vitamin BU levels reflect a disorder of cyanide detoxification. Cyanide
is a demonstrable ingredient in cigarette smoke (83, 132. 134, 138, l.&
153,1X).

Vitamin C

Venulet and Danysz (195, 196) have demonstrated that the vitamin C
level is significantly lower in the serum of women who smoke
cigarettes during pregnancy, compared to values for their nonsmoking
counterparts.

Research Issues

Nutrients and oxygen provided by the maternal circulation are
essential to normal fetal growth and development. It may be
anticipated that some alterations may be produced in the developing
fetus when the nutrients are accompanied by toxins in the inhaled
smoke of burning tobacco and paper and when carbon monoxide is
mixed with the oxygen. Some of the observed alterations may be
considered innocuous in themselves, but the evidence to date justifies
high priority investigation to determine whether they are indicators of
processes that are fundamentally dangerous to either the immediate or
long-term health of the fetus and the child.

A number of important questions relating to the possible biological
effects of tobacco smoke and its constituents on the fetus in utero and
the newborn infant remain unanswered. The ethical issue of experi-
ments in pregnant human subjects and newborn infants affects
further research. The problems of such studies are obvious but will not
be resolved in the foreseeable future. Mathematical models, while
useful, require considerable data based on human or animal studies.
Models, in addition, possess serious limitations and restrictions because
any mathematical abstraction encompasses only a very minute portion
of the finite world or a given problem. Thus, future progress in our
understanding of the effects of tobacco products in these areas of
investigation will require appropriate animal studies with extrapola-
tion to humans.

The research objectives are (1) to identify risk of perinatal loss or
damage in women who smoke during pregnancy, and (2) to define the
effects on the fetus and the new-born infant resulting from maternal-
ly-inhaled tobacco smoke.

In considering the epidemiologic, biologic, and pharmacologic facets
of the problem of cigarette smoking and its impact on fetal and infant
well-being, the following areas of study are suggested:

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Fetal Death

1. Do availabi? data sets confirm the evidence that maternal
smoking may lead to anoxic death in ,utero of a normal fetus in an
uncomplicated pregnancy?

2. Can the risk of such a death be calculated in terms of the mother's
capacity to offset the hypoxic stress of smoking by such mechanisms as
increasing hemoglobin or hematocrit; increasing cardiac output;
increasing placental ratio, surface area, and area of attachment; or by
other mechanisms?

3. Are there indications in existing data sets that anoxic fetal deaths
occurred in smoking mothers with, for example, anemia, poor cardiac
function, poor pulmonary function, poor general health, unfavorable
age (older), or low socioeconomic status?
4. Do these deaths occur more frequently in mothers who, besides
being heavy smokers, are anemic or live at high altitudes?
5. Do these deaths occur later in pregnancy when there is less reserve
capacity to supply oxygen because of the greater oxygen demand of
the larger fetus, the reduction of the placental ratio, and the reaching
of the natural limits of increase of hematocrit and cardiac output?
6. Can pregnant women at particular risk of anoxic fetal death if
they smoke be identified prospectively by measurement of exhaled CO
and carboxyhemoglobin, relating these levels to hematocrit, cardiac
output, and other tests of reserve capacity to increase oxygen supply to
the fetus?

7. Can pregnant women at particular risk of anoxic fetal death if
they smoke be identified by use of exercise testing during prenatal
care?

8. Do available data sets confirm the evidence that maternal
smoking during pregnancy causes fetal death by increasing the
incidence of abruptio placentae, other antepartum bleeding, and
related complications?
9. Do available data sets confirm the evidence that the above
complications occur more frequently among women with other risk
factors such as low socioeconomic status, older age, higher parity,
unfavorable previous pregnancy history, and more frequently the more
the mother smokes?

10. Are the higher incidences of placental complications and fetal
deaths among women who smoke due to poorer diet and lower levels of
vitamin C, vitamin BE, folic acid, and other substances that help to
maintain tissue integrity?

11. Is there a relationship between the increased incidence of vaginal
bleeding in the above cases and the pathological changes in placental
blood vessels from smoking women observed by Asmussen?
12. If there is a generalized effect of smoking on the integrity of
blood vessel linings and other tissues, what role does this play in the
bleeding and abruptio placentae observed in such cases?

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13. Can fetal death associated with maternal smoking and placental
complications be predicted by careful monitoring of any pregnancy
with signs of bleeding after 20 weeks of pregnancy?
14. Can these deaths be prevented by cessation of smoking,
supplements of vitamins and folic acid, and other treatment to
maintain fetal oxygenation?

Neonatal Death

15. Do available data sets confirm the evidence that maternal
smoking leads to neonatal death of otherwise normal babies by
increasing the occurrence of preterm birth?
16. What proportion of preterm deliveries of smoking mothers is
associated with a history of bleeding early in pregnancy?
17. What proportion of preterm deliveries of smoking mothers is
associated with premature rupture of membranes?
18. What is the relationship of maternal smoking to the incidence of
bleeding early in pregnancy and of premature rupture of membranes,
whether or not there is a preterm delivery and whether or not there is
a fetal or neonatal death?

19. Through investigation of characteristics such as age, parity,
socioeconomic status, and reproductive history, is it possible to identify
women who will be at particularly high risk of pregnancy complica-
tions and pregnancy loss if they smoke?
20. Besides the warning sign of bleeding, what other measurements
wiI1 help to identify the woman who must stop smoking in order to
maintain the pregnancy?

21. Will measurement of levels of carboxyhemoglobin, vitamin C,
vitamin BE, folic acid, and other indices help to elucidate the
mechanisms leading to bleeding and to premature rupture of
membranes among smoking mothers?
22. Is there evidence that the tensile strength of fetal membranes is
reduced if the mother smokes?

23. Is there evidence that amniotic fluid infection plays a part in the
smoking-related increase in the incidence of premature rupture of the
membranes?

24. Will elucidation of the mechanisms whereby maternal smoking
causes complications of pregnancy, early delivery, and neonatal death
help to persuade pregnant women to stop smoking-particularly if
they have bleeding early or late in pregnancy-and to persuade
obstetricians that cessation of maternal smoking is of crucial
importance for a successful pregnancy?

25. Will monitoring of exhaled CO levels in all prenatal care clinics
help to reverse the recent trend toward more frequent and heavier
smoking among young women?

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Spontaneous Abortion

26. Can the increased incidence of spontaneous abortion with
maternal smoking be confirmed by further studies, allowing for
measurement of dose-response relationships and an accurate estimate
of risk ratios?

27. Can the mechanisms of action be worked out, using the same
approach as has been done for perinatal mortality?
28. To what extent is a previous spontaneous abortion in a smoker
related to a subsequent unfavorable outcome of pregnancy if the
woman continues to smoke?

29. Is there an overall increase in the risk of spontaneous abortion as
a result of maternal smoking, or is the increased risk confined to
women already at risk for other reasons?
                    .

Preeclampsia

30. What is the mechanism linking smoking during pregnancy to a
reduced incidence of preeclampsia and toxemia?
31. Could components of this mechanism, if understood, be applied so
that the risk of preeclampsia could be reduced without incurring the
risks associated with smoking?

Sudden Infant Death Syndrome

32. Do existing data sets with postnatal follow-up confirm the
association of maternal smoking with an increased risk of SIDS?
33. Do the smoking mothers of SIDS victims have other signs of
impairment of their oxygen supply system such as anemia, heart
trouble, impaired pulmonary function, or high altitude residence, as
indicated in prenatal records?
34. Do the smoking mothers of SIDS victims have early or late
bleeding, premature rupture of the membranes, abruptio placentae, or
preterm delivery?

Long-Term Follow-Up

35. Can studies with long-term follow-up of growth and development
identify groups with smoking-related impairment of a serious nature
as opposed to very slight changes in overall means?
36. Could case-control studies using prospective long-term follow-up
data (such as that from the British Perinatal Mortality Study) identify
maternal smoking patterns and other prenatal factors associated with
the problems of physical, intellectual, and emotional development of
the children?

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Birth Weight and Placenta

37. To what extent does the reduction of birth weight of smokers'
babies represent a physiological adaptation to reduced oxygen
availability?

38. What are the combined effects on birth weight of maternal
smoking, anemia, and high altitude?
39. What are the combined effects of maternal smoking, anemia, and
high altitude on weight, shape, area and site of attachment, and
placental-fetal ratio?

40, How are these relationships affected by other maternal
antecedent factors, such as age, socioeconomic status, and previous
history?

41. Is the increased incidence of placenta previa with maternal
smoking and high altitude related to an adaptive increase in the
placental site of attachment?

42. To what extent do placental changes with maternal smoking
represent physiological adaptations to hypoxic and other stresses?
43. To what extent do placental changes represent pathological
effects of smoking and what is their role in unfavorable pregnancy
outcomes?

Experimental Studies

44. Can experimental studies of exposure to cigarette smoke or to
the components of cigarette smoke elucidate the mechanism of reduced
birth weight?

45. Is the smoking-associated reduction of fetal growth due to a
reduction in the rate of mitosis resulting in a decreased number of
cells?

46. Is the smoking-associated reduction of fetal growth rate due to a
decreased number of cells in some parts of the body but not in others?
47. Is the smoking-associated reduction of fetal growth rate
accompanied by deficiencies in learning ability, emotional develop-
ment, or physical growth?

Lactation and Breast Feeding

48. Does smoking inhibit milk production in humans? This question
could be approached through epidemiological and experimental
studies. Surveys of a large population of smoking and nonsmoking
women are desirable to correlate the number of cigarettes consumed
and the pattern of smoking with the amount of milk produced and the
concentration of nicotine and other constituents of smoke in milk
throughout the lactation cycle.

49. How does nicotine affect prolactin release, and can this
phenomenon be reversed? Appropriate experimental animal research

8-78


could provide the basis for understanding mechanism(s) of action and
the mapping of appropriate interventions.
50. How much nicotine is excreted in breast milk ingested by the
nursing infant? A well-planned pharmacokinetic study should be done
involving the mother-infant dyad.

51. Is it possible to determine the complete profile of other
components of cigarette smoke in breast milk? The answer to this
question will permit the identification of potential carcinogenic agents
and their degree of ingestion by the infants.

52. Does the interaction between nicotine and other drugs excreted
in breast milk affect the physiology of the infants? The presence of
DDT and henso(a)pyrene, inducers of the activity of drug-metabolizing
enzymes, may cause unexpected, subtle side effects in the growing
infant which may manifest at a later date.

Tobacco Smoke

53. To what extent does maternal smoking in humans affect
maternal and fetal blood catecholamine concentrations?
54. To what extent does maternal smoking affect uterine and
placental blood flow?

55. To what extent does maternal smoking affect fetal heart rate,
breathing pattern, electroencephalographic activity, or other parame-
ters that can he monitored (that is, dose-response relationships)?
56. To what extent does smoking marijuana differ in its effects on
the mother and fetus as compared with smoking tobacco in cigarettes?
57. To what extent are there interactions between the effects of the
major (and perhaps minor) components of tobacco smoke?
58. How can efforts to actively discourage smoking during pregnan-
cy he made more effective?
59. To what extent will smoking withdrawal during pregnancy result
in changes in infant weight, perinatal mortality, and long-term
sequelae?

Nicotine

60. How does nicotine affect ganglionic development in the embryo
and fetus?

61. What is the relationship between development of essential
hypertension and nicotine imprint on fetal development?
62. Does nicotine accumulation in the fetal adrenal glands, heart,
and kidneys modify development of these organs?
63. What is the effect of nicotine on the hormonal systems of the
adrenal and those organs regulating adrenal function?
64. To what extent is nicotine accumulation in the fetal kidney
involved in a possible antidiuretic hormone abnormality or other
complications in later development?

8-79


65. What factors are involved in prolonging gestational length in
laboratory animals?

66. Since nicotine modulates neurological function in adults at
several areas (central nervous system, skeletal-muscular, ganglia, and
so forth), how does it modify development and function?
67. To what extent does the effect of nicotine on neurological
function contribute to hyperkinetic syndrome in children?
68. What is the potential for nicotine metabolites being carcinogenic
in combination with benzo(a)pyrene?

Carbon Monoxide

69. To what extent are embryonic, fetal, or newborn tissues more or
less sensitive to the effects of carbon monoxide than those of adults?
70. How does exposure to carbon monoxide physiologically affect the
developing fetus or newborn?

71. To what extent do dose-response relationships exist for various
carboxyhemoglobin concentrations?
72. Does a "threshold" level result in adverse effects?
73. Does the fetus adapt to low CO concentrations, and if so, by what
mechanism?

74. To what extent does CO affect oxygen consumption by the fetus
or by individual organs?

75. How does the decrease in blood oxygen tension physiologically
affect oxygen availability to the fetal brain, heart, and other vital
organs?

76. To what extent do decreases in the mean partial pressures of
capillary oxygen affect cellular respiration?
77. How does increased carboxyhemoglobin concentration affect
tissue oxygenation?

78. To what extent are the patterns of growth, development, and
maturation of the central nervous system and other organ systems
interrelated and affected by chronic low-level carbon monoxide
exposure?

79. How does carbon monoxide affect developing neuroblasts?
80. To what extent does carbon monoxide increase the risk of
prematurity or adversely affect the rate of infant growth?
81. To what extent does the interference with fetal oxygenation
result in problems such as mental retardation, cerebral palsy, and
perhaps subclinical neurologic, intellectual, or behavioral deficits?
82. Can modifications significantly decrease carbon monoxide levels
in tobacco smoke?

83. Do the carbon monoxide concentrations encountered in associa-
tion with maternal smoking adversely affect the infant's physical or
psychomotor development?

8-80


84. What are the legal and regulatory considerations concerning the
maximum carbon monoxide exposure allowed for pregnant women and
newborn infants?

Polycyclic Hydrocarbons

85. To what extent does benzo(a)pyrene cross the placenta and enter
the fetus?

86. What is its distribution in the fetal organs and tissues?
87. To what extent do the benzo(a)pyrene concentrations encoun-
tered in smoking mothers affect the growth and development of the
fetal brain and other organs?

88. To what extent does benzo(a)pyrene have long term effects on
the developing embryo and fetus; that is, to what extent are fetuses so
exposed subject to the later development of neoplasms or malignan-
cies?

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8-93


9. PEPTIC ULCER DISEASE.

National Institute of Arthritis, Metabolism, and
      Digestive Diseases


CONTENTS

Epidemiology ............................................................. 5
Prevalence of Smoking in Persons with Peptic Ulcer
   Disease ............................................................ 5
Prevalence of Peptic Ulcer Disease in Smokers.. ....... 6

Course of Peptic Ulcer Disease.. ................................... 8
  Effect on Healing and Recurrence .......................... 8
  Effect on Mortality ............................................. 10

The Question of the Etiological Role of Smoking in Peptic
Ulcer Disease ........................................................ 11
  Gastric Secretion ................................................. 12
  Pancreatic Secretion ............................................. 14
Pyloric Reflux and Gastric Ulcer.. ......................... 16
Summary ........................................................... 16

Medical-Economic Implications .................................... .17

Conclusions .............................................................. .17

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18

LIST OF TABLES

Table I-Peptic ulcer prevalence in smokers and
nonsmokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . 7

Table 2.-Percentage of patients whose duodenal ulcers
were healed by endoscopic examination at 4 weeks . . . . . 10

Table %--Ulcer mortality of male cigarette smokers and
nonsmokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..lO

9-3


Epidemiology

For over half a century the medical literature has carried reports of an
association between peptic ulcer disease (PUD), including gastric ulcer
and duodenal ulcer, and cigarette smoking. Barnett (2) in 1927 was the
first to examine the epidemiological evidence for this suspected
relationship. Although he found that patients with duodenal and
gastric ulcer smoked more than controls, the difference was not
significant, and he concluded that the purported relationship between
smoking and PUD did not exist. However, the majority of subsequent
reports have found a significant association between smoking and
PUD. Some recent reviews of the older studies (3, 59, 60) present
support for the conclusions that (1) the prevalence of smoking is
increased in persons with PUD, and (2) both gastric and duodenal
ulcers are more prevalent in smokers than in nonsmokers. During the
past decade several studies have been published which support these
conclusions. These will now be considered.

Prevalence of Smoking in Persons with Peptic Ulcer Disease
Kasanen and Forsstroem (33) studied the stresses and habits of 100
patients with gastric or duodenal ulcer and found that 90 percent of
ulcer patients smoked compared to 60 percent of controls and that 61
percent of ulcer patients smoked one or more packs per day as opposed
to 36 percent of controls (p < .Ol). Smoking was the only variable
significantly related to ulcer in this study, as no relation to stress
(financial, work, or family) was found.

Monson (~38) studied 10,600 Massachusetts physicians and found that
those with gastric or duodenal ulcers smoked significantly more than
comparable control subjects. About 1.3 times as many duodenal ulcer
patients as control subjects smoked. He did not find a difference
between PUD patients and controls in years of smoking or in number
of packs per day smoked.

In a Danish study (32), 78 percent of PUD patients smoked compared
to 71 percent among controls, a difference which was not statistically
significant. Bock (6), in a South African study, found that 89 percent of
men and 45 percent of women with gastric ulcer smoked, but he did not
study a control group.

Doll (18), who has written extensively on the subject of smoking and
ulcer disease (17, 19), found a significantly increased frequency of
smoking in both duodenal and gastric ulcer patients as compared to
controls: gastric ulcer-91 percent smokers, control-79 percent
smokers; duodenal ulcer-35 percent smokers, control-81 percent
smokers (p < 0.01).
Although there is some problem in determining the adequacy of
controls in these studies, all five in which controls as well as ulcer

9-5


patients were studied (6, 19, d2? 33, 58) show a higher proportion of
smokers among ulcer patients than among controls.

Prevalence of Peptic Ulcer Disease in Smokers

We turn now to studies of the prevalence of PUD among smokers and
nonsmokers, which are described below and summarized in Table 1.

Edwards and coworkers (22) examined 1,753 men over age 59 in
regard to smoking and health. A history of peptic ulcer was present in
6.0 percent of nonsmokers and in 10.0 percent of cigarette smokers
(p < .Ol). Also, the prevalence of peptic ulcer increased with increasing
number of cigarettes smoked daily.

Higgins and Kjelsberg (28), in a large community health study in
Tecumseh, Michigan, discovered a greater frequency of peptic ulcer in
male and female smokers and ex-smokers than among nonsmokers (the
increased frequency reached statistical significance only in women).

The interrelationships among coffee, alcohol, and smoking were
examined by Friedman, et al. (23). They studied 36,656 men and
women, aged 30 to 59, 2,597 of them with a history of peptic ulcer
disease. They found that men who smoked had a 2.1-fold greater
frequency of ulcer disease than those who did not smoke, and women
had a l&fold greater frequency. The degree of smoking was evaluated
by looking at three variables: quantity, years of smoking, and
inhalation; all showed positive relationships with the frequency of
PUD. On the other hand, since neither coffee drinking nor alcohol
consumption was related to an increased occurrence of peptic disease,
they concluded that the association of cigarette smoking with PUD is
independent of any possible association between smoking and alcohol
or coffee consumption.

Similar results were found in a study of 4,000 Polish men and women
(31) in which the prevalence of PUD was evaluated. Among men,
ulcers were found with greater frequency in smokers and ex-smokers
than among nonsmokers; and, among smokers, the prevalence of ulcers
was greater in those persons who had smoked for more than 5 years
and in those smoking more than 14 cigarettes per day. Women smokers
did not show an increased frequency of PUD, but only `7 percent of
those studied were current smokers. Among women smokers, however,
PUD prevalence was higher for those with a longer smoking history
and for heavier smokers. On the other hand, in a study of 402
Czechoslovakian men with PUD (&3), smoking did not make a strong
contribution to a stepwise regression predicting the presence of PUD
(the data were not provided in the paper and therefore could not be
included in Table 1).

In the only truly prospective study &I), a 16 to 50-year follow-up
study using smoking history in college, PUD was found in 2.2 percent
of those who smoked in college as opposed to 1.5 percent of

9- -6


TABLE l.-Peptic ulcer prevalence in smokers and nonsmokers (no. per 100)

                                                            Current
      Reference           HOW      No. wth    Rates: age-      sex      cigarette
                 diagnosed      UlOeE.     adjusted                smokers

Non-        Ratio        Dose
smokers                 f=vJ~

Edwards, F. (1959) (2%`)
Higgins, M.W. (19%) (28)

Friedman, G.D. (1974) (23)

Jedrychowski, W. (1974) (31)

Patfenbarger, R.S. (1974) (41)
Goldbourt, U. (1975) (25)

Doctor
Doctor

Histq

Doctor

History
X-ray

143
100
47
15207
1w
1OlP
26b
389
395

no
yes
yes
Yes
yes
no
no
Yes
no

10.1         6.0         1.7'          Yes
7.1         5.2         1.4           -
28         1.4         2.0           -
12.2         5.8         2.P          yes
6.3         3.9         1.6          Yes
6.4         1.9         3.4           yes
.8         1.3          .6          Yes
2%         1.3         1.P          yes
10.2         6.2         1.6           no

    `Also. ratio > 1 within age and wcial class.
    *Not given -estimated, using total population and reported rales.
    ~Al.w. ratio > 1 within occupation.4 gmup.
    Smoking categories in college, ulcers developed in 16 to 60 year follow-up.
e