References ABBOUD, R.T.. JOHNSON, A.J., RICHTER. A.M.. ELWOOD. R.K. Comparison of in vitro neutrophil elastase release in nonsmokers and smokers. Anwr-km Re~Yaw, of Rc.spirutry\ Disease 128(3):507-S IO. 1983. AMERICAN CANCER SOCIETY. Unpublished tabulations. AMERICAN COLLEGE OF CHEST PHYSICIANS-AMERICAN THORACIC SOCIETY. Pulmonary terms and symbols. A report of the ACCP-ATS Joint Committee on Pulmonar) Nomenclature. Chesr67(5):58.3-593. May 1975. AMERICAN THORACIC SOCIETY. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. ,+rtc,r-rc.u/1 RcI.I'(JM. c!l'Rc.s~i,-[/ro,:\, Disease 136( 1):225-244. July 1987. ANDERSEN, P.. CHRISTENSEN. K.M. Serum antibodies to pigeon antigens in smokers and nonsmokers. Acta Medka Scumlina~~ic~u 2 13(3): 19 l-l 93. 1983. ANDERSEN, P.. PEDERSEN. D.F.. BACH. B.. BONDE. G.J. Serum antibodies and immuno- globulins in smokers and nonsmokers. C/irtic,o/ urrd E\prr-inrc,,ltcr/ /ntnrn,x>/o,q\, 37(2 ):467- 473. February 1982. ANDERSEN. P.. SCHONHEYDER. H. Antibodies to hen and duck antigens in poultry workers. Chid AIlergy 14(.5):421428, 1984. ANDERSON. H.R. Chronic lung disease in the Papua. New Guinea highlands. T/rt)x~r 34:647653. 1979. ANDO. M.. SUGIMOTO. M.. NISHI, R., SUGA. M.. HORIO. S., KOHROGI. H.. SHIMAZU. K.. ARAKI. S. Surface morphology and function of human pulmonary alvjeolar macrophagex from smokers and non-smokers. TIIo/.ur 39( I I ):SSO-856. 1984. ANTHONISEN. N.R. Lung Health Study. (Editorial.) Anwric~u,~ Rer,im c!fRr.spiruto~~v Disrusc~ 140(4):871-872. October l98Y. ANTHONISEN. N.R., WRIGHT, E.C., HODGKIN. J.E.. IPPB TRIAL GROUP. Prognosis in chronic obstructive pulmonary disease. Amer-icu/~ RelYebt, ofRe.spiru/or-x Diseuse 133: 14-20. 1986. ASHLEY. F.. KANNEL. W.B.. SORLIE. P.D., MASSON. R. Pulmonary function: Relation to aging. cigarette habit, and mortality. The Framingham Study. At~nu/.s of/r~fcmrr/ Mvdir inc, 82:739-74s. 197s. BABBOTT, F.L. JR.. GUMP, D.W., SYLWESTER, D.L.. MACPHERSON. B.V.. HOLLY. R.C. Respiratory symptoms and lung function in a sample of Vermont dairymen and industrial workers. Americun ./r~ur~~w/ of Pddic~ Heulth 70(3 ):24 I-245. 1980. BAHOUS, J., CARTIER. A.. PINEAU, L., BERNARD. C.. GHEZZO. H.. MARTIN. R.R.. MALO. J.L. Pulmonary function tests and airway responsiveness to methacholine in chronic bronchiectasis of the adult. Bn//~tjrr E(o-qx%r~ (1~ P/~~.sio~~trth,j/r)~/e Rcspir-atoire 70(4):375- 380. July/August 19X4. BAKE, B.. OXHGJ, H.. SIXT. R., WILHELMSEN. L. Ventilatory lunp function following two years of tobacco abstinence. S~~undirturiurt JOIII.II(I/ of'Re.spiru/og Di.sca.se.c S8(6):3 I I-3 IX. December 1977. BALLAL. S.G. Cigarette smoking and respiratory symptoms among Sudanese doctors. Etrst Afbicon Mcdic~ulJ~~~rrxul 6 I (2):95-l 03. February 10x4. BARTELIK. S.. ZIOLO. H.. BARTELIK. M. Physiological and biochemical blood parameters in non-smokers and tobacco smokers. PolsXi Txgod,~iX LeXursAi 39( I ):7-X. January 1983. BECK. G.J.. DOYLE, C.A.. SCHACHTER. E.N. Smoking and lung function. Antc,j.ic.rr/t Relie\c, of'Rc.spiru~c~r~, Di.\crr.tc l23( 2): I49- 15.5. February 19X 1 BECK. G.J.. DOYLE, C.A.. SCHACHTER. E.N. A longitudinal study of resptratory health in a rural community. ;Irnc,/.ic,tr!r Rc,~~im. ofRcspirotoy\~ Dircw.tc 125(4):375-3X 1. April 19X2. is I BECKLAKE. M.R.. PER.MUTT, S. Evaluation of tests of lung function for "screening" for early detection ofchronic obstructive lung disease. In: Machlem. P.T., Permutt. S. (eds.) T/w Llor,c irr T/xn.s/tiorr Betueot Hdrlr trrttl I)i.sc~ure. New York Marcel Decker. 1979. pp. 345-387. BELL. D.Y.. HASEMAN. J.A.. SPOCK. .4.. MCLENNAN.G.. HO0K.G.E.R. Plasma proteins of the bronchoalveolar surface of the lungs of smokers and nonsmokers. Anwrkc~n Rmicw ofRc,.spirutor~~ Di.rcusc, 123172%79. I98 I BEST. E.W.R. A Cu~ru~~iu~l .Strtd~ ofSnwXit~,g ottd Hro/t/z. Department of National Health and Welfare, Epidemiology Division. Health Services Branch, Biostatistics Diviston. Research and Statistics Directorate. Ottawa, 1966. p. 137. BODE. F.R.. DOSMAN. J.. MARTIN. R.R., MACKLEM. P.T. Reversibility of pulmonary function abnormalities in smokers. A prospective study of early diagnostic tests of small airways disease. Anrcric~u,l Jo~rmcrl of`Mrdicitw 5% I ):33-52. July 1975. BOLIN. J.F.. DAHMS. T.E.. SLAVIN, R.G. Effect of discontinuing smoking on Mecholyl sensitivity in asthmatic smokers. (Abstract. l Jo~mal of A//er,q~ UN/ Cliniwl Imntw~o/og~ 6it:207-208, 1980. BONINI, S. Smoking, IgE and occupational allergy. (Letter.) B/.irish Mrrlic,n/Jo~cr.r~ol Wt:5 I?- 5 13, February 13, 1982. BOSISIO. E.. GRISETTI. G.C.. PANZUTI, F.. SERGI. M. Pulmonary diffusing capacity and its components (DM and VC) in young. healthy smokers. Re.spirurion 40(6):307-3 IO. 1980. BOSSE, R., SPARROW. D.. GARVEY. A.J.. COSTA. P.T. JR.. WEISS. S.T.. ROWE. J.W. Cigarette smoking. aging. and decline in pulmonary function: A longttudinal study. Aj.c,hit,c.\ of En~~irxtmetltal Hrulrll 35(4):247-252, July/August 1980. BOSSE. R.. SPARROW. D.. ROSE, C.L.. WEISS. ST. Longitudinal effect of age and smoking cessation on pulmonary function. Anwr~ic~~n Rel,ierr, of`Re.spirufo/.\. Di.wn.sr~ I2?(~):37X-3X I . 1981. BOYD. G.. MADKOUR. M.. MIDDLETON. S.. LYNCH. P. Effect of smoking on circulattng antibody levels to avjian protein in pigeon breeder's disease. 7`/rorx1.\ 32:613452, 1977. BRIDGES, R.B.. WYATT. R.J.. REHM. S.R. Effect of smoking on pertpheral blood leukocytes and serum antiproteases. Er,,.ol7~cl,l./0111.11111 of`R~spir.uror~ Ditcwscs 66t Supplement 139):23- 33. 1985. BRODER. I.. MINTZ. S.. HUTCHEON. M., COREY. P.. SILVERMAN. F.. DAVIES. G.. LEZNOFF. A.. PERESS. L.. THOMAS. P. Comparison of respiratory variables in pram elevator wsorkers and civic outside workers of Thunder Bay. Canada. ;\ntc,r./c,cll~ Re\,icrc, of R~.spiraror:\ Discwe 1 I Y( 7): 193-203. February 1079. BROWN. N.E.. MCFADDEN. E.R. JR.. INGRAM. R.H. JR. .4trway responses to inhaled histamine in asymptomatic smokers and nonsmohers. Jortrtrol cfApp/ic,t/ Plr?sc~~lo,c!' 12c-1 t: 508-S 13. April 1977. BUCZKO, G.B.. DAY. A.. VANDERDOELEN. J.L.. BOUCHER. R.. ZAMEL. N. Effectr of cigarette smoking and shon-term smoking cessation on airway responsiveness to inhaled methacholine. Anwiwrr RrGm ofRe.\pir-cm,yv Di.wu.tt~ l2Y( I j: 12-I-l. January 19x4. BUIST. A.S..GHEZZO. H.. ANTHONISEN. N.R.. CHERNIACK, R.%l.. DUCIC. S.. MACK- LEM. P.T.. MANFREDA. J.. MARTIN. R.R.. MCCARTHY. D.. ROSS. B.B. Relationship between the single-breath N? text and qe. sex. and smoking habit in three North American cities. Anwrktrn Re~icti, of`Rc.sp~-otm:\ Disc~usa I2Ot2 ):305-3 I X. August I9 79. BUIST. AS.. NAGY. J.M.. SEXTON. G.J. The effect of smoking cessation on pulmonary function: A 30.month follow-up of two smohin g cessation clinics. Anro-rc U/I Rc~,~c,\c, of Respirc~rov~ Disetrse I2Ot4): 953-957. October 1979. BUIST. AS.. SEXTON. G.J.. NAGY. J.M.. ROSS. B.B. The effect of smohing cessatton and modification on lung function. Americ un Reiert~ of Ra.spivoror\~ Dr.wc/.w I I-h I t: I I S-122. July 1976. 352 BUIST. A.S.. VOLLMER. W.M. Prospective investigations in asthma. What have we learned from longitudinal studies about lung growth and senescence in asthma'? Chesr 9 I (Supple- ment):119S-126s. June 19X7. BURNEY. P.G.J.. BRITTON. J.R..CHINN. S..TATTERSFIELD. A.E.. PAPACOSTA.A.0.. KELSON. M.C.. ANDERSON. F.. CORFIELD. D.R. Descriptive epidemiology of bronchial reactivity in an adult population: Results from a community ctudy. Thor.cr\ 42( I ):3844. January 1987. BURROWS. B. An overview of obstructive lung di>ea\e\. Mcclictrl C/in/(.v cff Norrh Anwlc tl 65(3):455-47 1. May I YX I. BURROWS, B.. HALONEN. M., BARBEE. R.A.. LEBOWITZ. M.D. The relationship of serum immunoglobulin E to cigarette smoklnp. Amcric.c/t, Rc\~im of Re.\prrc~ro~;~ Di.wtr.ve 124 (5):523-525. November 1981. BURROWS. B.. HASAN. F.M.. BARBEE. R.A.. HALONEN. M.. LEBOWITZ. M.D. Epidemiologic observations on eosinophilia and its relation to respiratory disorder\. Americu~ Re~,ieti, of Rc.spirntoi;\~ Diseo,sc 1 22(5):709-719. November 19X0. BURROWS. B.. KNUDSON. R.J., CAMILLI. A.E.. LYLE. S.K.. LEBOWITZ. M.D. The "horse-racing effect" and predicting decline in forced cxpiratory volume in one second from screening spirometry. An~,,.rt,u,r Rc\?ew, ~!~RPs~JII-u~~/~~\~DI.T~~~I.sc 135(4):7X8-793. April 1987. BURROWS. B.. KNUDSON. R.J.. CLINE. M.G.. LEBOWITZ, M.D. Quantitative relation- ships between cigarette smoking and ventilatory function. AnwrYc~un R~I+cM, ofRe.cpiru'lor.> Disrcrsc 1 I S(2): 195-205. February 1977. BURROWS. B.. LEBOWITZ, A.D.. BARBEE. R.A. Respiratory disorders and allergy skin-test reactions. Ar,t~r/.s of/?~t(~).& Medicine 84(?): 134-l 39, February 1976. BURTON. R.C.. FERGUSON. P..GRAY. M., HALL. J.. HAYES. M.. SMART. Y.C. Effects of age. gender. and cigarette smoking on human immunorepulatory T-cell subsets: Estab- lishment of normal ranges and comparison with patients with colorectal cancer and multiple sclerosis. Diqnosfic Intmurzologq? 1(3):2 16223. 1983. CAMILLI. A.E.. BURROWS, B., KNUDSON. R.J.. LYLE. S.K.. LEBOWITZ. M.D. Lonei- tudinal changes in forced expiratory volume in one second in adults. Effects of smoking and smoking cessation. Americ~on Re\.ieti. oJ"Rr.spir~~fo~~ Dis~use 13%4):794-799. April 19X7. CAMNER. P., PHILIPSON. K.. ARVIDSSON. T. Withdrawal of ciparette smoking: A study on tracheobronchial clearance. Al-chives r,fEll\,ir.onmerlrcl/ Hwlfl~ 26:90-92. February 1973. CARSTENSEN. J.M.. PERSHAGEN. G.. EKLUND, G. Mortality in relation to cigarette and pipe smoking: I6 years' obsetvation of 25,000 Swedish men. ./olrr~trl of` Epiden~idr~gy urd Conmw~i~~ Health 4 I : 166 172. 1987. CASALE, T.B., RHODES, B.J.. DONNELLY. A.L.. WEILER. J.M. Airway responses to methacholine in asymptomatic nonatopic cigarette smokers. .lolcr-rzul of` Applied Ph~iolo,~~ 62(5):1888-1892, 19X7. CENTERS FOR DISEASE CONTROL. Chronic disease reports: Chronic obstructive pul- monary disease mortality-United States. 1986. Morhidiry UN/ Morrulity Wee/& Reporr 38(X ):549-552, August IX. 19x9. CERVERI. 1.. BRUSCHI.C..ZOIA.M.C..MACCARINI.L..GRASSI. M.. LEBOW1TZ.M.D.. RAMPULLA. C.. GRASSI, C. Smoking habit and bronchial reactivity in normal subject>. A population-based study. Amer-iwrr Rel,ien. ofRe.vpb-uroq .!li.wusc 140: I Y l-l 96. 1989. CHAN-YEUNG, M., VEDAL. S.. KUS. J.. MACLEAN. L.. ENARSON. D.. TSE. K.S. Symptoms. pulmonary function. and bronchial hyperreactivity in western red cedar worker\ compared with those in office workers. Anrericu/r RclYc~r, r/f Rr.rpi/uto,-v f>i.wu.se 130: 103% 1041. 19x4. COCKCROFT. D.W.. Rl!FFIN. R-E.. FRITH. P.A.. C.4RTIER. A.. JUNIPER. E.F.. DOLOVICH. J.. HARGREAVE. F.E. Determinants of allerpcn-induced asthma: Dose of allergen. circulating IgE antibody concentration. and bronchial re\pon\ivene\s to inhaled histamine. ,+w~./( tl,j Kc,\ icw o~~Rc~s/~/~zr/o,;v /Ii\cwsc~ 130: IOS3~105X. 1979. COMSTOCK. G.W.. BROWNLOW. W.J.. STONE. R.W., SARTWELL. P.E. Ciparettc smok- in2 and change\ in rwpiratory tindins\. :I,~cl~il~~~.\ ~/`E/II ir-/wtw~~/~/l H<~ultlr 2 1 ( I ):50-57. Jul) 1970. CORMIER, Y.. BeLANCER. J. The tluctuant nature of precipitating antIhod& in daiq farmers. Thwr~ 43:369173. 1 WY. CORRE, F.. LELLOUCH, J., SCHWARTZ. D. Smoking and leucocyte-counts. Results of an epidemiological survey. h7wt 2:6324,3-1. September 18. 197 1. COSIO. M.. GHEZZO, H.. HOGG. J.C.. CORBIN. R.. LOVELAND. M.. DOSMAN. J.. MACKLEM. P.T. The relations between structural changes in hmall airways and pulmonary- function tests. NCM. &r,qlur7tl .lourxctl of`Medic.ir~e 29X(33): 1277-I 3X I. June 8. 1977. DALES. L.C.. FRIEDMAN. G.D.. SIEGELAUB. A.G.. SELTZER. C.C. Cigarette smokinp and serum chemistry tests. Jorr7~77ul c$Chr-ourc, Di.scw.w.c ?7(6 ):293-307. August 1973. DANIELE. R.P.. DAUBER. J.H.. ALTOSE. M.D.. ROWLANDS. D.T. JR.. GORENBERG. D.J. Lymphocyte studies in asymptomatic cigarette smokers. A comparison between lung and peripheral blood. An7cric ~177 Rclicw of`Re.s~,ir.clt,jr-~ Di.srrr.w I 16:997- 1005. 1977. DAVIS. R.M.. NOVOTNY. T.E. The epidemiology of cigarette smoking and its impact on chronic obstructive pulmonary disease. Anwt~7c~trt7 Rrj.itw of` Rrspirolwy Di.sraw 140( Sup- plement):SX?-SX-l. I9X9. DEAN. G.. LEE, P.N.. TODD. G.F.. WICKEN. A.J.. SPARKS. D.N. Factors related to respiratory and cardiovascular symptoms in the United Kingdom. Jo77rr7c7/ ~4'Epideemro/o,q~ o77d Convnnrrit~ Hcu///7 32(2):X6-96. June I97X. DEMONCHY, J.C.R.. KAUFFMAN, H.F., VENGE. P., KOl?TER. G.H.. JANSEN. H.M.. SLUITER. H.J.. DE VRIES. K. Bronchoalveolar eosinophilia during allergen-induced 1ate asthmatic reactions. Anwic~un Rct.lm. ofRcvp~ruror;v Di.wu.w 13 1(3):173-376. March 19X5. DESHAZO. R.D.. BANKS, D.E.. DIEM. J.E.. NORDBERG. J.A.. BASER. Y.. BEVIER. D.. SALVAGGIO. J.E. Bronchoalveolar lavage cell-lymphocyte mteractions in normal non- smokers and smokers. Analysis wth a novel system. Awcric un RcIim. of Rcspir-urot.\ Discuse I27:535-548. I YX3. DIRKSEN. H.. JANZON. L.. LINDELL. S.E. lntluence of smoking and cessation of smoking on lung function. A population study ofclostng volume and nitrogen ua+out. .S~.unclitrrr\~r~rtr ./o~,,w/ o~~Rr,.\/,ir.trfor~~ Diwuws XS(Supplement ):266-273. 1973. DOCKERY. D.W.. SPEIZER. F.E.. FERRIS, B.C. JR.. WARE. J.H.. L0UIS.T.A.. SPIRO. A. III. Cumulative and rever\ible effects of lifetime smokinp on simple te\ts of lung function in adults. Anwir~m Rn,icu ,!f`RP.s/`r/.nro/,~ Discu.se 137:2X&-29I!, I98X. DODGE. R.R.. BURROWS. B. The prevalence and incidence of acthma and asthma-like symptoms in a general population sample. Anwric~m Rmiott. of`Rr.s/,ir-cllr,r? Di.seusc 122:567- 575. 1980. DOLL. R.. GRAY. R.. HAFNER. B.. PETO. R. Mortality in relation to smoking: I!? years' observations on female Brttijh doctorx Briti.\h MPdrc,a/ Jour~77ul 2X0(62 I9 ):967-97 I. April 5. 19x0. DOLL. R.. PETO. R. Mortality in relation to \mohing: 20 years' observations on male British doctors. British Mediwl .loww/ 3(605 I ):153,5-l 536. December 25. 1976. DOPICO. G..4.. REDDAN. W.. TSIATIS. A.. PETERS. M.E.. RANKIN. J. Epidemiologic study of clinical and physiologic parameters in grain handlers of northern United State<. Anwr-ic,ut, Rmim of'Rc.cpir-urot;v Disrnsr 130:759-765, I984. EBI-KRYSTON. K.L. Predicting I5 year chronic bronchitis mortality in the Whttehall i;tudy. .lowm~l ofEpidemio/o,qv ur7d Conmm~ir~ Health 33(2): 16X-l 72. June 1989. 354 EDELMAN, N.H., M1TTMAN.C.. NORRIS, A.H.,COHEN. B.H., SHOCK, N.W. Theeffects of cigarette smoking upon spirometric performance of community dwelling men. Amer-ic,un Reek of Respiraror;y Disease 94(3):42 i-429. September 1966. ENARSON, D.A., CHAN-YEUNG, M., TABONA. M., KUS. J.. VEDAL. S.. LAM. S. Predictors of bronchial hyperexcitability in grainhandlers. Chesr 87(4):452-455, April 1985. ENJETl, S.. HAZELWOOD. B., PERMUTT. S., MENKES. H.. TERRY. P. Pulmonary function in young smokers: Male-female differences. American Reviebr, of Respil-utol:\ Disease I 18:667+76, 1978. FANTA. C.H., INGRAM, R.H. JR. Airway responsiveness and chronic airway obstruction. Medical Clinics ufNiorfh Amerka 65(3):4734X7. May I98 I. FEINLEIB. M., ROSENBERG, H.M., COLLINS. J.G., DELOZIER. J.E.. POKRAS. R.. CHEVARLEY, F.M. Trends in COPD morbidity and mortality in the United States. American Revim ofiiespiratrq Disease I40( Supplement ):S9-S IX, 1989. FENNERTY, A.G., BANKS, J., EBDEN. P.. BEVAN, C. The effect of cigarette withdrawal on asthmatics who smoke. E~OZ)~EU)I Journul of Respiruror-y D~.sruse,s 7 I (5):395-399. November 1987. FERRIS. B.C. JR., ANDERSON. D.O. The prevalence of chronic respiratory disease in a New Hampshire town. Americun Review. of Respirutqv Diseases X6: 165-177, 1962. FERRIS. B.C. JR.. HIGGINS, I.T.T.. HIGGINS. M.W., PETERS. J.M., VAN GANSE, W.F.. GOLDMAN, M.D. Chronic nonspecific respiratory disease. Berlin. New Hampshire, l96l- 1967: A cross-sectional study. American Rel,ieut of Respirator-y Disease IO4(2):232-244. 1971. FERSON, M., EDWARDS. A., LIND. A.. MILTON. G.W., HERSEY, P. Low natural killer-cell activity and immunoglobulin levels associated with smoking in human subjects. Internatiorlul Journal ofcancer- 23:603409, 1979. FINKLEA, J.F., HASSELBLAD. V., RIGGAN, W.B., NELSON. W.C., HAMMER. D.I.. NEWILL, V.A. Cigarette smoking and hemagglutination inhibition response to influenza afternatural disease and immunization. Amerkan Rel~iew~ofRespirator~Diseuse 104(3):368- 376, September 1971. FINKLEA, J.F., SANDIFER, S.H., SMITH, D.D. Cigarette smoking and epidemic influenza. American Journal of Epidemiology 90(5):390-399, November 1969. FISHER, G.L., MCNEILL, K.L., FINCH, G.L., WILSON. F.D.. GOLDE. D.W. Functional evaluation of lung macrophages from cigarette smokers and nonsmokers. Jou/-nul of the Reticuloendothelial Snciefi 32(4):3 I l-32 I, October 1982. FLETCHER, C., PETO, R. The natural history of chronic airflow obstruction. British Medic,u/ Journal 1(9):1645-1648, June I, 1977. FLETCHER, C.M., ELMES. P.C., FAIRBAIRN, A.S., WOOD, C.H. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. British Medical Journal 5 1471258-266, August 29, 1959. FLETCHER, C.M., PETO. R., TINKER, C.. SPEIZER. F.G. The Nut~rul Hi.stor:v ofChr.onic, Brunchiris and EmphTsemu. An Eight-Year Stud! ofEu1.1~ Chronic, Obstructive Lto7,g Diseuse in Working Men in London. New York: Oxford University Press, 1976. FLETCHER, C.M., TINKER, C.M. Chronic bronchitis: A further study of simple diagnostic methods in a working population. British Medical Journal 5238: 149 1 -I 49X. May 27, I96 I FRANS, A., STANESCLJ, D.C.. VERITER, C.. CLERBAUX, T.. BRASSEUR. L. Smoking and pulmonary diffusing capacity. Scundirmr?un Journal c$Respiruto~? Diseases S6(3 ): 16% 183, September 1975. FRIEDMAN. G.D.. SIEGELAUB, A.B. Changes after quitting cigarette smoking. Circ.ll/urio/l 61(4):71&723. 1980. FRIEDMAN. G.D.. SIEGELAUB, A.B.. SELTZER. C.C.. FELDMAN. R.. COLLEN. M.F. Smoking habits and the leukocyte count. Arc+~i~,t~.r of'Eni~rl'orlmrrr/ul Health 26: 137-143. March 1973. GADEK, J.E., FELLS, G.A., CRYSTAL. R.G. Cigarette smoking induces functional anti- protease deficiency in the lower respiratory tract of humans, .%ience 206(4424): 13 15-l 3 16. December 1979. GADEK, J.E., FELLS, G.A., ZIMMERMAN, R.L., RENNARD. S.I.. CRYSTAL. R.G. Anti- elastases of the human alveolar structures: Implications for the protease-antiprotease theory of emphysema. Journal of Clinical Investigation 68(4):889-898, October 198 I. GALDSTON, M.. LEVYTSKA, V., SCHWARTZ. MS., MAGNUSSON, B. Ceruloplasmin. Increased serum concentration and impaired antioxidant activity in cigarette smokers, and ability to prevent suppression of elastase inhibitory capacity of alphat-proteinase inhibitor. American Relxieu' of Respirator?: Disease 129:258-263, 1984. GERRARD, J.W., COCKCROFT, D.W., MINK, J.T.. COTTON, D.J.. POONAWALA. R.. DOSMAN, J.A. Increased nonspecific bronchial reactivity in cigarette smokers with normal lung function. Amerkan Re\.iett' ofRespiratory Disease 122(4):577-581. October 1980. GERRARD, J.W., HEINER, DC.. KO. C.G., MINK, J., MEYERS, A.. DOSMAN, J.A. Immunoglobulin levels in smokers and non-smokers. Annals ofAl/rr 14:45-47. 1984. HOIDAL, J.R.. FOX, R.B., LEMARBRE. P.A., TAKIFF. H.E., REPINE, J.E. Oxidative metabolism of alveolar macrophages from young asymptomatic cigarette smokers. Increased superoxide anion release and its potential consequences. Ches/ 77(2. Supplement):27&27 I, February 1980. HOIDAL, J.R., FOX, R.B., TAKIFF, H.E., REPINE. J.E. Alveolar macrophages (AM) from young, asymptomatic cigarette smokers (CS) and nonsmokers (NS) use equal amounts of oxygen (OI-) and glucose ( I-`4C), but smoker AM make more superoxide anion. (Abstract.) American Review ofRespirarory Disease I 19(4, Supplement):222A. April 1979. HOIDAL, J.R., NIEWOEHNER, D.E. Lung phagocyte recruitment and metabolic alterations induced by cigarette smoke in humans and in hamsters. Amerir,an ReGeM. c!f Re.spiruto/-> Disease 126:548-552, 1982. HOLT, P.G. Immune and inflammatory function in cigarette smokers. Thoruv 32:23l-21Y. 1987. 357 HOLT. P.G.. KEAST. D. Environmentally Induced changes tn immunological function: Acute and chronic effects of inhalation of tobacco smohe and other atmospheric contaminants in man and experimental animals. Hoc /o?o/o~rc~r~/ /?rr.rcu`s -I I ( I ):205-7 16. March 1977. HORN. B.R.. ROBIN. ED.. THEODORE. J., VAN KESSEL. A. Total eostnophil counts in the management ofbronchtal asthma. IVL~M~EII,~/~/~~~~,/~~~/J.~~~I/~!~ML~~/I(~III~~ 29322): I 152-l 155. May 29. 1975. HUGHES, D.A.. HASLAM. P.L.. TOWNSEND. P.J., TURNER-WARWICK. M. Numerical and functional alterations in circulatory lymphocytes in cigarette smokers. C/,,~ic,u/ und E.\/w~inre/~rul Inmrow/o,~~ 6 I (2):459%466. AuXust 1985. HUGHES. J.A.. HUTCHISON. D.C.S.. BELLAMY. D.. DOWD. D.E.. RYAN. KC.. HUGH- JONES. P. The influence of cigarette smoking and its withdravval on the annual change of lung function in pulmonary emphysema. Q~tur.tt~r-/~ .lorr~-no/ of Medic i,rc 5 I(202): I I S-123. Spring! 19X2. HUHTI. E.. IKKALA. J. A IO-year follow-up study of respn-atory symptoms and ventilatory function in a middle-aped rum1 population. E~o~o~~eun ./onr.nu/ c$Rc~q~ircrrr~~~v Discuses 61( I ): 3345. February 1980. HUNNINGHAKE. G.W.. CRYSTAL. R.G. Cigarette smoking and lung destruction. Accu- mulation of neutrophils in the lungs of cigarette smokers. Anrer?c (I/I RclYw of Re.cpirufor~~ Disetrsc 12X(5):833-838. November 1983. HUNNINGHAKE.G.W..GADEK. J.E., KAWANAMI.0.. FERRANS. V.J..CRYSTAL. R.G. Inflammatory and immune processes in the human lung in health and disease: Evaluation by bronchoalveolar lavage. Anrcr-ic,ctrr J~~lrr~,la/ r!f`Purho/o,qr 97: 149-206. 1979. HYLAND. R.H.. KRASTINS. R.R.. ASPIN. N.. MANSELL. A.. ZAMEL. N. Effect of body position on carbon monoxide diffusing capacity in asymptomatic smokers and nonsmokers. An7wic~urr R~rien~ ,,~R~,.\/,i,.tr/or.~ Discuse I l7( 6): IO5S- 1053, June 197X. INGRAM. R.H. JR.. O'CAIN. C.F. Frequency dependenceofcompliance in apparently healthy smokers versus nonsmokers. B1r//f~ti/7 de Pk~.s/o/~/f/rlro/~/,~if~ Rc~pi7zuoi71~ 7( I 1: 195-z IO. January-February I97 I. INGRAM. R.H. JR.. SCHILDER. D.P. Association of a decrease in dynamic compliance with a change in gas distribution. Jorr7~7ul /f.+/~/ircl Plrv%o/qq 23(6):9 1 l-9 16. December 1967. JANOFF, A.. WHITE. R..CARP. H., HAREL. S.. DEARING. R.. LEE, D. Lung injury induced by leukocytic proteases. Antr7Ytu77 Jouu~u/ of`fufhrdo,~~~ 97~ I ): I I I -I 79. October 1979. JONES. J.G.. MINTY. B.D.. LAWLER. P.. HULANDS. G.L.. CRAWLEY. J.C.W.. VEALL. N. Increased alveolar epithelial permeability in cigarette smokers. I.(~hc.cr 1(X159):6=8. January I?. 1980. JOSEPH. M.. TONNEL. A.B.. C.4PRON. A.. VOISIN. C. Enzyme release and superouide anion production by human alveolar macrophaXes stimulated with immunoglobulin E. C/i~ric~ol~& E.\/win7r/rtf// /n7//777/7o/o,i'\~ 3o:`l I c-412. 19x0. KABIRAJ. M.U.. SIMONSSON. B.G.. GROTH. S.. BJORKLUND. A.. SirLOW. K.. LIN- DELL. S.E. Bronchial reactivity. smokinp. and alpha-I-antitqpsm. A population-based study of middle-aged men. Ar~/c/./c (,)r Kei~ic~n. ofR~r~.\/,ir.clto7.\. D7.wtr.w 126:X64-869. 19X2. KANNER. R.E.. RENZETTI. A.D.. STANISH. W.M.. BARKMAN. H.W:.. KLAUBER. M.R. Predictors of sumival m sub.jects with chronic airllow limitation. .A/?rr/-lc~fr/r .lolr/~/7fll 01 Mrclrc~it7e 74:249-255. February 19X3. KARK. J.D.. LEBIUSH. LI. Smoking and epidemic intluenra-like illness in female military recruits: A brief survq .&rir,/.ic.clrl ./~~/r,./rtrl off ~rh/,c, H&r/r 7 I(5 ~:53&532. May IYX I KARK. J.D.. LEBIUSH, M.. RANNOY. L. Cigarette smoking as a risk factor for epidemic A(H I N r ) influenza in young men. %c+i, E/7,gIt//7d ./o~tnm/ of .Mecl~~ I/W .307( I 7): 1042-l OJ%. October 2 I. 19X2. 35X KASZUBOWSKI. P.. WYSOCKI. J.. MACHALSKI. !vl. T-lymphocytes and their T-gamma and T-mu subpopulation\ in cigarette smokers. PoltXlc Arc,/rr\r,lrnr Mr~c!\`c:vr~~ H'e\+.rlc,,-:/lc,i 65(2):101-105, February 1981. KAUFFMAKN. F.. NEUKIRCH. F., KOROBAEFF. M.. MARNE. M.-J.. CLAUDE. J.-R.. LELLOUCH. J. Eosinophils. smoking. and lunp function. An epidemiologic survey among 9 I2 working men. Amv?c (I,[ RCI.;CM, ofRc.\pi,.c~tor-~ l1i.\~~/.sc~ 133(h): 1 l72- I 175. December 1986. KAUFFM.4NN. F.. QUERLEUX. E.. DROUET. D.. LELLOUCH. J.. BRILLE. D. Evoltition du vems en I2 ans et tabagisme chew 556 travailleur\ de la region parl\ienne. [Twelve year FEVl chan_ge\ and the \moLing habit\ among 556 uorkrrs In the ParI\ area.1 Rlf//frill Europc~e~~ de P /I~.\io/,l///lo/o~ic, Rcy~iru/oiw 15: 723-737. 1979. KILBURN. K.H.. WARSHAW. R.. THORNTON, J.C. A\besto\ drsease\ and pulmonq symptoms and sign\ in shlpjard worher\ and their familiz\ in Lo\ Angele\. A/-clril~c~.\ of l~~~er~w/ Medic iur 146:22 13-2220. November I YX6. KIVILOOG, J., IRNELL. L.. EKLUND. G. The prevalence of bronchlal asthma and chronic bronchiti\ in smokers and non-smokers in a representative local Shedi\h population. Sr,tr!l- dirlul,iut? .lo~tr~wl of Resprr-ciroyv Discwscs 55~262-276. 1973. KLEIN, R.C.. SALVAGGIO, J.E. Nonspecificity ofthe bronchoconstricting effect of histamine and acetyl-beta-methylcholine in patients with obstructive airway diseace. .lorr/.rztrl c!f'A//c,j.$> ?7(3):158-168. March 1966. KNOWLES. G.K.. TAYLOR. P.. TURNER-WARWICK. M. A comparison of antibody responses to admune inactivated influenza vaccine in serum and respiratory secretions of healthy non-smokers. healthy cigarette-smokers and patients with chronic hronchiti\. Bl.irr.tlr Jowd o~fDiseusc.c of /he Chest 75:2X-2'30. 19X I KNUDSON. R.J.. BLOOM. J.W.. KNUDSON. D.E.. KALTENBORN. W.T. Subclinical effects of smoking. Physiologic comparison ofhealthy middle-aged smokers and nonsmokers and interrelationships of lung function measurements. Chest X6:20-2Y. July 1984. KNUDSON. R.J.. BURROWS. B.. LEBOWITZ. M.D. The maximal expiratov flow-volume curve: Its use in the detection of ventilatory abnormalities in a population study. Anreric (I/I RerieM. ofR~s~irz/or:v Diseuse I 14(3):87 l-879. November 1976. KNUDSON. R.J.. KALTENBORN. W.T.. BURROWS. B. The effects of cigarette smoking and smoking cessation on thecarbon monoxide diffusing capacity of the lung in asymptomatic subjects. Ameriwn Re\,ien, ofiiespir-rrtory Disease 140(3):645+5 I . 1989. KORN. R.J.. DOCKERY. D.W.. SPEIZER. F.E.. WARE, J.H.. FERRIS. B.G. JR. Occupational exposures and chronic respiratory symptoms. A population-based study. Ametm~z Re1ieH. of Respir-utoy Diseuse 136:298-304, 1987. KOSMIDER. S.. FELUS. E., WYSOCKI. J. Evaluation of some humoral resistance deter- minants in cigarette smokers. Pols~i T~godnik Lekurrki 28(2):47-S& January 8. 1973. KRUMHOLZ, R.A., HEDRICK. E.C. Pulmonary function differences in normal smoking and nonsmoking, middle-aged. white-collar workers. Americ,un Rel,ieM. of`Re.~pirutorv Di.w~.w~ 107(2):225-230. February 1973. KUSAKA. H.. HOMMA. Y., OGASAWARA, H., MUNAKATA. M.. TANIMURA. K.. UKITA, H.. DENZUMI. N.. KAWAKAMI, Y. Five-year follow-upofMir,,-opo!\sl)or.u ,fueni antibody in smoking and nonsmoking farmers. Americnn Re\`ie~, of' Respil-utorv Drreose 140(3):695-699. 1989. LABEDZKI.L..MAGNUSSEN,H..HARTMANN. V.,LOOS,U.. MACKES.G.. SCHWABE. H.. BRAUMSCHWEIG. D., TIPPELMANN. G., FROST-HENSEL. E. Bronchoalveolar lavage in persons with lung disease: Cytology and macrophage function. P,.trti.v loul K/it,ik derf'n~wnologie 37( I ):832-X35. October 1983. LANGE. P., GROTH. S.. NYBOE. J., MORTENSEN. J.. APPLEYARD, M.. JENSEN. G.. SCHNOHR. P. Effects of smoking and changes in smoking habits on the declme of FEVt. EloYJpeu,7 Re.spirutor~~ .Jowxu/ 7:x I I-8 16. 19x9. LAURELL. C.-B.. ERIKSSON. S. The electrophoretic 1 -globulin pattern of serum in 1 -antitryp- sin deficiency. .S~~u/ldincll?o,? Jorlr.r?ol of`C/j/li~~u/ und Lhwu/or~~ In~~esri~qa~ion I5( 2 ): 133- 140. 1963. LEBOWITZ. M.D.. BURROWS. B. Quantitative relationships between cigarette smokmp and chronic productive cough. /77~r7~7tionc1/ ./07rr~7a/ ofEpidemio/qqy 6( 3): 107-I 13. 1977. LEEDER. S.R.. COLLEY. J.R.T., CORKHILL. R.. HOLLAND. W.W. Change in respiratory symptom prevalence in adults who alter their smoking habits. Amer~ico/7 Jmtrnal oj Epidemio/o,q~ 105(6):52'-529. 1977. LEITCH. A.G.. LUMB. E.M.. KAY. A.B. Mediatorsof hypersensitivity in the sputum of young. symptomatic cigarette smokers. C/btit,o/A//e/;q I 1:257-262, I98 I. LOURENCO. R.V.. KLIMEK. M.F.. BOROWSKI. C.J. Deposition and clearance of 2% particles in the tracheobronchial tree of normal subjects-Smokers and nonsmokers. Jm~mu/ of Clinicul /nw\ri,q7tiorl 50: I4 I I - 1410. I97 I MACKENZIE. J.S.. MACKENZIE. I.H.. HOLT. P.G. The effect of cigarette smoking on susceptibility to epidemic intluenza and on serological responses to live attenuated and hilled subunit influenza vaccines. J~7wnal ofHx,qie,lr 77(3):409417. December 1976. MALO. J.L.. FILIATRAULT. S.. MARTIN. R.R. Bronchial responsiveness to inhaled methacholine in young asymptomatic smokers. Jrwr.77ul ofApp/ird Ph~siolo~cp 52~6~: 1464 1470, June 1982. MANFREDA. J.. NELSON. N.. CHERNIACK, R.M. Prevalence of respiratory abnormalities in a rural and an urban community. Americ,clfi RE\.I'PH. ofRe.spirum~ Diseu.\e I l7:2 I S-216. 1978. MARCQ. M.. MINETTE. A. Lung function changes in smokers with normal conventional spirometry. An7r,.icn/1 Re\,reM, cfRe.sprru/or-x f~~.seuse I 14:723-73X. 1976. MARCUS. E.B., BUIST. A.S.. MACLEAN. C.J.. YANO. K. Twenty-year trends in mortality from chronic obstructive pulmonary dlsea\e: The Honolulu heart program. Amerrc,u77 Rc~~im ~~RE.~~J~I~uIoI~~ Di,sr~usc~ I JO(Supplement):S64-S68. 1989. MARTIN, R.R., LINDSAY. D.. DESPAS. P.. BRUCE. D.. LEROUX. M.. ANTHONISEN. N.R.. MACKLEM. P.T. The early detection of airway obstruction. Amerkm Re\w\t, c,f Re.~piruroi-\ Diserrsc I 1 I : I 19-l 15. 1975. MARTIN. R.R.. WARR. G.A. Cqarette smoking and human pulmonary macrophage\. Hi+- tal Ptxtic,c I39):97- 103. September 1977. MARTINEZ. F.D.. ANTOGNONI. G.. MACRI. F., BONCI. E.. MIDULLA. F.. DE CASTRO. G.. RONCHETTI. R. Parental smokiq enhances bronchlal responsiveness in nine-year-old children. Anler.ic ~,III Re,,ieM, ofRr~.~/7i,.c1t~~,.~ Di.wc~sc 13X:5 I X-523. 1 9x8. MASON. G.R.. USZLER. J.M.. EFFROS. R.M.. REID. E. RapIdly reversible alteration\ of pulmonary epithelial permeability induced bq \mokin_e. C/test 83 I ):6-l I. January 1983. MCCARTHY. D.S.. CRAIG. D.B..CHERNIACK. R.M. Effect of modification of thesmokmg habit on lung function. ;In?c~,.ic,o,r Rc~irw ofRe.\p/7-~7top Discc7.s~ I l-l( I ): 103-l 13. Jul\ 1976. MCSHARRY. C.. BANHAM. S.W.. BOYD. G. Effect of cigarette smoking on the antibody response to inhaled antisens and the prevalence of extrinsic allerLglc al\eolitls among pigeon breeders. C/i,~ic ul Al/e,.p~ I .5(5):1X7104. September 1985. MCSHARRY. C.. BANHAM. S.W.. LYNCH. P.P.. BOYD. G. .4ntibody measurement in extrinsic allergic alveoliti5. E~r~-opcu~ .101077~1/ o~~`R~,.cl~i/.rrror.~ Dr.\etrtes 65(4):25Y-165. Ma> 19x3. MCSHARRY. C.. WILKINSON. P.C. Cqarette jmohins and the antibody response to inhaled antigen\. In7n77~7rolog~ Todr~~ 7:9X-102, 1986. MICHAELS. R.. SIGURDSON. M.. THURLBECK. S.. CHERNIACK. R. Elastic recoil of the lung in cigarette smokers: The effect of nebulized bronchodilator and cessation of smoking. Americ~un Reviews ofRe.~pir~aror~~ Disease 1 19(5):707-7 16. May 1979. MILLER. A.. THORNTON. J.C.. ANDERSON. H.A.. SELIKOFF. I.J. Clinical respiratory abnormalities in Michigan. Prevalence by sex and smoking history in a representative sample of the adult population. Chest 94(h): 1187-l 194. December 19X8. MILLER, A.. THORNTON. J.C.. WARSHAW. R.. ANDERSON. H.. TEIRSTEIN. A.S.. SELIKOFF, I.J. Single breath diffusing capacity in a representative sample of the population of Michigan. a large industrial state. An~ericarr Re\,ic~~ of Rcspiwror~~ Disease 127(3 ):77O- 277. March 1983. MILLER, L.C.. GOLDSTEIN. G.. MURPHY. M.. GINNS. L.C. Reversible alterations in immunoregulatory T cells in smoking. Analysis by monoclonal antibodies and flow cytometry. Chest 82(5):5X-529, 1982. MlNTY. B.D.. JORDAN, C.. JONES. J.G. Rapid improvement in abnormal pulmonary epithelial permeability after stopping cigarettes. B~irislr Mcclic~ul ./o~~/xN/ 2X2: I 183-l 186. April I I. 1981. MORGAN, D.C.. SMYTH. J.T.. LISTER. R.W.. PETHYBRIDGE. R.J. Chest symptoms and farmer's lung: A community survey. &i/&/r ./or(/~ul c$//rcllr.sr,-r& Me&%re X)(3 ):X9-265. July 1973. MORGAN. D.C.. SMYTH. J.T.. LISTER, R.W.. PETHYBRIDGE. R.J.. GILSON. J.C.. CAL- LAGHAN. P.. THOMAS. G.O. Chest symptoms in farming communities with special reference to farmer's lung. Brir&Ir Jotcr-tzul of Indust,-iul Medic& 32(3):22X-234. August 1975. MUELLER. R.E., KEBLE. D.L.. PLUMMER. J., WALKER, S.H. The prevalence of chronic bronchitis. chronic airway obstruction, and respiratory symptoms in a Colorado city. Americun Review, ofRespiruror:v Disease 103:209-228, 197 I. NAGAI, A., WEST, W.W.,THURLBECK, W.M. TheNational Institutesof Health intermittent positive-pressure breathing trial: Pathology studies. II. Correlation between morphologic findings, clinical findings, and evidence of expiratoty air-flow obstruction. Anrel-ic,urr Re\?ev, ofRespiraror:v Disease 132(5):946-953. November 1985. NIELSEN, H. A quantitative and qualitative study of blood monocytes in smokers. Oo.o/Teu)r ./our-nal of`Respir~aror-x Diseases 66(5):327-332, May 1985. NIEWOEHNER. D.E.. KLEINERMAN, J.. RICE, D.B. Pathologic changes in the peripheral airways of young cigarette smokers. Nen. En&z& Jou,-no1 of Medicine 29 I( 15):755-7X October IO. 1974. NOBLE, R.C.. PENNY. B.B. Comparison of leukocyte count and function in smoking and nonsmoking young men. Infecrion and Immunir! 12(3):550-5.55. September 1975. O'CONNOR. G.T., SPARROW, D., WEISS, S.T. The role of allergy and nonspecific airway hyperresponsiveness in the pathogenesis of chronic obstructive pulmonary disease. Anrer-ic,art Rerienv of Respir-uroty Disease 140:225-252, 1989. ONARI, K., SADAMOTO, K., TAKAISHJ, M., JNAMJZU, T.. JKUTA, T., YORJOKA. N.. ISHJOKA, S., YAMAKIDO, M., NISHIMOTO, Y. Immunological studies on cigarette smokers. Part II. Cell mediated immunity in cigarette smokers and the influence of the water-soluble fraction of cigarette smoke (WSF) on the immunity of mice. Hiroshima ./rw/.na/ of Medical Science 29(2):29-34, June I, 1980. PAOLETTJ, P., CAMILLI. A.E., HOLBERG, C.J., LEBOWJTZ, M.D. Respiratory effects in relation to estimated tar exposure from current and cumulative cigarette consumption. Chcs/ 88(6):849-855, December 1985. PARKER, C.D., BILBO, R.E.. REED, C.E. Methacholine aerosol as test for bronchial asthma. Awhives of Irrternul Medicine I 15(4):452-458, April 1965. 361 PARNELL. J.L.. ANDERSON. D.O.. KINNIS. C. Cigarette smoking and respiratory infections in a class of student nurse\. RII~M. EII,~/(I& ./or~,.f?n/ of`Mpr/ir i77p 274( 1X):980-984. May 5, 1066. PAYNE. M.. KJELSBERG. M. Respiratory symptom<. lung function. and r;mokinp habits in an adult population. Anwic~m .Iown~/ ofP~rh/ic~ Heulth S4(2 ):Zh l-777. February 1964. PEAT. J.K.. WOOLCOCK. A.J.. CULLEN. K. Rate of decline of lung function in subjects with asthma. E7rrwpccu7 .lortr~r7a/ of-Rc~.~/`if.trro/~~ Di.w~.w~.~ 70( 3 ): I 7 l-l 79. March 1987. PETERS. J.M.. FERRIS. B.G. JR. Smoking and morbidity in a college-age group. Amrricur7 R~I%+I of RPS/J~~U~WJ Discw.rc 95(53:7X3-789. May 1967. PETO. R.. SPEIZER. F.E., COCHRANE. A.L.. MOORE. F.. FLETCHER. C.M.. TINKER. C.M.. HIGGINS. I.T.T.. GRAY. R.G.. RICHARDS. SM.. GILLILAND. J.. NORMAN- SMITH. B. The relevance in adults of air-now obstruction. but not of mucus hypersecretion. to mortality from chronic lung disease. Results from 20 years of prospective observation. An7c~ricor7 Rc~,im, c!fRerpircrror.~ Di.wase 12X(3):49 l-500. 1983. PHAM. Q.T.. MUR. J.M.. CHAU. N.. GABIANO. M.. HENQUEL. J.C.. TECULESCU. 0. Prognostic value of acetylcholine challenge test: A prospective study. BI-iris/f Jmr77rrl r,f /,7rlusrr~ict/ Medic ir7c 4 I :267-27 I, 1984. POLLARD. R.B.. MELTON, L.J. 111. HOEFFLER. D.F.. SPRINGER. G.L.. SCHEINER. E.F. Smoking and respiratory illness in military recruits. Arc~hi~~s of Et71~ir-otln7o7tol He1rltl7 30:533-537, 197s. POSTMA. D.S.. DE VRIES. K.. KOCTER. G.H.. SLUITER. H.J. Independent Influence of reversibility of air-flow obstruction and nonspecific hyperreactivity on the long-term course of luns function in chronic air-flow obstruction. An7c/.ic.(lf7 RCGPM~ of`Rc~.s/~i,.clfo/:\, Disrn.w 134(2):276-2X0. August 1986. POSTMA. D.S.. GIMENO. F.. VAN DER WEELE. L.T.. SLUITER. H.J. Assessment of ventilatory variables in survival prediction of patients with chronic airflow obstruction: The importance of reversibility. EU~YI/JW~I ./014777~1/ ,!f` Rc.\/J~~u/cu~\ Disrr~scs 67( 5 ):360&36X. November 1985. POUKKULA. A.. HUHTI. E.. MAKARAINEN. M. Chronic respiratory disease among worker\ in a pulp mill. A ten-year follow-up study. C/7cssr X1(3):285-289. March lYX2. PRE. J.M.. BLADIER. D.. BATTESTI. J.-P. Cytolo_eical and immunochemical reactions of human alveoli to tobacco aggression: Importance and characteristics. /RCS .low~nu/ oj Me&r u/ S~~icwc e. Biodwmisryv X(9):637-63X. 1980. PRIDE. N.B.. TATTERSALL, S.F.. BENSON. M.K.. HUNTER. D.. MANSELL. A.. FLETCHER. C.M.. PETO. R. Peripheral lung function and spirometry in male smokers and exsmokers. C/7cJ.s7 77(2. Supplement):2XY-290. February 19X0. RAMAN. A.S.. SWlNBURNE. A.J.. FEDULLA. A.J. Pneumococcal adherence to the buccal epithclial cell\ of cigarette smohcr\. Cl7cs7 X32-27. 19X3. RAMSDALE.E.H.. MORRIS.M.M..ROBERTS. R.S.. HARGREAVE.F.E. BronchIal respon- sivcnesj to methacholme in chronic bronchlti\: Relationship to airflow obstruction and cold air responsivene\\. Tlro/.tr.\ 39( I?):9 12-9 18. December 19X-I. RAMSDELL. J.W.. NACHTWEY. F.J.. MOSER. K.M. Bronchial hyperreactivit! in chronic obstructive bronchitis. Anrc~ric~trt7 Rc~~,ic,~c,ot'R~,.s/~i7.cltl~~-\, D7,tcww l26( 5):X29-832. November 1982. RAZMA. A.G.. LYNCH. J.P. III. WILSON. B.S.. WARD. P.A.. KUNKEL. S.L. Human alveolar macrophagr activation and DR antigen expression in cifaretre smokers. Chc,.\r X5(6. Supplement I:4 I S13.5. June 1984. REYNOLDS. H.Y.. NEWBALL. H.H. Aalysis of proteins and respiratory cells obtained from human lungs by bronchial lavage. ./oro.~rc~/ of`ltrhr~r.trt~~/-\~ o/1(/ Clitlic (I/ Mdic~rw X4(1):559- 573. October IY71. 362 RICHARDS. S.W.. PETERSON. P.K.. VERBRUGH. H.A.. NELSON. R.D.. HAMMER- SCHMIDT. D.E., HOJDAL. J.R. Chemotactic and phagocytic responses of human alveolar macrophages to activated complement components. /7$~Yio77 u77d /n?rmmify 43(2):77S-778. February 1984. RIJCKEN. B., SCHOUTEN. J.P., WEISS. S.T.. SPEIZER. F.E., VAN DER LENDE. R. The relationship of nonspecific bronchial responsiv,eness to respiratory symptoms in a random population sample. Americ~un RPI.I'cM, of'Re.spirator~v Disru.re 136:62-6X. 19X7. ROBERTSON. J.. CALDWELL. J.R.. CASTLE. J.R.. WALDMAN, R.H. Evidence for the presence of components of the alternative (properdin) pathway of complement activation in respiratory secretions. .Iri~rr& ofInvmrno/o~~ I l7(3 ):YOO-903. September 1976. ROBERTSON, M.D., BOYD. D.E., FERNIE. J.M.. DAVIS. J.M.G. Some immunological studies on coalvvorkers with and without pneumonoconio~is. Anwic~un Jow77d o~f/r7d7t,srri~7/ Medic,ine 4(3):467-476. 1983. ROGOT, E., MURRAY. J.L. Smoking and causes of death among U.S. veterans: I6 years of observation. P~thlic Neoltlt Repwts Y5(3):2 13-222. May-June I YXO. SAETTA. M., GHEZZO, H., KIM. W.D.. KING. M., ANGUS. G.E.. WANG. N.-S., COSJO. M.G. Loss of alveolar attachments in smokers: A morphometric correlate of lung function impairment. Amer-icat? Re\,ieH, of`liespirutoryv Diseuse 132:894-900. 19x5. SCHACHTER. E.N., DOYLE, C.A.. BECK, G.J. A prospective study of asthma in a rural community. Chesr 85(5):623430, May 1984. SCHENKER, M.B.. SAMET, J.M., SPEJZER, F.E. Effect of cigarette tar content and smoking habits on respiratory symptoms in women. Amel-ic,un ReCen, of Respirutog Di.seuse I25:68&690. 1982. SCHLESINGER, Z., GOLDBOURT. U., MEDALIE. J.H.. RISS. E.. NEUFELD. H.N.. ORON. D. Pulmonary function and respiratory disease among adult male Israelis. Variations by age and birth place. Isrue/ Jour-,ra/ r,f`Medicu/ Scienc,es X( 7):957-964. July 1972. SHARP, J.T., PAUL, 0.. MCKEAN. H.. BEST. W.R. A longitudinal study of bronchuic symptoms and spirometry in a middle-aged, male, industrial population, Anreric,nn Reriebc, of Respir-atop Disease I OS(5): I066 1077, November 1973. SIMANI, AS., JNOUE, S., HffiG, J.C. Penetration of the respiratory epithelium of guinea pigs following exposure to cigarette smoke. Luhorato,;v /!ri,e.rtj,qario,r 3 I( I ):75-X 1. July 1974. SIMONSSON. B.C., ROLF. C. Bronchial reactivity to methacholine in ten non-obstructive heavy smokers before and up to one year after cessation of smoking. Europeon Jour~7al of Respiratory Diseases 631526534, 1982. SMART. Y.C.. COX. J., ROBERTS. T.K.. BRJNSMEAD. M.W., BURTON. R.C. Differential effect of cigarette smoking on recirculating T lymphocyte subsets in pregnant women. Journul of lmmunolog,v l37( I ): l-3. July I, 1986. SNIDER, G.L. Chronic bronchitis and emphysema. In: Murray, J.F.. Nadel. J.A. teds.) Te.t-thook ofRespiruro,lv Medicine. Philadelphia: W.B. Saunders Co.. 1988, pp. 1069-l 106. SNIDER. G.L. Chronic obstructive pulmonary disease: A definition and implications of structural determinants of airflow obstruction for epidemiology. Americm7 Ret,iew, of Respirafor~ Disease. 140(3. Supplementl:S3-S8, September 1989. SPARROW, D.. O'CONNOR, G.. COLTON. T., BARRY. C.L.. WEISS, S.T. The relationship of nonspecific bronchial responsiveness to the occurrence of respiratory symptoms and decreased levels of pulmonary function. American Re\ie>t, ofRespir-urog Discvse 135: 12SS- 1260. 1987. SPEJZER, F.E., FAY. M.E., DOCKERY, D.W.. FERRIS. B.G. JR. Chronic obstructive pulmonary disease mortality in six U.S. cities. Anier-ic,un Re\.ieM. cf Respirurory Diseusr 140:s49-s55,1989. SPEIZER. F.E.. TAGER. I.B. Epidemiology of chronic mucus hypercecretion and obstructive airways disease. E@enrio/o,cir~ Rei,ien,s I :124-l 42. I97Y. 363 STEIN, R.. EVANS, S., MILNER. R.. RAND. C.. DOLOVICH. J. Isotopic and enzymatic IgE assays in non-allergic subjects. A/lrr.,qv 38(6):38%398. August 1983. SUCIU-FOCA. N., MOLONARO. A., BUDA. J., REEMTSMA. K. Cellular immune respon- siveness in cigarette smokers. (Letter.) Lancer I: 1062. May 25, 1974. TABONA, M.. CHAN-YEUNG. M.,ENARSON. D.. MACLEAN. L.. DORKEN. ESCHUL- ZER. M. Host factors affecting longitudinal decline in lung spirometty among grain elevator workers. Chert 85(6):782-786. June 1984. TAGER. I.B.. SEGAL, M.R., SPEIZER. F.E.. WEISS. S.T. The natural history of forced expiratory volumes-Effect of cigarette smoking and respiratory symptoms. Ameriml Rel,ieM, o$Respirafor~v Di.sca.w 138:837-838. 1988. TAGER. I.B., WEISS. S.T.. MUNOZ. A., ROSNER. B.. SPEIZER. F.E. Longitudinal study of the effects of maternal smoking on pulmonary function in children. Neu E/r,glondJolo.na/ of Medicine 309:699-703, September 22. 1983. TASHKIN. D.P., CLARK. V.A.. COULSON. A.H.. SIMMONS. M.. BOURQUE. L.B.. REEMS. C.. DETELS. R.. SAYRE. J.W.. ROKAW. S.N. The UCLA population studies of chronic obstructive respiratory disease. VIII. Effects of smoking cessation on lung function: A prospective study of a free-living population. Amz/.it.un Re\,ieM. cf Respiraror-y Disecrw I30(5):707-7 15. November 1983. TAYLOR. R.G.. GROSS. E., JOYCE. H.. HOLLAND, F.. PRIDE. N.B. Smoking. allergy. and the differential white blood cell count, Thora\- 40: 17-22. 1985. TAYLOR. R.G.. JOYCE. H.. GROSS. E.. HOLLAND. F.. PRIDE. N.B. Bronchial reactivity to inhaled histamine and annual rate of decline in FEVt in male smokers and ex-smokers. Thoruv 40:9-I 6. 1985. TECULESCL. D.B.. STANESCLI, D.C. Lung diffusing capacity. Normal values in male smokers and non-smokers usins the breath-holding technique. S~~m7dir7a\Yan /orrrr7ul r,f Re.spirufor.\ Diseuws 5 I (3 ): I 37- 149. I Y 70. THOMSON. M.L.. PAVIA. D. Long-term tobacco smoking and mucociliary clearance from the human lung in health and respiratory impairment. Arc~l~i~~ex of E77r,i7-o77nr~,,7fal Hrtrl7l7 26: 86-89. February 1973. THURLBECK. W.M. Chronic airflow obstruction in lung disease. In: Bennington. J.L. (ed.) .MujorProh/m7.s irl Pufl7o/o,g~. Volume 5. Philadelphia: W.B. Saunders Company. 1976. pp. 235-287. TOCKMAN. M.S., COMSTOCK. G.W. Respiratory risk factors and mortality: Longitudinal studies in Washington County. Macland. Anwr-ic~~~~7 Re~?r~n, of`R~~p/r~~~~/~~ Di.wuse I JO(Sp- pIement):S56S63. 1989. TOLLERUD.D.J..CLARK.J.W..BROWN.L.M..NEULAND.C.Y.. MANN.D.L..PANKIW- TROST. L.K.. BLATTNER. W.A.. HOOVER. R.N. The effects of cigarette smohinp on T cell subsets. A population-bawd survey of healthy Caucasians. AM,,-rc~trtr Re,~ie~ of Re.spiruto,:v Disc~c~sc~ I 39: I446 I I5 I 1989. TOWNSEND. M.C.. DLCHENE. A.G.. MORGAN. J.. BROWNER. W.S. Cigarette smoking intervention in the Multiple Risk Factor Intenention Trial: Results and relationships to other outcomes. Pulmonary function in relation to cigarette smoking and smohing cessation. Pf-cJ\.c171I'1~c Medic~ifie. in press. TRAVER. G.A.. CLINE. M.G.. BURROWS. B. Predictors of mortality in chronic obstructive pulmonary disease: A 15year follow-up study, Ilnw/~/c~c/,r Rc~rm ctf Rc.~/J~~u/cN~ Distwse ll9(6):895-902. June 1979. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. 717~ Hrwlth Co/7rcc/rrc,/rc~~.\ of .Sn7oXi77,14: Chro/iic Ohsrr~~tr~rrw Lw7g D/scc~.w. A Rrpwr oj thr Sirr,qmt7 Get7rr-ul. U.S. Department of Health and Human Services. Public Health Service. Office on Smohing and Health. DHHS Publication No. (PHS) X-l-50205. 1983. 364 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. T/~P Hrultl7 Co/7wq/to7ces ov Sn7oXir7g: Cunr~er and Chrot/ic, L~rn,q Di.wu.sc i/l the U'WX~IU~~C~. A Rc~Jo/-t of the S///;yeot/ Ge/7e/uI. U.S. Department of Health and Human Services. Public Health ServJice. Office on Smoking and Health. DHHS Publication No. (PHS) 85-50207. 198.5. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. 717~ Hcwlth Cons~~p~w~e.s c/j //71~c/lrr/7rur~ SnroXi/7~q. A Rep//T of' rlie Sri).,q~fon Ge/re/.uI. U.S. Department of Health and Human Services. Public Health Service. Centers for Disease Control. DHHS Publication No. (CDC) 87-839X. 1986. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Rcrl/rc~//7,g tk Hrolrh Co/7.w- yltc'r7c'es of Sn7oXi,7,g. 25 Yeurs of P/Yq/Y.s.s. A RC/JO/Y of 1171, S11/3co/7 Gc~r7c~wl. U.S. Department of Health and Human Services. Public Health Setvice. Centers for Disease Control. Center for Chronic Disease Prevention and Health Promotion. Office on Smoking and Health. DHHS Publication No. (CDC) X9-841 1. 1989. U.S. DEPARTMENT OF HEALTH, EDUCATION. AND WELFARE. T/re Hrc//rh CO//.\C~- ylrerrr'es ofSn7oXi/7g. A Re/Jo).f of rhe S///~,~tw/7 Go7~/u/. /Y7/, U.S. Department of Health. Education. and Welfare, Public Health Service. Health Services and Mental Health Ad- ministration. DHEW Publication No. (HSM) 7 l-75 13. 1971. U.S. DEPARTMENT OF HEALTH. EDUCATION. AND WELFARE. Sn7oXir7p n/7t/ H~ultl7. A Repoi.1 ofrhcSrr/yo/t G~/7cw/. U.S. Department of Health. Education. and Welfare. Public Health Service. Office of the Assistant Secretary for Health. Office on Smoking and Health. DHEW Publication No. (PHS) 79-50066, lY79. US. PUBLIC HEALTH SERVICE. S n7o rtr,q und Her/Irk. Repwr of/he Ad\,i.so~~ Conmitree X' lo rhe S/rrqeon Ger7eral of tlte P~thlic, Heulth .Ser~\,icr. U.S. Department of Health. Education. and Welfare. Public Health Service. Center for Disease Control. PHS Publication No. 1103. 1964. VAN DER LENDE. R.. KOK, T.J.. REIG. R.P., QUANJER. P.H.. SCHOUTEN. J.P.. ORIE. N.G.M. Diminutions de cv et de vems avec Ie temps: Index des effets du tabagisme et de la pollution de l-air. [Decreases in VC and FEVt with time: Indicators for effects of smoking and air pollution. ] B/r/let;// Eur-&en de Ph?siorutl7oloaie Rrspir-utoiw 171775-792. 198 I VAN GANSE. W.F.. FERRIS, B.G. JR., COTES. J.E. Cigarette smoking and pulmonary diffusing capacity (transfer factor). An7e/~`c~u/7 Re,,ieu, ofRespi/zrlo/;v Diseuse lOS( I ):3031. January 1972. VELLUTI, G.. CAPELLI. 0.. LUSUARDI. M.. BRAGHIROLI, A.. PELLEGRINO. M.. MILANTI. G.. BENEDETTI. L. Bronchoalveolar Iavage in the normal lung. First of three parts: Protein. enzymatic and ionic features. Respi/urio// 44(6):303-1 IO. November-Decem- ber 1983. VILLIGER, B.. BR0EKELMANN.T.. KELLEY. D..HEYMACH.G.J. III. MCD0NALD.J.A. Bronchoalv,eolar fibronectin in smokers and non-smokers. Anro~icun Rerie~~ of Revpir-uto/;\ Disease 124(5):652-654. November 198 I. VOLLMER. W.M., JOHNSON, L.R., BUIST. AS. Relationshipofresponse toa bronchodilator and decline in forced expiratory volume in one second in population studies. Anwrca// Review of Re.spi/ato/:v Disease 132: I 186-l 193, 1985. VOS-BRAT, L.C., RUMKE. P.H. Immunoglobuline concentraties. PHA reacties van lym- focyten in vittro en enkele antistof titers van gezonde rokers. Juur-bock \`a/7 KunXer-ortderx~ek en Kunket-hest/.ijdin~~ in Nederlund 19149-53, 1969. WARR. G.A., MARTIN, R.R. Chemotactic responsiveness of human alveolar macrophages: Effects of cigarette smoking. Infection and /mmu/7i~ 9(4):769-77 1, April 1974. WARR, G.A., MARTIN, R.R. Immune receptors of human alveolarmacrophages: Comparison between cigarette smokers and nonsmokers. .Im/~nul of the Rerj~.l~loe/7dorhelic/l .kier,v 22(3):181-187. September 1977. 365 WARREN. C.P.W.. HOLFORD-STREVENS. V.. WONG. C.. MANFREDA. J. The relation- ship berween smoking and total immunogJohuJin E levels. ./~~fo?rm/ f'f`A//cqv uJ~d c/iJJiC'O/ /,WJJJt/JOhJ~~ 69(4):37(2-375. 19X2. WEISS. S.T.. TAGER. J.B.. MUNOZ. A.. SPEJZER. F.E. The relationship of respiratory infections in early childhood to the occurrence of increased levels of bronchial responsiveness and atopy. AMT~UUJ Rcr,ie~, ~fR~,~pi~-rtf~JJ~~ Disc~se I.31 (4):573-57X. April 19X5. WEISS. W.. BOUCOT. K.R.. COOPER. D.A.. CARNAHAN. W.J. Smoking and the health of older men. JJ. Smoking and ventilatory function. Aw/J~I,~.T r~~`,J),i,.rnJnJP,J~u/ Healrh 7:538- 553. November 1963. WELTY. C.. WEISS. S.T.. TAGER. J.B.. MUNOZ. A.. BECKER. C.. SPEJZER. F.E.. JN- GRAM. R.H. JR. The relationship of airways responsiveness to cold air, cigarette smoking. and atopy to respiratory symptoms and pulmonary function in adults. A~JJ~J~UJI Re~k-t~ of Rcspiruror~\ D;.w~.w 130: 198-203. 19X4. WHITEHEAD. R.H.. HOOPER. B.E.. GRJMSHAW, D.A.. HUGHES, L.E. Cellular immune responsiveness in cigarette smokers. Lm~cvr 1(786X): 1232-1233. June IS. 1974. WJLHELMSEN. L.. ORHA. I.. TJBBLJN. G. Decrease in ventilatory capacity between ages of SO and 54 in representative sample of Swedish men. B,?rish Medicvl JOIIUJNJ 3:SS3-556. September 1969. WJLHELMSEN. L.. TJBBLJN. G. Tobacco smoking in fifty-year-old men. I. Respiratory symptoms and ventilatory function tests. Smndimn~iutJ JOUJYJOI I++` Respiruto,:v DiseuseJ 47:121-130. 1966. WJNGERD. J.. SPONZJLLJ. E.E. Concentrations of serum protein fractions in white women: Effects of age. weight. smoking. tonsillectomy. and other factors. C'/jttic,ul Chenrist~;v 37): 1310-1317. 1977. WOOLCOCK. A.J.. PEAT, J.K., SALOME. C.M.. YAN, K.. ANDERSON. S.D.. SCHOEF- FEL. R.E.. MCCOWAGE, G.. KJLLALEA, T. Prevalence of bronchial hyperresponsiveness and asthma in a rural adult population. Thortr.( 42:361-36X. 1987. WOOLF, C.R., SUERO. J.T. The respiratory effects of regular cigarette smoking in women. Anrf~~-ic~~~~r Rm.im. ~~fRr.~p~~~u~o~~~ Diseuse 103 1 ):26-37. January 197 I WOOLF. C.R.. ZAMEL. N. The respiratory effects of regular cigarette smoking in women. A five-year prospective study. Chesr 7X(5):707-7 13. November 1980. WRIGHT. J.L. Small airway disease: Structure and function. In: Hensley, M.J.. Saunders. N.A. (eds.) C/i!ticc// Epitkn~ido,y~ of`~l~rwric ~hsrr~~rc~tir~c~ f'dmt~J~u~~ Di.sea.sr. New York: Marcel Dekker. Inc.. 19X9. p. 55. WYATT. R.J.. BRIDGES. R.B.. HALATEK. D.G. Complement levels in cigarette smokers: Elev,ations of serum concentrations of CS. C9 and C I -inhibitor. JOUJYJ~~ c$ Clinic,tr/ tJ/~d LuhoJ~rtr~J~v /JJJ~JJJJJo/cJ,~~ 6: I 3 I-l 35. 19X I ZAMEL. N.. LEROUX. M.. RAMCHARAN. V. Decrease in lun~g recoil pressure aftercessation of smoking. AJJJCJ.~CYIJJ R~rerc, CJ~RC.S~~J-UJCJJ~~ Drscuse I I9(2):2OS-2 I I. February I Y7Y. ZAMEL. N.. WEBSTER. P.M. Amelioration de la dynamique du debit expiratoire apres at-ret du tabac. [Improved expiratory airflow dynamics with smoking cessation.] Bllllt~/l,l ~~rrq~crJr t/c PlrcsrrJ/,u/lJo/ogic Rc.\piruroir-c> 20: 19-23. 19X4. ZETTERSTRGM. 0.. OSTERMAN. K.. MACHADO. L.. JOHANSSON. S.G.O. Another smokinp hazard: Raised serum JgE concentration and increased rish ofoccupatronal allergy. Brirrsh Mcdrcd ./ouJ~JJo/ 783: I7 I S- I2 17. November 7. 19X I 366 CHAPTER 8 SMOKING CESSATION AND REPRODUCTION 367 CONTENTS PartI. Female ................................................... ..37 I PregnancyandPregnancyOutcome ................................ ..37 I Introduction ................................................. ..37 1 Pathophysiologic Framework ..................................... 37 I Nonexperimental Studies ......................................... 374 Fertility and Infertility ......................................... 374 Ectopic Pregnancy and Spontaneous Abortion ...................... 375 Fetal, Neonatal, and Perinatal Mortality ........................... 376 Birthweight and Gestational Duration ............................ 379 Introduction ................................................ 379 Continued Smoking .............. .`. .......................... 381 Cessation Before Conception .................................. 381 Cessation After Conception ................................... 383 Birthweight ............................................. 3X3 Preterm Delivery ........................................ 386 Complications of Pregnancy ................................... 387 Randomized Trials of Smoking Cessation During Pregnancy ............ 387 Prevalence of Smoking and Smoking Cessation During Pregnancy and Time Trends in Prevalence and Cessation ............................... 390 Introduction ............................................... ..39 0 Prevalence of Smoking and Smoking Cessation ..................... 390 Time Trends in Smoking and Smoking Cessation ................... 393 Estimates of Attributable Risk Percent .............................. 393 AgeatNaturalMenopause..........................................39 6 Introduction ................................................... 396 Pathophysiologic Framework ..................................... 396 Studies of Former Smokers ....................................... 39X PartII. Male ___..~ ~ ~. ................................... Introduction ................................. Pathophysiologic Framework .................... Sexual Activity and Performance ................ Sperm Density and Quality ..................... Conclusions ............... ..j ................. Referencer .................................... . . . . . . . . . PART I. FEMALE Pregnancy and Pregnancy Outcome Introduction Since the late 1940s. cigarette smoking during pregnancy has been linked with poor pregnancy outcome (Bernhard 1949; Athayde 1948). Adverse effects of smoking on pregnancy began to receive considerable attention after publication of the results of a study of 7,499 pregnant women in San Bernardino County, CA. in which the rate of prematurity, defined as birthwjeight less than 2.500 g. was found to be about twice as high among smokers as among nonsmokers during pregnancy (Simpson 1957). Early reports of the Surgeon General (US DHEW I97 I. 1973. 1978) concluded that maternal smoking during pregnancy retards fetal growth and is a probable cause of late fetal and infant mortality (US DHEW 1973). The 1977 Report of the Surgeon General (US DHEW 1978) concluded that smoking during pregnancy has dose-response relationships with abruptio placentae. placenta previa. bleeding during pregnancy. premature and prolonged rupture of the membranes. and preterm delivery. The 1979 and 1980 Reports of the Surgeon General (US DHEW 1979; US DHHS 1980) comprehensively reviewed information on the association of maternal smoking with pregnancy outcome and further concluded that the risk of spontaneous abortion in- creases with the amount of smoking and that the risk of sudden infant death syndrome (SIDS) is increased by maternal smoking during pregnancy. The 1980 Report (US DHHS 1980) also indicated the possibility of a link between cigarette smoking and impaired fertility. Two earlier reports of the Surgeon General (US DHEW 1979; US DHHS 1980) concluded that mean gestational duration is not affected by maternal smoking and that data are not sufficient to support a conclusion that maternal smoking increases, decreases, or has no association with risk of congenital malformations. This Section reviews observational studies of smoking cessation and the following reproductive outcomes: fertility and infertility; ectopic pregnancy and spontaneous abortion; fetal, neonatal, and perinatal mortality; birthweight and gestational duration: and complications of pregnancy. Three randomized trials of smoking cessation and pregnancy outcome are described and discussed in detail. Information on the prevalence of smoking during pregnancy and time trends in prevalence is presented, along with estimates of the attributable risk of several pregnancy outcomes. SIDS and congenital malformations are not considered because of the limited information on smoking cessation. Pathophysiologic Framework The effects of smoking that might mediate adverse effects on the developing fetus and on fertility, fetal loss, and pregnancy complications have been reviewed in other publications (Long0 1982; Mattison 1982: US DHHS 1980). These reviews are summarized with attention to the temporal course of the relation between exposure to 371 cigarette smoking and pregnancy outcome as well as the distinction between reversible and irreversible effects of smoking. Reversible effects would be espected to result in similar risks for never smokers and former smokers. whereas irreversible effects would be expected to lead to different risks in both current and former smokers compared with never smokers. Several pathways have been postulated by which tobacco smoke might adversely affect fertility (Mattison 1982) (Table I ). These include disturbance of hypothalamic- pituitary function, interference with motility in the female reproductive tract (Chow et al. 1988). and impairment of implantation, all of which are thought to be reversible consequences of exposure to absorbed chemicals in tobacco smoke (principally nicotine). It has also been suggested that smoking results in oocyte depletion through direct toxicity (Mattison 1980), which would have irreversible consequences for fertility. Chow and colleagues (1988) postulated that altered immune function (Hersey. Prendergast, Edwards 1983) may predispose smokers to pelvic inflammatory disease. which in turn can result in permanent scarring and occlusion of the fallopian tubes. Alterations in the neuroendocrine control of ovulation have been suggested to account for increased amenorrhea reported among smokers (Pettersson. Fries, Nillius 1973): this mechanism, as an effect of smoking on fertility. would be reversible. TABLE I.-Possible mechanisms for the effect of smoking on pregnancy and pregnancy outcome OUtCWlle Po\ublr mechant\m Hormonal effwth Impaired tubal motilir) lmpalrrd implantatton Ooq te drpkrion Altered lmmunit> Ieadmg to peI\ ic intlammator) di\ea\e spwltaneou\ ahntlon Reduced birth\rsight Mechanisms for an effect of cigarette smoking on apontaneou\ abortion have not been clearly defined. partly because so little i5 known about the pathophysiologic basis for spontaneou\ abortion. The cause\ of spontaneous abortion are broadly divided into genetic and nongenetic causes (Kline 19X-1). Because smoking seems to have its primary impact on chromo\omally normal spontaneous abortions (Kline 1984: Alber- man et al. 1976). nongenetic pathways are implicated for hmokinp (Table I ). 372 Most attention has been focused on the mechanisms mediating a reduction of fetal growth among smokers (Table 1). An indirect, nutritionally based mechanism in which smokers are postulated to eat less and gain less weight during pregnancy. thus delivering smaller infants, has been prominent in discussions of fetal growth retardation in smokers (Papoz et al. 1982: Rush 1974; Meyer 1978; Davies and Abernethy 1976). This subject has been reviewed in depth in previous reports of the Surgeon General (US DHEW 1979; US DHHS 1980) and more recently by other researchers (Werler. Pober. Holmes 198.5). Differences in weight gain do not entirely explain fetal growth retardation in smokers because differences in weight gain during pregnancy between smokers and nonsmokers are very small and have not been observed consistently and because a relationship between growth retardation and smoking persists after adjusting for mater- nal weight gain. In this context. however, the studies of weight gain in women who quit smoking during pregnancy are of interest. Pulkkinen (1985) found that women who quit smoking during the first trimester gained more weight than nonsmokers or continuing smokers (I .O vs. 1.3 kg average difference. respectively). Kuzma and Kissinger ( I98 I ) also found that women who quit smoking during pregnancy gained more weight compared with women who did not smoke during pregnancy (average difference of 4.7 kg) and women who smoked throughout pregnancy (average difference of 5.6 kg). Also, women who quit smoking before the onset of pregnancy were reported to gain more weight during pregnancy than nonsmokers or smokers ( I .3 kg and 0.9 kg average difference, respectively) (Anderson et al. 1984). Rush (1974) reported a reduction in weight gain of 0.12 pounds per week among continuing smokers compared with those who quit. This pattern may reflect the well-established tendency to gain weight following smoking cessation (Manley and Boland 1983: Rabkin 1984). as discussed further in Chapter 1 I. There are several hypotheses that attempt to explain the mechanism by which fetal growth is affected by cigarette smoking (Table I), but cigarette smoking is believed to impact on fetal growth through intrauterine hypoxia (Long0 1977). Carbon monoxide. a component of cigarette smoke, has the ability to cross the placenta and bind with the hemoglobin in both the mother and the fetus producing carboxyhemoglobin. Car- boxyhemoglobin reduces the ability of the blood to carry adequate levels of oxygen to the fetus. Smoking is also believed to cause vasoconstriction of the umbilical arteries. and therefore. impact on placental blood flow (Lehtovirta and Forss 1978; Naeye and Tafari 1983; Longo 1982). Cigarette smoking during pregnancy decreases the availability of oxygen to the fetus by both mechanisms. These mechanisms imply a reversible effect of cigarette smoking for fetal growth because normal function would resume shortly after nicotine or CO is cleared from the system. Support for the suggestion that these effects are reversible is derived from several sources. Davies and coworkers ( 1979) found that 48 hours of smoking cessation late in pregnancy increased oxygen availability to the fetus. ViSnjevac and Mikov (1986) found similarly low levels of carboxyhemoglobin (COHb) in mothers and newborns when the mother was a former smoker or never smoker; mothers who smoked during pregnancy and their newborns had high levels of COHb. 373 Mechanisms for the effects of smoking on neonatal. perinatal. and infant mortality are poorly understood. although the reduction in birthweight is often considered to be the mediating process. However. smoking appears to cause a shift in the distribution of birthweight without having much effect on mean gestational age (US DHEW 1979; US DHHS 1980), and shifts in birthweight distribution across different populations do not always produce corresponding shifts in mortality (Wilcox 1983: Wilcox and Russell 1983a.b). That gestational age is little affected by smoking, whereas birthweight is reduced at every gestational age. explains why small infants of smokers have a better prognosis than small infants of nonsmokers (Yerushalmy I97 I; MacMahon. Alpert. Salber 1966). Increases in perinatal mortality among smokers may result not from the reduction in birthweight, but rather from the modest increases in preterm delivery, very low birthweight, and specific pathologic conditions such as placenta previa and abruptio placentae. However, this has not been addressed explicitly in any study. Because the smaller smoking-related increases in less frequent, more severe outcomes parallel the pronounced smoking-related reduction in birthweight. birthweight serves as a useful empirical marker of smoking's harmful consequences. even if it is not the direct mediator of those effects. Nonexperimental Studies Fertility and Infertility Consistent evidence indicates that smokers have lower fertility than nonsmokers (Dal@ et al. 1987: Howe et al. 1985: Baird and Wilcox 1985; Hartz et al. 1987). as noted in the 1989 Report of the Surgeon General (US DHHS 1989). The studies that have assessed indicators of fertility in former smokers are summarized in Table 2. Pettersson. Fries. and Nillius ( 1973) studied secondary amenorrhea. one mechanism for reduced fertility, and found an increased prevalence among smokers. However. prevalence among former smokers was even higher than among continuing smokers. Hammond ( 196 I ) found that irregular menstrual cycles were more common among smokers than never smokers and that former smokers were at slightly lower risk than never smokers. Howe and colleagues (19X5) analyzed data on more than 4.000 women in a British cohort study. which assessed the safety of oral contraceptives. Compared with never smokers, women who smoked 20 cigarettes or more at entry into the study were twice as likely to be undelivered 5 years after ceasing contraceptive use with the intention of becoming pregnant. whereas former smokers had the same likelihood of being un- delivered as never smokers. Baird and Wilcox ( 1985) reported that the time period until pregnancy was the same for 3 I women who quit smoking in the year prior to attempting to conceive as it was for never smokers. Daling and coworkers (1987) conducted a large case-control study in Washington State and found that. compared with never smokers. the relative risk of primary tubal infertility was 1.7 among current smokers and 1. I among former smokers. Information 374 TABLE 2.-Summary of studies of fertility among smokers and former smokers Relatme mh of meawrr of fertlllt!" Reference Location Meaure ol fertilit! SlllddX\ Prttrrwm. Frm. NllliU\ t IY73) Sweden Secondary amenorrhea I.3 I .6 Hov.e et al. (10X5) Bad and Wilco\ (19X.5) England Minnewto 2.11h I (I 3.4 I .(I Ihlltlf er 31. t 19x71 Seartle Prtmq tuhd infertilit> `7 -. I .o Dalq! er 31. (lYX.5) Se;rttlr Secondary tubal infertilit) I .6 I.3 on secondary tubal infertility from the same study (Daling et al. 1985) revealed a smaller difference between current and former smokers. Although the study focused on prior induced abortion, data are presented that allow computation of crude odds ratios for current and former cigarette smokers. Current smokers had a I .6-fold increase in the risk of secondary tubal infertility. and former smokers had a I .3-fold increase in risk. It is difficult to assess the causal effect of smoking on tubal infertility independent of the effects of sexually transmitted diseases (STDs) known to co-v'ary with smoking in many populations. In summary, the data suggest that impairment of fertility measured as delay in time to conception is related to smoking near the time of attempting to conceive and that smoking cessation prior to conception returns fertility to that of never smokers. Conclusions about smoking and the risk of tubal infertility cannot be drawn because of concern about uncontrolled confounding. Ectopic Pregnancy and Spontaneous Abortion Tubal (ectopic) pregnancy occurs at about the same time in the reproductive process as fetal loss. However, the mechanisms are thought to be similar to those operating in tuba1 infertility and largely concern tubal motility and patency. Several reports indicate an increased risk of ectopic pregnancy in smokers (Campbell and Gray 1987: Mat- sunaga and Shiota 1980), but only Chow and associates ( 198X) examined the associa- tion with prior smoking in detail. In a case