lov

Premature by

TABLE 3.—Maternal smoking and prematurity
(Figures in parentheses are the absolute number of premature births)

 

 

 

 

 

 

 

 

 

 

 

Author, —————— Percent of premature infants Mean duration of pregnancy
reference Duration of a Comments
Weight gestation Nonsmokers Smokers Nonsmokers Smokers
Yerushalmy <514 lbs. 5.9 (36) 8.1 (30)
(54).
Murdoch <2,500 g. 3.3 (8) 13.6 (35)
(30).
O’Lane <2,500 g. 5.1 (29) 11.8 (55)
(33).
Zabriskie <2,500 ge. 3.83 (40) 9.93 (95) Cigarettes
(58). per day: Prematurity
<10 ........ 6.54 (260)
10-20 - 9.11 (395)
20-30 ......14.39 (264)
>30 ........10.53 (38)
Yerushalmy <5 Ibs. $ oz. White .. 3a (112) 6.4 (188) (p<0.01) Infants of smoking mothers
(54). Negro . 49 (46) 18.4 (64) weighed less than infants of
nonsmoking mothers in each
gestational age.
<(37 weeks White pee cease  T5.9 (188) 6.5 (140) + Difference between smokers and
Negro .. 13.4 (125) 16.7 (80) nonsmokers not significant.

McDonald <2,500 g. Cigarettes per day
and 4.6 (4) <10 48 (2)

Lanford >10 8.3 (A)
(26).

Peterson <2,500 g. Cigarettes per day Overall incidence of prematurity
etal, 2.5 (111) 1-10 3.0 (35) in smokers vs. nonsmokers
(34). 11-20 4.8 (80) significant at p<0.001.

(16)

>20 3.4

 
cor

TABLE 3.—Maternal smoking and prematurity (cont.)
(Figures in parentheses are the absolute number of premature births)

 

Premature by

 

 

 

 

 

 

Author, Percent of premature infants Mean duration of pregnancy
reference Duration of Comments
Weight gestation Nonsmokers Smokers Nonsmokers Smokers

Peterson <87 weeks Cigarettes per day

et al., 1.3 (58) 1-10 1.4 (16)
(contd.) 11-20 2.3 (38)
(34). >20 2.4 (11)

Robinson <2,500 g. 16.5 (152) 31.0 (181)
(37).

Underwood <2,500 g. Cigarettes per day Percentages and absolute num-
etal., Group: ber of premature births are
(50). I 4.5 (108) <10 4.2 based on 16,158 pregnancies

10-20 5.9 recorded in 4,440 women.
<20 7.2 Group I. Smokers vs. non-
u 71.5 (42) <10 12.6 smokers p<0.025.
10-20 12.8 Group II., III. Smokers vs.
>20 15.9 nonsmokers p<0.001.
TIT 9.9 (770) <10 14.1
10-20 14.8
>20 10.2

Downing No data No data 2.2 (66) 3.3 (88)
and
Chapman
(7).

Reinke and <2,500¢. 10.6 (163) 16.7 (270) 37.7 weeks 37.67 weeks p<0.001
Henderson <35 weeks 20.8 (313) 22.8 (368) p>0.05

(86).

 
TABLE 3.—Maternal smoking and prematurity (cont.)
(Figures in parentheses are the absolute number of premature births)

Premature by

£0p

 

 

 

 

 

Author, a Percent of premature infants Mean duration of pregnancy

reference Duration of Comments
Weight gestation Nonsmokers Smokers

Underwood = <2,500 g. Cigarettes per day Prematurity by birth weight rose
et al., 5.7 (1,417) 1-10 7.6 (671) directly to a significant degree
(51). 11-30 9.4 (1,358) (p<0.01) with each smoking

>30 11.2 (176) category.
<86 weeks 5.8 (1,442) 1-10 6.9 (525) Data suggested that smoking in
11-30 7.5 (1,084) any trimester decreased birth
>30 7.5 (118) weight.

Buncher 1 Smokes 20 cigarettes per day.
(4).

Female 39.69 weeks

Butler and <2,500 g. 5.4 (602) 9.8 (433)

Alberman
(5).

Terris A significant (p<0.01) difference
and was found between percent of
Gold mothers who smoked and
(47). those who had premature

deliveries and the control
group.
mortality rate was found for both stillbirths and neonatal deaths,
and was somewhat greater for stillbirths but not significantly so
(see Butler, tabie 4). The authors state that “...the differences
between mortality rates in babies of smokers and nonsmokers prac-
tically disappear when they are compared within groups of similar
birthweights ... It therefore seems reasonable to conclude that the
increased mortality found in babies of mothers who smoke is ac-
counted for by the overall excess of low birthweight babies in this
group...” with their attendant high risks.

In 1964, Yerushalmy (54) reported on a group of 6,800 women
whose pregnancies terminated in single, live births, excluding still-
births and abortions. The study was prospective and was controlled
for maternal age and parity. He noted that neonatal mortality in
infants born to smoking mothers and weighing less than 2,500
grams was significantly less than that of small infants born to
nonsmoking mothers. He referred to these small infants of smoking
mothers as being “apparently healthier” than those infants weigh-
ing less than 2,500 grams who were born to nonsmoking mothers.

As this report showed, when compared to infants weighing more
than 2,500 grams, a small (<2,500 grams) infant faces a greatly
increased risk of neonatal mortality, whether it is born to a smok-
ing mother or to a nonsmoking mother (54). The neonatal death
rate for the small infants of smoking mothers was less than that for
small infants of nonsmoking mothers, but neither group can be
considered “healthy,” having sharply elevated death rates. The
overall neonatal mortality for babies born to white smoking
mothers was 12 percent higher than that for babies born to non-
smoking mothers. This is not significantly greater than the neo-
natal mortality of infants born to nonsmoking mothers. On the
other hand it is also not significantly different from the 31 percent
excess mortality reported by Butler, et al. (5), which is statistically
significant.

Interpretation of the neonatal mortality among the infants
weighing less than 2,500 grams in the Yerushalmy study is dif-
ficult. By considering only live births, the series may have included
a higher proportion of infants whose smaller birthweight was pri-
marily due to a modest growth retarding influence of maternal
smoking and not to other more serious congenital defects and intra-
uterine influences. Butler, et al. (5) have shown that smoking
mothers have significantly more stillbirths than nonsmoking
mothers, and Russell, et al. (29) have found this to be true for both
stillbirths and abortions.

For reasons which aren’t clear, smoking mothers have been
found to have a reduced incidence of preeclamptic toxemia as com-
pared to nonsmoking mothers (51). However, given the presence of

404
TABLE 4.—Comparison of abortion, stillbirth, and neonatal death in smoking and nonsmoking mothers
NS = Nonsmokers SM = Smokers

 

 

Sov

 

 

 

 

 

 

 

 

Numbers Kates/1,Uuu total births
Neonatal Neonatal Comments
Author, Total births Abortions Stillbirths deaths deaths
reference NS SM NS SM NS SM NS NS SM
Lowe 1,155 668 t47 t Includes first-day
(23). deaths.
Frazier 1,717 1,019 fll F16 40 23.3 27.5 t “Fetal death”.
et al.,
(12).
Savel White
and 383 428 2 3 4 10.4 47
Roth Negro
(41). 364 240 8 4 5 13.7 12.5
O’Lane 1,027 887 91 112
(93).
Zabriskie 2,850 2,769 250 348
(58).
Yerushalmy White
{54). 3,218 2,163 40 12.4 13.9
Negro
939 480 22 23,4 22.9
Peterson 4,455 3,285 4.0 0.9
etal.
(34).

 
90P

TABLE 4.—-Comparison of abortion, stillbirth, and neonatal death in smoking and nonsmoking mothers (cont.)
NS = Nonsmokers SM = Smokers

 

 

 

 

 

 

 

Numbers Rates/1,000 total births
Neonatal Neonatal Comments
Author, Total births Abortions Stillbirths deaths Abortions Stillbirths deaths
reference NS SM NS SM NS SM NS SM NS SM NS SM NS SM

Downing 3,029 2,630 126 107 $3820 t29 41.6 40.7 $10.6 t11.0 ¢ Stillbirth plus
and neonatal death.
Chapman
(7).

Tnderwond 24 ROR 23,620 8.4 8.7 T1230 F121 } Excludes perinatal
et al., deaths in premature
(51). infants (p>0.05).

Russell TBP: t Includes abortion,
etal., <140/90 984 496 727) $32 127 65 stillbirth, and
($9). ==140/90 340 117 $14 t8 41 68 neonatal death.

>140/90 188 35 t20) «tit 145 314 { Blood pressure.

Tokutata White Data based on use of
(49). 2,555 743 $246) «$112 +96 151 cigarettes only.

Nonwhite t Includes stillbirths
1,285 350 174 tée4 fl4i 183 and miscarriages.

Butler 11,145 4,660 215 129 146 80 19.3 27.6 13.1 17.2
and
Alberman
(5).

 

Source: Modified and expanded from Butler and Alberman (5).
preeclampsia, smoking appears to increase the risk to the fetus be-
cause of low birthweight and increased perinatal mortality (8).

In a case-control study of sudden, unexpected death in infancy,
Steele, et al. (46) observed that the percentage of smokers among
mothers of cases of sudden, unexpected death, 61.2 percent, was
significantly greater than the percentage among mothers of con-
trols, 39.5 percent.

The possible teratogenic effect of maternal smoking has not been
adequately evaluated. Although it does not appear to be a major
factor, there have been too few studies to determine whether ma-
ternal smoking is a significant teratogenic risk (5, 23, 28, 50).

Concern has been expressed about the possible long-term effects
on the children of women who smoke during pregnancy. Butler (6)
recently reported the results of a follow-up at age seven of the
babies studied in the British Perinata] study of 1958. He found that
the children of the mothers who were “heavy” smokers during
pregnancy showed significantly decreased height, retardation of
reading ability, and lower ratings on “social adjustment” than the
children of nonsmoking mothers. The differences were independent
of such factors as social class, age of mother, and parity.

EXPERIMENTAL STUDIES

In the past decade, research on the effect of smoking on pregnancy
has increased. Summaries of human and animal experimental data
in this area of study are found in tables 5 and 6. Elevated carbon
monoxide levels have been found in maternal and fetal blood in
women who smoke. Carbon monoxide is an inhibitor of carbonic
anhydrase and as might be expected the activity of this enzyme is
decreased in the cord blood of infants whose mothers smoke. The
significance of elevated fetal carbon monoxide is not clear; how-
ever, in an extensive monograph on this subject, Longo, (22) has
concluded that “...the decreased availability of oxygen resulting
from elevated (fetal) carboxyhemoglobin levels is probably in-
jurious to fetal tissues.” Other changes noted in the infants of
smoking mothers have included a mild metabolic acidosis and a
higher mean hematocrit (56). Two studies (9, 52) have shown that
placentas of women who smoke have a significantly greater ability
to hydroxylate benzo[a]pyrene than the placentas from nonsmok-
ers. Such findings suggest the possibility of fetal exposure to car-
cinogens; however, the significance of these findings is presently
speculative.

Early animal studies (10, 42) showed that rats and rabbits ex-
posed to nicotine or cigarette smoke have smaller offspring and
more unsuccessful pregnancies than control animals. Recent radio-

407
80

TABLE 5.—Human experimental data on smoking and pregnancy

 

 

 

Author,
year,
country, Design of study Results Comments
reference
Sontag and Fetal heart rate before and after smoking was Average fetal heart rate before smoking was 144.0.
Wallace, studied 81 times in 5 patients. The average fetal heart rate for the eighth to the
1935, twelfth minute after starting to smoke was 149.0.
ULS.A. (45).
Hadden et al., Carbon monoxide levels were measured in 50 (a) Carbon monoxide levels were significantly
1961, smokers and nonsmokers in a prenatal clinic. (p<0.01) higher in smokers than in nonsmokers.
U.S.A. (14). Twenty-six paired maternal and umbilical vein (8) Carbon monoxide concentrations in paired cord

blood specimens were obtained at parturition
and tested for CO levels.

and maternal blood specimens were approximately
equal,

e) Oo; carrying capacity jin enrd and maternal
blood was reduced in smokers compared to non-
smokers.

 

Heron, 1962,
New Zealand
(15).

58 pregnant smoking women were studied during
labor to determine the effect which smoking
might have on the ‘grading’ of the infant at
birth. CO levels were measured in both mother
and fetus.

(a) CO levels in maternal and fetal blood were
higher in patients who smoked.

(b) Respirations in infants of mothers who smoked
took longer to be established and peripheral cy-
anosis was more common.

A control group who
had never smoked
was compared with
the survey group.

 

Kumar and
Zourlas,
1963,

U.S.A. (20).

The in vivo effects of cigarette smoking on uterine
activity were studied in 17 pregnant gravidas
near term and not in Jabor. The in vitro effect
of nicotine on human pregnant and nonpreg-
nant myometria] strips was studied.

(a) In more than half (10/17), a definite increment
in uterine activity was noticed during cigarette
smoking.

(b) Ne oxytocie effect of nicotine on myometrial
strips was noted.

 

Young and
Pugh
1963,

England (55).

Blood CO levels were studied in 19 full-term par-
turient women, 16 of whom had normal deliv-
eries, Six of these smoked 10 to 20 cigarettes a
day. Maternal blood was analyzed 15 to 30
minutes prior to delivery. Fetal blood was taken
from the placental end of the umbilical vein.

CO content of umbilical vein blood at normal deliv-
eries was .52 and .36 volumes percent in infants
of mothers who smoked and motherg who did not
smoke, as compared with .33 and .28 volumes
percent, respectively, in the maternal venous
blood.

Blood CO levels were
also studied in non-
smoking male labo-
ratory workerg in
London and in
males in Antarctica.

 
607

Author,
year,
country,
reference

Mantell,
1964,

New Zealand
(25).

Scoppetta,
1968,
Italy (43).

Younoszai et al.,
1968,
Canada (56).

Engel et al.,
1969,
ULS.A. (9).

TABLE 5.—Human experimental data on smoking and pregnancy (cont.)

Design of study

Cord bloods from 50 smokers and 50 nonsmokers
were analyzed for carbonic anhydrase activity.

CO concentrations were measured in the venous
blocd of 46 pregnant women, including smokers
and nonsmokers. Funicular venous blood was
analyzed at the time of delivery.

32 women with normal pregnancies were studied
of whom 16 smoked >20 cigarettes a day. Both
groups of women had normal deliveries and
healthy infants. Biochemical changes in the first
48 hours of life were studied in the infants.

37 experiments were performed on Placental blood
samples obtained from 15 pregnancies to deter-
mine relative affinity of human fetal Hb for CO
and O,-

Results

A decrease in carbonic anhydrase activity in the
cord bloods of infants whose mothers smoked was
noted,

CO levels were higher in smokers than in non-
smokers. CO concentrations were approximately
the same in maternal and funicular venous blood.

(a) Mean CO saturation of Hb in the venous blood
of the cigarette smoking mothers at the time of
delivery was 8.3 percent and in the nonsmoking
mothers 1.2 percent. The corresponding mean um-
bilical vein blood levels were 7.3 percent and .7
percent,

(6) The blood Ph, pCo,, and bicarbonate and lac-
tate values in both groups of infants were within
normal limits.

(ce) The infants of smoking mothers showed a
higher mean hematvcrit and mild metabolic acid-
Osis.

Human placental blood has a lower relative affinity
for CO than adult bloed. It was calculated that the
affinity constant of fetal Hb was approximately
20 percent less than that of Hb A.

Comments

Carbon monoxide is

an inhibitor of

carbonic anhydrase.
Oly

TABLE 5.—Human experimental data on smoking and pregnancy (cont.)

 

Author,
year,
country,
reference

Design of study

Results

Comments

 

Nebert et al..
1969,
U.S.A. (81),

Aryl hydrocarbon hydroxylase activity was de-
termined in the placentas obtained from 97
women at the time of childbirth; 46 of the
women smoked between 20 and 40 cigarettes per
day during pregnancy and 51 women were non-
smokers.

Significantly higher (p<0.001) levels of aryl hydro-
carbon hydroxylase were found in women with
a history of cigarette smoking.

 

Welch et al.,
1969,
U.S.A. (52).

Benzpyrene hydroxylase and aminoazo dye:
N-demethylase activity was measured in 17 hu-
man placentas obtained after childbirth from
smokers and in 17 human placentas obtained
from nonsmokers.

Enzymes were found in the placentas from all 17
smokers. No detectable activity was observed in
the placentas of nonsmokers.

 
Ly

TABLE 6.—Animal experimental data on the effect of smoking and nicotine on pregnancy

 

Author,
year,
country,
reference

Animal

Design of study

Results

Comments

 

Essenberg et al.,
1940,
U.S.A. (10).

Albino rat.

393 ‘‘young”’ from pregnant rats exposed to
tobacco smoke and 113 young from preg-
nant rats which received parenteral nico-
tine were studied.

The young of treated mothers were under-
weight; the young from nicotine injected
mothers were more underweight than those
from smoked mothers. Increased fetal wast-
age and neonata)] deaths were observed in
treated animals as compared to controls.

113 “young” served as
controls.

 

Schoeneck,
1941,
U.S.A. (42).

Rabbit.

Smoke from one cigarette was blown into
the nostril of healthy does by means of a
catheter each day. The does were ‘‘smoked”
daily throughout pregnancy and lactation.
170 young from 28 litters of 7 “smoked”
dees were studied. The offspring were not
subjected to smoking at any time.

(a) Offspring from “‘smoked’’ female rabbits
were smaller at birth than controls (17
percent).

(6) The stillbirth rate was 10 times as great
in the “smoked” group.

(c) The mortality rate was greater in the
offspring of the ‘‘smoked’’ does.

Litters from the pre-
vious generation
served as controls.

 

Nishimura and
Nakai,
1958,
Japan (82).

Mouse.

230 pregnant mice were injected, parenter-
ally, with nicotine. Animals were sacrificed
at term and mid-pregnancy to investigate
the state of the pregnancy and the develop-
ment of the offspring.

Nicotine had a lethal effect upon mice em-
bryos and also had a teratogenic effect on
their skeletal systems.

225 full-term fetuses
removed from 29
untreated mice were
used as controls.

 

Gatling,
1964,
U.S.A. (18).

Chick embryo.

Chicken embryos were treated with doses of
nicotine varying from 12 pe. to 1,000 pe.
The effects of phenothiazines, corticoste-
roids, and catecholamines were also studied.

Nicotine induced cephalic hematoma forma-
tion and central nervous system depression.
aly

Author,
year,
country,
reference

Becker and
King,
1966,
U.S.A. (2).

Animal

Design of study

100 primipara pregnant rats received a sin-
gle heavy subcutaneous injection of nico-
tine on the 21st day of pregnancy, one
day prior to expected term delivery. Fetal
wastage, weight of newborns, neonatal
deaths, and pregnant animals’ responses
were noted.

Results

{a) Mortality was greater among pregnant
rats than among controls.

{b) Pregnant rats showed more marked hy-
perventilation and less body temperature
depression than controls.

(c) Delivery was delayed 2 to 4 days.

(d) The young weighed less than normal and
survived ‘‘poorly’’ during the first 48 hours
of life

TABLE 6.—Animal experimental data on the effect of smoking and nicotine on pregnancy (cont.)

Comments

100 nonpregnant rats
served as controls.

 

King and
Becker,
1966,

US.A. (127).

Pregnant and nonpregnant rats were in-
jected subcutaneously with heavy doses of
a 2 percent solution of pure nicotine for
the purpose of determining the LD 0 for
females of this strain (Osborne-Mendel).
The LD,, for neonates of this strain was
also determined within 6 to 24 hours of
norma] birth.

Osborne-Mendel rats LD, 9: mg./kg.
Pregnant adults ................ 27.4
Nonpregnant females .......... 33.5
Neonates 2.0.0... -.. 0.0 c eee eee ee 14.55

Pregnant rats tended to die significantly later
than nonpregnant rats, but their tolerance
for nicotine was less.

 

Mosier and
Armstrong,
1967,

U.S.A. (27).

Alternate pregnant rats received oral nico
tine in the dosage of either .05 mg./g. or
10 mg./g. of food. On the 20th day, the
rats were killed and the fetuses were re-
moved.

(a) On higher nicotine intake, there was
lowering of food intake.

(6) There was no change in fetal weight or
length on either concentration.

(c) There appeared to be no effect on the
number of live and “absorbing’’ fetuses.

 
 

 

El

TABLE 6.—Animal experimental data on the effect of smoking and nicotine on pregnancy (cont.)

 

Author,
year,
country,
reference

Animal

Design of study

Results

Comments

 

Becker et al., Rat.
1968,
U.S.A. (8).

Controlled populations of pregnant rats were
injected twice daily with doses of nicotine
varying from .5 mg./kg. to 5 mg./kg. Ef-
fects on pregnant rats and newborn were
studied.

(a) With the lower dosage of nicotine, the
birthweights, survival, and developmental
status did not differ from controls.

(6) With thhe higher dosage, pregnant rats
consumed less food and gained less weight
than control mothers. Delivery dates were
prolonged 2 to 4 days or more. Young
were underweight and fetal in appearance.
There were no abortions and no premature
young.

Contro] rats were in-
jected with saline.

 

Tialve et al., Mouse.
1968,

Sweden (48).

The passage of 'C-nicotine and its metabo-
lites from the mother into the fetuses was
studied.

(a) Nicotine and its metabolites accumulated
in the placenta and passed into the fetus.

(6) The metabolites present in the fetus
originated from the mother.

(c) The passage of nicotine into the fetus
was the same during the last four days of
pregnancy.

 

Fabro and Rabbit.
Sieber,
1969,

U.S.A. (11).

(1-methyl-C)-caffeine and G-(°H)-nicotine
were given to 6-day pregnant rabbits. The
dose for nicotine was 50 ps-/ke., intra-
venous, producing plasma levels similar to
those attained in man by cigarette smok-
ing (.06-.09 pe-/mi.).

(a) One hour after (°H)-nicotine treatment,
a high level of radioactivity compared with
that in maternal plasma was found in
uterine secretion (ratio = 10.8).

(6) Unchanged radioactive nicotine and some
of its metabolites were present in the pre-
implantation blastocyst (blastocyst/plasma
ratio = 3).

Radioactivity in
uterine secretion
was not found in
nonpregnant con-
trols.

 
ble

Author,
year,
country,
reference

Welch et al.,
1969,
U.S.A. (52).

Younoszai
etal,
1969,

Canada
(57).

Design of study

Rats which were pregnant for 18 days were
given 40 mg./kg. of 3,4-benzpyrene; 1,2-
benzanthracene; 1,2,5,6-dibenzanthracene;
chrysene; 3,4-benzofluorene; anthracene;
pyrene; fluoranthene; perylene; or phen-
anthrene orally, and BP-hydroxylase ac-
tivity in the placenta was measured 24
hours later.

Pregnant rats were exposed to smoke from
regular tobacco cigarettes, non-nicotine cig-
arettes made with lettuce leaves, and non-
nicotine cigarettes (lettuce leaves) to which
15 mg. of nicotine was added. The rats
were forced to inhale cigarette smoke by
placing their cages in a smoking chamber.
CO levels were maintained between 2 and
& percent by exposing the animals to smoke
5 times a day at 2-hour intervals. Other
groups of rats were fed restricted diets,
receiving from 55 to 80 percent of the
food consumed by control rats.

Results

All compounds tested stimulated:
BP-hydroxylase activity in the placenta.
1,2-benzanthracene was the most active in-
ducer of BP-hydroxylase.

(a) Fetuses of all smoked rats were growth
retarded compared to control animals, those
exposed to tobacco smoke (cigarette) being
most severely affected.

(b) The amount of food consumed by rats
exposed tu cigarette smoke was reduced.
(c) There was a significant direct relation
between fetal body weight and the average
amount of food eaten during pregnancy.
(d) Fetal weight was reduced in prpportion
to the decrease in maternal food intake in
the two groups of rats exposed to the let-
tuce leaf cigarette smoke. In rats exposed
to tobacco cigarettes, fetal weight was re-
duced more than expected from the de-

crease in maternal food intake.

TABLE 6.—Animal experimental data on the effect of smoking and nicotine on pregnancy (cont.)

Comments

Placenta from control
rats possessed very
low BP-hydroxylase
activity.

Control rats were
handled in the same
way except that
they were not ex-
posed to cigarette
smoke.

 

Canada (51).

Kirschbaum
et al.,
1970,
U.S.A. (18).

Intravenous injection of fresh solutions of
nicotine, and simulated smoking of ciga-
rettes, were carried out upon pregnant
ewes. Cardiovascular functions, including
gaseous exchange and blood flow of both
the ewes and their fetuses were studied
for acute effects.

No significant changes were observed as a
result of either nicotine administration or
smoke inhalation.

Eath experiment in-
eluded a control
period during which
attainment of a
steady state was
the aim.
isotope studies in mice (48) have indicated that nicotine and its
metabolites accumulate in the placenta and are passed into the
fetus.

Many of the experimental studies were designed to determine the
pathophysiology of the effect of maternal smoking on the fetus.
The experimental conditions in the several studies varied greatly as
did the results. No unified concept of the effect of maternal smoking
on fetal growth or on the outcome of pregnancy can be derived from
the presently available research.

SUMMARY

Maternal smoking during pregnancy exerts a retarding influence
on fetal growth as manifested by decreased infant birthweight and
an increased incidence of prematurity, defined by weight alone.
There is strong evidence to support the view that smoking mothers
have a significantly greater number of unsuccessful pregnancies
due to stillbirth and neonatal death as compared to nonsmoking
mothers. There is insufficient evidence to support a comparable
statement for abortions. 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.

REFERENCES

(1) ABERNATHY, J. R., GREENBERG, B. G., WELLS, H. B., FRAZIER, T. M.
Smoking as an independent variable in a multiple regression analysis
upon birth weight and gestation. American Journal of Public Health
and the Nation’s Health 56(4) : 626-633, April 1966.

(2) Becker, R. F., KING, J. E. Studies on nicotine absorption during preg-
nancy. II. The effects of acute heavy doses on mother and neonates.
American Journal of Obstetrics and Gynecology 95(3) : 515-522, June
15, 1966.

(8) Becker, R. F., Lirtie, C. R. D., Kine, J. E. Experimental studies on
nicotine absorption in rats during pregnancy. III. Effect of sub-
cutaneous injection of small chronic doses upon mother, fetus, and
neonate. American Journal of Obstetrics and Gynecology 100(7):
957-968, April 1, 1968.

(4) Buncuer, C. R. Cigarette smoking and duration of pregnancy. American
Journal of Obstetrics and Gynecology 103(7) : 942-946, April 1, 1969.

(5) Butier, N. R., ALBERMAN, E. D. (Editors). The effects of smoking in
pregnancy. Chapter 5. IN: Perinatal Problems. Edinburgh, E. & S.
Livingstone, Ltd., 1969. pp. 72-84.

(6) BuTLER, N. R. A national long term study of perinatal hazards. Pre-
sented at the Sixth World Congress of Gynaecology and Obstetrics,
New York, April 12-18, 1970, 11 pp.

(7) Downina, G. C., CHapMan, W. E. Smoking and pregnancy. A statistical
study of 5,659 patients. California Medicine 104 (3) : 187, March 1966,

415
(8)

(9)

(10)

(11)

(12)

(18)

(14)

(15)
(16)

(17)

(78)

(19)

(20)

(21)

(22)

(22)

(24)

(25)

416

Durrus, G. M., MacGmtiivray, I. The incidence of pre-eclamptic
toxaemia in smokers and nonsmokers. Lancet 1(7550) : 994-995, May
11, 1968.

ENGEL, R. R., RopKEy, F. L., O’NEaL, J. D., CoLiison, H. A. Relative
affinity of human fetal hemoglobin for carbon monoxide and oxygen.
Blood 33(1): 37-45, January 1969.

ESSENBERG, J. M., SCHWIND, J. V., Patras, A. R. The effects of nicotine
and cigarette smoke on pregnant female albino rats and their off—
springs. Journal of Laboratory and Clinical Medicine 25: 708-717,
1940.

Fasro, S., SIEBER, S. M. Caffeine and nicotine penetrate the pre-implan-
tation blastocyst. Nature 223 (5204): 410-411, July 26, 1969.

FRAZIER, T. M., Davis, G. H., GOLDSTEIN, H., GOLDBERG, I. D. Cigarette
smoking and prematurity: A prospective study. American Journal of
Obstetrics and Gynecology 81(5) : 988-996, May 1961,

GATLING, R. R. Effect of nicotine on chick embryo. Archives of Pathology
78(6) : 652-657, December 1964.

Happon, W., Jz., NESBITT, R. E. L., Garcia, R. Smoking and pregnancy:
Carbon monoxide in blood during gestation and at term. Obstetrics
and Gynecology 18(3) : 262-267, September 1961.

HERON, H. J. The effects of smoking during pregnancy: A review with a
preview. New Zealand Medical Journal 61:545-548, November 1962.

HergIoTT, A., BILLEWIcz, W. Z., HyTTen, F. E. Cigarette smoking in
pregnancy. Lancet 1: 771-773, April 14, 1962.

KING, J. E., BECKER, R. F. Studies on nicotine absorption during preg-
nancy. I. LD.,: for pregnant and nonpregnant rats. American
Journal of Obstetrics and Gynecology 95 (4): 508-514, June 15, 1966.

KirscuBauM, T. H., Divts, P. V., JR., BRINKMAN, C. R., III. Some acute
effects of smoking in sheep and their fetuses. Obstetrics and Gynecol-
ogy 35(4): 527-536, April 1970.

Kizer, S. Influencia del habito de fumar sobre el embarazo, parto y recien
nacido. (Effect of the smoking habit on pregnancy, delivery, and the
newborn.) Revista de Obstetricia y Ginecologia de Venezuela 27(4):
595-648, 1967.

Kumar, D., Zourvas, P. A. Studies on human premature births. II, Jn
vivo effect of smoking and in vitro effect of nicotine on human uterine
contractility. American Journal of Obstetrics and Gynecology 87(3):
413-417, October 1, 1963.

Lasz.o, V. A dohanyzas karos hatasai a gestatios folyamatokra, (The
deleterious effects of smoking on the sequences of gestation.) Magyar
Noorvosok Lapja 32(2): 168-167, March 1969,

Lonco, L. D. Carbon monoxide in the pregnant mother and fetus, and its
exchange across the placenta. Annals of the New York Academy of
Sciences 174(1): 313-341, October 5, 1970.

Lowe, C. R. Effect of mothers’ smoking habits on birth weight of their
children. British Medical Journal] 2: 673-676, October 10, 1959.

MACMAHnown, B., ALPERT, M., Sarper, E. J. Infant weight and parental
smoking habits. American Journal of Epidemiology 82(3): 247-261,
November 1963.

MANTELL, C. D. Smoking in pregnancy: The role played by carbonic
anhydrase. New Zealand Medical Journal 63: 601-603, September
1964.
(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

McDona cp, R. L., LANFORD, C. F. Effects of smoking on selected clinical
obstetric factors. Obstetrics and Gynecology 26 (4) : 470-475, October
1965.

Mosier, H. D., Jr., ARMSTRONG, M. K. Effect of maternal nicotine intake
on fetal weight and length in rats. Proceedings of the Society for
Experimental Biology and Medicine 124 (4): 1135-1137, April 1967.

Muccany, R., Knaces, J. F. Effect of age, parity, and cigarette smoking
on outcome of pregnancy. American Journal of Obstetrics and Gyne-
cology 101(6) : 844-849, July 15, 1968,

MuLcany, R., Murpuy, J., Martin, F. Placental changes and maternal
weight in smoking and nonsmoking mothers. American Journal of Ob-
stetrics and Gynecology 106 (5) : 703-704, March 1, 1970,

Murbocu, D. E. Birth weight and smoking. Nebraska State Medical
Journal 48(11): 604-606, November 1968.

NeBert, D. W., Winker, J., GELBOIN, H. V. Aryl hydrocarbon hydro-
xylase activity in human placenta from cigarette smoking and non-
smoking women. Cancer Research 29(10) : 17638-1769, October 1969.

NIsHimura, H., Nakal, K. Developmental anomalies in offspring of
pregnant mice treated with nicotine. Science 127 (8308) : 877-878,
April 18, 1958.

O’LANE, J. M. Some fetal effects of maternal cigarette smoking. Obstet-
rics and Gynecology 22(2): 181-184, August 1963.

PETERSON, W. F’., MorESE, K. N., KALTREIDER, D. F. Smoking and pre-
maturity. A preliminary report based on study of 7,740 Caucasians.
Obstetrics and Gynecology 26(6) : 775-779, December 1965.

RAVENHOLT, R. T., LEVINSKI, M. J., NELLIST, D. J., TAKENAGA, M. Effects
of smoking upon reproduction. American Journal of Obstetrics and
Gynecology 96 (2): 267-281, September 15, 1966.

REINKE, W. A., HENDERSON, M. Smoking and prematurity in the pres-
ence of other variables. Archives of Environmental Health 12(5):
600-606, May 1966.

RosBINsoN, P. ’Yshwn nshym Bwrmmywt vamn hhrywn whshp’tw ’1 h’m
h’wbr whylwd. (Smoking by Burmese women during pregnancy and
its influence on the mother, the fetus and the newborn.) Harefuah
69(2): 37-89, 1965.

RUSSELL, C. S. Another hazard of smoking. New Scientist 41(631) : 64—
65, January 9, 1969.

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 Preven-
tive and Social Medicine 22(3) : 119-126, July 1968.

RUSSELL, C. S., Taytor, R., Mappison, R. N. Some effects of smoking in
pregnancy. Journal of Obstetrics and Gynecology of the British Com-
monwealth 73: 742-746, October 1966.

SAVEL, L. E., Rotu, E. Effects of smoking in pregnancy: A continuing
retrospective study. Obstetrics and Gynecology 20(3): 313-316,
September 1962.

SCHOENECK, F. J. Cigarette smoking in pregnancy. New York State
Journal of Medicine 41: 1945-1948, October 1, 1941.

Scopretta, V. Sul contenuto di ossido di carbonio nel sangue circolante
di gestanti fumatrici. (Carbon monoxide content in the blood circu-

417
(44)

(45)

(46)

(47)

(48)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

418

lating in pregnant smckers.) Archivio di Ostetricia e Ginecologia
73 (3): 869-375, May-June 1968.

SIMPson, W. J. A preliminary report on cigarette smoking and the
incidence of prematurity. American Journal of Obstetrics and Gyne-
cology 73(4): 808-815, April 1957.

Sontac, L. W., WALLACE, R. F. The effect of cigarette smoking during
pregnancy upon the fetal heart rate. American Journal of Obstetrics
and Gynecology 29: 77-83, 1935.

STEELE, R., LaNGworru, J. T. The relationship of antenatal and post-
natal factors to sudden unexpected death in infancy. Canadian Medi-
eal Association Journal 94: 1165-1171, May 28, 1966.

TERRIS, M., GoLp, E. M. Ar epidemiologic study of prematurity. I. Rela-
tion to smoking, heart volume, employment, and physique. American
Journal of Obstetrics and Gynecology 103(8) : 358-370, February 1,
1969.

TJALVE, H., Hansson, E., SCHMITERLOW, C. G. Passage of ?‘C-nicotine
and its metabolites into mice foetuses and placentae. Acta Pharma-
cologica et Toxicologica 26(6) : 539-555, 1968.

TokunaTa, G. K. Smoking in relation to infertility and fetal loss.
Archives of Environmental Health 17(3): 853-359, September 1968.

UNDERWOOD, P. B., HESTER, L. L., LaFirteE, T., JR., GREGG, K. V. The
relationship of smoking to the outcome of pregnancy. American
Journal of Obstetrics and Gynecology 91(2): 270-276, January 15,
1965.

UNDERWoop, P. B., Kesimr, K. F., O’LANE, J. M., CALLAGAN, D. A.
Parental smoking empirically related to pregnancy outcome. Obstet-
rics and Gynecology 29(1): 1-8, January 1967.

WELCH, R. M., HARRISON, Y. E., GomMI, B. W., Poppers, P. J., FINSTER,
M., Connery, A. H. Stimulatory effect of cigarette smoking on the
hydroxylation of 3,4-benzpyrene and the N-demethylation of 3-methyl-
4-monomethylaminoazobenzene by enzymes in human placenta. Clini-
cal Pharmacology and Therapeutics 10(1): 100-109, January-
February 1969.

YERUSHALMY, J. Statistical considerations and evaluation of epidemio-
logical evidence. IN: James, G., Rosenthal, T. (Editors). Tobaeco and
Health. Springfield, Charles C. Thomas, 1962. pp. 208-230.

YERUSHALMY, J. Mother’s cigarette smoking and survival of infant.
American Journal of Obstetrics and Gynecology 88(4): 505-518,
February 15, 1964.

Young, J. M., Pucu, L. G. C. E. The carbon monoxide content of foetal
and maternal blood. Journal of Obstetrics and Gynecology of the
British Commonwealth 7( (4): 681-684, 1963.

Younoszal, M. K., Kacic, A., HAWorTH, J. C. Cigarette smoking during
pregnancy: The effect upon the hematocrit and acid-base balance of
the newborn infant. Canadian Medical Association Journal 99(5):
197-200, August 3, 1968.

Younoszal, M. K., PEtoso, J., HAworru, J. C. Fetal growth retardation
in rats exposed to cigarette smoke during pregnancy. American Jour-
nal of Obstetrics and Gynecology 104(8) : 1207-1213, August 15, 1969.

ZABRISKIE, J. R. Effect of cigarette smoking during pregnancy. Study of
2,000 cases. Obstetrics and Gynecology 21(4): 405-411, April 1963.
CHAPTER 6

 

Peptic Ulcer
Contents

Page
Summary 1.6... 0. ce eee cette etter nens 423
References 2.0.0... ccc ccc ccc eee een ene ne eeae 429
LIST OF TABLES
. Smoking and peptic ulcer disease mortality ........... 424
. Summary of results of retrospective and cross sectional
studies of peptic ulcer and smoking .................. 425
. Methods used in retrospective and cross sectional studies
of peptic ulcer and smoking ................. 0.0000 427

421
PEPTIC ULCER

It has been estimated that 10 to 12 percent of all people will suf-
fer from peptic ulcer disease at some time in their lives (17). In
the U.S.A. in 1967, there were 5,323 deaths from gastric ulcer and
4,502 deaths from duodenal ulcer (22). Several studies have docu-
mented an association between smoking and peptic ulcer disease,
which is stronger for gastric ulcer than for duodenal ulcer.

Prospective studies indicate that male cigarette smokers have
increased peptic ulcer mortality ratios (see table 1). Although a
trend toward increased mortality from gastric ulcer is seen in cigar
and/or pipe smokers, the data do not allow significant conclusions
to be drawn. Similarly, no firm conclusions can be drawn about
female smokers,

Retrospective studies have consistently shown smaller numbers
of nonsmokers in the peptic ulcer groups than in matched control
populations (tables 2 and 3),

Cigarette smoking has been shown to reduce the efficacy of
antacid therapy in documented peptic disease (3) and to slow peptic
uleer healing (7). One study indicated that smokers who had
undergone surgical treatment for their peptic disease had more
major complications, including recurrence of peptic disease, than
nonsmokers (14).

Numerous studies in both animals and man have been performed
to investigate the effect of smoking or the administration of nico-
tine on the gastrointestinal tract. Studies of gastric secretion and
motility in normal controls and in patients with peptic ulcer dis-
ease as well as in experimental animals have produced conflicting
results (4, 16, 18, 19, 20).

SUMMARY

Cigarette smoking males have an increased prevalence of peptic
ulcer disease and a greater peptic ulcer mortality ratio. These rela-
tionships 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.

423
ver

TABLE 1.—Smoking and peptic ulcer disease mortality
(Numbers in parentheses represent actual number of deaths)

 

 

 

 

 

 
 

 

SM = Smokers NS = Nonsmokers G = Gastric D = Duodenal
Author, Mortality ratios
year, Number and Data Actual
country, type of collection deaths Cigarettes/day Pipe Cigar Comments
reference population SM NS Gastric Duodenal Gastric Duodenal Gastric Duodenal

Doll and 41,000 male Questionnaire 54 tPeptic Pipe/cigar t+ Total number of
Hill, British and follow-up NS 1.00 4.00 deaths were too
1964, physicians. of death All cigarette 7.00 small to allow
Great certificate. 1-14 gs. per day 2.33 separate examin-

Britain 15-24 10.33 ations.

(5, 6). >25 7.33
Hammond; 440,658 Interviews by G-83 ..11 NS .......... 1.00 (11) 1.00 (22)
1988, males 35- ACS volunteers D-93 ..22 SM (awe 45-64) 2.95) ... 2.86)...
U.S.A. 84 years of SM (age 65-79) 4.06( ‘°°’ 1.50¢°"°?
(11). age in 25
States.

Kahn, U.S. male Questionnaire G-78 ...... 12 NS ...........0. 1.00(12) 1.00(25) 1.00(12) 1.00(25) 1.00(12) 1.00(25)
1966, veterans and follow-up D-119 -25 SM 2.84 (4) 1.59 (5) 2.90 (7) 1.58 (8)
U.S.A. 2,265,674 of death All cigarette . 4.18(389) 2.98 (57)

(12). person years. certificate. 5: rr 3.95 (5) 2.30 (6)
10-20 .......... 2.77(18) 2.74(26)
21-39 .- 5.45(15) 3.98 (22)
>39 ». 11.57 (6) 2.89 (3)

Weir and 68,153 males Questionnaire 44 NS oo. 1.00 No deaths from
Dunn, in various and follow-up All cigarette a 0.53 gastric ulcer oc-
1970, occupations of death 10 woe ee eee 1.00 0.40 curred in non-
U.S.A. in California. certificate. #20 1.67 0.59 smokers and risk
(28). 230 2.38 0.32 of those smoking

£10/day was set
at 1.00. NS in-
cluded pipe,
cigar, and
ex-smokers.

 
Sty

TABLE 2.—Methods used in retrospective and cross sectional studies of peptie

uleer and smoking

 

 

 

 

 

 

 

Author,

year, Controls

country, Cases Comments
reference Sex Number Method of selection Number Method of selection

Barnett, M 66 Gastric. Patients admitted between 1913 and 500 Selected at random from the gen- 1. Retrospective review
1927, 178 Duodenal 1926. Only cases with complete eral admissions-males, 20-60 years records at Peter Bent
U.S.A. (2). smoking history selected. of age. Brigham Hospital.

2. Uleer diagnosis prob-
ably well established.

Trowell, M 50 Duodenal Not stated 400 Selected at random from wards of 1. Interviewed by inves-
1934, a general hospital. tigator.

England 2. Uleer diagnosis con-
(21). firmed by X-ray and/or
surgery.

Allibone and MandF 107 Consecutive admissions to hospital 107 Matched by age, sex, and time of Patients and controls in-
Flint, of patients with gastric and du- admission from acute general sur- terviewed by same
1958, odenal hemorrhage or perforation. gical emergency admissions. observer.

England
(2).

Doll et al., MandF 327 Gastric. Ulcer patients in Doll and Hill Lung 1,143 Patients with non-ulcer diseases. 1. Same interviewers and
1958, 338 Duodenal. Cancer Study plus additional pa- Each case matched with 2 con- questionnaire in cases
England tients in Central Middlesex Hospi- trol patients of same sex, 5-year and controls.

(7). tal. age group, and same type of 2. Ulcer diagnosis prob-

Place of residence. Male patients
matched by social class.

ably well established,

 

Edwards et al.,
1959,
England
(8).

M 1,737

Men aged 60 and over on 11 General
Practioners’ lists were examined
and interviewed by these practi-
tioners. Represents about 84 per-
cent of all such men on_ these
lists.

(9 percent non-response due to death
and/or untraced.)

Of 143 considered to have
a peptic ulcer, 53 were
confirmed by X-ray.