Maternal Smoking During Pregnancy and Childhood Cancer

Transcription

1 American Journal of Epidemiology Copyright O 1996 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved Vol. 144, No. 11 Printed In U.SA. Maternal Smoking During Pregnancy and Childhood Cancer Mark A. Klebanoff, John D. Clemens, and Jennifer S. Read The association between maternal smoking during pregnancy and childhood cancer was investigated using prospectively collected data from 54,795 livebom children in the Collaborative Perinatal Project ( ). Cases of cancer had a histologic diagnosis and/or a compatible clinical course. There were children with cancer, for a cumulative incidence of cancer of 1.1 per 1,000 by 96 months of age. Maternal smoking was determined at each prenatal visit; 52% of mothers reported smoking at one or more visits. By age 8 years, cancer had occurred in 1.4 per 1,000 children whose mothers did not smoke during pregnancy, compared with 0.9 per 1,000 children whose mothers smoked (p = 0.15 by log rank test); the hazard ratio was (95% confidence interval (Cl) ). There was no dose-response effect of smoking compared with nonsmokers (hazard ratio for one to 10 cigarettes/day = 0.45, more than 10 cigarettes/day = 0.83). The hazard ratio for leukemia among children whose mothers smoked was 0.82 (95% Cl ); the hazard ratio for cancers other than leukemia was 0.60 (95% Cl ). Adjustment did not change the hazard ratio substantially. Although the relatively small number of cases precluded extensive study of individual types of cancer, the authors conclude that maternal smoking during pregnancy is not associated with an increased risk of childhood cancer in this cohort. Am J Epidemiol 1996; 144: carcinogens; cohort studies; neoplasms; pregnancy; smoking Tobacco smoking accounts for approximately 30 percent of the cancer deaths in the United States (1). However, the role of prenatal smoke exposure in the pathogenesis of cancer during childhood is less certain (2). Cancer during childhood is a rare event, and most studies of childhood cancer have used the case-control design. Retrospective studies of a risk factor that is socially disapproved, such as maternal smoking during pregnancy, may be particularly susceptible to recall or reporting bias. Mothers of children with cancer may be more likely than mothers of normal children to recall smoking during pregnancy, falsely elevating the risk of smoking. Conversely, even in the presence of accurate recall, guilt may make case mothers more likely than control mothers to deny the presence of a risk factor widely known to cause cancer, falsely reducing the risk of smoking. There have been only three prospective cohort studies of maternal prenatal smoking and childhood can- Received for publication April 16, 1996, and accepted for publication July 25, Abbreviations: Cl, confidence interval; CPP, Collaborative Perinatal Project. From the National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD. Reprint requests to Dr. Klebanoff, Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Hearth and Human Development, National Institutes of Health, 6100 Building, Room 7B03, Bethesda,. MD cer. One (3) found a significantly increased relative risk of 2.47 for cancer among children of smokers, another found a mildly increased risk of 1.3 (4), and a third found a relative risk of 0.99 (5). The present study is the fourth prospective cohort study of maternal prenatal smoking and childhood cancer. MATERIALS AND METHODS The subjects of this study were members of the Collaborative Perinatal Project (CPP) cohort, participating in a prospective, multicenter study designed to evaluate risk factors for various neurodevelopmental disorders of childhood (6-8). Pregnant women were enrolled from 1959 to 1966 at 12 university-affiliated medical centers in the United States. Their children were followed to age 7 years (approximately 80 percent (7)) or 8 years (approximately 36 percent (8)) and were examined according to a common protocol. Each child's guardian was interviewed at regular intervals during the first 2 years of life and annually thereafter. Whenever study personnel learned (usually by interview of the guardian) that a child had died or had been hospitalized, the relevant medical and, when appropriate, autopsy records were obtained. The methods used to ascertain potential cases of cancer have been described in detail previously (9, 10). Potential cases were ascertained by several mechanisms. Study identification numbers of children with 1028

2 Maternal Smoking and Childhood Cancer 1029 cancer were obtained from the authors of a previous investigation of cancer and exposure from radiographic examination in this cohort (11). In addition, diagnostic summary forms were completed for all subjects at birth and at 1 and 7 years of age. All summary forms reporting a neoplasm were identified. The study records of these children were reviewed to obtain a specific diagnosis. Reviews were done by two pediatricians (M. A. K. and J. S. R.) who were unaware of the mother's smoking habit. Definite cases were required to have a histologic diagnosis of cancer noted on a medical record summary or a clinical course (including treatment administered) consistent with the diagnosis. A previous analysis from this cohort (9) excluded cases of cancer diagnosed in stillboms or on the first day of life. As maternal smoking might be associated with cancer in these children, the records of three stillborn infants and seven liveborn infants with neoplasia noted on the first day of life were reviewed by investigators who were blinded to maternal smoking history. Three cases of cancer diagnosed on the first day of life in liveborn children (leukemia, Wilms' tumor, and hepatoblastoma) were included after this review. Women were usually registered in the study at their initial prenatal visit and were seen subsequently according to local policy at each site. The median gestation at registration was weeks for white and weeks for black women; approximately 75 percent of women of both races had registered by 28 weeks (7). At study registration and again at each visit, the women were asked how many cigarettes per day they were currently smoking. Women who reported smoking at any visit were considered to be smokers, and their maximum daily consumption was used in analysis of dose response. To account for the varying time of follow-up, survival analysis methods were used. The children entered the cohort at birth and were followed until the earliest of the dates cancer was diagnosed, their last computerized CPP form was completed, or they reached 96 months of age. Differences in cumulative incidence were tested using the log rank test, with statistical significance defined as a two-tailed p value of The hazard ratio was estimated from the proportional hazards model; 95 percent confidence intervals were derived from the standard errors of the regression coefficients. The proportionality assumption was tested by including both fixed and timedependent terms for smoking and was found to be valid (12). Categorical variables were compared using the chi-squared test, and continuous variables were compared using the t test for means and the Wilcoxon rank sum test for medians. RESULTS The cohort comprised 44,621 women, who gave birth to 54,795 liveborn children. Maternal smoking data were available for 54,306 births. At study registration, 25,353 women (47 percent) were current smokers, and an additional 3,120 women reported smoking on at least one subsequent visit, for a total of 28,473 women (52 percent) who smoked during pregnancy. Characteristics of smokers and nonsmokers are shown in table 1. Women who smoked during pregnancy were less educated, more likely to be white, more likely to be primigravid, less likely to receive diagnostic radiation during pregnancy, less likely to breast feed their infants, younger, of lower socioeconomic status, taller, and lighter than nonsmokers. Children of women who smoked were on average 143 g lighter at birth and were followed a median of 4 months less than children of nonsmokers. All of these differences were statistically significant. Gestational age, birth date, and sex of the children of smokers and nonsmokers were comparable. Fifty-one children developed cancer, corresponding to a life-table probability of 1.1 per 1,000 children followed to 96 months of age. The leukemias were the most common malignancy (n = 17), although the records did not allow the reliable differentiation of lymphoblastic from other types of leukemia. There were eight brain tumors, seven Wilms' tumors, six neuroblastomas, five lymphomas (four non-hodgkin), three retinoblastomas, two each of hepatoblastoma and rhabdomyosarcoma, and one fibrosarcoma. The cumulative incidence of cancer for children of mothers who smoked and did not smoke during pregnancy is presented in figure 1 (data on maternal smoking were missing for one case). Children of women who smoked during pregnancy had a cumulative cancer incidence of 0.9 per 1,000 at 96 months of age, compared with 1.4 per 1,000 for children of women who did not smoke (p = 0.15). The corresponding hazard ratio was (95 percent confidence interval (CI) ). There was no evidence of a doseresponse association with smoking (hazard ratio for one to 10 cigarettes = 0.45, for more than 10 cigarettes = 0.83). Children of smokers were not at increased risk of developing leukemia (0.82, 95 percent CI ) or other cancers (0.60, 95 percent CI ). There were too few cases of individual types of nonleukemic cancer for analysis. Most of the characteristics in table 1 exhibited neither practically nor statistically significant associations with cancer. However, mothers of children with cancer

3 1030 Klebanoff et a). TABLE 1. Maternal and Infant characteristics associated whh smoking during pregnancy, Collaborative Perinatal Project, Characteristic No. Smokers % No. Nonsmokers % Race* White Black Other 14,613 12,317 1, ,265 12,098 2, Education (years completed)* <12 12 >12 17,055 8,174 3, ,726 7,964 4, Prior pregnancies* :>4 7,345 6,122 4,679 3,394 6, ,700 5,481 3,828 2,742 5, Diagnostic radiation In pregnancy* None Any Pelvimetry 11,892 16,6 1, ,353 16,465 1, Type of feeding in hospital* Breast only Mixed Formula No data 1,403 2,003 21,233 3, ,867 2,367 17,895 3, Infant sex Male Female 14, ,075 12, Maternal age (years) Education (years) Sodoeconomlc lndex Maternal height (cm) Prepregnant weight (kg) Infant blrthwelght (g) GestatJonal age (weeks) Mean (SO*) 24.1 (5.8)* 10.5 (2.4)* 4.6 (2.1)* 161-2(6.8)* 58.5(11.2) * 3,069 (581)' 38.6 (3.2) Mean (SD) 24.3 (6.2)* 10.7 (2.7)* 4.7 (2.2)* (7.0)* 59.5 (12.0)* 3,212 (576)* 38.6 (3.1) p< t Median date of delivery for smokers, February 4, 1963, and for nonsmokers, February 14, 1963; median age at last contact for smokers, 87 months, and for nonsmokers, 91 months (p < 0.001). t SD, standard deviation. Myrianthopoulos NC, French KS. An application of the US Bureau of the Census sodoeconomlc index to a large, diversified patient population. Soc Sd Mod 1968;2: had slightly greater prepregnant weights than mothers of children without cancer (63.0 vs kg; p = 0.052), and children with cancer were born earlier in the study than children without cancer (April 8, 1962, vs. February 2, 1963; p = 0.02). Infant birth weight was not associated with childhood cancer (p = 0.45). Because of the small number of cases, the hazard ratio for cancer among children of smokers compared with children of nonsmokers was adjusted in sequence for each of the factors in table 1 except infant birth weight and gestational age, as these outcomes are themselves strongly and probably causally associated with smoking. Results of these adjustments are shown in table 2. Adjustment had little effect on the hazard ratio, although increased maternal prepregnant weight and earlier delivery date were significantly associated with increased risks of childhood cancer in these analyses (p = 0.04 for both associations).

4 Maternal Smoking and Childhood Cancer Age (months) Non-smoker Smoker FIGURE 1. Cumulative incidence of cancer among children of women who did and did not smoke during pregnancy, Collaborative Perinatal Project, At registration, women who currently were nonsmokers were not asked about smoking since their last menstrual period. However, they were asked if they had smoked at least 100 cigarettes, and those who had were asked their age when they stopped. By comparing this age with their age at study registration, we TABLE 2. Adjusted hazard ratio* for cancer among children of women who smoked during pregnancy compared with children of nonsmoking women, Collaborative Perinatal Project, Characteristic controlled Maternal racet Maternal age* Maternal education* Maternal soctoeconornic Index* Maternal height* Maternal prepregnancy weight* Prior pregnancies* Diagnostic radiation during pregnancy PeMmetry Infant feeding In hospital!) Infant sex# Date of delivery* Hazard ratio tor smokers V8. nonsmokere * a, confidence Interval. t Coded as white, black, other. * Continuous variable. Coded as any, none. U Coded as bottle only, breast only, mixed, unknown. * Coded as male, female. 96% Cl* estimate that the occurrence of any smoking during pregnancy might have been as high as 58 percent. When women whose age at stopping was the same or 1 year less than their current age were reclassified as smokers, the hazard ratio was even less indicative of a positive association between maternal smoking and childhood cancer (hazard ratio 0.57, 95 percent CI ). Data were not collected on maternal smoking after the study child's birth, and some of the children unexposed in utero to maternal smoking might have been exposed postnatally. However, comparing smoking status during successive pregnancies with the 8,442 women who had second CPP pregnancies showed that 88 percent of women who did not smoke at any time during their first pregnancy also did not smoke at any time during their second, and that 91 percent of those who smoked during their first pregnancy also smoked during their second. Although the women's smoking habits may have changed due to the pregnancy itself, it therefore seems unlikely that a large fraction of children unexposed to maternal tobacco smoke prenatally was exposed postnatally. DISCUSSION This study found that children of women who smoked during pregnancy were not at increased risk of developing cancer in their first 8 years; the upper confidence limits indicate that even moderate in-

5 1032 Klebanoff et al. creases in risk are unlikely. Although there have been many case-control studies of maternal smoking and childhood cancer, there have been only three other cohort studies. These cohort studies reported relative risks of 2.47 (3), 1.3 (4), and 0.99 (5). When the four cohort studies were combined in a random effects model (13), there was significant heterogeneity between studies (Q statistic = 8.8, df = 3, p < 0.05), and a summary effect measure would not be meaningful. The CPP was not designed to study childhood cancer. Therefore, several indirect mechanisms were used to identify cases, and underascertainment is possible. Based on national age-, race- and sex-specific incidence data for (14), the expected probability of developing cancer by age 8 years in a cohort with the racial makeup of the CPP is 1.2 per 1,000, which is nearly identical to our observed incidence of 1.1 per 1,000, suggesting that there were very few missed cases. Nearly 20 percent of study children had younger siblings who were also enrolled in the CPP. Due to the rarity of childhood cancer and the lack of any instances of siblings developing cancer, the potential nonindependence of the data is not likely to influence the results. To verify this, the crude hazard ratio was adjusted, utilizing SUDAAN (15) software, for the possible concordance of risk among siblings. As the corrected 95 percent confidence limits for the hazard ratio were 0.37 and 1.19, virtually identical to the limits of 0.38 and 1.17 observed when nonindependence was ignored, this was not addressed further. The CPP did not collect data on paternal smoking or on smoking by other members of the mother's household or at her workplace. Paternal smoking has been associated with childhood cancer in some case-control studies (16) and might exert an effect either through damage to sperm or through passive exposure of the mother. Although unlikely to have much additional effect on the exposure of women who already smoke, maternal passive smoke exposure would result in misclassification of women with some smoke exposure as being unexposed. Such misclassification might bias an elevated risk of maternal smoking toward the null. If the fetus or child were vulnerable to tobaccoinduced cancer only at a specific point in development, the definition of smokers as women who reported smoking at any interview during pregnancy might be too crude. However, of the women who were nonsmokers at their initial visit, only 3,120 (11 percent) reported smoking at one or more subsequent visits. In addition, 81 percent of the women who smoked at their initial visit reported smoking at all subsequent visits. It is also probable that most women who smoked during pregnancy smoked postnatally, and most women who did not smoke during pregnancy did not smoke postnatally. Therefore, the vast majority of the women who smoked are likely to have smoked during the entire pregnancy and postnatal periods, minimizing the possibility of misclassification of maternal smoking during a time when the embryo or child was vulnerable to carcinogenesis. As in all studies relating prenatal exposures to postnatal outcomes, the role of pregnancy and postnatal losses should be considered. Spontaneous abortions comprise 30 percent of all pregnancies (17), and maternal smoking is associated with an increased risk of spontaneous abortion (18) and infant mortality (19). An increased risk of mortality from nonmalignant causes among fetuses and children destined to develop cancer had they survived could distort the association between prenatal tobacco exposure and childhood cancer (20). As it cannot be determined which fetuses or children dying of other causes would have developed cancer had they survived, this hypothesis cannot be tested. Childhood cancer is very different from cancer in adults. Epithelial tumors comprise the majority of cancers in adults compared with a small minority of tumors in children of the age range studied (21). As smoking is associated primarily with epithelial tumors in adults, it may not be biologically plausible to expect a positive association between in utero tobacco exposure and childhood cancer. However, prenatal and early childhood tobacco exposure may be associated with an increased risk of cancer in adulthood (22); as this cohort was not followed to adulthood, this hypothesis could not be tested. In summary, this study found that although the small number of cases limits the ability to draw conclusions regarding specific types of cancer, children exposed in utero to maternal smoking were not at increased risk of cancer in general. However, maternal smoking during pregnancy is associated with an increased risk of a variety of adverse outcomes, and there are many other valid reasons for pregnant women to refrain from smoking. ACKNOWLEDGMENTS The authors are thankful to Dr. Rebecca DerSimonian for calculating the pooled relative risk, confidence intervals, and heterogeneity of the prospective studies. REFERENCES 1. Fielding JE. Smoking: health effects and control. N Engl JMed 1985;313:491-8.

6 Maternal Smoking and Childhood Cancer Tre'daniel J, Boffetta R, Little J, et al. Exposure to passive smoking during pregnancy and childhood, and cancer risk: the epidemiologic evidence. Paediatr Perinat Epidemiol 1994;8: Golding J, Paterson M, Kinlen LJ. Factors associated with childhood cancer in a national cohort study. Br J CanceT 1990;62: Neutel CI, Buck C. Effect of smoking during pregnancy on the risk of cancer in children. J Natl Cancer Inst 1971;47: Pershagen G, Ericson A, Otterblad-Olausson P. Maternal smoking in pregnancy: Does it increase the risk of childhood cancer? Int J Epidemiol 1992;21:l Niswander KR, Gordon M. The women and their pregnancies. Philadelphia, PA: W. B. Saunders, Myrianthopoulos NC. Malformations in children from one to seven years: a report from the Collaborative Perinatal Project New York, NY: Alan R. Liss, Lassman FM, Fisch RO, Vetter DK, et al. Early correlates of speech, language, and hearing. Littleton, MA: PSG Publishing Company, 1980: Klebanoff MA, Read JS, Mills JL, et al. The risk of childhood cancer following neonatal vitamin K exposure. N Engl J Med 1993;329: Read JS, Clemens JD, Klebanoff MA. Moderate low birth weight and infectious disease mortality during infancy and childhood. Am J Epidemiol 1994;140: Shiono PH, Chung CS, Myrianthopoulos NC. Preconception radiation, intrauterine diagnostic radiation, and childhood neoplasia. J Natl Cancer Inst 1980;65: Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York, NY: John Wiley and Sons, 1980: DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7: Robison LL. General principles of the epidemiology of childhood cancer. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology. Philadelphia, PA: J. B. Lippincott, 1993: Shah BV, Bamwell BG, Bieler GS. SUDAAN user's manual, release Research Triangle Park, NC: Research Triangle Institute, John EM, Savitz DA, Sandier DP. Prenatal exposure to parents' smoking and childhood cancer. Am J Epidemiol 1991; 133: Wilcox AJ, Weinberg CR, O'Connor JF, et al. Evidence of early loss of pregnancy. N Engl J Med 1988;319: Harlap S, Shiono PH. Alcohol, smoking, and incidence of spontaneous abortions in the first and second trimester. Lancet 1980;2: Malloy MH, Kleinman JC, Land GF, et al. The association of maternal smoking with age and cause of infant death. Am J Epidemiol 1988;128: Hook EB, Regal RR. Conceptus viability, malformation and suspect mutagens or teratogens in humans: the Yule-Simpson paradox and implications for inferences of causality in studies of mutagenicity or teratogenicity limited to human livebirths. Teratology 1991;43: Miller RW, Myers MH. Age distribution of epithelial cancers. (Letter). Lancet 1983;2: Sandier DP, Everson RB, Wilcox AJ, et al. Cancer risk in adulthood from early life exposure to parents' smoking. Am J Public Health 1985;75: