T.luLE G.---Rclatix rirk q/ congenital Ina!formation -for irl~fants qf cigarette smoX-cr.7 and nonsmokers, comparing ai-ailablc stilr1ie.s with regard to study cfcsign, s/~tly popltiat;on, sample si:e. number 0-f injants urith ma!formations, and dcjnition of malformation I (b) Survlvlng Infants lnsg.31. I (a) ' Elffliwrn plus neonntnl deaths 1 and deaths to I 7. Cb) Neomtal deaths 1 (3-mooth study). ?3 37 59 1.744 1,382 43 700 88 204 I. 36 >fnJor. .31 >IoJor. cnuse of den&. .b7 >le]or. .97 I. 19 >If$x. Cz."SD of 1.07 (1) Congenital Xalformafion Summary Given the considerable variation in study design, st-udy population, sample size, number of affected infants, definition of malformation, and results, no conclusions can be drawn about any relationship between maternal cigarette smoking and conge.nitai malformation at the present time. 451 Lactation Introduction The following section is a review of available e\-idence which bears upon any interaction betxveen cl, `oarette smoking and lactation. Emphn- sis is placed upon the relationship of cigarette smoking to the quantity of milk produced, to the presence of constituents of cigarette smoke within the milk, and to eirects upon the nursing infant mediated through changes in either the quantity of milk available or the sub- stances within the milk. Epidemiological Studies cnderx-ood, et al. (99), in a stud1 of 2.000 rromen from various social and economic strata, observed a definite but statisticall? insig- nificant trend toward more frequent inadequacy of breast milk pro- duction among those smoking mother; Kho attempted to nurse compared to nonsmokers. Mills (Z), in a study of 520 women. found that among women who indicated either a desire to nurse or no desire to nurse yet continued to nurse, beyond 10 days, and riho had delivered their first live-born infant? the average period of nursing for mothers who smoked was significantly shorter than for nonsmokers. Moreover, among the W mothers who had given up smoking during at least the final 3 months of their pregnancies, the average length of nursing was identical to that of the nonsmokers. There was no significant difference between smokers and nonsmokers with regard to complete inability to nurse their offspring. This study is difficult to interpret because the author did not determine the reason(s) for the discontinuation of nursing among the women. Experimental Studies Nicotine Influence on the Lactation Process Blake and Sawyer (II) studied the influence of subcutaneously injected nicotine (4 mg. total over a s-minute period) upon lactation in the rat. They found that nicotine inhibited the suckling-induced 452 rise in prolactin. So ctfcct of injected nicotine was dcmonstratcd for ox>-tocin secretion since milk release was not, blocked. T\`ilson (110) examined the etfcc:s of nicotine supplied throcg'n drinking water (0.5. 1.0. and 2.0 mg. daily) on the weight rain of nursing rats. -\pp`arently: the nicotine had been avnilablc throughout gestation as well! because theauthor commented on a reduction in litter size among the experimental groups. more or less proportionate to the dose of nicotine; hence. a prenatal efrect could not have been dis- tinguished from a postnatal one. Average birth weight was similar for ex-pcrimtntal and control groups. Ko difference in weight gain wasseen for any of the groups. The lack of impact on birth weight suggests thnt dose was loser than that used in other studies. Presence of Nicotine in the Nilk Hatcher and Crosby (A??), using a frog bioassay, reported traces of nicotine in cotr? milk ?I hours after the intramuscular injection of 5.0 mg./kg. and 5 hours after the injection of 0.5 mg./kg. Evidence for an Effect Upon the Nursing Offspring Hatcher and Crosby (3;3).found that 0.5 mg./kg. nicot.ine injected into nursing cats had no apparent harmful effect upon the kittens. Apparently 4.0 mg./kg. suppressed Iactation. Kittens fed the miik from the cow trhich had been injected with 5.0 mg./kg. nicotine rrere also apparently unaffected. Nitrosamines Bohr (53) found that diethglnitrosamine and dibutylnitrosamine: when administered to lactating hamsters, were associated -with the deL*elopnwnt of typical trachea1 papillary tumors in the -oung? SU,O- gesting passage df these compounds in.;he milk. Although diethyl- nitrosamine and dibutvlrlitrosanline have not been identified in ciga- rette smoke, manv X-nitrosamines are potent carcinogens, and some- of them are present in cigarette smoke (37, 79). Sicotine and/or Tobacco Smoke Infiuence on the Lactation Process Emanuel (22') noted no reduction in milk production among 10 rret nurses who xere encouraged to smoke seven to 15 cigarettes daily; 453 some were observed to inhale the smoke. Hatcher and Crosby (39) noted that after a mother smoked seven cigarettes vSthin 2 hours, it was dificult to obtain a specimen of breast, milk. PerIman, et al. (71) found that of 55 women smokers with an adequate milk suppiy at t.he beginning of his study, 11 (20 percent) of the women had an inade- quate supply at the time of discharge from the hospital. No relation- ship was reported between the number of cigarettes smoked and the likelihood of developing an inadequate milk supply. The authors' im- pression was that there was no greater proportion with an inadequate milk supply among smokers than among nonsmokers, but no cur- roborating data were supplied. Presence of h'icotine in the hiilk Hatcher and Crosby (33) found, using a frog bioassay, that the milk of a woman collected after she had smoked seven cigarettes in 2 hours contained approximately 0.6 mg./liter nicotine. Emanuel (D?), using a leech bioassay, studied excretion of nicotine in the milk of wet nurses who were encouraged to smoke for the experiment. -1fter the subjects had smoked six to 15 cigarettes over a l- to 2-hour period, the author found nicotine in their milk 4 to 5 hours after smoking, with a maximum concentration of 0.03 mg./liter. Bisdom (10) demonstrated nicotine in the milk of a mother who smoked 20 cigarettes a day. Thompson (97) found approximately 0.1 mg./liter of nicotine in the milk of a mother who smoked nine cigarettes a day (plus three pipe- fuls). Perhnan, et ai. (71), using a Daphnia bioassay, demonstrated nicotine in the milk of all women who smoked in their study. Moreover, they found a direct. dose-relationship between concentration of nicotine and the number of cigarettes smoked. No comment is made by the authors on the possible inaccuracy introduced by examining only the residual milk following nursing, but it is well known that the composi- tion of the fore milk and hind milk is different and perhaps the concentration of nicotine also differs. Evidence for a Clinical Effect Upon the Offspring Emanuel (99) noted that among the infants in his study, loose stools were observed only in the one N-hose wet nurse had smoked 20 ciga- rettes in the previous 4 hours. Bisdom (10) observed a case of "nico- tine poisoning" in a 6-week-old infant -hose mother smoked 20 ciga- rettes a day. The symptoms included : restlessness, vomiting. diarrhea, and tachycardia. Nicotine was demonstrated in the milk, and the symptoms abated when smoking was stopped. Greiner (30) also de- scribed a case of possible nicotine poisoning in a 3-week-old nursling 454 ~1~os.e mother smoked 35 to JOcigarettes a dav. Thr symptoms incliitlcd vomiting and loose stools. Folloxvin~~ the curtailment of smoliinr. the symptoms gradually abated over a 3-da>- period. l'crlninn. et nl. (71) noted no etfect of smoking on the weight ~ train of the infants of the smokers in their study. Furthermore. no untoward symptoms wx-e obserr-ed. They therefore doubted an efcct of smoking on lactation. They noted that the dose received by the infants xas beneath the toxic level as computed from adult experience. and this accorded vcith their clinical observations. The fact that they admitted to the study only women with an apparently adequate milk supply mnp 11ave affected their results. The authors su ggested that perhaps the lack of effect of smoking upon lactation might represent the development of tolcrnnce to nicotine, as both the mother and the offspring had been exposed throughout the pregnancy. VITAMIX C Venulet (105, 106, 107), in a series of studies, demonstrated that the level of vitamin C was reduced in the milk of smoking mothers as compared with nonsmokers. The clinical si:nificnnce of this observa- tion has not been evaluated. 1. The t-rro pertinent epidemiologiczil studies suggest a possible in- fluence of smoking upon the ndequnc>- of milk supply However, with only limited numbers of women and without control of other potentially significant variables, no conclusions can be drax-n. 2. Studies in rats leave demonstrated that nicotine can interfere with suckling-induced rise iii prolnctin. The relet-ante for humans is uncertain. 3. Evidence exists that nicotine passes into breast milk. No clear evidence for an acute effect upon the nursing infant is available. I'otential chronic ctfccts have not been studied. 4. Sew cl-idcnce from esperimcnts wit]: niice suggests that nitros- amines. liuo\vn cnrcino~rns, pass througIr the milk to suckling pIIll-`. 455 Preeclampsia Previous epidemiologic4 studies of the relationship betxwen cig- arette smoking and preeclampsia were revielred in the 1971 nnd 13Z reports on t.he health consequences of smoking (~01,102) and form the basis of the following statements: The results of several large prospective and retrospective studies indicate a statistically significant lorrer incidence of prceclampsia among smoking women (I-6, @`,100). The results of one large retro- spective study demonstrated a significant inverse relationship between the incidence of preeclampsia and the number of cigarettes smoked (ZOO). When other risk factors, such as parity, social class; maternal weight before the pregnancy, and maternal weight gain during the pregnancy Kere controlled, smokin, n women retained a significantly decreased risk of prerclampsia (22). The lower risk of preeclampsia for cigarette smoking Tomen has been demonstrated in Britain and Scotland (14, 21, 46: 83), The United States (100, 228), Venezuela (@) , and Sweden (@) . If a maternal smoker does develop preeclamp- sia, however, available data suggest that her infant has a higher mor- tality risk than does the infant of a nonsmoker with preeclampsia (21,83). 1. Available evidence indicates that maternal cigarette smokers have a significantly loxrer risk of developing preeclampsia as compared to nonsmokers. 2. If a rroman who smokes cigarettes during pregnancy does develop preeclampsia, her infant has a higher mortality risk than the infant of a nonsmoker rrith preeclampsia. Pregnancy References (I) ABEBNATHY. J. R.. GBEENBEW, B. G., WELLB, H. B., Fruzroc. T. 11. Smoking as an independent rariahle in a multiple regression analysis upon birth weight and gestation. American Journal of Public Health and the Xintion's Health 56(4) : 62-3, April 1966. (2) ASTBUP, P. Patbologische Wirkuogen miissiger Koblenmonoxid-Konzen- trationen. (Pathological effects of moderate carbon monoxide concentra- tions.) Staub-Reinhnltongder Luft 32(4) : 146-150.1972. (S) BAILEY, R. R. The effect of maternal smoking on the infant birth n-eight. New Zealand Medical Journal 71(456) : 293-294, May 1970. 456 (4) BAKEa. F. D.. T~MA~OXI~. C. F. Carbon monoxide and avlan embryo- genesis. Archires of EZnrlronmental EIcalth 24(l) : X%61, January 192. (5) B=IBALD. L.. Yac0c-s. 11.. FALTBE. .I.. XALIXM. Y.. C.&v, G. L'oxyacar- bonemie de l'enfant ne de mere fumeuse. (Presence oC carbon monoxide ln the blood of a child born of a smoking mother.) Mwlecine Legale et Dommage Carpore 3(3) : 272-274. July-August-September 1970. (6) Bm, v. A. Nutritional studies during pregnancy. Journal of the Amerl- can Dietetic Association 58(4) : 321-326, April 1971. (7) BECK% R. F.. &SO. J. E. Studies on nicotine absorption during preg- nancy. II. The effects of acute heary doses on mother and neonates. American Journal of Obstetrics and Gynecology 93(3) : 515-522, June 15.1966. (8) BECKEB. R. F.. LII-TLK, C. R D.. 61x0. J. E. Experimental studies on nicotine absorption in rats during pregnancy. III. Effect of subcutaneous injection of small chronic doses upn mother. fetus, and neonate. Ameri- can Journal of Obstetrics and Gynecology lOCl(7) : 937-968, Apr. 1, 1968. (9) BECK=. R.. F., .\IARTIS, J. C. Vital effects of chronic nfcotine absorption and chronic hypoxic stress during pregnancy and the nursing period. American Journal of Obstetrics and Gynecology llO(4) : 522-533, June 15,1971. (10) BI~DOY. C. J. W'. Alcohol nnd nicotine poisoning in infants (sucklings), Jlnandshrift roar Kindergeneeskunde G : 3X-341, 1937. (11) B~-*lce C. A.. SAWVYER. C. II. Nicotine blocks the suckling-induced rise in circulnting prolactin in lactating rats. Science 177(4(X9) : 6IM21, Aug. 18. 19i2. (1-O) BCNCHES. C. R. 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Canadian Medical ?\ssocintion Journal 99(S) : lOi-200, -411;. 3. 19GS. 463 Chaprer 6 Peptic Ulcer Disease Source: 1973 Reporl, Chapter 5, pager 151 - 164 46.5 Contents Introduction___-__-.-----_------------------------------- 469 Epidemiolo$xl and Clinical Studies--- _ -_ _- _-_ _- -_ -_ _ _ __ - - 469 Esperimental Studies G~str2cSecretion_-_~ _______ _-___---_--_-___-_-_______ 471 Pancreatic Secretfon-- -___-_____ ---_---- ____________- - 473 Summnry of Recent Peptic Ulcer Disease Findings- _ _ _ _ - _ _ _ _ 476 Refcrcnces ___-__-____ __-__-_____ -- ___-___ --__-__-___-- 477 List of Figures I.`i,qre I.-Gastric ulcer tiortality ratios of Japanese (men and women combined) by age at initiation bf cigarette smoking (19GF-70)_-____-____________-__-__-_--_------~--~---- 470 Figure Z.-Effect of cigarett.e smoking on volume of secretin- stimulated pancreatic secretion in humans_--___--_-__-__- 474 Figure S.-Effect of cigarette smoking on secretin-stimulated pancreatic bicarbonnte output in humans-_-__-____-__-___ 475 467 Introdriction Preriouu epidemiological and erpcrimental studies of the relat.ion- sliip between cigarette smoking and peptic ulcer disease were review-ed in the 19i1 and 1972 reports on the health consequences of smoking (17,18) sntl form the basis of the folloxving summary : The results of epidemiological studies indicate that cigarette smok- ing males have an increased prevalence of pept.ic ulcer disease and a greater mortality from peptic ulcer as compared to nonsmoking males. _Ytnong mnlcs, the association betn-een cigarette smoking and peptic ulcer disease is stronger for gastric than for duodenal ulcer, but sig- nificant for both. For males, ciprette smoking appears to reduce the ctfcctiwness of standard peptic ulcer treatment and to slow the rate of peptic ulcer healing. The relationship between cigarette smoking and the prevalence of and mortality from peptic ulcer disease is less clear for females than for males. Experimental studies of the effect of cigarette smoking in man, and of the effect of injection and infusion of nicotine in animals, on gastric secretion and motilitv ha\-e produced conflicting results. In dogs, an infusiori of nicotine has been found to inhibit pancreatic and hepatic bicarbonate secretion, thus demonstrating a possible link between cirarctte snroking and duodenal ulcer. Recently, additional epidemiological, clinical, autopsy, and esperi- mental studies have confirmed the association between cigarette smok- ing and gastric ulcer mortality and have clarified a mechanism through which cigarette smoking might be linked to duodenal ulcer. Epidemiological and Clinical Studies Previous studies of the relationship between peptic ulcer- disease and cigarette smoking haw been conducted in predominantly white, We.+ em populations. A large prospective epidemiological study is currently being conducted in .Japan. From this study, Hirayama (6) reported 5-J-e3r folIowup data on 265,llS men and women, aged 40 years and older, reprcsentinF St to 99 percent of the total population in the area of the 3 health districts in xvhich thestudy was conducted. Both male and female cigarette smokers cq)erienced higher death rates from gastric ulcer as coml~awci with nonsmokers. The mortality ratio for ciznrctte smokers was 1.81 for males (r)25 <= -pothalamus, blocked the nicotine-induced gastric secretory stimula- tion in the presence of intact vagi. The authors concluded that chronic nicotine-induced gastric secretory stimulation is mediated via anterior hypothalamic activation and intact ragus nerves. The importance of local effects remained uncertain. Pancreatic Secretion Bpnum, et al. (3) studied the effect of cigarette smoking upon pan- creatic secretion in -23 healthy young males and females. Five control male nonsmokers xere compared with seven male and t\ro female light smokers (Iess than one pack of cigarettes per day for less than .7 years) and eight male and one female heavy smokers (more than one pack of 473 cigarettes per day for more than 3 years). Pancreatic secretion n-as measured by the double secretin test, using Boots secretin. The experi- ment was divided into two parts for the SJrlOk0~3: A basal collection period and an experimental period during which the subjects smoked seven nonfiltered cigarettes at the rate of four per hour. Light smokers had basal values for pancreatic secretory volume and bicarbonate out- put in response to secretin which were not significantly different from controls. After the subjects had smoked, significant depression of both pancreatic volume and bicarbonate output was noted (P<.oOl). Heavy smokers had basal values that were significantly less than in the control subjects (P