|Year : 2016 | Volume
| Issue : 2 | Page : 999-1005
Maternal smoking during pregnancy and risk of childhood neuroblastoma: Systematic review and meta-analysis
Ping Chu1, Huanmin Wang2, Shujing Han1, Yaqiong Jin1, Jie Lu1, Wei Han2, Jin Shi3, Yongli Guo1, Xin Ni4
1 Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
2 Department of Surgical Oncology, Beijing Children's Hospital, Capital Medical University, Beijing, China
3 Department of Surgical Oncology, Beijing Children's Hospital, Capital Medical University; Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, China
4 Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University; Department of Surgical Oncology, Beijing Children's Hospital, Capital Medical University, China
|Date of Web Publication||25-Jul-2016|
56, Nanlishi Road, Xicheng District, Beijing 100045
Source of Support: None, Conflict of Interest: None
Background: Prior epidemiological studies suggest a possible association between maternal smoking during pregnancy and risk of childhood neuroblastoma. A meta-analysis was performed statistically surmising all available observational studies on this topic in order to evaluate the potential correlation of maternal smoking during pregnancy and risk of childhood neuroblastoma.
Methods: Published literature was obtained from PubMed, Embase, ISI Web of Science, and Cochrane library, and all studies were inclusive until July 2014. Data from epidemiological studies were combined using a general variance-based meta-analytic method employing 95% confidence intervals. The outcome of interest was shown as odds ratio (OR) reflecting the risk of neuroblastoma development associated with smoking while pregnant. Newcastle–Ottawa Scale was used to assess the quality of studies.
Results: Seven case-control studies meeting protocol specified inclusion criteria were obtained through a comprehensive literature search. These studies enrolled a total of 1909 patients and 15,683 controls. Analysis for homogeneity demonstrated that the data were heterogeneous (P < 0.05) and could be statistically combined with randomized effect model. Combining all seven reports yielded an OR of 1.28 (1.01–1.62), a statistically significant result suggesting possible association between maternal smoking during pregnancy and risk of childhood neuroblastoma development (P = 0.005). There was no association between the dosage of maternal smoking during pregnancy and risk of neuroblastoma.
Conclusion: The available epidemiological data support a possible association between maternal smoking during pregnancy and pediatric neuroblastoma development.
Keywords: Meta-analysis, neuroblastoma, pregnancy, smoking, tobacco
|How to cite this article:|
Chu P, Wang H, Han S, Jin Y, Lu J, Han W, Shi J, Guo Y, Ni X. Maternal smoking during pregnancy and risk of childhood neuroblastoma: Systematic review and meta-analysis. J Can Res Ther 2016;12:999
|How to cite this URL:|
Chu P, Wang H, Han S, Jin Y, Lu J, Han W, Shi J, Guo Y, Ni X. Maternal smoking during pregnancy and risk of childhood neuroblastoma: Systematic review and meta-analysis. J Can Res Ther [serial online] 2016 [cited 2019 Sep 20];12:999. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/999/171367
Ping Chu and Huanmin Wang contribute equally to this work.
| > Introduction|| |
Neuroblastoma (NB) is the most common extracranial solid cancer in childhood, accounting for approximately 8% of childhood malignancies. Its incidence peaks in the 1st year (52 cases/million children) and then drops by half in the 2nd year, with most cases diagnosed before 5 years. This early age at diagnosis of neuroblatoma suggests that prenatal exposures might play an important role. Meanwhile, prognosis of neuroblastoma is quite variable including spontaneous regression and fatal disease despite multimodality therapy. In contrast to many adult cancers, this sporadic occurrence has made neuro blatoma particularly difficult to study. At present, few causative factors have been identified for this disease.
Previous epidemiological studies have indicated that there was an increased risk of neuroblastoma correlating to maternal use of certain medications during pregnancy, parental occupational exposures, and certain birth characteristics.
Tobacco smoke is a potential risk factor for a number of childhood cancers because of various mutagenic and carcinogenic compounds crossing the placenta.,, Maternal cigarettes consumption during pregnancy was associated with an increased risk of neuroblastoma in previous epidemiological studies. Schwartzbaum's study showed that compared with the nonsmoking pregnant women, women who smoked during pregnancy were extraordinarily more likely to have a baby with neuroblastoma. Meanwhile, a few studies have different conclusions., This inconsistency might due to relatively small study sizes, failure to consider specific time windows of exposure, and limited information on the confounding factors.
Therefore, a comprehensive analysis is necessary to identify the correlation of maternal smoking during pregnancy and the risk of neuroblastoma. In this study, we applied meta-analysis to estimate the effect of maternal smoking during pregnancy on the risk of neuroblastoma occurrence and anticipated the results will provide evidence that smoking-free is one of the measures for neuroblastoma prevention in childhood.
| > Methods|| |
This article does not contain any studies with the human participants or animals performed by any of the authors.
Studies relevant to the etiology of neuroblastoma will be included as [Table 1].
We tried to identify all relevant studies that assessed the correlation of maternal smoking during pregnancy and the risk of neuroblastoma. Two investigators and a professional librarian developed search strategies for locating all of the relevant studies published from 1946 to 2014 in the PubMed (http://www.pubmed.org), Embase (http://www.embase.com.proxy.medlib.iupui.edu/search), ISI Web of Science (http://apps.webofknowledge.com), and Cochrane Library (http://www.thecochranelibrary com/view/0/index.html), respectively. Then, we enhanced the computerized literature search by manually reviewing the reference lists, scanning abstracts from recent conference proceedings, and directly consulting neuroblastoma specialist.
Screening and selection of literature
Primary studies were selected based on the predesigned inclusion criteria. First, 2 reviewers independently assessed the identified records by reading the title and abstract according to the predeveloped inclusion questions. Records not excluded were promoted for further screening. Second, 2 reviewers independently evaluated the full text for each record. Disagreement in the assessment was discussed until consensus was reached. If consensus could not be reached, a clinical expert was responsible to resolve the disagreements. If the reviewer's selection was “unclear,” that particular question was resolved by rereading the text or through unanimous consensus if a resolution was not met. The main reasons for exclusion at this stage were recorded, and then a list of excluded records (with reasons) was created.
Two investigators designed a standardized abstract form. Thereafter, another two investigators extracted the data from eligible studies. During the process of report selection, a consultant resolved disagreements. The following variables were extracted from each study: Author, publication year, country of the study, study population demographic characteristics, study designation (retrospective or prospective), number of neuroblastoma cases and control, ascertainment of exposure, diagnosis method, neuroblastoma cases and control source, the study-specific odds ratios (ORs) with their 95% confidence intervals (CIs).
Assessment of risk of bias
In this study, the Newcastle–Ottawa Scale  was used to assess the quality of each literature. This scale has strict scoring criteria for studies. The total score was 9 points and scores no lower than 7 points were indicative of high-quality research; otherwise, of low quality.
In the present study, the OR in a 95% CI level was used to evaluate the effect of the degree of correlation between maternal smoking during pregnancy and risk of childhood neuroblastoma. The Cochrane Q statistic and the I2 test were applied for heterogeneity assessment. For the Q statistic, P ≤ 0.05 was considered statistically significant for heterogeneity; for the I2 statistic, heterogeneity was interpreted as absent (I2: 0–25%), low (I2: 25.1–50%), moderate (I2: 50.1–75%), or high (I2: 75.1–100%). Funnel plots combined with the Begg's test  and the Egger's test  were used for the assessment of publication bias. Statistical analyses of all of the above were carried out using Stata version 11.0 software (Stata Corp., College Station, Texas, USA).
| > Results|| |
The literature screening process is shown in [Figure 1]. According to the pre-established search strategy, 86 articles were found, with 24 from PubMed, 39 from Embase database, 21 from ISI Web of Science, 2 from Cochrane library, and 2 through hand searching. After eliminating the duplicate documents, 66 studies remained. After browsing titles and abstracts, we excluded 49 studies that did not fulfill the inclusion criteria. The remaining 17 articles were screened by reading the full text, and 10 documents were excluded (1 insufficient data, 3 nonoriginal research, 4 no neuroblastoma subgroup data, and 2 no relevant outcomes). Finally, 7 documents were included in this meta-analysis.
Characteristics of the studies included
The studies included in the meta-analysis were case-control studies.,,,,,, [Table 2] shows the basic information on seven studies, respectively. A total of 15,683 participants were involved in our study, 1909 individuals in the case group and 13,774 individuals in the control group. The sample size of individual studies varied from 456 to 7769. The diagnosis of all neuroblastoma patients was historically confirmed. Of the seven studies, six were population-based controls and one was hospital-based controls.
Maternal smoking during pregnancy and neuroblastoma association
There were seven sets of data in total, and OR plus 95% CI were used to evaluate the effect size of maternal smoking during pregnancy and neuroblastoma.,,,,,, The result of the heterogeneity test was I2 = 65% (P = 0.009), indicating a heterogeneity among studies; thus, a randomized effects model was employed. The summary effect [Figure 2] of seven studies showed a statistical significantly relationship between maternal smoking during pregnancy and neuroblastoma (OR = 1.28, 95% CI: 1.01–1.62, P = 0.04) [Figure 2].
|Figure 2: Random-effects models for the association between maternal smoking and the incidence of neuroblastoma|
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Dosage of maternal smoking during pregnancy and neuroblastoma association
Totally, three studies in total OR and 95% CI were used to evaluate the effect of the dosage of maternal smoking during pregnancy and neuroblastoma.,, According to the result of the heterogeneity test, randomized and fixed effect model was applied to combine the available data. [Figure 3] showed no association between the dosage of maternal smoking during pregnancy and risk of neuroblastoma.
|Figure 3: Odds ratio and 95% confidence interval for the associations between the dosage of maternal smoking during pregnancy in relation to the incidence of neuroblastoma: (a) ≥10 cigarettes per day versus nonsmokers; (b) <10 cigarettes per day versus nonsmokers; (c) ≥10 cigarettes per day versus <10 cigarettes per day|
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Assessment of publication bias
The Newcastle–Ottawa Scale indicated that 6 studies were high-quality research studies and 1 was low-quality studies [Table 3]. The funnel plot [Figure 4] showed a relatively symmetrical distribution; neither Begg's test (P = 0.070) nor Egger's test (P = 0.142) showed a significant publication bias among studies.
|Table 3: Methodological quality of the studies included in the meta-analysisa|
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|Figure 4: Publication bias in the studies. OR: Odds ratio; SE: Standard error|
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| > Discussion|| |
To our knowledge, this is the first meta-analysis that investigated the role of in utero exposure to cigarette associated with childhood neuroblastoma. Combined estimations suggested that when compared with nonsmoking pregnant women, the risk for women who smoked during pregnancy had 1.28 fold higher risk to have a baby with neuroblastoma, indicating the possible association between maternal smoking during pregnancy and neuroblastoma, even though the effect was not statistically significant on the dosage of cigarette consumption.
As is known tobacco smoke is estimated to kill 5.7 million people each year., A lot of studies have revealed solid evidence between consumption of cigarettes and human cancers., Among constituents of cigarette smoke, more than 40 carcinogens have been identified., Several hundreds of these compounds were known as animal carcinogens relevant to cancers of the oral cavity, larynx, pharynx, lung, esophagus, stomach, pancreas, liver, kidney, ureter, bladder, uterine cervix, and leukemia.,,,
Our study found a statistical significant relationship between maternal smoking during pregnancy and neuroblastoma (OR = 1.28, 95% CI: 1.01–1.62, P = 0.04). Schwartzbaum performed the first epidemiological study indicating an association between maternal cigarette consumption and neuroblastoma, which showed when compared with nonsmoking pregnant women, the risk for women who smoked during pregnancy was 1.9 fold higher to have a baby with neuroblastoma (OR = 1.90, 95% CI: 1.1–3.2). Consistent with what was discovered in our study, the possible association was found between maternal smoking during pregnancy and childhood neuroblastoma. Since our result was based on all the available data combined, it's reasonable that our results is not as significant as Schwartzbaum's study. Moreover, Pang' et al. study  also reported a statistically significant increased risk of developing hepatoblastoma in children whose mothers smoked during pregnancy (OR = 2.68, P = 0.02). Furthermore, prior epidemiological studies suggested a possible association between maternal smoking during pregnancy and childhood brain tumors. All the evidence showed that utero transfer of maternal smoke-related toxins plays a very important role in childhood neuroblastoma development.
The side effect of environmental tobacco smoke by parental smoking on children is also well established. Maternal smoking during pregnancy has been associated with various adverse outcomes, such as birth weight, preterm delivery, and higher risk of childhood tumors.,,,, Maternal smoking during pregnancy could represent as a high risk factor for the development of tumors during childhood. Recent evidence indicated that genetic changes that occur in certain childhood hematopoietic cancers might originate in utero, and the tobacco-related compounds were found in the placenta and fetal blood as well.,
In this paper, we did not access to the information on the dosage of cigarette such as ≥10 cigarettes per day versus nonsmokers, <10 cigarettes per day versus nonsmokers, and 10 cigarettes per day versus <10 cigarettes per day and the data related to the association of the neuroblastoma. Pang et al. also had the same conclusion as we found, there were nonsignificant trends of increasing risk with number of cigarettes smoked for maternal preconception smoking (P values for trend >0.05). The main reason could be that only three of seven studies mentioned the associations between the dosage of maternal smoking during pregnancy in relation to the incidence of neuroblastoma.,, Other studies mentioned maternal smoking during pregnancy and childhood cancer, but the subgroup data on neuroblastoma with the dosage of cigarette smoking was not referred to.,,
There are several limitations in our study. One limitation in our study was that one of seven studies included in the analysis  enrolled patients from hospital patient registries while the remaining studies used population-based data. Since selection bias may impact study outcome, further analysis may be made until other population-based epidemiological studies in this area. Another limitation of this study was that all the studies included in the meta-analyses were case-control studies. Hence, recall bias due to the stigma of smoking during pregnancy cannot be excluded. The third major limitation of the existing data base on this topic is the relatively small size of most studies addressing this issue. This is understandable given the rarity of the disease.
As far as we concerned, great attention has been paid to the maternal risk factors during pregnancy associated with childhood cancer with the method of meta-analysis. With the same study process as we applied in this paper, Latino et al. assessed the association between maternal alcohol consumption during pregnancy and childhood leukemia, and found that there was a significantly increased risk between them.
This is the first systematic review and meta-analysis of the risk of maternal smoking during pregnancy and neuroblastoma. By use of a comprehensive search strategy, we were able to identify a substantial body of evidence. In further, large birth cohort studies should investigate the influence of maternal smoking during pregnancy and the risk of childhood neuroblastoma and other cancers as well. Such studies may integrate accurate data collection not only on fetal exposure to smoking allowing dose response analyses, but also the collection of detailed potential confounding factors. The creation of an international consortium of birth cohort studies could provide the statistical power required to investigate the interaction of cigarette smoking with other environmental and genetic factors in relation to the risk of neuroblastoma in children.
This study was funded by the National Natural Science Foundation of China 81472369, 31401067, and Scientific Research Common Program of Beijing Municipal Commission of Education KM201510025021.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]