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.
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456


(4) BAKEa. F. D.. T~MA~OXI~. C. F. Carbon monoxide and avlan embryo-
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(8) BECKEB. R. F.. LII-TLK, C. R D.. 61x0. J. E. Experimental studies on
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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)<O.OOI) and 2.15 for fernaks
(P<O.OS). The mortality rntio for smokers (males and females com-
billed) was dose-dependent as measured by age at initiation of smoking
(fig. 1). The results of this study, in the contc.xt of the genetic and cul-
tural differences between Japanese and Western populations, provide
a significant confirmation of the association between cigarette smoking
ftnd gastric ulcer mortality.

Figure I.--Gastric ulcer mortality ratios of Japanese (men and women combined)
    by age at initiation of cigarette smoking (1966-1970).

  5.00

Nonsmoker

>25       <=        <I9
Age at initiatlon of cigarette smoking (years)

SOURCE: Hirayama. T. 161.

470


Alp, et al. (1) conducted a retrospective survey of 63s patients,
admitted to txvo -Lustralinn teaching lrospitals between 135-1 and 1963,
with chronic gastric ulcer confirmed by rorntgcnogrxpl~ic, rntloscopic,
or surgical examination. The findings in the patients were compared
with information a\-ailable about the South -1ustrali:in population
obtained at census in 1331 and 1961, and with a control group of 233
subjects matched for age and sex with the ulcer patients. Cigarette
use, a family history of peptic ulcer, domestic stress, and aspirin and
alcohol intake occurred significantly more frequently among ulcer
patients. Alp, et al. (Z) found that after surgical treatment, recurrence
of the ulcer WLS significantly more likely to recur among those patients
who continued to smoke, drink, and use aspirin (P<O.OOl).

Fingerland, et al. (5) compared the autopsy findinbr; from 76.5 males
rrith their smoking history. Th e autopsies xet-c performed without
selection during 1965 and 1966 at the University of Hradec Kralov6,
Czechoslovakia. Peptic ulcer -~-as significantly more frequent among
male es-smokers and male lifelong smokers than among male non-
smokers (P<O.O;?). Among males, a dose-response relationship was
found between estimated total cigarette consumption and the presence
of peptic ulcer at autopsy.

Cooper and Tolins (4) reported results from a retrospective study
of the relationship between cigarette smoking and postoperative com-
plications among 2:9SS males, admitted to I9 Veterans Administration
hospitals, for the surgical treatment of duodenal ulcer. Smoking his-
tory xas obtained for 1,441 of the men. and of these 273 were non-
smokers, 1,015 smoked cigarettes only, and 93 smoked cigarettes plus
a pipe and/or cigars. The authors found no evidence of an association
betrreen either the number of cigarettes smoked per day, or the number
of years of cigarette smoking, and postoperative complications, opera-
tive mortality, or length of hospital stay. They emphasized that their
results must be viewed Kith considerable caution and listed several
potential sources of bias. In addition, they noted, "* * * that these
results apply only to the immediate postoperative findings and do not
apply to the long-range effects of smoking upon the patient after
surgery for duodenal ulcer disease."

Experimental Stu&ee

Gastric Secretion

S-I-L-DIES IS Hrix~xs

Morales, et al. (IO, II) studied the effect of cigarette smoking on
gastric secretion in a group of 312 patients. The patients included 138

471


with duodenal ulcer, 93 with gastric ulcer, and Sl with other gastro-
intestinal disorders, who served as controls. Cigarette smoking was
significantly more frequent among the patients \Cth peptic ulcer than
among the controls.

The chronic eflect of smoking on gastricsecretion -was quite variable.
Male smokers among the controls and in the group with duodenal
ulcers had a significantly increased baseline acid output as compared
with nonsmokers in the same groups (P<O.O5). -%fter a subcutaneous
injection of histamine, only the group of male smokers with gastric
ulcers had a significant increase in acid output over the values obtained
for nonsmokers in the same group (P<O.O5). Among the smokers in
the control group, the relationship between gastric acid out.put and the
number of cigarettes smoked daily was dose dependent. No such rela-
tionship was obtained for either of the trro groups with peptic ulcers.

In these experiments, the acute effect of smoking on gastric secre-
tion was slight. In one set of experiments, n group of eight smokers
served as its o=n control. The smoking of two cigarettes prior to
collection of gastric juice had no significant effect on acid output as
compared to baseline values. After smoking two cigarettes and also
receiving a subcutaneous injection of histamine, the patients experi-
enced no significant change in gastric acid output as compared to
baseline values; 21 male patients, including members from the groups
with ulcers and controls, smoked one cigarette 1 hour after an intra-
venous infusion of histamine. A transient depression of gastric acid
output was noted as compared with the values obtained from nine
patients who did not smoke.

STUDIES IN AXMALS

Konturek, et al. (8) studied the effect of intravenous infusion of
nicotine on the formation of acute, experimental duodenal ulcers in
cats. The authors infused nicotine intravenously in doses comparabIe
to the smoking of four, eight, and 16 cigarettes per hour into catsin
whom near maximal gastric acid output had been stimulated with
intravenous pentagastrin. The investigators. found that nicotine in the
two lower doses had no effect upon the gastric acid output stimulated
by pentagastrin, but that the highest dose produced a significant de-
crease in response, due to a fall in both volume and acid concentration.
Nicotine alone failed to alter a negligible basal gastric secretion. In
control animnls (pentagastrin alone), duodenal ulcers were found in
eight of 10 animals. Nicotine at the txvo lower doses, in combination
with pentagastrin, produced ulcers in all 26 animals. At the inter-
mediate dose of nicotine, the mean ulcer area was twice that found in

472


the control group . At the hi,Thcst (lose of nicotine. peptic ulcers np-
peared in only two of six animals and the area of ulcer was reduced
compared to controls.

Shaikh, et al. (I$) studied th e acute and chronic ctfccts of sub-
cutaneously injected nicotine on gastric secwtion in rats. Under bnsai
conditions, the volume of gastric secretion eras initially depressed,
then stimulated, and depressed again as the dose of nicotine KEG
increased. Xcid output eras decreased over the entire range of nicotine
dosage. Pepsin output reflected a similar triphasic response to in-
creasing nicotine doses as did gastric secrebry volume. In the absence
of nicotine, pentagastrin stimulated gastric volume, acid, and pepsin
output. The injection of nicotine, in increasing doses, administered
simultaneously with pentxgastrin, resulted in a gradual decrease in
response for all parameters. Volume of gastric juice, acid output, and
pepsin output were all increased significantly by chronic exposure to
nicotine aIone. Based on an average smoking dose of nicotine, the dose
of nicotine employed in the chronic experiments corresponded to the
smoking of three to fire cigarettes per day.

Thompson, et al. (16) extended the study of rats described above
b_v studying the cflects of chronic nicotine injections in vngotomized
rats and rats with discrete lesions in the hypothalamus. In sham-
operated animals, chronic nicotine injections significantly increased
baseline volume of gastric juice, acid output, and pepsin output. FoI-
lowing vagotorny, the nicotine response was completely suppressed.
Caudal hypothalamic lesions did not influence the response to nicotine
in the presence of intact vagus nerves. Anterior hypothalamic lesions,
ranging from the anterior hypothalamic area to the ventromedial
h>-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<O.Ol). Smoking, horrever, did not further depress
the response to secretin (figs. 2 and 3).

Solomon and Jacobsen (15) reviexed some possible mechanisms
whereby the increased prevalence and mortality from duodenal ulcer
among cigarette smokers might be produced. They concluded that
evidence from studies in animals, coupled with the findings of Bynum,
et al. (a), supported the hypothesis that the mechanism active in
humans involves impaired neutralization of acid secondary to the
inhibition of pancreatic bicarbonate secretion.

Figure 2.-Effect of cigarette smoking on volume of secretin-stimulated pancre-
       atic secretion in humans.

MeanOY'"me
MeanOY'"me  2.5
         2.5
paff"ucrw;c 2.0
paff"ucrw;c 2.0
milliliters 1.5
milliliters 1.5
per kilogram
per kilogram
body weight 1.0
body weight 1.0

1       2.4

1 ~~gnlflc.ntly dinerant from nonsmoking test within group of light smokers (P <O.OOl).
I Signmc.ntiy different from nonrmoklng controls (P <O.Ol).

SOURCE l3ynUm. o ? ai. 0)

474


Figure 3.-Effect of cigarette smoking on secretin-stimulated pancreatic blear.
      bonate output in humans.

12

10

Mean hourty a
output of
bicarbonate 6
    in
milliequiva- 4
tents per hour
          2

0

i

a.4

1 Sqnifbcantly dufferent from nonsmoksng test wilhin group of light smokers (P <O.oOl).
1 Significantly different from nonsmoking conlrols (P 40.01).

SOURCE Eynum. at al. (3).

Konturek, et al. (7) extended his research on the mechanism of
nicotine-induced inhibition of pancreatic secretion in the dog, using
the design previously employed (9). Infused secretin alone led to a
sustained increase in pancreatic bicarbonate output. Intravenous nico-
tine, at all four doses of infused secretin, produced a significant in-
hibition of pancreatic volume and bicarbonate output (P <0.05).
                                                       -
Infused nicotine appeared to inhibit competitively the elect of secre-
tin on pancreatic secretion of fluid and bicarbonate. Topical (intraduo-
denal) nicotine failed to affect significantly the response to infused
secretin. Stimulation of endogenous secretin by an acid infusion into
the duodenum produced the expected pancreatic secretory response.
Sicotine either applied to the duodenal mucosa or injected intra-
venously significantly inhibited the pancreatic secretory response to
rndogcnous secretin. Sicotine had no significant effect on total pancrea-
tic protein output. Nicotine did not alter the cholecystokinin-induced
stimulation of pancreatic secretion. The authors concluded that nico-
tine may inhibit pancreatic secretion of fluid and bicarbonate both

475