, preterm labor, fetal distress, gestational age, pre-eclampsia, multiple birth offspring, risk factors, epidemiology, etiology

Introduction

Hepatoblastoma is a malignant liver tumor in young children which accounts for >90% of liver cancers in children less than 5 years of age [1,2]. Incidence peaks in infancy and declines rapidly in the following years, with few diagnoses occurring after age 5. Internationally, incidence is observed to be high in Japan, parts of China, and the US, with the highest US rates seen in California [3]. Hepatoblastoma is more common in males than females and there is some evidence of variation by ethnicity, with US rates lowest in African Americans [4]. The incidence of hepatoblastoma has risen in the US over the past 40 years, from 0.8 per million in the 1970’s to 1.5 per million in the early 1990’s [4], which suggests non-genetic factors are likely to be important in its etiology.

Due to its rarity there are only a small number of published epidemiologic studies of hepatoblastoma, making it difficult to draw conclusions regarding causality. The strongest risk factor observed thus far is low or very low birthweight [5–15]. Hepatoblastoma has been additionally linked to medical treatments, such as neonatal oxygen supplementation and furosemide treatment, which may reflect necessary interventions in low birthweight or preterm infants [14–16]. There are additional associations between hepatoblastoma and congenital abnormalities, notably trisomy 18 and organomegaly (such as Beckwith-Wiedemann syndrome or hemihypertrophy) [1,17–21], however the proportion of patients with a congenital anomaly is estimated to be only 7% [19]. Hepatoblastoma is more common in families with familial adenomatous polyposis, a syndrome caused by germline mutations in the APC tumor suppressor gene [22]. Apart from low birthweight and rare genetic syndromes, the only other established risk factor is parental smoking [23]. A small number of studies have reported on other risk factors, in particular parental occupational exposures or pesticides [24,25].

Since most epidemiologic studies have been quite small (<100 cases), we wish to capitalize on the availability of our large California statewide database, linked with birth certificates, to investigate the associations between birth characteristics and hepatoblastoma. This study updates an earlier report of California hepatoblastoma cases in relation to gestational characteristics, adding 10 additional years of cases [8].

Materials and Methods

The present investigation collected incident cases of hepatoblastoma born 1983–2007 and diagnosed 1988–2007 from the California Cancer Registry [26,27]. Based upon first and last names and date of birth, we were able to match 89% of cases to a California birth certificate. Controls were frequency-matched by year of birth to all childhood cancer cases during the study period and randomly selected from California birthrolls. Controls had no record of a cancer diagnosis in California prior to age 6. After exclusion of 3 controls for which no sex was identified on the birth certificate, the final dataset included 261 hepatoblastoma cases and 218,277 controls.

As this was a record-based study, we did not seek informed consent from individual subjects. The study received approvals from the human subject protection boards of the University of California Los Angeles and the California Health and Human Services Agency.

Our source of data were birth certificates, which report demographic and socioeconomic information, birth characteristics, pregnancy history, complications in pregnancy and labor and delivery, and abnormal conditions and clinical procedures relating to the newborn. Not all variables were collected on birth certificates over the entire period under study: maternal and paternal education, the source of payment for prenatal care, meconium staining of the amniotic fluid, NICU admission, any abnormal condition and any procedure conducted at birth was reported 1989–2007; fetal distress was reported 1983–2005; dysfunctional labor, method of delivery, transfer to another facility within 24 hours of delivery, breech presentation, and any congenital anomaly was reported 1983–2007. With regards to general birth certificate variables, pregnancy and labor complications, and clinical procedures, we report on those variables reported for at least 5 cases and on those factors previously reported as potential risk factors for hepatoblastoma in other studies: polyhydramnios [14], maternal tobacco use [28], and fertility treatment [7]. As the use of assisted reproductive technologies began to be reported on California birth certificates in 2006, we examined presumptive fertility treatment, as defined by McLaughlin et al as any reported fertility treatment or a triplet or higher-order plural birth [7]. Parity was defined as the number of viable previous pregnancies.

As the child’s race/ethnicity was not collected on birth certificates for the entire time period under study, we report maternal and paternal race/ethnicity only. Socioeconomic status was measured using maternal and paternal educational attainment as well as the method of payment for prenatal care (private insurance vs. Medi-Cal, other government-funded care or self-pay), which we have previously found to be a good predictor of family income [29]. To further assess socioeconomic status, we used a multifactorial socioeconomic index which used principal components analysis to develop a single, 5-level measure from seven census tract-level indicators of socioeconomic status (census-tract average education, median household income, percent living 200% below poverty, percent blue-collar workers, percent older than 16 years without employment, median rent, and median house value) [30].

Size for gestational age was defined as small if birth weight was less than the 10th percentile and defined as large if greater than the 90th percentile of the birthweight standards for a given gestational age. The 10th and 90th percentile values were obtained for each gestational week (20–45 weeks) by maternal race/ethnicity (non-Hispanic white, Hispanic of any race, black, Asian/Pacific Islander, and other) and child’s sex based on the total singleton live births in California using the method described by Alexander [31]. California birth certificates report estimates for gestational age based on the first day of the last normal menses. When this length of time was implausibly long (>45 weeks) we considered it as missing.

We calculated odds ratios (ORs) and 95% confidence intervals using unconditional logistic regression with SAS 9.1 (SAS, Cary, NC). We report unadjusted and adjusted results, with adjusted regressions controlling for year of birth, maternal age and maternal race/ethnicity. Although other papers on this topic have additionally adjusted for birthweight, we felt it may introduce bias to adjust for a likely intermediate in the cancer pathway [32], thus we only adjusted for birthweight for factors which occurred after birth, e.g. NICU admission, newborn transferred to another facility within 24 hours of delivery, and any clinical procedure on the newborn. We also compared our findings to the earlier study in California by Reynolds [8]. Because it is has been speculated that hepatoblastoma may be caused by a procedure that the child undergoes in a neonatal intensive care unit (NICU)[33], we compared the ages at diagnosis of cases admitted to a NICU vs. cases not admitted.

Results

Of the 261 hepatoblastoma cases, 113 (43.3%) had localized disease, 76 (29.1%) regional, 58 (22.2%) distant, and 14 (5.4%) unknown. The proportions of children with localized, regional, and distant disease stayed consistent over the 20 year period (2-sided p=0.7).

Hepatoblastoma was more common among male children (Table 1). In comparison to mothers in their 20’s, hepatoblastoma occurred more frequently among children whose mothers were both younger (<20 years) and older (35+ years). The risk remained increased for mothers over 35 after adjustment for presumptive fertility treatment or multiple births (data not shown). Disease risk was lower among children of Black mothers compared to non-Hispanic White mothers. None of the paternal characteristics that we examined were associated with disease. We also observed little association between socioeconomic characteristics and hepatoblastoma, with no associations observed with either maternal or paternal years of education. Families whose prenatal care was paid by government sources or self-pay did not differ in hepatoblastoma risk (OR=0.87, 95% CI 0.67, 1.12), nor was there evidence for differential risk by neighborhood socioeconomic index. No evidence of a trend was seen with any SES measure (data not shown).

Table 1.

Demographic characteristics in relation to hepatoblastoma among California children

Characteristic Case n(%)
n=261
 Control n(%)
n=218,277
 Crude OR (95% Cl)
Child’s sex
  Male 154 (59.0) 111450 (51.1) 1.38 (1.08, 1.77)
  Female 107 (41.0) 106827 (48.9) 1 (ref)
Mother’s age (years)
  <20 39 (14.9) 23842 (10.9) 1.77 (1.23, 2.56)
  20–29 106 (40.6) 114946 (52.7) 1 (ref)
  30–34 61 (23.4) 50157 (23.0) 1.32 (0.96, 1.81)
  35+ 55 (21.1) 29290 (13.4) 2.04 (1.47, 2.82)
Mother’s race/ethnicity
  White non-Hispanic 97 (37.2) 80503 (36.9) 1 (ref)
  Hispanic (of any race) 129 (49.4) 96913 (44.4) 1.10 (0.85, 1.44)
  Black 9 (3.4) 15378 (7.0) 0.49 (0.25, 0.96)
  Asian/Pacific Islander 24 (9.2) 21022 (9.6) 0.95 (0.61, 1.48)
  Other/not specified 2 (0.8) 4461 (2.0) 0.37 (0.09, 1.51)
Mother’s birthplace
  US 142 (54.4) 124289 (57.0) 1 (ref)
  Mexico 79 (30.3) 54732 (25.1) 1.26 (0.96, 1.66)
  Other Foreign 40 (15.3) 38997 (17.9) 0.90 (0.63, 1.28)
Father’s age (years)
  <20 8 (3.2) 8431 (4.1) 0.84 (0.41, 1.73)
  20–29 104 (41.6) 92409 (45.2) 1 (ref)
  30–34 67 (26.8) 52440 (25.7) 1.14 (0.83, 1.54)
  35+ 71 (28.4) 50997 (25.0) 1.24 (0.91, 1.67)
Father’s race/ethnicity
  White non-Hispanic 96 (36.8) 76621 (35.1) 1 (ref)
  Hispanic (of any race) 125 (47.9) 92850 (42.5) 1.07 (0.82, 1.40)
  Black 12 (4.6) 16876 (7.7) 0.57 (0.31, 1.03)
  Asian/Pacific Islander 18 (6.9) 18307 (8.4) 0.78 (0.47, 1.30)
  Other/not specified 10 (3.8) 13623 (6.2) 0.59 (0.31, 1.12)
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Gestational characteristics are shown in table 2. There was a higher risk for hepatoblastoma among children with low (1500–2499 g) and very low (<1500 g) birthweight. When examining singleton pregnancies only, the increased risk of hepatoblastoma was still evident among children with low (OR=1.83, 95% CI 1.10–3.06) and very low birthweight (OR=14.6, 95% CI 9.72–22.0). Children who were born very preterm (<33 weeks gestation) also had a higher risk of hepatoblastoma, as were children who were small for gestational age. Hepatoblastoma cases were more likely to have been delivered by Cesarean section and to have been a twin or higher order multiple birth.

Table 2.

Gestational characteristics and maternal medical history in relation to hepatoblastoma

Characteristic Case n (%)
n=261		 Control n (%)
n=218,277		 Unadjusted OR
(95% Cl)		 Adjusted OR (95%
Cl)a
Child’s birth weight (g)
  <1500 g 35 (13.4) 2366 (1.1) 15.1 (10.5, 21.7) 15.4 (10.7, 22.3)
  1500–2499 22 (8.4) 11133 (5.1) 2.01 (1.29, 3.13) 2.02 (1.29, 3.15)
  2500–3999 178 (68.2) 181134 (83.1) 1 (ref) 1 (ref)
  4000 g + 26 (10.0) 23427 (10.7) 1.13 (0.75, 1.70) 1.12 (0.74, 1.69)
Gestational age (weeks)
  Very preterm (<33) 33 (13.3) 4507 (2.2) 7.04 (4.86, 10.22) 7.27 (5.00, 10.6)
  Preterm (33–36) 26 (10.5) 17242 (8.4) 1.45 (0.96, 2.19) 1.44 (0.95, 2.17)
  Term (37–42) 183 (73.8) 176064 (85.3) 1 (ref) 1 (ref)
  Postterm (43+) 6 (2.4) 8651 (4.2) 0.67 (0.30, 1.51) 0.73 (0.32, 1.64)
Size for gestational age
  Small 42 (17.0) 21922 (10.6) 1.77 (1.26, 2.47) 1.75 (1.25, 2.45)
  Normal 177 (71.7) 163193 (79.2) 1 (ref) 1 (ref)
  Large 28 (11.3) 20863 (10.1) 1.24 (0.83, 1.84) 1.24 (0.83, 1.85)
Method of delivery b
  Vaginal 172 (66.4) 159785 (76.2) 1 (ref) 1 (ref)
  Cesarean 87 (33.6) 49782 (23.8) 1.62 (1.25, 2.10) 1.55 (1.19, 2.01)
Multiple birth
  Singleton 244 (93.5) 212769 (97.5) 1 (ref) 1 (ref)
  Twin or more 17 (6.5) 5507 (2.5) 2.69 (1.65, 4.40) 2.52 (1.54, 4.14)
Start of prenatal care
  During 1st trimester 210 (80.8) 171948 (79.8) 1 (ref) 1 (ref)
  No care or after 1st trimester 50 (19.2) 43416 (20.2) 0.94 (0.69, 1.28) 1.01 (0.73, 1.38)
Parity
  0 110 (42.1) 86505 (39.7) 1 (ref) 1 (ref)
  1 75 (28.7) 68785 (31.5) 0.86 (0.64, 1.15) 0.87 (0.64, 1.18)
  2 or more 76 (29.1) 62798 (28.8) 0.95 (0.71, 1.28) 0.90 (0.65, 1.24)
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a

Models adjust for maternal age, race, and birth year.

A number of pregnancy and labor complications were associated with hepatoblastoma (Table 3). Preeclampsia, fetal distress, premature labor, and breech presentation all increased risk for hepatoblastoma. Cases had a higher risk of any congenital anomaly. Cases who had been admitted to a NICU after birth had a similar age at diagnosis (mean=14.8 months) to cases who had not been admitted to a NICU (mean=13.9 months, 2-sided p=0.9).

Table 3.

Complications of pregnancy and labor, concurrent illnesses of the mother, and procedures conducted in the perinatal period, comparins hepatoblastoma cases to controls.

Case n(%)
n=261		 Control
n(%)
n=218,277		 Unadjusted OR
(95% CI)		 Adjusted OR (95%
Cl)
Complications and procedures of pregnancy and concurrent illnesses of the mothera
Chronic diabetes 5 (1.9) 3906 (1.8) 1.07 (0.44, 2.60) 0.93 (0.38, 2.27)
Preeclampsia 13 (5.6) 3943 (2.1) 2.70 (1.54, 4.73) 2.62 (1.49,4.58)
Complications or procedures of labor and deliverya
Dysfunctional labor 14 (6.0) 6633 (3.6) 1.71 (1.00, 2.94) 1.70 (0.99, 2.92)
Premature laborb 18 (8.4) 4439 (2.5) 3.54 (2.18, 5.74) 3.52 (2.17, 5.71)
Breech presentation 17 (6.5) 6555 (3.0) 2.25 (1.38, 3.68) 2.27 (1.39, 3.72)
Moderate/ heavy meconium in amniotic fluid b 12 (5.2) 7671 (4.2) 1.25 (0.70, 2.23) 1.27 (0.71, 2.27)
Fetal distress b 15 (6.2) 6696 (3.2) 2.00 (1.19, 3.38) 2.08 (1.23, 3.51)
Abnormal conditions and clinical procedures relating to the newbornb
NlCU admission c 27 (11.6) 5493 (3.0) 4.26 (2.85, 6.37) 1.40 (0.86,2.30)
Newborn transferred to another facility within 24 hours of delivery c 7 (3.0) 1029 (0.6) 5.51 (2.59, 11.72) 1.54 (0.69, 3.44)
Any clinical procedure on the newborn c 30 (12.9) 7065 (3.8) 3.70 (2.52, 5.44) 1.27 (0.79, 2.05)
Any congenital anomaly a 6 (2.3) 1408 (0.7) 3.51 (1.56, 7.90) 3.59 (1.59, 8.08)
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a

Models control for maternal age, race, and birth year.

b

Variable was not collected on birth certificates in all years of the study.

c

Models control for maternal age, race, birth year, and birth weight.

Of the complications associated with increased risk in other studies, we observed an increased risk with presumptive fertility treatment, although this was based upon only 3 cases (adjusted OR=7.45, 95% CI 2.35–23.6). We did not observe associations between polyhydramnios/oligohydramnios and hepatoblastoma (1 case mother and 965 control mothers exposed). Maternal smoking began to be reported on California birth certificates in 2007. Of the 6 cases born that year, all mothers were listed as nonsmokers.

In comparing our findings to the earlier report by Reynolds [8] which used California cases diagnosed 1988–1997, we observed similar associations across most demographic and gestational risk factors. Due to the larger sample size, we observed higher risks of hepatoblastoma among older mothers as well as more sharply decreased risks among children of Black mothers. Reynolds observed a later age at diagnosis among lower birthweight infants; while we observed differing average ages at diagnosis according to birthweight, there was no evidence of a trend (p=0.2). Children of very low birthweight had an age at diagnosis (mean=21.1 months) close to that of children of average birthweight (mean=18.3 months), while children with low (mean=13.6 months) or high birthweight (mean=13.8 months) were diagnosed earlier.

Discussion

In this large population-based study of California children, we found several demographic and gestational characteristics to be associated with hepatoblastoma. We observed strong increased risk with low birthweight, as noted in other studies [6–15], and also when examining singleton births only. Similarly, hepatoblastoma was associated with being small for gestational age, and with preterm birth. Hepatoblastoma was further associated with a spectrum of neonatal complications associated with preterm birth and low birthweight. Non-vertex presentation, precipitous labor, and caesarian section are all more common in prematurity [34,35]. Preeclamptic pregnancies are more likely to be delivered prematurely because of concerns for maternal and child safety. Overall our findings suggest that some insult in pregnancy that is related to both birth weight and prematurity can also result in hepatoblastoma as well as a number of perinatal conditions and interventions.

The positive association seen with young maternal age (<20 years) has been reported elsewhere [7,36]. We also observed increased risk with older maternal age (>35 years), even after additional adjustment for presumptive fertility treatment or for multiple births. We were not able to confirm earlier reports of associations between hepatoblastoma and high birthweight [12] or large size for gestational age [5]. However, our record-linkage approach allowed only for the measurement of fetal growth with size for gestational age, and there are several other metrics which may be used to assess accelerated growth.

We did not observe an increase in risk among children of Asian mothers, as was reported in a small study in Minnesota; in that study, authors did not report the specific country of origin of Asian mothers, but stated that most were of Southeast Asian descent [17]. The varying findings may in part reflect the differing Asian immigrant populations in California and Minnesota. Of our Asian cases, the largest proportions identified their country of origin as China, the Philippines, or Vietnam, with small numbers from several other countries. Asian nations have reported a wide variance in hepatoblastoma rates, with the highest rates seen in China (Tianjin) and Japan, and lower rates observed in India, Singapore, and Vietnam [3]. Rates in smaller countries, however, may fluctuate greatly given the small number of cases diagnosed in any given time period.

The lower risk of hepatoblastoma that we observed among children of Black mothers is consonant with rates reported by SEER [3]. Paradoxically, Black mothers in the US are twice as likely to deliver preterm babies as non-Hispanic White mothers [37], which suggests that the causes of preterm delivery generally are different from the causes of hepatoblastoma.

We observed associations with a number of labor complications and medical procedures, some of which have been reported elsewhere. One study reported a sharply increased risk for hepatoblastoma (OR=52.5) among children of severely preeclamptic pregnancies [14], and a case series also reported one case of hepatoblastoma that occurred after a preeclamptic pregnancy [15]. A large study in Denmark reported that children of mothers who had preeclampsia had elevated risks for any cancer in childhood or young adulthood (OR=1.3, 95% Cl 1.0–1.6); that study did not report which cancer types were associated with increased risk [38]. Although the mechanisms for such a relation are not known, studies have shown that estrogen levels are reduced and testosterone levels increased in preeclamptic pregnancies, likely due to poor placental aromatization of the precursor androgens, dehydroepiandrosterone and androstenedione, to estrogen. Preeclampsia is also characterized by varying levels of other hormones: elevated progesterone, human chorionic gonadotropin (hCG), and Cortisol, and lowered insulin-like growth factor-1 (lGF-1). Alterations in these hormones have been described among hepatoblastoma cases and in liver cancers in adults [39–42].

We observed an increased risk of hepatoblastoma among children of multiple birth pregnancies, and with presumptive fertility treatment. The findings for presumptive fertility treatment were based upon 3 cases of hepatoblastoma among children who were part of triplet pregnancies. Some previous epidemiologic studies have linked hepatoblastoma to fertility treatment [7,14]. There have also been case reports and record-linkage studies which reported cases of hepatoblastoma in children whose parents underwent treatment for infertility [13,43–46]. Parental treatment for infertility has been previously hypothesized to be a cause of childhood cancers. Studies of multiples prior to 1980, when the use of fertility treatments became more widespread, observed no association or a decreased risk for childhood cancers in multiples compared to singletons [47,48]. A more recent study, which includes some of the same cases from our study, reported an increased risk of hepatoblastoma among twins in crude analyses (OR=2.6); after adjustment for birthweight no relation remained (OR=0.9) [49].

Birth certificates are a data source with varying validity depending on the factor under study. In other US states, validation studies of several demographic variables reported on birth certificates (maternal age, race, education, parity) suggested a validity of >90%. In general, factors associated with the pregnancy, labor and delivery of the infant tend to have reasonably good validity. Sensitivity is lower for factors such as previous pregnancy history and pregnancy complications [50–52]. The possibility for differential reporting of complications on the birth certificate between cases and controls exists, as there may be increased provider vigilance of reporting of pregnancy complications among children born preterm.

The literature to date examining risk factors for hepatoblastoma has been very limited due to its rarity, making epidemiologic research challenging. Apart from sample size, a strength of our study was the objective nature of exposure data reported on birth certificates, with misclassification expected to be non-differential. The study design is likely to be free of selection bias, as all children cancer-free at age 6 and born in California had equal likelihood of being selected into the control sample. Our findings necessitate confirmation in other populations, ideally with linkage to medical records.

Acknowledgments

The study was supported by grants from the US National Institute of Environmental Health Sciences (R21ES018960, R21ES019986, P30ES007048).

Footnotes

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Conflict of interest statement

None.

Contributor Information

Julia E Heck, Email: jeheck@ucla.edu.

Travis J Meyers, Email: meyerstj87@gmail.com.

Christina Lombardi, Email: clombard@ucla.edu.

Andrew S Park, Email: apark1986@gmail.com.

Myles Cockburn, Email: myles@ccnt.usc.edu.

Peggy Reynolds, Email: Peggy.Reynolds@cpic.org.

Beate Ritz, Email: britz@ucla.edu.

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