Ounsted ((8) offered evidence that the best predictor of thr tjirth xveight of a mother`s future offspring TWS the birth weight of her previous children. Hcrriott: et al. (3.5) found prcmnturit_v rates for prex-ious prepnncics among smokers to be markedly 1Iiplrer than among nonsmokers, independent of parity, height, and social class. Evidently n woman \Tlioze previous infants lin~t: been small trntls to roritiniie to have relatix-cl\- srnaller tlran avcrn~e infants in srlbaequfnt prepxncies. The question is- will those infants be even sm:lllcr than expected if 511~ smokes? Goldstein, et al. (I'S). in a comprehrnsiw re~icw, proposed a research dcsi? in which :I u-omen ~~oultl sewe as her own control to compare outcomes of l>rewIancics tlririn_rr \rhich she sInoked with those during .: \rhich she did not, xitli consideration of the effect of parity on the outcome. Terushnlrtiy (213) has recently tested this type of research design. using data from his O:Ikland Growth Study. \\`ith information on the aye ;It wlIjclI a \I~ornnn Iwpn to .srnoke ci,carcttes, her smoking status during the prr,yancx- nctunllv studied, her prior rcproductir-e experience. and the outcome of her present pregnancy, the author compared the outcomes of pre-gnancx during periods of smoking and nonsmoking using the Toman as her orrn control. -AS the author noted, "If smoking cnuer; tlIe increase in lo\~--birtli-~~ei,nlIt infants. then the incidence of low birth n-eight for infants born to smoking mothers during the period before they acquired the smoking habit. should be relatirelv lo\\-. If, on the other hand, the high incidence of Ior birth weigf>t is due to the snooker. then it should behigh for infantsof future smokers also rrhen they rrere born before their mothers started to smoke." Yerushalmy then proceeded to compare the reproductive experiences of four groups of women: (a) Those n-110 smoked in none of their .pregnancies, (b) those who smoked in all of their pregnancies. (6) those x-ho n-ere smoking no-x but preriously had not smoked during some pregnancies (future smokers), and (d) those who mere ex- smokers norm but had prrviouslr smoked during some pregnancies. These outcomes are shorrn in fi-pre 5. The incidence of lox--birth- weight infants in the pre;qancips of the future smokers. before they started to smoke, was similar to that for n-omen who smoked in every prepancy, which rws significantly higher than that of infant-s from 426 There at-e se\-cral considerations which limit the interpretations rrilicl1 ran be dra\rn from this study. The information on smoking bcli:~~ior of the ~vottwtt (luring past prcgttnticies was nppnrently de- riwd from the lvomntt's :tee x-hen she began to smoke, her smoking bcllnvior carI~- in the stuc!v pregnancy, and the age at which she hnd Ilcr prior prcgn3ncics. `I`! 1~. if t.he wotnnn reported that site began smokitt~ at :I ccr-taitt age, and that she vns still smoking at Ihe time of the study. it \vns apparently inferred that ahe hnd smoked during ali of her pt-cgttnncirs. Since no questions wx-e specificnlly asked about actual sntokinr behavior during ench previous pregnancy, it is possible that tlw woulnn indeed had not smoked duritq erery pregnancy or that the amount or wny she smoked had differed from current smoking Figure L-Percent of low birth weight white infants by smoking status of their mothers. Gravidas' smoking habits in previous pregnancies Nonsmoker (during all pregnancies) Percent low birth weight infants . 2,529 Nonsmoker (future smoker) 9.5 o 210 Smoker .* (during all pregnancies) . 8.9 2,076 Smoker (future ex-smoker) . . 651 2 4 6 8 10 Percent *Difference is statistically significant (P ~0230-i3-9 429 a X-minute period. The injection of nicotine in the larger, single dose into the mother produced a rise in maternal blood pressure and a fall in maternal heart rate, and an immediate fall in both fetal hlno(l pressure and fetal heart rate followed by pcrsistcnt hypotcnsion and tachpcardia in the fetus. Subsequent to the injection of 1.0 mg./kg. of nicotine into pregnant monkeys, in a single dose, significant chnnqcs in the arterial blood of the older fetuses included a fall in pII, a rise in base deficit, and a fall in oxvgen tension. Carbon dioside tension remained unchanged. Sicotine injected directly into the fetus prompted an immediate rise in fetal blood pressure and a fall in fetal heart rate. These responses were similar to those previously seen in the mot,hers follorring a direct injcct.ion of nicotine. The changes mere more prominent in older rather than in younger fetuses. The authors sum- marized their findings by stating that: (a) fetuses in different ges- tational stages are difrerentially responsive to a given dose of nico- tine, probably because of the different stages of development of the autonomic nervous system; (b) diminished intervillous space per- fusion resulting from vnsotonstriction in the uterine circulation np- pears to be mainly responsible for the fetal asphyxia following the injection into the mother, because fetal hypotension and bradycnrdin were not preceded by the transient hypertension seen following the direct administration of nicotine to the fetus; (c) the differences he- tween the results obtained hy Kirschbaum and by Suzuki, et al. may reflect either the considerable dosage differences or species differences: and (d) the doses xhich the authors empioyed were much larger than those which a human mother would absorb from usual cigar-ette smok- ing, but that differences in tolerance to nicotine between tile Rhesus monkey and humans would imply that the dosages were, in fact, com- parable and that, "Hence, it can be envisaged that the concentration of nicotine which could be reached in the organism of a smoking mother xould reduce oxygen availability to the fetus." Carbon Monoxide Long0 ($5) has reviewed the work of several investigators which has demonstrated the transplacental passage of carbon monoxide from mother to fetus in animals. A recent study n-hich related CO to birth xeight was published by Astrup (2). He found that continuous es- posure throughout gestation of pregnant rabbits to different levels of ambient carbon monoside resulted in a statistically significant dose- related reduction in birth weight (table 2). The actual significance level was not reported. 430 Sumber of pregnnrlt rabbits __________ 17 14 17 Total number of babies .___.__________ 116 Sl 123 Xwrnge weight uf babies in grams.. _ _. 53. 7 5 1 0 44. 7 SOC`RCE: Astrup, P. (f). PoIpc\-cIic nromntic ~~yd~xxxr~ons (I'-IH) such 3s bcnzo(:l)pyrene (B_IP) nre const,ituents of cigarette smoke which have been impli- cated in the generat,ion of cancers in many animal species (112). So studies presently available relate brnzo(n)p~rcne to a reduction in birth n-eight. of esposed offspring. Evidence wggests, however, that. UAP does reach and cross the placenta. Xryl I~>-drocarbon hydrosylase (.~HH) is a part of the cytochrome P-GO- containing microsomal enzyme system, present in many tissues of different species. This enzxrnc system is induced to hydroxylate pol~cyclic aromatic hydra- carbons after exposure of cells to PdH. Several investigators have utilized the inducibiiity of the enzyme system to demonstrate indirectly that benzo(x)pyrene and other polycyclic IIydrocnrbons reach the plncenta and fet,us. IreIch, et al. (108) extended this work by administering the poly- cyclic hydrocarbon, 3-metlly~cholnnthrene (3-MC), to rats during late gestation. The metabolism of t)enzo(ajpyrene ~-as studied in viva (us- ing t.ritium-labelled benzo(a)pyrene) and in vitro. AHH activity KLS increased in fetal livers to adult levels by pretreatment with 3-NC Since B relatively high dose of polycyclic hydrocarbon was requird to stimulate enzyme activity in the fetus, compared to the dose which stimulated placental enzyme activity, the authors suggested that the placenta may protect. the fetus from esposure to polycyclic hydro- carbons. However, immaturity of the fetal rnzvme qstenl rni,nIlt aiso account for its apparent rclntive insensiti\-ity to pal!-q-clic llydro- carbons. Thwefore, an exposure of the fetus to levels of poly- cyclic h>-drocnrbon similnr to those experienced b- tile motllcr cannot bo ruled out by the available data. 431 Schlede and Merker (86) hare studied the effect of benzo(a) pyrene administration on nryl hydrocnrbon hydroxylnse nctivity in the mnter- nal lir-er, placenta, and fetus of the rat during the latter half of gestation. The pregnant animals were treated with large oral doses of benzo(u)p\-rene 24 hours prior to sacrifice. Co!ltrol rats had no detectable levels of aryl hydrocarbon hydrosylnse in their plnccnt*?s. Treatment with benzo(a) pyrene resulted in barely detectable plnccntal levels on gestation day 13, but steadily rising values until day 15, and then constant levels thereafter. No activity was detected in the fetuses of untreated controls. In the treated animals, the fetal enzyme activity rose steadily from the 13th to the 16th 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. STUDIES IN IImraxs Carbon Monoxide Smokers and their newborn infnnts have significantly elevated levels of carbon monoxide as compared with nonsmokers and their infants (31,3.j, 88,116). Recently, Raribaud, et al. (5) studied 30 nonsmokers and 27 ciF"rette 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 volumes percent compared with 0.679 volumes per- cent in the blood of smokers. The values for blood samples from the umbilical cords of tlleir ne\vborns were 0.352 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. (116) found, in addition to elevated cnrbosyhcmo- globin levels among the infants of smoking mothers, significant elevation of mean capillary hemotocrits and significant reduction of standard bicarbonate levels, as compared to the infants of nonsmoking mothers. Since no evidence for nicotine effects upon blood glucose, serum FFA levels, or urinary catecholamines, or for hypoxia was present, they concluded that the higher hematocrit levels in the infants of smoking mothers may have represented a compensatory response TV the decreased oxygen-carrying capacity of the blood due to the presence of csrboxyhemoglobin. Long0 (45) pointed out that a level of 9 percent carboxyhemoglobin in the fetus is the equivalent of a 41 percent decrensc in fetal blood flow or fetal llemoglobin concentration. In reviewing tllc studirs of CO lewls in human mothers and their newborns, llc made the follolr- 432 inp comments: "Tlicse samples xrerc obtained at the time of vaginal delivery or Cfsnrenn section 2nd rnnv not accurntelv rcHect the normal values of (COIIb) F for several rcason~. T!ie nrimber of cigarettes sm0ked by the mothers during labor niay be less than their normal consumption and was not specified in these studies. The blood snm- pies were collrrtetl :it I-arving time periods folloxing the cessation of smoking. In addition, JW111y of the samples were probably taken early in the day beforr C'OIIb le\-els had built up to the levels reached after prolonged periods of smoking. Thus actual lcl-els of (COHb),, and ( COIlb) E. may be higher than the report4 values." Polgcyclic Hydrocarbons The results of several studies concur that cigarette smoking is strongly associated with the induction of ar-yl hydrocarbon hydros- y-lnse in the human placenta (Z&38, 61,99? 109). This finding implies that benzo (a) p~rcne or other polycyclic hydrocarbons reach the placenta. To date. evidence to support the pnssa,ge of polycyclic hydro- carbons through the placent,z to the human fetus has not been published. Vitamin B ,? and Cyanide Detoxification McGarry and ,Andrews (48) determined serum vitamin B,, levels in 8% women at their first prenatal clinic visit. The\- found that the _ serum levels for smokers were significantly lower than for nonsmokers. Sfter adjustnwnt for gestatioiial age, parity, social class, hemoglobin levell hypertension, and maternal weight, smokers still had signifi- cantly Ion-cr levels of B,?. They also found a direct. statistically sig- nificairt dose-respoirse relatioiiship betrreen cigarettes smoked and serum vitamin B,, level. They again confirmed the relationship be- tween smoking and lox birth weight. The authors suggested that the lowered vitamin B,, levels reflect a disorder of cyanide detoxification. Cyanide is a demonstrable ingredient in cigarette smoke (39, 6'0, 62, 64:68,74,91). Vitamin C Penulet (105, 10.6, IO?`) has demonstrated that the vitamin C level is significantly lovrer in the serum of xvomen xv110 smoke cigarettes during pregnancy, compared to values for their nonsmoking counter- pa&i. The following mechanisms have been proposed for the production of low birth weight and other unfavorable outcomes of pregnancy follo~ringevposuretocignrettesmoke: 433 1. A dirwt toxic influence of constituentsof cignrettc smokeupon the fetus (2, $5, 50, 51, 217). 2. Decreased placent31 perfusion (94). 3. Decreased maternal appetite and diminislrcd mnternnl wright gain xvith secondnry effects upon the fetus (G, 33, 36, 65, 75: 9% 117). 4. A direct effect upon the placenta (x,Lz', 65,110). 5. An omytocic effect on uterine nctivity (d$). 6. A disturbance of vitamin B,, metabolism (48). 7. A disturbance of vitamin C metabolism (1/X,106, IW). 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 remnining mechanisms. Timing of the Injlucnce of Cigarette Smoking on Birth Weight Several investigators have published results which bear on the time period during which exposure to cigarette smoke most affects fetal grolvth. 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 xomen who 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 louver socioeconomic classes w-ho 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 Ivere small and the results were not atat.istically significant. Cndern-ood, et al. (ZOO) found that cigarette smoking in any single trimester was associated xvith a louver birth weight. of the infant, although the difference between the birth xveiglrts of infants of -omen n-ho smoked only during a single trimester and infants of non- smokers was not statistically significant because of srnnll numbers. Several investigators have detected a nearly constant difference be- tween the birth weights of the infants of smokers and nonsmokers. delivered during the last month of pregnancy, follnvrinp gestations of comparable length [fig. 1, (zI)]. Although this observation is 434 compatible rrith the suggestion that the infurnce of cignrrtte smoking upon the fetus occurs prior to tile last month of pr-e,~n:~nc>-. it is b:~-ed upon data derived from cross-sectionnl r;\tllcr ti~nn longitudinal studies. The results of many human epidemiol<~gicni studies suggest that maternal smoking prior to pregnancy does not influence fetal weight gain (1$25,46,@, 113). Site of Action at the Tissue and Celldar Level The use of labelled nicotine (98) and the preparations of autoradio- grnms have permit.ted the localization of nicotine within the tissues of the fetus and mother. Tjalve, et al. (95') found high levels of nico- tine in the respiratory tract, adrenal, kidney, and intestine of 16- to 1% day mice fetuses. The use of other labelled constituents during various parts of gestation might. further the understanding of horn certain ingredients in cigarette smoke produce an impact upon birth lveight. Haworth and Ford (33) have reported data which suggest that the reduction of birth weight of rat fetuses caused by the action of the ingredient(s) of tobaccosmoke results from a reduction in celi number, but not in cell size. Signifinnce of the Association Among nil women in the United States, cigarette smokers are nearly twice as likely to deliver lowbirth-n-eight infants as are non- smokers. Assuming that 20 percent of pregnant women in the fi:nited States smoked cigarettes through the entire pregnancy (estrapolated 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 neight less than 2,500 grams born to Caucasian and non-Caucasian n-omen, an excess of nearly 43,000 occurred in the 286,000 low-birth-weight infants among the 3,500,000 infants born in the United States in 1968, because of the increased risk among women who smoke of having smxll-for- dates infants. Since neonatal mortality is higher for lov-birth-weigth infants, with gestational age held constnnt, the excess of small-for-dates infants among smoking moth& would imply a significant excess mortality risk as well. 435 Birth Il-tight Summury A causal association betxwtn cigarette smoking nnd fetsl growth retardation is supported by the following evidence: 1. The results of all 12 studies in xv-hi& the relationship betrreen smoking and birth weight ~cas examined have demonstrated a strong association betrreen cigarette smoking and delir-cry of small-for-dates infants. On the nverage, the smoker has nearly twice the risk of delivering n lov-birth-lveight infant as that of a nonsmoker. 2. This association has been cotirmed by both retrospective and prospective study designs. 3. A strong dose-response relationship has been established betxveen 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 the 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 weight have been controlled for, cigarette smoking has consistently been shorn 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. New evidence suggests that if a woman gives up smoking by the fourth month of pregnancy, her risk of delivering a lore-birtb- 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 ingredfents results in the delivery of low-birth-weight offspring. New evidence demonstrates that chronic exposure of rabbits to carbon monoxide during gestation results in a dose-related reduction in the birth weight of their offspring. 9. Data from studies in humans have demonstrated that smokers' fetuses are exposed directly to agents within tobacco mloke, such as carbon monoxide, at levels comparable to those vrhich have been shown to produce low-birth-weight offspring in animals. 436 Cigarette Smoking nrld Fetal and Tnfarlt ;\Iortalit> Introduction Sex-era1 previous studies of-the relationship betrreen cigarette smok- ing and higher feta1 and infant mortality among the infants of smokers have been revie\red in the 1971 and 1972 reports on the health con- sequences of smoking (201, 102). In many of these studies, the authors combined two or more categories of fetal and infant mortality. Diifer- ent mortality outcomes, such as spontaneous abortion, stillbirth, and neonatal death, are influenced by different sets of factors. Among other factors, the frequency of abortion is influenced by congenital infections, hormonal deficiencies, and cervical incompetency. In adtli- tion to other factors, the frequency of stillbirth is influenced by prc- mature separation of the placenta, uterine inertia, and dyst.ocia. .Ilong with other factors, the frequency of neonatal denth is influenced by gestational maturity, birth injuries, and delivery room and nurses-y care. Separate analysis of the relationship of cigarette smoking to each different mortality outcome, with control of the unique set of factors xyhich 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 reviewed in the 1971 and 19i2 reports on the health consequences of smoking (101, 10.2) form the basis of the following statements: The results of several studies, both retrospective and prospective, have demonstrated a statistically significant association bettreen ma- ternal cigarette smoking a~rd spontaneous abortion (4~7, 65, 70, 99, 118). Data from some of these studies hare documented a strong dose- response relationship between the number of cigarettes smoked and the incidence of spontaneous abortions (`iO,99, 118). In general, rari- ables other than cigarette smoking (e.g.: maternal age, parity, health, desire for the pregnancy, and use of medication), which may influence the incidence of spontaneous abortions, have not been controlled. The results of the one study, in n-Irich adjustment for the xroman'n desire for the pregnancy was performed, indicated that after such adjust- ment cigarette smoking during the pregnancy retained an association with spontaneous abortion of borderline significance (4s). The time period during which cigarette smoking might exert an influence on the incidence of spontaneous abortions has not been determined. Abor- 437 tions have been produced in animals only with large doses of nicotine (A?,%, 20;) ; t 1 le rc!er-ante of the3 studies for humans is uncertain. -1Ithough several investigators have found a significantly higher, dose-related incidence of spontaneous abortion among cigarette smokers as compared to nonsmokers, the lack of control of significant a-ariables other than cigarette smoking doe.s not permit a firm con- clusion to be drarrn about the nsturoof the relationship. Epidemiological studies of the association bet,r;een cigarette smok- ing and stillbirth previously reviewed in the 1971 and 19-;2 reports on the health consequences of Emoking (101,102) form the basis for the follorringstatements: In one group of retrospective and prospective studies, a higher stiII- birth rate ~WS found for the infants of smokers as compared to those of nonsmokers (14, 2.5, $3). In another group of retrospective and prcqective studies, co significant difference eras detected in the still- birch rate among the infants of smokers and nonsmokers (16,20,85,99, . 100). Differences in stud\- 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. Siswander 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. d random sample of rromen who presented to hospital prenatal clinics were enrolled in the study. The authors reported no increase in stillbirths among white smokers as compared rrith Khite nonsmokers. -4 higher incidence of stillbirths was found among black women xho smoked than among nonsmoking black Komen. and a dose-response relationship Kith ciprettcs smoked xvas suggested, although the findings did not attain statistical si3qificnnce. The results rrere not adjusted for other vari- ah&. FL&~ and Kass (82) found, in a prospective study of 3,296 prepancies at, Boston Cit- I%ospital, a nonsignificant hCre3Se in 438 stillbirths among white Tomen who smoked, but a statistically signifi- cant increase in dillbirths among black women who smoked (PO.l). The infants of black smokers, however, had a significantly higher mortality risk than did those of black nonsmokers; the mor- tality ratio was 1.15 (P- StUd~~,emplo~-ed n. log-it transformation analysis of variance, and demonxrated that maternal height, age, parity, social class, and sewre preeclampsia all had a signiticsllt independent clfect on late fetal and neonatal mortality. Rumeau-Roquette (81) provided cvi- dence that a previous stillbirth or lo\\---birth-weight infant significantly increased the risk of a future stillbirth. Meyer and Comstock (51) pro\-ided examples of 110~ the ditfercntisl distribution of smoking and other factors which arc related to perinatal mortality, in a population of \vomenl can bias data (e.g., black women have higher perinatal mortality ratei than do white women, but black women smoke less than white n-omen do. Hence, nonsmokers will tend to include more black Komen. and smokers more \vhite womell. This will tend to reduce any differences between the groups in mortality rates.) Meyer and Comstock concluded, "Comparisons of mortality rates of smokers' and nonsmokers' babies should be made within subgroups according to parity, socioeconomic status, and other appropriate risk factors, and not xparated by birth n-ei$t." In three of the studies in which a significantly higher mortality risk wx demonstrated for the infants of smokers, adjustment for other variables was performed. The result s indicated that, after such ad- justment, a significant. independent association between cigarette smoking and infant mortality persisted (13 and 15, 17, 82). Of the studies rrhich rei-ealed no significant increase in mortality risks for smokers' infants, one (115) controlled for race alone. Hence, at least part of the discrepancy in results between the two groups of studies may be explained by a lack of control of variables other than smoking. -bother possible, at least partial, esplanation of th,: discrepancy - in results obtained by the two sets of studies is that cigaret.te smoke may be more harmful to the fetuses of certain viomen than others. Se\-era1 de\-eloping lines of evidence suggest that t.his may be the case: 1. Cigarette smoking and socioeconomic background. DutIer. et al. (15) noted that IThen data from the British PeAnatal JlortnIity Study are grouped by social class of the mother's husband, the late fetal plus neonatal mortality ratio for infants of smokers and nonsmokers in the upper social classes I and II is 1.10; the mortality ratio for the entire sample was 1.28. Rush and Kass (82) reviewed the British Perinatal lfodality Study, along xx-ith several other studies, nnd noted that a]] have shoEn the strongest aSSO&hn betxrwn excess infant mortality and cigarette smoking among the infants of those mothers rrith loser socioeconomic status. Comstock and Lundin (16) found t.~~e.ss martalit>- among smokers' infants almost entirety con- fhd to those whose fathers had a grammar school education or 1~s. Several of the studies which revealed no significant diderence in mor- tality among the infants of smokers and nonsmokers nsere conducted in predominately middle class populat.ions (20, ZOO, 115). 2. Cigarette smoking and previous obstetrical experience. Peterson, et al. (72) had rigid criteria for entry into his study population of 7,7-N women. He included only those women who pre- viously had healthy infants with a birth weight greater than 2,500 grams. He found a significant decrease in birth weight among smokers' infants, but no significant increase in mortality rates. Rumeau- Roquette (81) found that nmong women who previously had delivered onIy healthy infants rreighing more than 2,500 grams, cigarette smok- ing was not associated rrith an increased risk of stillbirth ; among those women with a previous stillbirth, smoking was significantly associated with incre,ased risk of a future stillbirth. 3. Cigarette smoking and gtnetic differences. The consistent finding that the mortnlity risk for the infants of black smokers is higher than the risk for the infants of v.-hite smokers, even when the socioeconomic background for both is ostensibly similar, suggests that genetic factors also may interact with smoking to pro- duce enhanced risk (SZ? 99, 11.5). Available eridence suggests that if those women, Kho ate already likely to have small infants for reasons other than smoking, smoke during pregnancy, their infants ~-ill be most unfavorably affected. This means that the women in the United Ststfs whose infants Trill be most affected by cigarette smoking are those who have an unfnvor- able socioeconomic situation, have a history of previously unsuccessful pregnancies, and are bIack. Studies in Animals Studies previously reviewed in the 1971 and 1972 reports on the health consequences of smoking (101, 102) demonstrate that exposure of rabbits and rats to tobacco smoke and to injections of large dose2 of nicotine resulted in significantly increased late fetal and neonatal mortality. Astrup (9) has recently studied the effect of continuous exposure of pregnant rabbits to carbon monoxide on stillbirth rates. He found a sipificantly higher, dose-related incidence of stillbirths and deaths within the first 21 hours of life among the offspring of the experimental rabbits (table 4). 446 T.IBLE 4.-Ejfcct qf rnrbon monnride erpowre nf pregnant rabbits on birth weight and neorlcltal mortality -___ Sumber of prepnent rabbits--. ._.______ Total number of babies--.-_-. -- _. _. Stillborn and babies died within first 24 hou~~.~.~--~---~~-~~~~~~---~~~-~~. 17 14 17 116 Sl 123 ' 1 `8 1 44 (P- -!lG~~O of t,he 87,2F3 stillbirth and neonatal deaths in the Cnitcd States in JNX. LATE FETAL ASD SEOSATAI, DEATIE SUXJIARY A strong, probably causal association between cignrctte smoking and higher late fetal and infant mortality among smokers' infants is supported by the following evidence : 1. Twelre retrospective and prospective studies hare revealed a sta- tistically significant relationship betiveen cicnrrttc smoking and an elevated mortality risk amon, n the infants of smokers. In three of these studies, of sufficient size to permit adjustment for other risk factors, a highly significant independent association between smokng and mortality was established. Part of the discrepancy in raults between these studies and those in XThich a significant association between smoking and infant mortality was not dem- onstrated may be explained by a lack of adjustment for risk fac- tors other than smoking. 2. Evidence is converging to suggest that cigarette smoking rnaF be more harmful to the infants of some women than others; this may also, in part, explain the discrepancies between the results of the studies in which a significantly higher mortality risk was shown for the infants of smokers compared to those of nonsmokers and the results of those studies in which significant differences in mortality risk were not found. -- 3. Within groups of similar birth weight, the infants of nonsmokers appear to have a higher mortality risk than do the infants of ciga- rette smokers. This results from the fact that the infants of non- smokers within such similar birth rreight groups are on the ax-ernge gestationally less mature than the infants of cigarette smokers. Available evidence indicates that within groups of sim- ilar cestational age, infants of lower birth weight experience a higher mortality risk. Since the infants of cigarette smokers are `Ras~d on ~xtmpolatlon of data on smoking behnrlor chance durlnr prrgnancr from the Brltlsh Perlnatnl Mortality Studs. which probably rlelds R conscrratlre esttmnte. 448 small-for-gcst:~tion:lI age. onoshould eslwct thnt if the infants of cigarette smokers and non~mokcrs HTC compared within similar geGnti*nal sge cIssces, the infants of ci y:rrctte SIrlOliCr5 trollId have the higher nrortnlitv rete. -1. The results of recent studies hnvc documented a stntisticnlly sig- nificant dose-response rclntionship between the number or nmount of cignrettes smoked and late fetal and nconzrtal mortality. 5. Sew data suggest that if 3 Roman gives up smoking by the fourth month of pregnancy: she will 11nve tile s:rrne risk of incurring n fetal or neonatal loss 3s n nonsmoker. 6. --Imilable evidence strongly supports cigarette smoking as one cause of fetal growth retardation. The causes of excess deaths among the infants of smokers arc those associated with snnril- for-d:rtes babies. 7. I>nta from experiments in animnls have demonstrated thnt espo- sure to tob:rcro smoke or some of its ingrcdicnts, such 2s nicotine or cxrbon monoxide. results iri a significant incrfzrse in late fetal and or neonatal deaths. S. Tire results of studies in humans lrnre shown that the fetus of 3 snrnking niottlrr mnv be tlirectlv exposed to ngclltS Such X3 c:jrbnn nionositlc wit bin tobacco smoke, at levels conipamble to tlrose xhich haw been shown to produce stillbirth in cspcrimrntnl animnls. Sex Ratio .\lt!rough n number of small studies have found a slight, usually 5t:rtistically nonsignificnnt, increase in the proportion of female infants born to smokers, tire tlrrre Inrgest studies of Underwood, et al. (46,505 preLgnanries), Butler (15,791 pregnancies), and Aiac3lahon (12,155 pregnancies) have found similar infant sex ratios among both Smok- ing and rrorismoking r;rotlrer-s, with the cspected slight excess of males ~II~OII~~ZIC~I (table j)* .I\-nilxl,le evidence strongly indicates that mnternal cignrette smok- ing do:~s not inffucncc tltr SW r:ltio of newborn infants. 449 TABLE 5.-f'roportion of mob infants delivered to smoking and non- smokinmg mothers Underwood, et al. (100) ___. ---__----_._ 48,505 Butler and Albennan (14)-------- ______ 15, 791 hlachfahon, et al. (49) _____________ -__- 12, 155 Kullander and Kiillen (43) - - _ _ _ _ - - -_ _ _ _ 6,363 Reinke and Henderson `(78)__- ____ --__- 3, 156 Frazier, et al.1 (26) .___.________________ 2, 915 Kizer (:.2)-- ___.___ - _.___ ---_.- __.____ 2,095 Herriott, ct al. (36)_.-- ____ -- ____ - _____ 2,745 Rnvenholt, et al (77). __-_ _ _______._____ 2,052 Lowe (46)--_.-.-.---__-----------.--- 2,042 Russell, ettd. (83)_--- _..____ - -____ -_-- 2,002 _ 518 .518 .>I3 515 : 498 _ 472 _ 502 .492 -501 .532 .513 -519 - 516 .512 _ 501 _ 517 . 305 _ 493 . 517 .533 . 529 .512 sane. Do. DO. DO. Do. DO. (p>O.OS) NOW. Do. P