List of Figures Figure I.-Alean birth n-eight for week of gestation arcording to maternrtl smoking habit: control I\-eek singletons_--_- ---- Figure 2.-Percentqe distribution b!- birth n-eight of infants of mothers \t ho did not smoke during pregnancy and of those I\ ho smokccl 1 pilck of cGg:arettc* or more per da>----- - - _ - _ Figure X.--Percentage of pregnancies with inftint, \veighing les than 2,500 grams, by cigarette smoking category--.-------- Figure 4.-mmdrerapc birth \\-eight by maternal smoking habit. (a) before current pregnancy and (b) during current peg- ni~t~c\-__------_--_-~--~--~-~----~~-------~----~------- Figure 5.-Percent of loll- birth weight \r-hite infants b>- smok- ing status of their nlothers----__-_-_~-_--~------~--~-~-- Figure (I.-Xconatnl mortality rate< among hingle 11 hite births in hospitals (by detailctl birth x\-eight and ~pccified pe,t ;ttion grorlp: 1Tnitetl Stntes)-m _ _ _ _ _ - _ - _ - - _ - _ _ - _ - _ _ - _ _ ~. _ Figure 7.--Perinatnl mortalit\- riite l)er 1,000 total births b>. c.i~urette~;mokingrcateeorv---- ___-_. --_-_--_-_----_--_- Page 104 105 108 110 113 128 129 List of Tables Table l.-Infant birth ~v-cight by maternal and paternal smok- ing habits- __.___ ____ ~__~___-~--~--_----~-------~---- 111 Table 2.-Effect, of carbon monoxide exposure of pregnant rabbit5 on birth \\-ei~ht._--~-_-~-_--_-__-_~-_-__-_~-_-__ 117 Table :3.-Comparison of the perinat al mortality for infants xvrighing less than 2,500 grxm+, of smokers and nonsmokers- 127 Table 4.-Efl'ect of carbon monoxide exposure of pregnant rub- bits on birth n-eight and ncomctal Inortalitv--_--~-----~--~- 133 Table 5.-Proportion of male infants delivered to smoking and rlonimokinpmotheri--___-_-~-_-_~-_~__-__-_-_--_--_--- 136 Table 6.--Relative risk of congenital malformation for infants of cigarette smokers and nonsmokers, comparing available studies with regard to stutly design, sttldy population, samI)lc size, number of infants with malformations, and definition of malformation- ____._ ________ --_----_--_--_----_------ 137 101 Introduction Smoking and Birth Weight frequent among cigarette smokers as among nonsmokers. Subsequent,ly, Lowe (.&I?) &udied 2,042 women in Birmingham, England, and dem- onstrated in his ret,rospective study that, the infants of smoking mothers were delivered oilIs slightly earlier (1.4 days on the average) than those of nonsmokrrs. He further noted that for gestations of 260 days and over: the infants of smokers were consistently lighter in weight during each week of gestation than those of the nonsmokers. This finding has been confirtnrd since, and figure 1 from the British Perinatal Mortality Study (13) provides illustration of this relationship. Given the nearly constant disparity present between the birth weights of the infants of smokers and nonsmokers for gestations of 260 days and over, but absent prior to that time, and given the similar birth weights of infants of rlonsmokers and of women who gave up smoking early in pregnancy ancl did not begin to smoke again, Lowe inferred that the intluence of smoking upon birth weight might lie mainly in the later months of pregnancy. He emphasize,d the tentative nature of this conclusion. since the number of infants with a gestation of less than 260 thrys and the nunlb~r of women who gave up smoking early in the pregnancy and did not begin to smoke again were both small. Figure 1 .-Mean birth weight for week of gestation according to maternal smok. ing habit: control week singletons.' 125 3400 E" 3150 g .5 2900 g : 2650 $ I 85 2400 75 2150 3650 36 37 38 39 40 41 Gestation in completed weeks 42 43+ `This term refers to singleton births in England, Scotland, and Wales occurring during the week of March 3-9, 1958, which are included in the Parinatal Mortality Survey. These comprise 97 percent of all births notified in England and Wales or registered in Scotland during this week. SOURCE: Butler, N. R.. Alberman. E. D. (13). 104 Low found that, the infants whose mothers smoked throughout pregnancy weighed. on the avtmgr. 170 granls less than those Those ~notller~ did not smoke. In addition, he noted that the entire clistribu- tion of weights of infants of smokers was shifted to the left (to\\-ard lower weights) relatii-r to that, for the infants of nonsmokers. This finding! too, has been confirmed hy other investigators. Figure :! offers a11 illustration fronl JIacJIahon, et. al. (@). Given that the infants of smokers and nonsmokel~ differed only slightly with respect. to the duration of gestation. Lowe concluded that the lowx birth weight of smokers' infants must be attributed to a direct retardation of fetal gr0wt.h. In other word+, on the IAs of his data, the infants of snlokers were small-for-dates: rather than truly piwiiatnre. JTany investigators have subsequently confirmed this point (22. 14. 2.5. -3:;. ET 78.85, 113). Buncher (12)) in a study of 49.897 birth5 among T-3. naval wive.s. in the same, population studied 1)~ I-ndcrwood, et al. (100). found that, the infants of smokers were, on the avcrapc, de- livfred only 1 day earlier than those of nonsmokcl~. This finding awnunted for only 10 percent of the discrepancy in birth n-eight be- twen the, two groups of infants. The remainder of the studies rvsultcd in the detection of citlicr siniilnr variations in gwtatinnal length 01 no average difference. In a recent study, JIulcah~ and bIurpll>- (56)Y Figure 2.- Percentage distribution by birth weight of infants of mothers who did not smoke during pregnancy and of those who smoked 1 pack of cigarettes or more per day. INFANT WEIGHT AND PARENTAL SMOKING HABITS ,`~`,~~`l~`~1"`1~"1~~`1"~1 10 8 6 7 8 9 10 11 BIRTH WEIGHT (SCALE IN POUNDS; INTERVALS OF 4 OZ.) SOURCE: MacMahon. et al. (4%. 105 in a sample of 5>099 Irish mot.hers, concluded that although the babies born to cigarette smokers were delivered slightly earlier t,han those of nonsmokers, independent of age and parity, the direct effect of smoking in retarding fetal growth was more significant. The following points, based upon the results from many different studies, can be made about the relationship between cigarette smoking during pregnancy and lower infant birth weight : 1. Women n-ho smoke cigarettes during pregnancy have a higher proportion of low-birth-Keight infants than do nonsmokers. This excess of low-birth-weight infants among cigarette smokers pre- dominantly consists of infants who are small-for-gestational age rather than gestationally premature. 2. The entire distribution of birth weights of the infants of ciga- ret,te smokers is shifted toward lower weights compared to the birth lyeights of the infants of nonsmokers. 3. The birth weights of the infants of cigarette smokers are con- sistently lighter t,han those of the infants of nonsmokers when the birth weights of t,he two sets of infants are compared within groups of similar gestational age beyond the 36th week of gestation. The results of the studies which have been conside.red so far identify a relationship betPreen cigarette. smoking and lower infant birth weight and illustrate some aspects of that. relationship, but do not indicate whether the association is causal or indirect. The succeeding tn-o sections of this chapter cont.ain evaluations of the available evi- dence rvhich bears upon the nature of the association bet,ween cigar- ette smoking during pregnancy and the incidence of small-for-dates infants. EVIDENCE FOR A ~A~SAI, A~~~~~~.4~~~~ RETWEEX (~ARETTE SMOHIXG AXD S~MALL-FOR-DAWAS INF&~NTS Evidence prel-iously revien-ed in t.he 19'71 and 1972 reports on t,he health consequences of smoking (101? 102) suggests that cigarette smoking is causally associated with the delivery of small-for-dates infants. Thr follo\Cqz is a summary of this evidence : 1. The reeults from all 30 studies in which the relationship between smoking and birth weight n-as examined have demonstrated a strong association betKeen maternal cigarette smoking and delivery of low- birtll-weight infants. On thla average, the smoker has nearly Wice. the risk of delivering a lowbirth-Keight infant as that of a nonsmoker 106 (3, 13, 17, 20, 25, 29, 35, 42, jJ3: 46, .$7> 49. 57: 58, 59, 65, 70, 72, 73, 77,78? 80,83,85,90,95,99,1007 113,118). 2. The strong association between cigarette smoking and the de- livery of small-for-dates infants first demonstrated 1vit.h results from studies of retrospective design (3! 12, 17, 35, 46, .$7? 49, 57> 58, 59? 65, 70,72? 73, 77,80,85,90,95,9LJ3! ZO!?, 118) has been repeatedly confirmed subsequently by data from studies of prospective design (.20,25,29,&J, /$x3', 7483,113). 3. A strong dose-response relationahip has been established between cigarette smoking and the incidence of lo\~-bil~h-~~-eigl~t infants (25, 49,46,49,100,213). 4. When a variety of knowi or suspected factors which also exert. an influence upon birth weight have been controlled for, cigarette smok- ing has always been shown to be independently related to low birth weight (I, 13, %5, & 46, 7,3,78,&Y). 5. The association has been clenionstrated in many different coun- tries, among different races and cultures, and in different geographical settings (13.17.25,29,31i . $2. .$3,69.7.?, 78,80> 113). 6. Prerioiis smoking does not appear to influence birth n-eight if the mother gives up the habit prior to the start of her pregnancy (2,s. $6,49,2 13) . 7. The infants of smokers experience an accelerated growth rate during the first 6 months after delivery, compared to infants of nonsmokers. This finding is compatible with viewing birth as the re- moval of the smoker's infant from a toxic influence (8C3). 8. Data from experiments in animals have documented that ex- posure to tobacco smoke or some of its ingredients results in the delivery of low-birth-weight offspring (7, 8, 9? 23, 40, 87, 117). Several recently published studies have provided additional wp- porting evidence for a causal relationship betjveen cigarette smoking and small-for-dates infants. The Ontario Perinatal Mortality Study (66) was conducted among 10 teaching hospitals during 1960 and 1961. The authors of this retrospective study of 50,267 births demon- strated a significant excess of infants weighing less than 2,,500 grams among cigarette smokers as compared with nonsmokers (Pxperienced by the mother cannot h rulei out by the available data. 117 Schlede and Merker (86) have studied the effect of benzo (a) pgre,ne administration on aryl hydrocarbon hydroxylase activity in the mater- nal liver, place.nta. and fetus of the rat during the latter half of gestation. The pregnant animals were. treated with large oral doses of benzo (a) pyrene d-1 hours prior to sacrifice. Control rats had no det,ect.able levels of aryl hydrocarbon hydroxylase in their placentas. Treat.ment wit,11 benzo (a) pyrene resulted in barely detectable placenta] levels on gestation day 13. but steadily rising values until day 15, and then constant levels thereafter. Ko activity was detected in the fetuses of untreated controls. In t,he treated animals, the fetal enzyme activity rose steadily from the 1M to the 18th day of gestation. The authors concluded that the stimulatory effect of benzo (a) pyrene treatment, on aryl hydrocarbon hydroxylase activity in the fetus demonstrates that benzo( a) pyrene readily crosses the rat placenta. Carbon Monoxide Smokers and their newborn infants have significantly elevated levels of carbon monoxide as compared with nonsmokers and their infants (3f,3& 88,116). Recently, Raribaud, et al. (5) studied 50 nonsmokers and 27 cigarette smokers and their newborns. All smokers inhaled. The authors found that the mean level of CO content in the blood of non- smokers was 0.211 volunies percent compared with 0.672 volumes per- cent in the blood of smokers. The values for blood samples from the umbilical cords of their newborns were ().%?r! and 0.949 volumes per- cent, respectively. Moreover. a definite dose relationship was found between CO levels and number of cigarettes smoked. Younoszai, et al. (Ill;) found, in addition to elevated carboxyhemo- plobin levels among the infants of smoking mothers, significant elevation of mean capillary hemotorrits and significant reduction of standard bicarbonate level', as compared to the infants of nonsmoking mothers. Since no el.idencr for nicotine efl'ects upon blood glucose, serum FFA lrrels~ or urinary catecholamines, or for hypoxia was present, they concluded that the higher hematocrit levels in the infants of smoking mothers may hare represented a compensatory response to the decreased oxygen-carrying capacity of the blood due to the presence of carboxyhemoglobin. 1,ongo {dlj) pointed out that a level of 9 percent carboxyhemoglobin in the fetus is the equivalent of a 41 lwrcent decreasr in fetal blood flow or fetal Iwmoglobin concentration. In reviewing the studies of CO levels in human niothcrs nud their uewborus. he made the follow 118 ing comments: "These samples were obtained at the time of vaginal delivery or Cesarean section and may not accurately reflect the normal values of (COHb), for se.veral reasons. The number of cigarettes smoked by the mothers during labor may be less than their normal consumption and was not specified in these studies. The blood sam- ples were collected at varyin g time periods following the cessation of smoking. In addition, many of the samples were probably taken early in the day before COHb levels had built up to the levels reached after prolonged periods of smokin g. Thus actual levels of (COHb)~r and (COHb) F may be higher than the reported values." Polycyclic Hydrocarbons The results of several studies concur that cigarette smoking is strongly associated wit.h t.he induction of aryl hydrocarbon hydrox- ylase in the human placenta (18,38: 61,99? 109). This finding implies that benzo( a) pyrene or other polycyclic hydrocarbons reach the placenta. To date! evidence to support t,he passage of polycyclic hydro- carbons t,hrough the placenta to t,he human fetus has not been published. Warnin B,, and Cyanide Detoxification McGarry and Andrews (48) determined serum vitamin B,, levels in 826 women at their first prenat.al clinic visit. They found that the serum levels for smokers \vere significantly lower than for nonsmokers. After adjustment for gestational age, parity, social class, hemoglobin level, hypertension, and maternal weight, smokers still had signifi- cantly lower levels of B,,. They also found a direct. statistically sig- nificant dose-response relationship between cigarettes smoked and serum vitamin B,, level. They again confirmed the relat.ionship be- tween smoking and low birth \veight.. The authors suggested that. the lowered vitamin B,, levels reflect a disorder of cyanide detoxification. Cyanide is a demonstrable ingredient in cigarette smoke (39, 60, 6'2> 64,68,74 91). Vitamin C Venulet (105,106,107) has demonstrated that the vitamin C level is significantly lower in the serum of women who smoke cigarettes during pregnancy, compared to values for their nonsmoking counter- parts. Possible Mechanisms The following mechanisms have been proposed for the production of low birth weight and other unfavoralble outcomes of pregnancy following exposure to cigarette smoke : 119 1. *4 direct toxic influence of constituents of cigarette smokeupon the fetus (2, &5, 50, 51, 117). 2. Decreased placental perfusion (94). 3. Decreased maternal appetite and diminished maternal weight gain \vith secondary effects upon the fetus (6, 33, 36, 65: 75, Qg. 117). 4. A direct effect upon the placenta (36: 57, 65,110). 5. An oxytocic effect on uterine activity (44). 6. A disturbance of vitamin B12 metabolism (&?). `i. a disturbance of vitamin C metabolism (205,106,107). Of the potential mechanisms, available evidence suggests that neither decreased maternal appetite and decreased maternal weight gain nor a direct effect upon the placenta are responsible for a sig- nificant reduction in birth weight. Existing evidence does not permit firm conclusions concerning the relative significance of the remaining mechanisms. Timing of the Influence of Cigarette Smoking on Birth Weight Several investigators have published results which bear on the time period during which exposure to cigaret*te smoke most affects fetal growth. Lowe (46) and Zabriskie (118) have offered evidence which suggests that cigarette smoking influences fetal growth most during the second half of pregnancy. Butler, et al. (15) found that the birth weights of infants of women n-ho did not smoke after the fourth month of pregnancy were essentially the same as those of the infants of nonsmokers. This implies that the influence is most probably exerted after the fourth month of pregnancy. Herriott, et al. (35), however! found that women in lower socioeconomic classes who gave up smoking early in pregnancy tended to have intermediate weight babies as com- pared with nonsmokers and persistent smokers, but his numbers of women were small and the results were not statistically significant. I'ndervood, et al. (100) found that cigarette smoking in any single trimester was associated with a lower birth weight of the infant, although the difference between the birth lveights of infants of women who smoked only during a single trimester and infants of non- smokers was not statistically significant because of small numbers. Several investigators hare detected a nearly constant difference be- tween the birth weights of the infants of smokers and nonsmokers. delivered during the last month of pregnancy. following gestations of comparable length [fig. 1, (12)-j. ,4lthough this observation is 120 compatible with the suggestion that the influence of cigarette smoking upon the fetus occurs prior to the last month of pregnancy, it is based upon data derived from cross-sectional rather than longitudinal studies. The results of many human epidemiological studies suggest that maternal smoking prior to pregnanq does not influence fetal \reight gain (15, 25: 46, ~$9, 123). Site of Action at the Tissue and Cellular Level The use of labelled nicotine (98) and the preparations of autoradio- grams have permitted the localization of nicotine within the tissues of the fetus and mother. Tjalve, et al. (98) found high levels of nico- t.ine in the respiratory tract, adrenal, kidney, and intestine of 16- to 18- day mice fetuses. The use of other labelled constituents during various parts of gestation might further the understanding of how certain ingredients in cigarette smoke produce an impact upon birth weight. Haworth and Ford ($3) have reported data which suggest that, the reduction of birth Keight of rat fetuses caused by the action of the ingredient (s) of tobacco smoke results from a. reduction in cell number, but not in cell size. Significance of the Association Among all women in the United States, cigarette smokers are nearly twice as likely to deliver low-birt,h-weight infants as are non- smokers. Assuming that 20 percent of pregnant, women in the United States smoked cigarettes ~through the entire pregnancy (extrapolated from data on changes in smoking behavior during pregnancy collected for the British Perinatal Mortality Study), taking into account the apparently different risks of delivering a small-for-dates infant, for Caucasian and non-Caucasian women who smoke during pregnancy, and considering the number of infants with a birth weight less than 2,500 grams born to Caucasian and non-Caucasian women, an excess of nearly 43,000 occurred in the 286,000 low-birth-weight infants among the 3,500,OoO infants born in the I'nited States in 1968, because of the increased risk among women who smoke of having smnll-for- dates infant,s. Since neonatal mortality is higher for low-birth-weigth infants. with gest,ational ape held const,an#t, the escess of small-for-dates infants among smoking mothers would implv a significant excess mortality ., risk as well. 121 A C3llS~Il association between cigarette smoking and fetal growth retardation is supported by the following evidence : 1. The IXS& of all 42 studies in which the relationship between smoking and birth weight was examined have demonstra+t& a strong association between cigarette smoking and delivery of small-for-dates infants. On the average, the smoker has nearly twice the risk of delivering a low-birth-weight infant as that of a nonsmoker. 2. This association has been confirmed by both retrospective and prospective study designs. 3. A strong dose-response relationship has been established between cigarette smoking and the incidence of low-birth-weight infants. Available evidence suggests that the effect of smoking upon fetal growth reflects the number of cigarettes smoked daily during a pregnancy, and not t,he cumulative effect of cigarette smoking which occurred before the pregnancy began. 4. When a variety of known or suspected factors which also exert an influence upon birth rreight have been controlled for, cigarette smoking has consistently been shown to be independently related to low birth weight. 5. The association has been found in many different countries, among different populations, and in a variety of geographical settings. 6. Kew evidence suggests t,hat if a woman gives up smoking by t,he fourth month of pregnancy, her risk of delivering a low-birth- weight. infant is similar to that of a nonsmoker. `7. The infants of smokers experience a transient acceleration of growth rate during the first 6 months after delivery, compared to infants of nonsmokers. This finding is compatible with viewing birth as the removal of the smoker's infant. from a toxic influence. 8. The results of experiments in animals have shown that exposure to tobacco smoke or some of its ingredients results in the delivery of low-birth-weight offspring. New evidence demonstrates that chronic exposure of rabbits to carbon monoxide during gestatioll results in a dose-related reduction in the birth weight of their off spring. 9. Data from studies in humans have demonstrated that smokers' fet,uses are exposed directly to agents within tobacco smoke, such as carbon monoxide, at levels comparable to those which haye been shown to produce lore-birth-weight offspring in animals. 122 Cigarette Smoking and Fetal and Infant Mortality Introduction Several previous studies of the relationship between cigarette smok- illg and higher fetal and infant mortality among the infants of smokers have been reviewed in the 1971 and 1972 reports on the health con- sequences of smoking (101, 102). In many of these studies, the authors coinbined two or more categories of fet.al and infant mortality. Differ- cjnt morta1it.y outcomes, such as spontaneous abortion. stillbirth, and neonatal death, are influenced by different sets of factors. Among other factors, the frequency of abort.ion is influenced by congenital infections, hormonal deficiencies, and cervical incompete.ncy. In addi- tion to other factors, the frequrncy of stillbirth is influenced by pre- wuure separation of the placenta, utcrinc inertial and dystocia. Along with other factors, the frequency of neonatal dcat,h is influenced by ,zestational maturity, birth injuries. and delivery room and nursery ~`~re. Separate analysis of the relationship of cigarette smoking to each different mortality outcome, with control of the unique set of factors which influences it, may facilitate understanding of the relationship. Spontaneous Abortion Previous epidemiological and experimental studies of the relation- ship between spontaneous abortion and cigarette smoking revielved in the 1971 and 1972 reports on the hea.lth consequences of smoking (101, I@%`) form the basis of the following statements : The results of several studies, both retrospective and prospective, have demonstrated a statistically significant association between ma- ternal cigarette smoking and spontaneous abortion (43, 65. 70. 99, 118). Data from some of t.hese studies have documented a strong dose- response. relationship between the number of cigarettes smoked and the incidence of spontaneous abortions (70,%9,118). In general, rari- ables other than cigarett,e smoking (e.g., maternal age, parity, health, desire for the pregnanc,y, and use of medication) : whic,h may influence the incidence of spontaneous abortions, have not been controlled. The results of the one studv. in which adjustment for t.he woman's desire for the pregnancy was `performed, indicated that after such adjust- inent cigar& smoking during the pregnancy retained an association aith spontaneous abortion of borderline significance (49). The time Period during xvhich cigare.tt,e smoking might exert an influence on the incidence of spontaneous abortions has not been determined. Abor- 123 tions have been produced in animals only with large doses of nicotine ($3, 96, 104) ; the relevance of these studies for humans is uncertain, SPOSTAXEOKTS ABORTION; SUXMARY Although several investigators have found a significantly higher, dose-related incidence of spontaneous abortion among cigarette smokers as compared to nonsmokers, t,he lack of control of significant variables other than cigarette smoking does not permit a firm con- clusion to be drawn about the nature of the relationship. Epidemiological st.udies of the association between cigarette smok- ing and stillbirth previously reviewed in the 1971 and 1972 reports on the health consequences of smoking (102,10.$) form the basis for the following statements : In one group of ret'rospective and prospective studies, a higher still- birth rate was found for the infants of smokers as compared to those of nonsmoker-s (14, 25, 43'). I n another group of retrospective and prospective studies, no significant difference was detected in the still- birth rate among the infants of smokers and nonsmokers (16,20,&j, 99, 100). Differences in study size, numbers of cigarettes smoked, or the presence or absence of control of variables, such as age and parity, which may influence stillbirth rates, were probably not sufficient to explain the differences in results obtained. Several recent epidemiological studies have added to our under- standing of the relationship between cigarette smoking and stillbirth. Niswander and Gordon (63) have reported data from 39,215 preg- nancies followed prospectively and collected between 1959 and 1966 at 12 university hospitals in the United States. A random sample of women who presented to hospital prenatal clinics were enrolled in t,he study. The authors reported no increase in st.illbirths among white smokers as compared with white nonsmokers. A higher incidence of stillbirths was found among black women who smoked than among nonsmoking hla.ck women. and a. dose-response relationship Kith cigarettes smoked was suggested, although the findings did not attain statistical significance. The results mere not adjusted for other vari- able. Rush and Kass (82) found, in a prospective study of 3,296 pregnancies at Boston Cit,y Hospital, a nonsignificant increase in 124 stillbirths among white women who smoked, but a st.at,istically signifi- cant increase in stillbirths among black women who smoked (P