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National Institute of Child Health and Human Development CONTENTS Introduction .............................................................. 9 Biomedical Aspects of Smoking .............................. 9 Historical Considerations ........................................ 9 Smoking, Birth Weight, and Fetal Growth.. .................. 11 Birth Weight ...................................................... 11 Placental Ratios .................................................. 14 Gestation ........................................................... 17 Fetal Growth ................ .._ ................................... 19 Long-Term Growth and Development .................... .21 Role of Maternal Weight Gain .............................. 24 Evidence for Indirect Associations Between Smoking and Birth Weight.. .......................................... .26 Summary ........................................................... 27 Cigarette Smoking and Fetal and Infant Mortality.. ...... .28 Overview ........................................................... 28 Spontaneous Abortion ........................................... 30 Perinatal Mortality .............................................. 32 Cause of Death.. ................................................ .36 Complications of Pregnancy and Labor.. ................ .39 Preeclampsia ...................................................... .41 Preterm Delivery ................................................ .42 Pregnancy Complications and Perinatal Mortality by Gestation. ........................................................ 43 Sudden Infant Death Syndrome ............................. 44 Summary .......................................................... .46 Lactation and Breast Feeding ..................................... 48 Introduction ........................................................ 43 Epidemiological Studies ....................................... .43 Experimental Studies ........................................... 49 Studies in Animals ....................................... 49 Nicotine ................................................... 49 Studies in Humans ....................................... 50 Nicotine and Tobacco Smoke.. .................... .50 Physiologic-Experimental Studies ................................. 52 Studies in Animals .............................................. 52 8-3 Tobacco Smoke ............................................. 52 Nico:il>e ...................................................... 53 Carbon Monoside.. ....................................... .57 Carbon Monositie Cptake and Elimination .... .58 Effec;s on Fetal Growth and Development .. .60 Carbon MMoiloside Effects on Tissue Oxygenation ......................................... .61 Effects on Newborn -4nimais . ...................... 65 Polycyclic Hyclroc;lrbons ................................. 65 Studies in Humans. ............................................. 67 Tobacco Smoke., .......................................... .67 Carbon Monoxide .......................................... 70 Vitamin Blz and Cyanide Detoxification.. ......... .73 Vitamin C.. 74 . ................................................. Research Issues ......................................................... .74 Fetal Death ........................................................ 75 Neonatal Death ................................................... 76 Spontaneous Abortion .......................................... .77 Preeclampsia ....................................................... 77 Sudden Infant Death S.yndrome ............................. 7i Long-Term Follow-Up .......................................... 77 . Birth Weight and Placenta.. ................................ .78 Experimental S'.udies .......................................... .78 Lactation and Breast Feeding ...... ..-*r ....................... 78 Tobacco Smoke ................................................... .79 Nicotine ............................................................. 79 Carbon 11onoside ................................................. 80 Polycxclic Hydrocarbons ........................................ 81 References ..................................................... .......... i;i! _ LIST OF FIGURES Fipre 1. --Perccntqc cia:riiwtioll hy birth weight of infants of mot&rs \vho (ii11 not smoke &ring pregntrnq and of those whc, sm&tul r>ne l)ack or I:~~)I*L' of cigarettes per day . . . . . . . . . .._..._................................................ li - Figure 2.--Ratio of IJhXctid weight to uirth weight by length of gestation and maternal smoking category.. . . . 18 Figure 3.-Mean birth weight for week of gestation according to maternal smoking habit: control week singletons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Figure $.-Percentage of birth weights under 2.500 grams by maternal smoking level for early, average, and late- term births . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20 Figure 5.-Theoretical cumulative mortality risk according to smoking habit, in mothers of different age, parity, and social class groups . . . . . . . . . . . . . . . . . . . . .._..................... 31 Figure 6.-Percentage distribution by weks of gestation of births to nonsmokers, smokers of less than one pack per day, and smokers of one pack per day or more.. . . . 43 Figure 7.-Probability of perinatsl death for smoking and nonsmoking mothers, by period of gestational age.......45 Figure &-Risks of selected pregnancy complications for smoking and nonsmoking mothers, by period of gestational age at delivery.. . . . . . . . . . . . . . . . . Y . . . . . . . . . . . . . . . . . . . 46 Figure O.-Time course of carbon monoxide uptake in maternal and fetal sheep exposed to varying carbon monoxide concentrations.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Figure lO.-Human maternal and fetal oxyhemoglobin saturation curves showing carbon monoxide effect.. . . . . .62 Figure Il.-The partial pressure at which the oxyhemoglobin saturation is 50 percent, P59, for human maternal and fetal blood as a function of blood carboxyhemoglobin concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Figure 12-Fetal values of oxygen partial pressure as a function of carboxyhemoglobin concentrations during pm&steady-state conditions.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64 Figure I3.-Thermogram from a near-term pregnant patient before and after smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Pigme 14.-Percent carboxyhemoglobin in maternal and fetal blood as a function of car!mn monosidc partial 8-5 pressure and concentration (parts per million) in inspired air..............................................................,..,.....71 Figure 15.-The degree of compensation necessary to offset the effects of elevated fetal carboxyhemoglobin concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..*.............. 73 LIST OF TABLES Table l.-Birth weight under 2,500 grams by maternal smoking habit, relative and attributable risks derived from published studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .,. . . . . . . . . . 13 Table 2.-Mean birth weight of infants of smoking and nonsmoking mothers, by other biologic and socioeconomic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Table 3.-Birth weight under 2,500 grams by maternal smoking and other factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16 Table 4.-Spontaneous abortions by maternal smoking habit and desideration of pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Table 5.-Perinatal mortality rates per 1,900 live births to smoking and nonsmoking mothers, and relative risks for infants of smokers by maternal age, parity, and years of school . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Table 6.-Examples of perinatal mortality by maternal smoking status related to other subgroup characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Table `7.-Cause of stillbirth related to smoking habit.. . . . 36 Table %-Cause of neonatal death related to smoking habit.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Table 9.-Stillbirths according to cause in relation to maternal smoking during pregnancy.. . . . . . . . . . . . . . . . . . . . . . . . . 3'7 Table lO.-Fetal and neonatal deaths by coded cause and maternal smoking habit.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 8-6 Table Il.-Perinatal mortality and selected pregnancy complications by maternal smoking levels.. . . . . . . . . . . . . . . . . .40 Table 12.-Fetal and neonatal deaths by maternal smoking and other coded conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Table 13.-Preterm births by maternal smoking habit, relative and attributable risks, derived from published studies.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Table 14.-The relation of the concentrations of fetal to maternal carboxyhemoglobin in mothers who smoke during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . `72 8-7 Introduction Biomedical Aspects of Smoking Data accumulating in the scientific literature during the past decade strongly corroborate findings reported in the 1960's that cigarette smoking during pregnancy has a significant and adverse effect upon the well-being of the fetus, the health of the newborn baby, and the future development of the infant am! child. Adverse effects on pregnancy range from increased risk for reproductive loss, fetal mortality, preterm birth, and neonatal tltath, to retardation in fetal growth as reflected in birth mcasuremtants of lo\\er mean body weight, shortened body length, and smaller head circumference, as well as to a number of problems of adaptation ir, the neonatal period. In addition, there is suggestive evidence of long-term impairments in physica! growth, diminished intellectual function, and deficiencies in behavioral development for those babies who survive the first 4 weeks of life. It appears that children of smoking mothers do not catch up with the offspring of nonsmoking mothers in various phases of development. The present chapter highlights previously reported and recent studies on the relationships between cigarette smoking and pregnancy outcome, including sections on historical considerations, birth weight and fetal growth, feta! and infant mortality, lactation and breast feeding, and physiologic-experimental studies. The concluding section of this chapter, entitled Research Issues, identifies questions and areas of concern that need clarification and further investigation. Historical Considerations In 1957, Simpson (1~) reported that infants born to women who smoked during their pregnancies were of significantly lower birth weight relative to babies born to nonsmokers. During the intervening 20 years, there has been increasing concern, coupled with the conduct of a large number of related studies, about the effect of smoking during pregnancy upon the well-being t)f the developing fetus and infant. Concern about the effects of exposure to tobacco and cigarette smoking during pregnancy upon reproductive loss, maternal health, Pregnancy outcome, and infant well-being dates back a century. In 1902, Ballantyne (9) questioned what might be the effect of tobacco Poisoning upon antenatal life. While he did not specifically mention maternal smoking during pregnancy, he summarized the opinions of a number of authors writing during the latter part of the 19th century about the risks of spontaneous abortion for women who worked in tobacco factories. He referred specifically to an 1879 paper by Decaisne from France and to an 1868 report by Kostial from Austria about female tobacco workers. Ballantyne wrote that both of these authors "were quite convinced that abortion was very frequent in women 8-9 workers in tobacco [factories]...." Ballantyne concluded by stating, "While there is much doubt, therefore, regarding the evil effect of nicotism in cutting short antenatal life, there seems to be no shadow of doubt that there is a very large infantile mortality in postnatal life among the offspring of women workers in tobacco. Possibly this may be due in part to the influence of the milk, but it is more probable that it is on account of congenital debility." Discussion of the problem of smoking during pregnancy at the turn of the century appears to have been based on empirical evidence and anecdotal reports. Until the end of the 1920's, there was a sparsity of reports on this topic in the scientific literature. Thereafter, several articles were published reporting the results of animal studies and clinical investigations pertinent to the effects of nicotine and smoking during pregnancy upon reproductive loss, maternal health, and pregnancy outcome. In 1935, Sontag and Wallace (175) investigated the effects of cigarette smoking during pregnancy upon fetal heart rate. Their observations were made during the last 2 months of pregnancy on eight mothers and their fetuses. Their data revealed that the smoking of one cigarette by the pregnant woman generally produoed an increase in the rate of the fetal heart beat, and sometimes a decrease. They concluded that there was "a definite and real" increase in the fetal heart rate after the mother began to smoke a cigarette and that this was probably due to transplacental transfer of nicotine into the fetal circulation. In 1935 and again in 1936, Campbell (23, 2.4) reported that heavy cigarette smoking was prejudicial to efficient childbearing as a result of chronic nicotine poisoning. Campbell warned that excessive smoking in certain cases was detrimental to maternal health. He noted that, in general, a woman who smoked during pregnancy was likely to have more difficulty during the course of pregnancy, parturition, and lactation than a woman who did not smoke. In 1940, Elssenberg and associates (46), in a well-designed study, investigated the effects of nicotine and cigarette smoke on pregnant female albino rats and their offspring. The three groups of subjects included a group of animals that received intraperitoneal or subcuta- neous injections of solutions of chemically pure nicotine, a second group of animals that were exposed to tobacco smoke that approximatr ed human smoking of one pack of cigarettes a day, and a third group of animals that were untreated. The immediate effects on the animals in the two treated groups were similar, although more severe in the injected group. It was reported that: 1. Two-thirds of all the young of treated mothers were underweight; the young from nicotine-injected mothers were more underweight than those from mothers exposed to tobacco smoke. 8-10 2, The underweight group remained underweight during the entire period of observation; many of the young of this group were undersized and died early. 3. Of the females injected, 63.0 percent lost one or more young before weaning, and 33.3 Percent lost all of their young. 4. Of the mothers exposed to tobacco smoke, 23 percent lost one or more of their young before weaning, and 25 percent were underweight. 5. Of the mothers exposed to smoke prior to mating, 23.3 percent lost one or more of their young before weaning, and 25 percent were underweight. 6. In both groups of treated mothers, temporary sterility, resorption of young in utero, and abortions were noted. 7. Alteration of maternal behavior was observed, consisting of cannibalism and neglect of the young as to care and feeding. The findings of &se&erg, et al. (46), reported in 1940, raised important questions regarding the effects of smoking on pregnancy outcome that were not investigated in depth until some 29 years later when Simpson reported her findings (I 72). Results of epidemiological surveys and experimental studies appear- ing in the literature over the past two decades owe much to improvements in research technology which contributed to more accurate and reproducible measurements in the laboratory. For example, nicotine concentrations in minute amounts can be determined with gas chromatography, and the degree of carbon monoxide displacement of oxygen from hemoglobin can be assessed with Considerable precision by biophysical methodology. Use of new technology has often permitted scientists to confirm earlier impres- sions obtained with the use of crude but ingenious bioassays. Such Wnfirmation is a tribute to the perception and the dedication of these Pioneering investigators and astute clinicians. Smoking, Birth Weight, and Fetal Growth Birth Weight Babies born to women who smoke during pregnancy are, on the average, 269 grams lighter than babies born to comparable women who do not smoke. Since 195'7, when Simpson reported this finding from her original study (172), it has been confirmed by over 45 studies of more than half a million births (1, 2, 7, 20, 22, 29-31, 37, 41, 47, 54, 61, 62, 71, % 86, 89,90,101-103, 115, 118,119,123-127, 137,141-143,144 147,151, l55-157, 161, 163-166, 168, 169, 185, 188, 189, 190-192, 208, 212). Reds of these studies are expressed as mean birth weights of smokers' and nonsmokers' babies, or alternatively, as the percentage of babies who Weigh less than a specified amount, usually 2,500 grams. The methods and results of 28 studies carried out between 1957 and 1970 were 8-11 summarized in the chapter on smoking and pregnancy in The Health bt.sequ~n~~~~ of Snwkirlg, A R~por? of the Surgeon General: 1971, which concluded: "Maternal smoking during pregnancy exerts a retarding influence on fetal growth as manifested by decreased infant birth weight and an increased incidence .)f prematurity, defined by weight alone" (:Yo). The same conclusion has been drawn from subsequent studies. In the chapter on pregnancy in Thu He&h Cmseguewes of Smoking in 1973, a detailed, critical review is given of studies published to that date. The chapter summary of the evidence that the association between maternal smoking and reduced birth weight is one of cause and effect includes the following (192): 1. Results are consistent in all studies, retrospective and prospective, from many different countries, races, cultures, and geographic settings (2, 7, 20, 22, 30, 31. 61, $7. 54, 62, 72, 81, 86, 89, 109, 115, 118, 119, 125- 127, 137. 141-l&7, 147, l.il, 1.52, 1.57, 161, 163, 164, 166, 169, 172, 185, 189, 192, 193, 206, 212). 2. The relationship between smoking and reduced birth weight is independent of all other factors that influence birth weight, such as race, parity, maternal size, socioeconomic status, sex of child, and other factors that have been studied (1 ) 2, 7, 20, 22, 31, 47, 54, 71, 101, 102, 115, ll?, 119, 142, 145, 1.52, 1.57. 164, 169, 192, 193). It is also independent of gestational age (2, 19, 20, 22, 54, 72, 115, 141, 157, 163, 166,169,193,206). 3. The more the woman smoke:; during pregnancy, the greater the reduction in birth weight; this is a dose-response relationship (2, 22, 31, 47, 54, 83, 101, 102, 103, 115, 118, 119, 137, 142, 143, 169, 189, 192, 193, 206). 4. If a woman gives up smoking during pregnancy, her risk of delivering a low-birth-weight baby is similar to that of a nonsmoker (22, 54, 101, 103, NC~). To iliustrate typical results of studies showing the association between maternal smoking and an increased proportion of low-birth- weight infants, five published studies with an aggregated total of almost 113,000 births in Wales, the United States, and Canada are summarized in Table 1. In these populations, 34 to 54 percent of the mothers smoked during pregnancy and on the average had twice as many low-birth-weight babies as the nonsmokers. Under these conditions, from 21 to 39 percent of the low-birth-weight incidence in the total population could be attributed to maternal smoking (2,20,47, 115,137,1iz, 143). An outstanding feature of the relationship between maternal smoking and birth weight is its dependence on the level of maternal smoking and its independence of the large variety of other factors that influence birth weight, such as maternal size, maternal weight gain, age, parity, socioeconomic status, and sex of child (1, 2, 20, 22, 31, 47, 8-12 TABLE I.-Birth weight under 2,500 grams by maternal smoking habit, relative and attributable risks derived from published studies Smokers Births

4 previous pmgnancie3 Smokem Nonsmokers Previous birth <2.500 grams Smoker3 Nonmolten Gnvida's height <60 inches Smokers Nonsmoken Gnrvida's prepwgnancy weight