2 0- 1935-44 1945-54 1955-64 1965-74 1075-79 FIGURE S.-Mean annual incidence rates per 100,000 population for males of bronchogenic carcinoma by cell type, Olmsted County, MN, 193% 79, by decade SXKCE Bed c`t .II , IYXFl. a reduced effect. Statistical methods are used with epidemiologic data to describe in- teractions. Either an additive or a multiplicative scale may be used to measure interac- tion statistically (Saracci 1987). For two exposures, on an additive scale, the sum of the two independent relative risks reduced by one is compared with the relative risk ob- served when both exposures are present. On a multiplicative scale. the comparison rela- tive risk value is the product of the two independent relative risks. For public health purposes, a positive departure from additivity is considered to represent synergism (Saracci 1987). As the extent of interaction increases, the proportion ofthe excesscases attributable to the interaction also increases (Saracci 1987). This Section briefly reviews the current evidence on host characteristics and environ- mental agents that may modify the risk of cigarette smoking. Familial Factor\ The I963 Report considered and dismissed the "constitutional hypothesis" that predilections to cigarette smoking and t,a lung cancer share a common genetic origin. The Report did consider that i-- (renetic factors might determine susceptibility for a minority, ofcases. Subsequent epidemiologic studies have provided empirical evidence of possible genetic or familial determin;..nt\ of susceptibility (Tokuhata and Lilienfeld I963a. 1963b: Samet. Humble. Pathak 13X6: Ooi et al. 19X6). For example. in a recent case-control study in Nevv Mexico (Samet. Humble. Pathak 19X6). a parental history of lung cancer vva\ associated with a fivefold increase in lung cancer risk, after adjust- ment for cigarette smoking. Clinical studies of selected families have also indicated familial aggregation (Brisman et al. 196'7: Lynch et al. 1982; Goffman et al. 1982). Research has not yet identified the mechanisms underlying the familial aggregation of lung cancer. In 1973. Kellermann. Shaw, and Luyten-Kellerman (1973) reported the promising observation that patients with lung cancer had a higher degree of in- ducibility of aryl hydrocarbon hydroxylase than did control subjects. Because this en- zyme converts polycyclic aromatic hydrocarbons to more active carcinogens and be- cause enzyme concentrations are under genetic control. this observation suggested a possible genetic determinant of lung cancer risk. However. not all subsequent studies have been confirmatory. and the inheritance of inducibility in humans has not yet been fully described (Mulvihill and Bale 19X-1). Other Host Factors Acquired host characteristics have also been examined as determinants of lung can- cer rish including pulmonary tuberculo4s. chronic bronchitis, COPD. disorders as- sociated with interstitial fibrosis ofthe lung. and peripheral pulmonary scars. However, the evidence related to these disorders i5 incomplete and frequently is derived from case series rather than from epidemiologic investigations. Recent epidemiologic evidence, however. has indicated increased lung cancer risk for smokers with COPD compared with unaffected mohers (Peto et al. 19X3: Samet. Humble. Pathak 1986; Skillrud. Of- ford. Miller 19X6). Occupational Exposures Diverse agent\ inhaled in the workplace have been shown to cause lung cancer. In- teraction between occupational expo\ur:s and smokin, ~7 was the focus of the 19X5 Report of the Surgeon General (US DHHS 19X5). That Report concluded that "For the ma.jority of American workers who make. cigarette smoking represents a greater cause of death and disability than their workplace environment." The Report also highlighted the limitations of the evidence on interactions between smoking and occupational ex- posure\. Little new information ha\ become available since the 1985 Report. The evidence remains strongest for interactions of smoking with exposure to radon decay products and with exposure to asbestos (Saracci 1987). For both exposures. the preponderance of the evidence indicates synergism (Doll and Peto 1985; National Research Council 198X). although the results of some individual investigations are inconsistent vvith synergism. Ambient Air Pollution The 1964 Report noted that lung cancer mortality rates tended to be higher in urban than in rural locations. Air pollution was considered a plausible explanation for these differences. The association of lung cancer with atmospheric pollution derives biologi- cal plausibility from the presence of carcinogens in polluted air and has some support from epidemiologic data. However. epidemiologic investigation of ambient air pollu- tion as a risk factor for lung cancer has been hampered by methodological problems. including the necessity of considering cigarette smoking and the difficulty of assessing pollution exposure (NIH 1986). Recent epidemiologic investigations have not shown strong effects of air pollution (Samet et al. 1987: Buftler et al. 198X): and Doll and Peto ( 19X I ). in their review of the causes of cancer. estimated that only I to 2 percent of lung cancer was related to air pollution. Indoor Air Pollution As the hazards posed by ambient air pollution from conventional fossil fuels have diminished in some countries. the relevance of indoor air quality for health has become increasingly apparent. Studies of time-activity patterns demonstrate that residents of more developed countries, including the United States. spend on average little time out- doors (Spenglerand Sexton 1983: Samet. Marbury. Spengler 1987). Indoor spaces may be polluted by entry of contaminants from outdoor air and by indoor sources including those related to human activity. such as tobacco smoking, building materials. combus- tion devices, personal care and other household products. and other sources. A trend of reduced building ventilation in the aftermath of the energy problems of the 1970s may have worsened indoor air quality. Two pollutants in indoor air have been causally linked to lung cancer: environmen- tal tobacco smoke (ETS) (US DHHS 1986a) and radon (National Research Council 1988). The evidence on ETS and cancer was comprehensively reviewed in the 1986 Report (see Section on Involuntary Smoking in this Chapter). Radon is an inert gas that is formed from radium during the natural decay of uranium. The predominant source of radon in indoor air is the soil beneath structures. Radon dif- fuses through the ground into basement and crawl spaces. and then throughout the air in a home. or crosses cracks and other penetrations in homes on concrete slabs to enter the indoor environment. Radon daughters are invariably present in indoor air and a wide range of concentrations has been observed in homes (Samet et al. 198X). Some homes have levels comparable to those measured in uranium mines, but the majority of homes probably have levels that are currently considered acceptable. Radon decays into short-lived particulate decay products. Two of the decay products emit alpha particles. which are highly effective in damaging cells because of their high energy and high mass. When these alpha emissions take place within the lung. the epithelial lining of the tracheobronchia, tree may be damaged and lung cancer may ul- timately result. Extensive epidemiologic data from studies of uranium and other un- derground miners have established a causal association between exposure to radon daughters and lung cancer (National Research Council 1988). The committee on the Biological Effects of Ionizing Radiation (BEIR) IV concluded that the studies of miners indicated synergism between cigarette smoking and radon decay products (National Research Council 1988). The evidence, however, was not considered adequate to deter- mine if the interaction was multiplicative or submultiplicative. To date, epidemiologic investigations of domestic radon daughters as a risk factor for lung cancer have been limited and preliminary (Samet et al. 1988). However, it is assumed that radon decay products are carcinogenic in the indoor environment as they are in the mining environment. Dosimetric analyses indicate equivalent car- cinogenicity in the domestic and mining environments (National Research Council 1988). Thus, radon must be considered one of the most important factors interacting with cigarette smoking. All smokers are exposed to radon, some at unacceptable levels. Quantitative estimates of the contribution of radon to lung cancer are variable. The es- timates vary with the underlying assumptions and the risk model employed (Samet et al. 1988). Although cigarette smoking is by far the major cause of lung cancer, radon must also be considered a cause of the disease. The public health burden of radon-related lung cancer is substantially increased by the synergism between cigarette smoking and radon exposure. Diet Diet has recently been considered as potentially influencing the risk of lung cancer in smokers. Nutrients of particular interest include preformed vitamin A, carotene, vitamin E, and vitamin C (Colditz, Stampfer, Willett 1987). An enlarging body of experimental and epidemiologic evidence supports the hypothesis that the risk for certain cancers varies inversely with consumption of preformed vitamin A or beta-carotene, its precursor (Peto et al. 1981; National Academy of Sciences 1982; Colditz, Stampfer, Willett 1987). The biological plausibility of this hypothesis derives from the known effects of vitamin A deficiency on the differentiation of epithelial surfaces, from in vitro and in vivo models, which show that retinoids can suppress the deve,lopment of malignancy, and from possible an- ticarcinogenic activity of beta-carotene. the principal dietary precursor of vitamin A (Peto et al. 198 I: National Academy of Sciences 1982). The epidemiologic evidence indicates a protective effect of dietary vitamin A intake from vegetable sources, but not of preformed vitamin A, which is derived from meat and dairy sources, and vitamin supplements. Clinical trials on vitamin .4 and lung cancer risk are in progress. Vitamins E and C are antioxidants, which might have anticancer effects. To date, the epidemiologic data on these vitamins are sparse and inconclusive (Colditz, Stampfer. Willett 1987). 54 Smoking Cessation Cessation of cigarette smoking results in a gradual decrease in lung cancer risk. Several of the prospective and retrospective epidemiologic studies have demonstrated a reduction in lung cancer risk over time following smoking cessation. One example is provided from the U.S. Veterans study (Kahn 1966) (Figure 9). Other recent studies have continued to confirm the benefit of smoking cessation for lung cancer risk (Lubin et al. 19X4b: Alderson. Lee, Wang 19X5: Pathak et al. 19X6; Higgins. Mahan. Wynder 19Xx). Forexample. Lubin and colleagues ( 1984b) described the pattern of reduction in risk following smoking cessation in a case are performed on diabetics. Ap- proximately 3 1,000 American diabetics undergo such surgery each year. The disease tends to be more progressive and occurs at younger ages in diabetic smokers than in nonsmokers. In a study in Sweden, practically all diabetic patients under the age of60 years with gangrene were cigarette smokers (Lithner 1983). The prevalence of lower extremity arterial disease was evaluated for diabetic subjects. One-third of the smokers had evidence of peripheral vascular disease compared with only I6 percent of the non- smokers. Diabetics who stopped smoking for at least 3 years had a 30 percent lower prevalence of lower extremity arterial disease than those who continued to smoke. Epidemiologic studies in a Rochester, MN, population (Zimmerman et al. 1981) demonstrated that for 1,073 residents over the age of 30 who were diagnosed with diabetes mellitus between 1945 and 1969. about 8 percent of men and 7 percent of women had clinical evidence of peripheral vascular disease at the time that diabetes was diagnosed. The annual incidence of lower extremity arterial disease among the diabetics was 21/1,OOO for men and 17.6/l ,000 for women; about 20 percent had gangrene and 36 percent had intermittent claudication. Among diabetics with lower extremity arterial disease, 77 percent of men and 43 percent of women had been cigarette smokers compared with 55 percent of normal control men and 36 percent of normal control women. Effective treatment of diabetes mellitus and smoking cessation are the two most im- portant interventions to prevent the development of atherosclerotic peripheral vascular disease. Atherosclerotic Aortic Aneurysm The I964 Report of the Surgeon General commented on the increased mortality rates fOJ aortic aneurysm in cigarette smokers compared with nonsmokers. The 1969 Report concluded that there is a close association between cigarette smoking and death caused by aortic aneurysm. The 1983 Report summarized the epidemiologic data and noted that the mortality rate forabdominal aortic aneurysm was 2 to 8 times greater in cigarette smokers than in nonsmokers. A\ already noted, pathology studie\ have shown a rig- 65 nificant association between cigarette srnoking and atherosclerosis that is most striking in the aorta (US DHHS 1983). Chronic Obstructive Pulmonary Disease In the 1950s increasing morbidity and mortality from chronic respiratory conditions prompted clinical and epidemiologic investigations of the etiology of chronic bronchitis, emphysema, and related disorders. A variety of terms have subsequently been applied to permanent airflow obstruction in cigarette smokers. In the 1984 Sur- geon General's Report, chronic obstructive lung disease (COLD) referred to chronic mucus hypersecretion, airways abnormalities, and emphysema. In this Report, the term COPD is used for the permanent airflow obstruction that develops in cigarette smokers. Thirty years ago, the most widely advanced hypothesis on the etiology of COPD linked progressive lung damage to recurrent respiratory infection and atmos- pheric pollution (Stuart-Harris 1954). However, epidemiologic investigations, largely carried out in the United Kingdom. quickly indicated the predominant role of cigarette smoking in causing COPD (Stuart-Harris 1968a.b). By 1964. the evidence was sufficiently compelling to support the conclusion by the Advisory Committee to the Surgeon General that "Cigarette smoking is the most im- portant of the causes of chronic bronchitis in the United States, and increases the risk of dying from chronic bronchitis and emphysema" (US PHS 1964). The Report stopped short of classifying the relationship between cigarette smoking and emphysema as causal. however. The Report also noted the increased prevalence of respiratory symptoms and the reduction of lung function in smokers. The epidemiologic data cited in support of these conclusions were drawn from seven prospective studies of mortality in relation to cigarette smoking and about a dozen surveys of respiratory morbidity; only one prospective study on lung function had been reported at that time. In the 25 years that have elapsed since the release of the 1964 Surgeon General's Report. the findings of numerous laboratory. clinical, and epidemiologic studies have continued to reaffirm the predominant role of cigarette smoking in causing COPD and have extended understanding of the pathogenesis. pathophysiology, and natural history of this disorder. As the evidence has accumulated, the conclusions of the Surgeon General's Reports on cigarette smoking and COPD have been strengthened. The 1967 Surgeon General's Report labeled cigarette smoking as the most important of the causes of COPD (US PHS 1968). In the I97 I and 1979 Reports. the conclusions of the 1964 and 1967 Reports were strengthened (US DHEW 1979). Increased morbidity and mor- tality from chronic bronchitis and emphysema were documented in cigarette smokers compared with nonsmokers. Additionally, autopsy evidence confirmed that the lungs of smokers were widely damaged, and the evolving protease-antiprotease hypothesis provided a framework for understanding mechanisms through which cigarette smoke causes emphysema. The 1984 Surgeon General's Report focusedon COLD (US DHHS 1984). The over- all conclusion of the Report was: "Cigarette smoking is the major cause of chronic obstructive lung disease in the United States fOJ both men and women. The contribu- tion of cigarette smoking to chronic obstructive lung disease morbidity and mortality 66 far outweighs all other factors." In contrast to the sparse evidence in the 1964 Report, the 1984 Report reviewed numerou\ cross-sectional and longitudinal studies of mor- bidity and mortality. The longitudinal studies described the evolution of the cigarette- related decline in lung function that leads to impairment sufficient to result in a clini- cal diagnosis of COPD. This Section provides an overview of the evidence on COPD that has accumulated since the 1964 Report in the areas of pathogenesic, pathophysiology. and natural his- tory of COPD and the role of cigarette smoking. Pathogenesis The 1964 Report described the deposition of cigarette-smoke particles and gases in the lungs and the effects of cigarette smoke on lung defense\ but did not address the mechanisms by which cigarette smoking causes COPD (US PHS 1964). Much of the subsequent investigation of the mechanism of lung injury by cigarette smoke was sparked by the observation that homorygous deficiency of alphat-antitrypsin. the major protease inhibitor. is associated with familial panlobular emphysema (Laurel1 and Eriksson 1963; Eriksson 1964). This observation led to the hypothesis. generally referred to as the protease-antiprotease hypothesis. that the development of emphysema results from an imbalance between proteolytic enzymes and their inhibitors (Janoff 1985: Niewoehner 1988). Cigarette smoking is postulated to produce unchecked proteolytic activity by increasing proteolytic enzyme activity in the lung while decreas- ing antiprotease activity. Experimental and clinical observations have been consistent with the protease-an- tiprotease hypothesis (US DHHS 1984). Observations that smokers, compared with nonsmokers. have an increased number of neutrophils in peripheral blood (Yeung and dy Buncio 1984). in bronchoalveolar lavage fluid. and in lung biopsy specimens (Hunninghake and Crystal 1983) provide indirect evidence for an increased elastase burden in smokers' lungs. since neutrophils are the primary source of elastase (Janoff 1985). Furthermore. elastase levels are elevated in bronchial lavage fluid immediate- ly after smoking cigarettes (Fera et al. 1986). Cigarette smoking has also been shown to decrease the levels and activity of antiproteases. an effect attributed to oxidants in cigarette smoke and the pulmonary macrophages of smokers (Janoff 1985: US DHHS 1984). Animal models confirm that unchecked proteolytic activity can cause em- physema (US DHHS 1984). The lungs of patients with COPD generally display both emphysema and abnor- malities of the small airways. Mechanisms by which cigarette smoke damages small airways have not been so extensively investigated as the factors determining the development of emphysema. Pathoph&ology The lungs of smokers with COPD generally have both thickening and narrowing of airways and emphysema, although the extent of these two processes is variable (US DHHS 1984). Both the airways changes and emphysema produce airflow obstruction. 67 The I Y6-l Report noted that smohcr\` I ung\ displayed air\bay> change\ and emphysema: however. the pathoph> Gological correlates of the\e changes Mere not explored. Suhquent in\c`stifution\. correl;tinf structural changes with function, have described the relationship between mohing-caused changes in lung structure and airtloti obstruction. Emphy~ttma and small-airway injury contribute to the phyciologi- cal impairment found in COPD: in individual\ with symptomatic airflow obstruction. either type of in,iuq ma> be predominant. but both are probably important (US DHHS IYXS). While the I%4 Report de\crihed effect\ of cigarette smoking on the airways. the importance of the small airMay\ as a \ite of airflow obstruction was not recognized until the late IYhOs (Hofg. Machlem. Thurlbech IY6Xj. More recent investigations have confirmed that measures of mall-airway injury are correlated with the degree of airflow obstruction (US DHHS I YX4: Hale et al. I YX-I: Nagai. West. Thurlbeck I YXS). Autopsy studies have shown that chan:;es in the small airways develop in the lungs of young smohers and antedate the development of symptomatic airflow obstruction (Niewoehner. Kleinerman. Rice lY71) The importance of emphysema in pro'.iucing chronic aifflow obstruction has also been amply documented %ince the IYh3 Report. Emphysema reduces the driving pressure for evpiratory tltru and contribute3 to i,lcrea\ed airways resistance by reducing tether- ing of small airMay\. In patient\ with symptomatic airflow obstruction. the extent of anatomic emphysema is correlated with the severity of airflow obstruction, as are small-airway abnormalities (US DHHS 1984; Hale et al. 1984; Nagai, West, Thurlbeck IYX5). Thux. the \mohlng-cau\etl lung changes in the air\vay\ and parenchyma have both been unquivocalt~ linhed to airt`l~)w oh all the epidemiologic e\,idenr,e reviewed in the lY64 Report M;I~ cross-sec- tional in nature. These data estahli\hed that cigarette smohing increased respirator) symptom\ and reduced the level of ventilator\ function. but they did not provide in- Gght into the temporal evolution of COPD. Sub\equent cro\s-sectional studies have provided more complete quantitative description\ of the effects of cigarette smoking on lung function. and ncn longitudinal studies have partially dehcribcd the evolution of lung function change\ in mohcrs and the factory determining the rate ofchange over time. The numcrou\ cro\\-\ection;ll \tudie+, published \incz the IY6-l Surgeon General's Report have shop n that cigarette mokin, (7 is a strong determinant of the level of ven- tilator! function. LI hich is most often asressed b! the measurement of the I -set forced expiratory volume (FEV, ). The level of FEVt declines ;I> the amount of smoking in- crea\e\ CL'S DHHS IYXJ). Multiple re:;re\sion techniques have been applied to data from se\,erat different population\ to de\cribe the quantitati\,e relationship between the amount smohed and lot\ of ventilator\ function. These anal>\es indicate that ven- tilator! function decline\ in ;I lineart;t\hion u ith cumulative consumption ofcigarettes. usualI> e\;pre\\ed ;I\ pa&>ears (Burrows et al. lY77: Docker) et al. IYXX). For ex- ample. bused on anal) s~s of data from X. I Y I men and women from six U.S. cities. Dock- er\ and other\ ( 1 YXX) reported that male kImohers of a\ erage height lose 7.J mL of FEV I 6X on average for each pack-year and that women lo\e 3.4 mL per pack-year. Although the decline in mean level of FEV I appears hmall. the distributions of lung function level in smokers and in nonsmokers are different: the distribution for smokers is skewed toward lower levels co that a much greater proportion of smokers than nonsmokers have levels below the usual limit of normal (Figure I 1) (US DHHS 19X4: Burrows et al. 1977: Dockery et al. 19X8). 30 - 0 Pn-TRS x 2o * N=3303 IO- lOA=. 0+ I -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0 .y ;ij~~:zs?"`" -3.0 -2.0 -1.0 3'. . 0.0 1.0 2.0 ~1409PK-TRS Ik638 -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0 SE] ,& ~~~fP,~~"' -3.0 -2.0 -1.0 0.0 1.0 2.0 70 30 7 fy3," PK-YRF 20 . S 10. I;lA..8*1 04 -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0 30 - s 2O . r E+,`,K-`"5 10. lOR1.966 07 -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0 HElGhT ROJUSTEO FEYI RESIDUF4L iLITERS FIGURE Il.-Percent distribution of predicted values of forced expiratory volume in I-set (FEV I) in subjects with varying pack- years of smok- ing. NOTE Trmgle Indlcotz\ 111e3311. IQR I\ mtrrquart~le rany SOLRCE: Dochery et ~1. I IWX, The longitudinal studies published Gnce the 1964 Report have partially described the natural history of lung function changes in COPD (Fletcher et al. 1976: US DHHS 1984). Ventilatory function. ;1s measured by FEVt. for example. increases during 69 childhood and reaches a peak level during early adulthood (Figure 12). From the peak level, ventilatory function declines with increasing age. In cigarette smokers who develop symptomatic airflow obstruction, a similar loss of function takes place, but at a more rapid rate than in nonsmokers and in smokers who do not develop disease. A physician is likely to diagnose COPD when continued excessive loss of ventilatory function results in sufficient impairment to cause dyspnea and limitation of activity. I I I I I t 25 35 45 55 65 75 FIGURE 12.-Decline of FEVI at normal rate (solid line) and at an accelerated rate (dashed line) The factors influencing rate of lung function decline in cigarette smokers have not yet been fully characterized. The rate of decline tends to increase with the amount smoked, and former smokers generally revert IO the rate of loss of nonsmokers. In fact, the excessive decline observed in some smokers may represent a common physiologi- cal consequence of different pathophysiological mechanisms. Habib and coworkers (1987) carefully characterized 13 subjects from a longitudinal study in Tucson with a mean annual decline in FEV I greater than 60 mL per year. Clinically, these subjects were not unique and none had alphat-antttrypsin deficiency. Physiological assessment 70 suggested that some were developing emphysema, whereas others appeared to have disease of the large and/or small airways. The studies of longitudinal change in lung function have spanned only segments of the full natural history of COPD. and many questions remain unanswered. It is unclear, for example, whether the excessive decline takes place at a constant rate in continuous smokers, as suggested by much of the epidemiologic evidence. or whether the exces- sive decline occurs intermittently after some triggering event. The factors determining the susceptibility of individuals to cigarette smoking are also unclear. Current hypotheses emphasize determinants of protease-antiprotease imbalance, level of non- specific airways reactivity, and severe respiratory illness during early childhood. Since the release of the 1964 Surgeon General's Report. abundant evidence has in- dicated the overwhelming importance of cigarette smoking in causing COPD: in fact, COPD would be an uncommon condition in the United States without cigarette smok- ing. Unfortunately, death rates due to COPD have paralleled those for lung cancer and have increased progressively over the last 25 years (National Center for Health Statis- tics 1986). The trends are consistent with cohort changes in smoking; in this regard, while age-specific rates for males have been increasing at older ages, a recent decline in COPD mortality has been observed at younger ages (US DHHS 1984). While im- portant scientific questions remain unanswered concerning the pathogenesis of COPD, the available evidence provides sufficient rationale for preventing COPD through smoking prevention and cessation. Pregnancy and Infant Health Several endpoints have been studied to evaluate the adverse effects of smoking on pregnancy, including (1) infant birthweight: (2) fetal and infant mortality; (3) congeni- tal malformations; (4) fertility; and (5) long-term effects on the child. The 1964 Report indicated an association between smoking and low-birthweight babies (US PHS 1964) but it did not consider the evidence sufficient to establish a causal relationship. The 1969 Report (US PHS 1969) confirmed the association between maternal smok- ing and low-birthweight babies. an increased incidence of prematurity, spontaneous abortions, stillbirths, and neonatal deaths. The 1971 Report (US DHEW 1971) con- cluded that maternal smoking during pregnancy exerts a retarding influence on fetal growth. The 1973 Report (US DHEW 1973) noted that cigarette smoking is a prob- able cause of increased late fetal mortality and infant mortality. The 1977-78 Report (US DHEW 1978) noted a dose-response relationship between smoking and abruptio placentae, placenta previa. bleeding during pregnancy. and prolonged premature rup- ture of membranes, as well as the association of smoking during pregnancy with im- paired physical and intellectual development of the offspring. The 1979 Report (US DHEW 1979) linked smoking with sudden infant death syndrome. The 1980 Report (US DHHS 1980) noted that up to 14 percent of preterm deliveries in the United States may be attributed to maternal smoking. It also surveyed studies of men and women suggesting that cigarette smoking may impair fertility. 71 In 19X5. the Center for Health Promotion and Education of the Centers for Disease Control. Atlanta. GA. defined the fetal tobacco syndrome as follows. (I) The mother smoked 5 or more cigarettes a day throughout the pregnancy. (2) The mother had no evidence of hypertension during pregnancy, specifically no preeclampsia and documentation of normal blood pressure at least once after the first trimester. (3) The nevvborn has symmetrical growth retardation at term, 37 weeks, defined as birthweight less than 3.500 g. and a ponderal index (weight in grams divided by length) greater than 2.32. (4) There is no obvious cause of intrauterine growth retardation. that is, congeni- tal malformation or infection (Nieburg et al. 1985). Infant Rirthweight A clear dose-response relationship exists between the number of cigarettes smoked during pregnancy and the birthweight deficit (US DHHS 1980; Committee to Study the Prevention of Low Birthweight 1985). Compared with nonsmokers, light and heavy smokers have a S4- and l30-percent increase. respectively, in the prevalence of new- borns weighing less than 2,500 g. A review of five studies including I I3.000 births in the United States. Canada, and Wales found that from 2 I to 39 percent of the incidence of low birthweight w*as attributed to maternal cigarette smoking (Committee to Study the Prevention of Low Birthweight 1985). Also, cigarette smoking seems to be a more significant determinant of birthweight than the mother's prepregnancy height, weight, parity, payment status. or history of previous pregnancy outcome. or the infant`s sex. The reduction in birthweight associated with maternal tobacco use seems to be a direct effect of smoking on fetal growth. Mothers who smoke also have increased rates of premature delivery. The newborns are also smaller at every gestational age. The infants display symmetrical fetal growth retardation with deficits in measurements of crown-heel length, chest and head circum- ferences. and birthweight. A recent study in Boston (Lieberman et al. 1985) attempted to evaluate the reasons for differences in rates of prematurity between blacks and whites. Of the 1,365 black women. 34.7 percent were cigarette smokers compared with only 23.4 percent of the white w'omen. Cigarette smoking and low hematocrit levels were two of the most im- portant risk factors accounting for the differences in prematurity rates between blacks and wjhites. Finally. a number of careful studie\ have found that the effect of cigarette smoking on birthueight is not mediated through decreased maternal appetite or weight gain (US DHHS 19X0). The most widely accepted hypothesis relating maternal smoking and the effects on the fetus and newborn is intrauterine hypoxia (Rush and Cassano 1983). The hypoxia could occur as a result of factors associated with smoking. such as increased levels of carbon monoxide (CO) in the blood. reduction of blood flow. or inhibition of respiratory enzymes. There is strong experimental evidence that maternal smoking causes fetal hyposia. 72 Several studies have demonstrated that smoking cessation prior to or during pregnan- cy can partly reverse the reduction in the child's birthweight (Rush and Cassano 1983; Hebel, Fox. Sexton 198X). In a large study using the 1970 British Birth Cohort (Lieber- man et al. 1987). an inverse relationship between measures of social class and the prevalence of smoking w/as demonstrated that was similar to that seen in the United States. In all social class groups. babies of the nonsmokers weighed more than those whose mothers had smoked during pregnancy. and the women who had stopped smok- ing either before or during pregnancy had babie\ with higher birthweight than women who continued to smoke throughout pregnancy. Fetal and Perinatal Mortality Kleinman and colleagues (19X8) from the National Center for Health Statistics used Missouri birth records from 1979-83 (Table 3) tn study the relationship betvveen cigarette smoking in mothers and infant mortality. Among the 133.429 primiparas, the infant mortality rates (adjusted for age. parity. education. and marital status) were (per I.000 subjects) IS.1 for white nonsmokers. 1X.X for whites who smoked less than I pack of cigarettes per day. and 23.3 for whites who smoked more than I pack of ciga- rettes per day. For black nonsmoking women. the infant mortality rate (per 1,000 women) was 26.0: for blacks who smoked less than I pack per day. 32.4: and for blacks who smoked greater than I pack per day. 39.9. Mortality was increased during the fetal. neonatal, and postneonatal periods. It was estimated that if all pregnant women stopped smoking. the number of fetal and infant deaths vvould be reduced by approximately IO percent. In the United States this would result in about 4,000 fewer infant deaths each year. A study conducted by the Office on Smoking and Health attributed approximate- ly 2.500 infant deaths to maternal smoking in 1984 (CDC 1987). Stein and associates (1981) have studied the causes of spontaneous abortion in three New York City hospitals. They compared women with spontaneous abortion to con- trols (women who carried their pregnancy to 2X weeks or more). Within the spon- taneous abortion groups. they then compared those with evidence of chromosomal ab- normalities and those with apparently normal chromosomes. The odds of a spontaneous abortion increased by 46 percent for the first IO cigarettes smoked per day and by 6 I percent for the first 20 cigarettes smoked. Smoking was not associated with the spon- taneous abortion of chromosomally abnormal conceptions. but only with those in which the chromosomes were normal. These results were not confounded by such factors as maternal age or race. Congenital Malformations Evidence that exposure to tobacco and cigarette smoking could be related to congeni- tal malformations is less clear. About 3 percent of all live birth5 have major congeni- tal malformations (Behrman and Vaughn 1987). Maternal smoking has not been demonstrated to be a major risk factor for the induction of congenital malformations, although elevated risks have been reported in some studies. Kelsey and coworkers (1978) reported an increased risk of 1.6 for congenital malformations among the 73 TABLE 4.-Infant mortality rates and odds ratios (95% confidence intervals), by maternal race, among 134,429 primiparas, based on multiple logistic regression, Missouri, 1979-83 Crude rates Adjusted rates (per I .ooo) (per I .ooo) Whites Blacks Whites Blacks Adjusted odds ratios Whites Blacks Marital status Married Unmarried Education (years) I2 Age (years) I pack/day 14.5 25.4 15.9 29.5 I .OO I .oo 24.0 2X.6 2 I .o 27.2 1.33(1.1X-1.50) 0.92 (0.73-I. 16) 22.9 13.2 !9.X 33. I 1.36(1.16-1.59) IS.2 25.9 16.7 28.8 l.l4(1.02-1.28) 12.8 21.5 14.6 25.3 1.00 24.0 33.7 18.X 32.2 I .24 ( I .06-l .45) IX.2 26.0 16.3 27.9 1.08 (0.95-I .22) 14.2 23.4 15.2 26.0 1.00 13.2 27. I 16.1 27.6 I.06 (0.94-I .20) 16.1 19.9 I X.6 31.9 1.23(1.01-1.50) 25.4 69.3 31.1 52.9 2.09 (I .49-2.93) 13.9 25.3 15.1 26.0 19.1 33.7 18.8 32.4 24.3 41.5 23.3 39.9 1.00 1.25(1.13-1.39) I .56 ( I .37-I .77) SOURCE: Kleinman et al. (1988) offspring of women smoking more than 1 pack of cigarettes per day compared with women reporting no smoking during pregnancy. Similarly, Himmelberger, Brown, and Cohen (1978) reported a 2.3-fold higher risk of congenital abnormalities for smoking mothers than for nonsmokers. One study has also reported an increased frequency of congenital malformations based on the smoking habits of the father (Schardein 1985). The trends with paternal smoking were independent of maternal smoking level, maternal and paternal age. and social class. The relatively low incidence of congenital malformations, the different types of mal- formations, and the various possible biological mechanisms have made the study of the relationship between environmental factors and congenital malformations extremely difficult. New techniques to monitor pregnancy outcomes may enhance our under- standing of the interrelationship between cigarette smoking, other environmental fac- tors, and congenital malformations. Fertility A recent study has substantiated previous reports that suggested that women who smoke may have reduced fertility (Baird and Wilcox 1985). Data on smoking history and number of noncontraceptive cycles until conception were collected from 678 preg- nant women. Of nonsmokers, 38 percent conceived in their first cycle compared with 28 percent of smokers. Smokers were 3.4 times more likely than nonsmokers to have taken greater than 1 year to conceive. After adjustment for other risk factors, it was es- timated that the fertility of smokers was 72 percent of that of nonsmokers. Heavy smokers experienced lower fertility than light smokers. Fertility was not affected by the husbands' smoking. The effects of cigarette smoking on sperm quality in men (Ablin 1986) were also evaluated in relation to density, motility, and morphological abnormalities in 238 age- related smokers and 135 nonsmokers. Spermatozoa from smokers possessed sig- nificantly decreased density and motility compared with those from nonsmokers. Mor- phological abnormalities of the sperm were also noted more frequently among smokers than among nonsmokers (Ablin 1986). Long-Term Effects on the Child Relatively few studies have evaluated the long-term consequences of smoking during pregnancy on the child. One of the larger recent studies looked at neurological hand- icaps among children up to 14 years of age whose mothers had smoked during preg- nancy and among control children born in northern Finland in 1966 (Rantakallio and Koiranen 1987). Seventy-eight children of smokers and 62 controls had mental retar- dation (IQs less than 85), cerebral palsy, or epilepsy. The incidence of mental retarda- tion alone was 15.9/1.000 among the children of the mothers who smoked and 13.9 among the controls. For any combination of mental Letardation, cerebral palsy, and epilepsy, the rates were 42.8/l ,000 for children of smoking mothers and 34/l ,000 for the controls, a relative risk of 1.27 with confidence limits of 0.90 to 1.79.