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78


CHAPTER 5


                   Pregnancy


Contents

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    83

Effect on Birth Weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    83

Effect on the Outcome of Pregnancy . . . . . . . . . . . . . . . . . . . .    83

Congenital Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . .    87

Cancer in Children Born to Smoking Mothers . . . . , . . , . . .    8'7
Long-Term Effects on Children Born to Smoking Mothers . .    88

Experimental Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    88
Summary  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    89

References  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    89

LIST OF TABLES

Table l.-Frequency of abortion and cigarette consumption    85

81


INTRODUCTION

The 1971 report, "The Health Consequences of Smoking" (23))
summarized the relationship between smoking and pregnancy as
follows :

Maternal smoking during pregnancy exerts a retarding in-
fluence on fetal growth as manifested by decreased infant
birth weight and an increased incidence of prematurity, de-
fined by weight alone. There is strong evidence to support the
view that smoking mothers have a significantly greater num-
ber of unsuccessful pregnancies due to stillbirth and neonatal
death as compared to nonsmoking mothers. There is insuf-
ficient evidence to support a comparable statement for abor-
tions. The recently published Second Report of the 1958
British Perinatal Mortality Survey, a carefully designed and
controlled prospective study involving large numbers of pa-
tients, adds further support to these conclusions.

New epidemiological, experimental, and pathologic studies lend
support to the foregoing statements.

EFFECT ON BIRTH WEIGHT

Analysis of data from more than 100,000 births has shown that
infants of mothers who smoke during pregnancy have a mean birth
weight of 6.1 ounces (173 grams) less than infants born to non-
smoking mothers (29). Several recent studies confirm this relation-
ship (1,2,6, 7,10,13,15,18,25).

EFFECT ON THE OUTCOME OF PREGNANCY

New studies have been published concerning the effect of maternal
smoking on the outcome of pregnancy.
Kullander and Kallen (IS) performed a prospective study in
Sweden involving 6,363 pregnant women. These women completed
several questionnaires during the course of their pregnancy, and
in this manner specific information was obtained on smoking habits
for the entire pregnancy. Forty-four percent of the women smoked
cigarettes during pregnancy and 97 percent of these smoked during
the whole pregnancy.

83


Stillbirths, neonatal deaths, and deaths occurring before one year
of age were recorded to determine a "total death risk." This risk
was approximately 60 percent higher for children born to smoking
mothers as compared to those born to nonsmoking mothers.

Deaths occurring before one week of age and also deaths taking
place between the age of one week and one year were significantly
more frequent in children born to smoking mothers. Among children
dying before one week of age, significantly more cases of abruptio
placentae were found in smoking mothers than in nonsmoking
mothers. The higher level of neonatal mortality in children born to
smoking mothers was confined to those weighing more than 2,500
grams. Live-born infants weighing less than 2,500 grams had
equally high neonatal mortality rates whether they were born to
smoking or nonsmoking mothers. The stillbirth rate was greater in
smoking mothers than in nonsmoking mothers, but the difference
was not statistically significant.

An overall increased risk of spontaneous abortion among smoking
women was found, but this was primarily due to an association be
tween unwanted pregnancy and smoking. The authors found that
significantly (P < .OOl) more women with unwanted pregnancies
were smokers than women with wanted pregnancies; in addition,
spontaneous abortions were significantly (P < .OOl) more frequent
among women with unwanted pregnancies than among women with
wanted pregnancies. When correction was made for the mothers'
acceptance of pregnancy, the contribution of maternal smoking to
spontaneous abortion was of only borderline significance.

Also in the Kullander and Kallen study (13)) a decreased fre-
quency of preeclampsia among smoking mothers was noted. Mater-
nal smoking had no effect on the mean Apgar score of surviving,
non-malformed children.

A prospective study from Sweden of abortions in 4,312 pregnan-
cies was reported by Palmgren and Wallander (17). Only those
women who smoked throughout pregnancy were considered smokers.
The lowest abortion rate was found among nonsmokers, 7.8 percent,
while the highest rate was found among heavy smokers, 14.5 per-
cent (table 1). The difference is statistically significant (P < .OOl) .
Heavier smokers appeared to abort earlier in pregnancy. A history
of previous abortion was obtained twice as often in heavy smokers
as in nonsmokers.

Yerushalmy reported in 1964 on pregnancies occurring in women
participating in the Kaiser Health Plan of the San Francisco-Oak-
land area (24). The 1971 report, "The Health Consequences of
Smoking" (23), commented in detail on that report. Recently,
Yerushalmy published data on 13,083 pregnancies occurring in this
plan between 1960 and 1967, which included the 6,800 cases pre-
viously reported. (24, 25).

84


TABLE L-Frequency of abortion and cigarette consumption.

Result
of the
pregnancy

Nonsmokers     510 cigarettes    >lO cigarettes       Total

Abortion          177          148          60         385
               7.8%        9.1%       14.5%       8.9%
Delivery        2,087       1,486         354       3,927
             92.2%       90.9%       85.5%       91.1%

Total          2,264       1,634         414       4,312

SOURCE: Palmgren. B., Wallander. B. (17)

As in the 1964 study, he again found an increase in the incidence
of low birth weight infants (less than 2,500 grams) among smoking
mothers. These small infants had a significantly lower neonatal
mortality rate and fewer congenital anomalies than the small in-
fants born to nonsmoking mothers. The neonatal mortality rate for
single, live-born infants born to white, smoking mothers was
11.3/1000, while that for single, live-born infants born to white,
nonsmoking mothers was ll.O/lOOO; the difference is not signifi-
cant.

Taylor analyzed Yerushalmy's data for the probability of fetal
death and found no difference between smoking and nonsmoking
mothers (22).

Some of these findings are different from those reported in the
other recent, large-scale prospective studies (5, 13, 17, 19)) and
some of the differences may be a consequence of the definition of
"smoker" used. In the study of Kullander and KBllen (13), multiple
interviews were performed during pregnancy which allowed more
precise separation of the pregnant women into smokers and non-
smokers. In the study reported by Palmgren and Wallander (17))
only those women who smoked throughout pregnancy were con-
sidered smokers. The British Perinatal Mortality Study (5)) which
was discussed in the 1971 report, "The Health Consequences of
Smoking" (El), defined "smokers" as those women who smoked
regularly after the fourth month of pregnancy. The smoking history
was obtained shortly after delivery of the infant.

In contrast, Yerushalmy (25) defined "smokers" as women who
were smoking one or more cigarettes a day during the pregnancy,
and "nonsmokers" as women who never smoked and those who
stopped smoking either before or during the pregnancy. Because
the smoking history was obtained only once, usually early in preg-
nancy, some of the women who were classified as smokers could
have gone through a significant portion of their pregnancy as non-
smokers, and similarly some of the women who were classified as


nonsmokers could have gone through a significant portion of their
pregnancy as smokers. If smoking by pregnant women increases the
risk of an unsuccessful pregnancy, an imprecise separation of preg-
nant women into smokers and nonsmokers would tend to diminish
the magnitude of any differences found. One Swedish study (13)
and the British Perinatal Mortality Study (5) seemed to be at vari-
ance in statements about the frequency with which smoking habits
vary from one portion of the pregnancy to another. If this is a cul-
turally determined phenomenon, there is no way of estimating the
extent to which it applies to the patients participating in the Kaiser
Health Plan described by Yerushalmy.
MacMahon, et al. (14) commented on Yerushalmy's analysis of
mortality rates in low birth weight infants. They observed that
there are ". . . factors that affect birth weight without influencing
mortality ; for example, females have lower birth weights than
males but not the higher mortalities that might be predicted for
them on that account. If cigarette smoking is another such factor,
the explanation of the higher weight-specific mortalities for non-
smokers becomes immediately clear : it is an artifact of the analysis.
It is meaningful to compare category-specific rates only when the
specification of the category has the same implication for each of
the populations compared."
Perinatal mortality rates were similar in infants born to smoking
and nonsmoking mothers in a recent prospective investigation of
1,300 pregnancies from New Zealand (1) . Women were classified
as smokers or nonsmokers during their first `booking" at an ante-
natal clinic, and this was not later amended. This method of classi-
fication is similar to that used in the Yerushalmy study.
Comstock, et al. (6, 7) have reported in 1967 and 1971 on the
relationship of maternal smoking to the outcome of pregnancy. In
their studies, all perinatal deaths and samples of live births occur-
ring during a lo-year period among children whose mothers were
residents of Washington County, Maryland, were matched against
the records of a special census based on a household interview taken
in 1963. Maternal smokers were defined as women who were smok-
ing in 1963 and who had started to smoke prior to the pregnancy in
question; maternal nonsmokers were women who denied ever hav-
ing smoked. When this study is compared to previously cited studies
(5, 13, 17')) the data on the smoking status of the mothers during
pregnancy are imprecise, which limits their value.
In the 1967 study (6), maternal smoking was associated with an
increased risk of mortality for the child, both in the neonatal period
and for several years thereafter; however, this effect was thought
to be related to factors such as adequacy of prenatal or postnatal
environment and care, rather than a direct effect of maternal smok-
ing. Stillbirth rates were similar for smokers and nonsmokers.


The more recently published study (7) includes a 32 percent
sample of live-born, low birth weight infants and a 3 percent sam-
ple of live-born, larger infants born during the lo-year period pre-
ceding the census. The total births represented by these samples
were 4,641 to smokers and 7,646 to nonsmokers. The neonatal mor-
tality rate, when adjusted for environmental and socioeconomic
factors, was approximately one-third higher among infants born to
smoking mothers than among those born to nonsmoking mothers
(7). The categories of asphyxia, atelectasis, and immaturity ac-
counted for the greater neonatal mortality among infants born to
smoking mothers as compared to those born to nonsmoking mothers
(7) *

CONGENITAL MALFORMATIONS

As noted in the 1971 report, "The Health Consequences of Smok-
ing" (zS), the possible teratogenic effect of maternal smoking has
not been adequately evaluated. Additional studies have been pub-
lished in the interim, but rather than investigating congenital mal-
formations in both stillborn and live-born infants, most of the recent
studies have dealt only with live-born infants.
Fedrick, et al. (8) analyzed data from the large British Perinatal
Mortality Study for the incidence of congenital heart disease in still-
born and live-born infants of smoking and nonsmoking mothers. An
incidence of 7.3/1000 births was found in infants born to smoking
mothers as compared to 4.`7/1000 births for infants born to non-
smoking mothers, a statistically significant difference (P < .OOl ) .
Kullander and Killen (IS) noted no teratogenic effect of maternal
smoking in children dying before one year of age or in children
surviving one year of age. However, they observed that published
studies have been too small to exclude this possibility.
In a study of perinatal death occurring in infants weighing more
than 1,000 grams, Bailey (1) found that maternal smoking did not
lead to an increased incidence of congenital anomalies.
Yerushalmy (25) reported only on live-born infants weighing
less than 2,500 grams and found significantly fewer (P < .02)
anomalies among infants born to smoking mothers.
Comstock, et al. (7) found fewer than the expected number of
Congenital anomalies among live-born infants of smoking mothers.

CANCER IN CHILDREN BORN TO SMOKING MOTHERS

Neutel and Buck (16) studied the relationship between maternal
Smoking during pregnancy and the development of cancer in the off-
spring. The ba+se population was obtained from the British and
Ontario Perinatal Studies and consisted of 89,302 babies who sur-

87


vived at least seven days. There were 65 cancer deaths and 32 can.
cer survivors in the period from birth to a minimum of 7 and a
maximum of 10 years of age. For cancer of all sites, the children
of smokers had a relative risk of 1.3. The authors concluded: "Al.
though these results make it most unlikely that in utero exposure to
tobacco smoke has a broadly carcinogenic effect on the fetus, a re-
sponse confined to one tissue or expressed over a narrow age range
cannot be ruled out."

LONG-TERM EFFECTS ON CHILDREN BORN TO
        SMOKING MOTHERS

Goldstein (9) analyzed data from the British Perinatal Mortality
Study to determine factors influencing the height of 7-year-old
children. In the 1958 study, information was collected on 16,994
singleton births. In 1965, heights were measured "to the nearest
inch" on 13,127 of these children who could be followed up. The dab
were analyzed for the influence of parity, birth weight, length of
gestation, maternal age, maternal height, social class, number of
younger siblings, and maternal smoking habits during pregnancy.
Allowance was made for the sex and age of the child at the time of
measurement. The author's conclusions included the following:
"After allowing for the other variables, the children of mothers who
smoked 10 or more cigarettes a day after the 4th month of preg-
nancy, are on average about 1.0 cm shorter at age seven than the
children of mothers who did not smoke."

EXPERIMENTAL STUDIES

Becker and Martin (3) continued their experiments concerning
the effect of nicotine on pregnant rats. Offspring of rats given nico-
tine weighed significantly less at birth than saline-injected controls.
There were fewer live births among the nicotine-injected rats.

Kelly and Roy (12)) using cinephotomicrography, demonstrated
that nicotine crosses the mouse placental barrier in amounts ade-
quate to produce a measurable cardiovascular response.

Stalhandske, et al. (21) studied the in vitro metabolism of nico-
tine in livers of fetal, young, and adult mice. Cotinine was found to
be the major metabolite at all ages investigated.

Using radioactive compounds, Sieber and Fabro (20) identified a
variety of drugs in the preimplantation blastocyst and in uterine
secretions of pregnant rabbits. In animals receiving dose levels of
nicotine comparable to that encountered in man, significant amounts
of radioactivity were found in the preimplantation blastocyet. A
markedly higher concentration of radioactivity was observed in
uterine secretion than in maternal plasma.


Juchau (11) studied the levels of benzpyrene hydroxylase in the
placentas of smoking and nonsmoking women obtained both early in
pregnancy and at term. This enzyme hydroxylates benzo (a) pyrene,
a carcinogenic hydrocarbon found in tobacco smoke. Previous stud-
ies had shown that placentas, obtained at term from smoking
women, have a greater ability to hydroxylate benzo (a) pyrene than
the placentas from nonsmokers (23). Juchau corroborated this, but
also found very low levels in placental tissues obtained from healthy
smokers during first trimester dilatation and curettage or hystero-
tomy for therapeutic abortion. This lack of significant placental
drug metabolizing activity during the first trimester was in-
terpreted as a possible hazard to the fetus, particularly if the sub-
stance were active in the unmetabolized form. Enzyme levels were
undetectable in placental homogenates of nonsmokers at 8 to 16
weeks gestation.

The carcinogenic effect on the newborn of rats receiving benzo-
(a) pyrene during the latter half of pregnancy was studied by Bulay
and Wattenberg (4). An increased incidence of pulmonary adenoma
and skin papilloma was observed.

SUMMARY

Maternal smoking during pregnancy exerts a retarding influence
on fetal growth as manifested by decreased infant birth weight and
an increased incidence of prematurity, defined by weight. There is
increasing evidence to support the view that women who smoke
during pregnancy have a significantly greater risk of an unsuccess-
ful pregnancy than those who do not.

PREGNANCY REFERENCES

(1) BAILEY, R. R. The effect of maternal smoking on the infant birth
   weight. New Zealand Medical Journal 71(456) : 293-294, May 1970.
(2) BEAL, V. A. Nutritional studies during pregnancy. Journal of the Amer-
   ican Dietetic Association 58(4) : 321-326, April 1971.
(3) BECKER, R. F., MARTIN, J. C. Vital effects of chronic nicotine absorption
   and chronic hypoxic stress during pregnancy and the nursing period.
   American Journal of Obstetrics and Gynecology llO(4) : 522-533,
   June 15, 1971.

(4) BULAY, 0. M., WATTENBERC, L. W. Carcinogenic effects of subcutaneous
   administration of benzo(a)pyrene during pregnancy on the progeny.
   Proceedings of the Society for Experimental Biology and Medicine
  135(l) : 84-86, October 1970.

(5) BUTLER, N. R., ALBERMAN, E. D. (Editors). Perinatal Problems. The
   Second Report of the 1958 British Perinatal Mortality Survey. London,
   E. and S. Livingstone Limited, 1969. 395 pp.
(6) COMSTOCK, G. W., LUNDIN, F. E., JR. Parental smoking and perinatal
   mortality. American Journal of Obstetrics and Gynecology 98 (5) :
   708-718, July 1, 1967.

09


(7) COMSTOCK, G. W., SHAH, F. K., MEYER, M. B., ABBEY, H. Low birth
    weight and neonatal mortality rate related to maternal smoking and
   socioeconomic status. American Journal of Obstetrics and Gynecology
    111(l) : 53-59, September 1, 1971.
(8) FEDRICK, J., ALBERMAN, E. D., GOLDSTEIN, H. Possible teratogenic ef-
    fect of cigarette smoking. Nature 231: 529-530, June 25, 1971.
(9) GOLDSTEIN, H. Factors influencing the height of seven year old children
    -results from the National Child Development Study. Human Biol-
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(10) GOUJARD, J., ETIENNE, C., EVRARD, F. Caracteristiques matemelles et
    poids de naissance. (Maternal characteristics and birth weight.)
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     1969.
(11) JUCHAU, M. R. Human placental hydroxylation of 3,Pbenxpyrene duri
    ing early gestation and at term. Toxicology and Applied Pharmacology
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(13) KULLANDER, S., KLLLEN, B. A prospective study of smoking and preg-
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(14) MACMAHON, B., ALPERT, M., SALBER, E. J. Infant weight and parental
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      November 1965.
(15) MURPHY, J. F., MULCAHY, R. The effect of age, parity, and cigarette
    smoking on baby weight. American Journal of Obstetrics and Gyne-
    cology 111(l) : 22-25, September 1, 1971.
(16) NEUTEL, C. I., BUCK, C. Effect of smoking during pregnancy on the risk
    of cancer in children. Journal of the National Cancer Institute 47 (1) :
    59-63, July 1971.
(17) PALMGREN, B., WALLANDER, B. Cigarettriikning oeh abort. Konsekutiv
    prospektiv undersokning av 4312 graviditeter. (Cigarette smoking and
    abortion. Consecutive prospective study of 4312 pregnancies)
    Llkarrtidningen 60 (22) : 2611-2616,197l.
(18) PETTERSSON, F. Medicinska skadeverkningar av tikning. Rijkning och
    gynekologisk-obstetriska tillstand. (Harmful clinical effects of smok-
    ing. Smoking and gynecological-obstetrical condition.) Social-Medi-
    cinsk Tidskrift Z(Special No.) : 78-82, February 1971.
(19) RUSSELL, C. S., TAYLOR, R., LAW, C. E. Smoking in pregnancy, maternal
    blood pressure, pregnancy outcome, baby weight and growth, and
    other related factors. A prospective study. British Journal of Pre-
    ventive and Social Medicine 22(3) : 119-126, July 1968.
(20) SIEBFX, S. M., FABRO, S. Identification of drugs in the preimplantation
    blastocyst and in the plasma, uterine secretion and urine of the preg-
    nant rabbit. Journal of Pharmacology and Experimental Therapeutics
    176 (1) : 65-75,197l.
(2.2 ) STALHANDSKE, T., SL~~NINA, P., TJALVE, H., HANSSON, E., SCHMITERL~W,
    C. G. Metabolism in vitro of 14C-nicotine in livers of foetal, newborn
   and young mice. Acta Pharmacologica et Toxicologica 27(5) : 363-
     380,1969.
(22) TAYLOR, W. F. The probability of fetal death. IN: Fraser, F. C.,
    McKusick, V. A. (Editors). Congenital Malformations. Proceedings
    of the Third International Conference, The Hague, The Netherlands,
   September 7-13, 1969. New York, Excerpta Medica, August 1970.
    pp. 307-320.


90


(28) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking.
   A Report of the Surgeon General: 1971. Washington, U.S. Departr
   ment of Health, Education, and Welfare, DHEW Publication No.
   (HSM) 71-7513, 1971. 458 pp.

(Z4) YEBUSHALMY, J. Mothers' cigarette smoking and survival of infant.
   American Journal of Obstetrics and Gynecology 88 (4) : 505-518,
    February 15, 1964.

(25) YERUSRALMY, J. The relationship of parents' cigarette smoking to out-
   come of pregnancy-implications as to the problem of inferring causa-
   tion from observed associations. American Journal of Epidemiology
   93(6) : 443-456, June 1971.

91


CHAPTER 6


           Gastrointestinal Disorders


Contents

Page

Highlights of Current Gastrointestinal Information . . . . . . .    98
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    98

95


GASTROINTESTINAL DISORDERS

The 1971 report, "The Health Consequences of Smoking" (4),
summarized the relationship between smoking and peptic ulcer as
follows :

Cigarette smoking males have an increased prevalence of
peptic ulcer disease and a greater peptic ulcer mortality ratio.
These relationships are stronger for gastric ulcer than for
duodenal ulcer. Smoking appears to reduce the effectiveness of
standard peptic ulcer treatment and to slow the rate of ulcer
healing.

Studies of the effect of smoking on gastric secretion in patients
with peptic ulcer and normal controls have produced conflicting re-
ports (4). Recently, Wilkinson and Johnston (5) reported a sig-
nificant inhibition of pentagastrin-stimulated gastric acid secretion
after cigarette smoking by normal volunteers, while Debas, et al.
(1) found no significant overall change. Wilkinson and Johnston also
studied patients with gastric and duodenal ulcers in whom a sig-
nificant inhibition of pentagastrin-stimulated gastric secretion was
observed after the patients smoked one or two cigarettes over a
Period of 10 to 15 minutes.
A study by Konturek, et al. (3) suggests that alterations in
pancreatic and biliary secretion may be responsible for the relation-
ship between smoking and peptic ulcer. Nicotine was infused in
mongrel dogs in doses corresponding to amounts absorbed from
smoking up to four cigarettes in one hour. In the pancreas, nicotine
inhibited the secretin-stimulated secretion of both fluid and bi-
carbonate, and the degree of inhibition was dose-related. Spontane-
OUs biliary secretion of bicarbonate was also depressed by the drug.
Nicotine had no effect on gastric secretion of acid, gastric mucosal
blood flow, or the mucosal barrier to hydrogen or sodium ions. This
inhibition of pancreatic and hepatic bicarbonate secretion may de-
prive the duodenum of sufficient alkaline secretion to neutralize gas-
tric acidity and may be one biomechanism linking cigarette smoking
and peptic ulcer.
Dennish and Caste11 (2) noted the clinical association between
cigarette smoking and heartburn. To investigate the biomechanism
of this relationship, lower-esophageal sphincter pressure determi-
nations were made before and after smoking in six normal male
volunteers. All of the volunteers were cigarette smokers. In each

97


subject after the onset of cigarette smoking, there was a rapid d+
crease in lower-esophageal sphincter pressure from the basal level.
This diminution in sphincter pressure persisted until smoking was
stopped, at which time the pressure returned rapidly toward nor.
mal. Mean basal pressure was 19.6 -C 2.1 (C 1 S.E.) mmHg. and
mean pressure during smoking was 11.4 2 2.2 mmHg. The differ.
ence between these pressures is statistically significant (P < .OOl),
No changes were noted when volunteers puffed on unlit cigarettes.
Variable responses were noted when volunteers smoked cigars and
pipes. The investigators concluded that cigarette smoking decrease
the effectiveness of the lower-esophageal sphincter as a barrier
against gastroesophageal reflux.

HIGHLIGHTS OF CURRENT GASTROINTESTINAL
           INFORMATION

In addition to the summary statement cited at the beginning of
this section, the following observations have been made:

1. A possible link between cigarette smoking and peptic ulcer has
been demonstrated in dogs in which nicotine was found to in-
hibit pancreatic and hepatic bicarbonate secretion. This
could lead to peptic disease by depriving the duodenum of suf-
ficient alkaline secretion to neutralize gastric acidity.

2. An investigation in human volunteers has suggested that
cigarette smoking decreases the effectiveness of the lower-
esophageal sphincter as a barrier against gastroesophageal
  reflux.

GASTROINTESTINAL DISORDERS REFERENCES

(1) DEBAS, H. T., COHEN, M. M., HOLUBITSKY, I. B., HARMKIN, R. C. Effect
   of cigarette smoking on human gastric secretory responses. Journal
   of the British Society of Gastroenterology 12: 93-96, 1971.
(2) DFNNISH, G. W., CASTELL, D. 0. Inhibitory effect of smoking on the
   lower esophagea! sphincter. New England Journal of Medicine
   284(20) : 1136-1137, May 20, 1971.

(9) KONTUREK, S. J., SOLOMON, T. E., MCCREICHT, W. G., JOHNSON, L. R.,
   JACOBSON, E. D. Effects of nicotine on gastrointestinal secretions.
   Gastroenterology 60 (6) : 1098-1105, June 1971.
(4) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking.
   A Report of the Surgeon General: 1971. Washington, U.S. Depart-
   ment of Health, Education, and Welfare, DHEW Publication No.
   (HSM) 71-7513, 1971. 458 pp.

(5) WILKINSON, A. R., JOHNSTON, D. Inhibitory effect of cigarette smoking
  on gastric secretion stimulated by pentagastrin in man. Lancet
  Z(`7725) : 628-632, September 18, 1971.

98


CHAPTER 7

Allergy