TABLE 3.-Maternal smoking and prematurity

(Figures in parentheses are the absolutr number of premature birth?)

Author.
reference

   Premature by

       Duration of -
Weight    gestation

Percent of premature infants

Nonsmokers   Smokers

  Mean duration of pregnancy
___~ -
    Nonsmokers    Smokers

Yerushalmy <5',C. lbs.
(54).

5.9   (36)   8.1    (30)

Murdoch
(30).

<2.500 g.                        3.3    (R) 13.6   (35)

O'L&ine     <2,500 B.                        5.1    (29) 11.x   (55)
(83).

Zabriskie    <2,500 g.                        3.83   (40)   9.93   (95)                            Ciparette.s
(58).                                                                           per day:       Prematurity
                                                                           <lO 6.54 (260)
                                                                           10-20  9.11 (396)
                                                                           20-30  .14.39 (264)
                                                                           >30 .10.53  (38)
                                 ___ ~~   -~~~___
Yerushalmy  <5 Ibs. 8 oz.        White  3.5   (112)   6.4   (138) (p<O.Ol)                      Infants of smoking mothers
(54).                   A'.egro  4.9    (46) 13.4   (64)                            weighed less then infants of
                                                                           nonsmoking mothers in each
                                                                           gestational age.

               <37 weeks  White .t5.9   (188)   6.5   (140)                            t DilPerence betwwn smokers and
                       Negro .13.4   (125) 16.7   (X0)                             nonsmokers not significant.
            -
MrDonald ,
        <2 500 I?.                      Cigarettes per day
and                           4.6   (4)     <lo     4.8   (2)
Lanfurd                                  >lO     8.3   (4)
(LO).

   Pctersnn    <2,600 g.                     Cigarettes pm day                                  Overall incidence of prematurity
    rt al.,                          2.5 (111)     I-10     3.0   (35)                              in smokers vs. nonsmokers
    (54).                                    11-20     4.x   (80)                             significant at p<O.OOl.
g --                                     >20     3.4   (16)                                     .-

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

Author,
reference

  Premature by

       Duration of ~
Weiaht    gestation

Percent of premature infants         Mean duration of pregnancy

Nonsmokers   Smokers             Nonsmokers   Smokera

Comme"ts

Peterson
et al.,
(contd.)
t.14 )

<37 weeks

      Cigarettes ncr day
1.3   (58)     l--l0     1.4   (16)
          11-20     2.3   (36)
          >20     2.4   (11)

Robinson    <2.500s.
(37).

Underwood <2,500 g.
et al..
(50).

Group:
   I

II

III

Downing   No data    No data

and
Chapman
(7).

16.5 (152)           31.0 (181)

Cigarettes per day

4.5 (108)     <IO     4.2
          10-20   5.9
         <20     7.2
7.5 (42)     <lO    12.6
          10-20   12.5
        >20    16.9
9.9 (770)     <IO     14.1
          lo-20   14.8
         >20    10.2

Percentages and absolute num-
ber of premature births 8re
based on 16.158 pregnancies
recorded in 4,440 women.
Group I. Smokers vs. "on-
smokers p<O.O26.
Group II., III. Smokers vs.
nonsmokers p<O.OOl.

2.2   (66)            3.3   (88)

Reinke and  <2,500 g.                10.6  (163)           16.7  (2'70)            37.7  weeks   37.67 weeks  p<O.OOl
Henderson        <35 weeks       20.3 (313)           22.8 (368)                            p>o.o5
(3-C).

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

           Premature by
Author, ~
reference           Duration of __
        Weight    gestation

Percent of premature infants

Nonsmokers   Smokers

Mean duration of pregnancy

Nonsmokers    Smokers

Underwood  <2,500 K.
et al..                          5.7
(51).

<36 weeks         5.R

Iluncher
(4).

   Cigarette8 .wec day
1,417)     l-10     7.6 (671)
       1 l-30     9.4 (1,358)
        >30     11.2  (176)
1,442)     l-10     6.9 (525)
       11-30     7.5 (1,084)
       >30     7.5  (118)

Prematurity by birth weight ro8e
directly to B significant degree
(p<O.Ol) with each smoking
category.

Data suggested that smoking in
any trimester decreased birth
weight.

                           _________
Birth                 t Smokes 20 cigarettes per day.
Male   39.55 weeks t 39.35 weeks
Female 39.69 weeks t 39.51 weeks

Rutler and   <2,600 g.                6.4 (602)            9.3 (433)
Alberman
(5).

Terris
and
Gold
(47).

A significant (p<O.Ol) difference
was found between percent of
mothers who smoked and
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, table 4). The authors state that ". . . the differences
between mortality rates in babies of smokers and nonsmokers pray-
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 (Si) 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, whe-n 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 srnoking 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 signilicantly 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. (39) 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 I.-Comparison. of abortion, stillbirth, and neonatal death in smoking and nonsmoking mothers

                                     NS = Nonsmokers   SM = Smokers
-                       Numbers                          kares/l.""" torai births
         _____--_                 .____  -___ .____  -__  ___~~

  Author,      Total births     Abortions    Stillbirths  NdY:2'                            Neonatal
                                                   Abortions                                Comments

reference     NS                                                  Stillbirths
                 SM     NS SM    NS SM                                     deaths
                                          NS SM    NS SM      NS SM     NS SM
-
LlJXVe        1,l.M     66X               t47               i23.0 t30.0             t Includes first-day
(28).                                                                 deaths.
                                 --                 ~___                          ____
Frazier       1.717    1,010              t11   t16 40   2x                t6.4 t15.5     23.3   27.5   t "Fetal death".
et al.,
(12).

Save1
and
Roth
(41).

O'Lane
(33).

White
  3x3
Negro
  364

  1.027

        -                                          ____-

42s               2 3     4 2                5.2    7.0     10.4    4.7

240               8    4     6 3                22.0   16.7     13.7 12.5
                   -..                   -___~-
X87     91   112                       8R.6   12fi.3

Zabriskie      2.x50    2.769    250   348                       87.7 125.7
(58).

                                     -.                           ~-___~         -~____
Yerushalmy  White
(54).       3.218    2,163                       40   30                           12.4   13.9
        Negro
           939     480                       22   11                           23.4   22.9
           -                                      ___--~         .____-
Peterson      4.455    3,285                                            0.6    1.2      4.0    0.9
et al..
(S4).

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

                Numbers                         Rates/l,000 total births

Author.
reference

Total births
NS    SM

Abortions
NS SM

Stillbirths
NS SM

Neonatal
deaths
NS SM

Abortions
NS SM

Stillbirths
NS SM

Neonatal
deaths
NS SM

Comments

Downing
and
Chapman
(7).

3.029    2,630

                                         --
126   107     t32   t29             41.6   40.7    $10.6   tll.0              t Stillbirth plus
                                                             neonatal death.

ITnrlrrwnorl    "J,YQ1:    73.fiE                                            8.4    8.7 +,,1 r,n* In...,..,
                                                                         ,.l.Y ,A,,,1   , YnCI""ra ikrkata:
et al..                                                                           deaths in premature
(52).                                                                           infants (p>0.05).

Russell     iBI':                                                                    t Includes abortion.
et al.,      <14Oi90 984 496             t27 t32                         t27    t65              stillbirth, and
(39).      =140/90 340 117              t14   ts                               63               neonatal death.
         >140/90 133 35              tzo   t11      { 41
                                                              145 1 314             t Blood pressure.

Tokutata    White                                                                        Data based on use of
(49).       2.555     743            t246 tll2                        t96   t151               cigarettes only.
        Nonwhite                                                                    t Includes stillbirths
          1,236     350            t174 t64                        t141   t1s3               and miscarriages.

Rutler       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 Perinatal 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


%
m

TABLE 5.--Human experimental data on smoking and pregnancy

Author.
ear.
country,
reference

Design of study                            Results                      comments

Sontag and
Wallace.
1935.
U.S.A. (45).

Fetal heart rate beforr and after smoking was   Average fetal heart rate before smoking ~8s 144.0.
studied Ii1 times in 5 patients.              The average fetal heart rate for the eighth to the
                                  twelfth minute after starting to smoke was 149.0.

Hlrddon et al.,
1961.
U.S.A. (14).

Carbon monoxide levels were measured in 50   (,I, Carbon  monoxide levels  were significantly
smokers and nonsmokers in a prenatal clinic.    (p<O.Ol ) higher in smokers than in nonsmokers.
Twenty-six paired maternal and umbilical vein   (b) Carbon monoxide concentrations in paired cord
blood specimens  wwr obtained at parturition    and maternal blood specimens were approximately
and tested for co levrls.                  equal.
                        ~-1 Oi rnrrying rapnrity  in rnrrl ?I$ m.aterz*!
                                 blood was reduced in smokers compared to non-
                                  smokers.

Heron. 1962,
New Zealand
(15).

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

-~~ -
Kumar and
ZOWkiS.
1963,
U.S.A. (?O).

The in rlir*o eftects of riaarette smoking on uterine
actively were studied in 1'7 pregnant gravidas
near term and not in labor. The in vitro effect
of nicotine on human pregnant and nonpreg-
nant myomrtriel strips was studied.

(a) CO levels in maternal and fetal blood were
higher in patients who smoked.
(b) Hespirntions in infants of mothers who smoked
took longer to be established and peripheral ey-
anosis w*s more common.

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

(a) In more than half (10/171. a definite increment
in uterine activity was noticed during cigarette
smoking.

(b) No oxrtoric effect of nicotine on myometrial
strips was noted.

Young and
Pugh
1963,
England (55).

Blood CO levels were studied in 19 full-term par-   CO content of umbilical vein blood at normal deliv-     Blood CO levels were
turient women. 16 of whom had normal deliv-    eries was .S2 and .36 volumes percent in infants      also studied in non-
e&s. Six of these smoked 10 to 20 cigarettes a    of mothers who smoked and mothers who did not      smoking male lake-
day. Mnternal blood was analyzed 15 to 30    smoke. as  compared with .33 and 28 volumes      ratcry workers in
minutes prior to delivery. Fetal blood was taken    percent,  rapeetively, in  the maternal venous      London and in
from the placental end of the umbilical vein.     blood.                                 males in Antarctica.

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

   Author,
    Year.
   country.                 Design of study                            Results
   reference                                                                           Comments


Mantell,          Cord bloods from 50 smokers and 50 nonsmokers   A decrease in carbonic anhydrase activity in the     Carbon monoxide is
1964,            were analyzed for carbonic anhydrase activity.    cord bloods of infants whose mothers smoked was
New Zealand                                                                           an inhibitor of
                                                noted.
(25).                                                                           carbonic anhydrase.



Seoppetta,         CO concentrations were measured in the venous   CO levels were higher in smokers than in non-
1968,            blood of 46 pregnant women, including smokers    smokers. CO concentrations were approximately
Italy (65).        and nonsmokers. Funicular venous blood was    the same in maternal and funicular venous blood.
               analyzed at the time of delivery.
       -
Younoszai et al.,    32 women with normal pregn+ncies were studied   (a) Mean CO saturation of Hb in the venous blood
1968,           of whom 16 smoked >20 cigarettes a day. Both
Canada (56).                                     of the cigarette smoking mothers at the time of
               groups of women had normal deliveries and    delivery was 8.3 percent and in the nonsmoking
               healthy infants. Biochemical changes in the first    mothers 1.2 percent. The corrffponding mean um-
               48 hours of life were studied in the infants.      hilical vein blood levels were 1.3 percent and .I
                                                percent.
                                 (b) The blood Ph. pCOz and bicarbonate and lac-
                                             tate values in both groups of infants were within
                                                normal limits.
                                            (c) The infants of smoking mothers showed a
                                               higher mean hematocrit and mild metabolic acid-
                                                osis.
__
Engel et al.,        37 experiments were performed on placental blood   Human placental blood has a lower relative affinity
1969,            samples obtained from 15 pregnancies to detcr-    for CO than adult hiowl. It was calculated that the
U.S.A. (9).        mint relative affinity of human fetal Hb for CO    affinity constant of fetal Hb was approximately
           and Oz.                            20 percent less than that of Hb A.

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

Author,
Year,
country.
reference

Nebert et al..
1969,
U.S.A. (92).

Welch et al.,
1969,
U.S.A. (51).

Design of study                           Results                      Comment.8

Aryl hydrocarbon hydroxylase activity was de-   Significantly higher (p<O.OOl) levels of aryl hydro-
termined in the placentas obtained from 97    carbon hydroxylase were found in women with
women at the time of childbirth: 46 of the    a history of cigarette smoking.
women smoked between 20 and 40 cigarettes per
day during pregnancy and 51 women were non-
smokers.

Benzpyrene hydroxylase and aminoazo dye:     Enzymes were found in the placentas from all 17
N-demethylase activity was measured in 17 hu-    smokers. No detectable activity was observed in
man placentas obtained after childbirth from    the placentas of nonsmokers.
smokers and in 11 human placentas obtained
from nonsmokers.


TABLE 6.-Animal experimental data on the effect of smoking and nicotine on pregnanq

Author,
yea=.
CalmtrY,
reference

Animal             Design of study

Results                  comments

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

Schoeneck,
1941,
U.S.A. (0).

Nishimura and
Nakai,
1958,
Japan (SZ).

Albino rat.

393 "young" from pregnant rats exposed to   The young of treated mothers were under-
tobacco smoke and 113 Young from preg-    weight; the young from nicotine injected
nant rats which received parenteral nico-    mothers were more underweight than those
tine were studied.                   from smoked mothers. Increased fetal wast-
                              age and neonatal deaths were observed in
                              treated animals as compared to controls.

Rabbit.









M0US.L

Smoke from one cigarette was blown into   (a) Offspring from "smoked" female rabbits
the nostril of healthy does by means of a    were smaller at birth than controls (17
catheter earh day. The does were "smoked"    percent).
daily throughout pregnancy and lactation.   (b) The stillbirth rate was 10 times as great
170 young from 28 litters of 7 "smoked"    in the "smoked" group.
does were studied. The offspring were not   (c) The mortality rate was greater in the
subjected to smoking at any time.         offspring of the "smoked" does.

230 pregnant mice were injected, parenter-   Nicotine had R lethal effect upon mice em-
ally, with nicotine. Animals were sacrificed    bryos and also had a tcrntogenic effect on
at term and mid-pregnancy to investigate    their skeletal systems.
the state of the pregnancy and the develop-
ment of the offspring.

113 "young" served as
controls.

Litters from the pre-
vious generation
served as controls.

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

Gatling.
1984,
U.S.A. (ZJ).

Chick embryo.

Chicken embryos were treated with doses of   Nicotine induced cephalic hematoma forma-
nicotine varying from 12 I.rg. to 1,000 $.    tion and central nervous system depression.
The effects of phenothiazinea. corticoste-
raids. and catecholamines were also studied.

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

   Author.
    Ye*=,
   countru,       Animal              Design of study                        Results                  comments
   reference

Becker and      Ret.         100 primipara pregnant rats received a sin-
King,                                               (a) Mortality was greater among pregnant   100 nonpregnant rats
                     gle heavy subcutaneous injection of nico-
1966,                                                  rats than among controls.               served as controls.
                      tine on the 21st day of pregnancy. one
U.S.A. (2).                                        (6) Pregnant rats showed more marked hy-
                      day prior to expected term delivery. Fetal    perventilation and less body temperature
                         wastage.  weight of newborns. neonatal    depression than controls.
                         deaths.  and pregnant animals' responses   (c) Delivery was delayed 2 to 4 days.
                         were noted.                    (d) The young weighed less than normal and
                                                 survived "poorly" during the first 48 hours
                                                       of life

King and       Rat.         Pregnant and nonpregnant rats were in-  Osborne-Made] rats LDSO:
Becker,                                                                      mg./kg.
                      jetted subcutaneously with heavy doses of
1966,                                                    Pregnant adults  27.4
                       a 2 percent solution of pure nicotine for
U.S.A. (17).                                               Nonpregnant females  _. 33.6
                the purpose of determining the LD60 for     Neonates  14.56
                     females of this strain (Osborne-Mendel).
                 The LDSO for neonates of this strain was   Pregnant rats tended to die significantly later
                        also determined within 6 to 24 hours of    than nonpregnant rats, hut their tolerance
                         normal birth.                      for nicotine WBS less.
-
Mosier and      Rat.         Alternate pregnant rats received oral nico-
Armstrong,                                          (a) On higher nicotine intake. there was
                     tine in the dosage of either .05 mg./g. or
1967,                                                  lowering of food intake.
                    .lO mg./g. of food. On the 20th day, the
U.S.A. 07).                                         (b) There was no change in fetal weight or
                      rats were killed and the fetuses were re-    length on either concentration.
                         moved.                       (c) There appeared to be no effect on the
                                                 number of live and "absorbing" fetuses.


TABLE 6.-Animal experimental #data on the effect of smoking and nicotine on pregnanq (cont.)

Author,
ye*=.
cour.trY,
reference

Animal              Design of study

Results                  C0mments

Becker et al..
196%
U.S.A. (8).









Tjiilve et al..
1968,
Sweden (48).

Rat.










MO"%?.

Controlled populations of pregnant rats were   (a) With the lower dosage of nicotine, the   Control rats were in-
injected twice daily with doses of nicotine    birthweights, survival, and developmental    jetted with saline.
varying from .5 mg./kg. to 5 mg./kg. Ef-    status did not differ from controls.
fects on pregnant rats and newborn were   (b) With thhe higher dosage, pregnant rats
studied.                      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 ap~)ea~ance.
                          There were no abortions and no premature
                              Young.

The passage of "C-nicotine and its metabo-   (a) Nicotine and its metabolites accumulated
lites from the mother into the fetuses was    in the placenta and passed into the fetus.
studied.                      (b) 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
Sieber,
1969,
U.S.A. (II).

Rabbit.

( l-methyl-"C) -caffeine and G-(3H) -nicotine   (a) One hour after ("HJ-nicotine treatment,   Radioactivity in
were given to 6-day pregnant rabbits. The    a high level of radioactivity compared with    uterine secretion
dose for nicotine was 50 Pg./kg.. intra-    that in maternal plasma was found in    was not found in
venous, producing plasma levels similar to    uterine secretion (ratio: 103).          nonpregnant curl-
those attained in man by cigarette smok-   (b) Unchanged radioactive nicotine and some    tro1s.
ing (.06-.09 pz/ml.).              of its metabolites were present in the pre-
                         implantation blastoeyst (blastocyst/plasma
                             ratio z 3)

e
w


f
P

Author,
year.
co"ntrY.
reference

TABLE B.-Animal experimental ,data on the effect of smoking and nicotine on pregnancy (cont.)



  Animal              Design of study                        Results

comments

Welch et al.,
1660,
U.S.A. (52).

Rat.

Rats which were pregnant for 18 days were
given 40 ma/kg. of 3.4 -benzpyrene: 1,2-
benzanthracene; 1.2.5.6 -dihenzanthracene;
chrysene: 3,4 -benzofluorene: anthracene;
pyrene: fluoranthene; perylene; or phen-
anthrene orally,  and BP-hydroxylase sc-
tivity in the placenta was measured 24
hours later.

All compounds tested stimulated:          Placenta from control
BP-hydroxylase activity in the placenta.    rats possessed very
1,2-benzanthracene wss the most active in-    low BP-hydroxylase
ducer of BP-hydroxylsse.               activity.

Younossai
et al.,
:3ca,
Canads
(57).

Canada (52).
Kirschbaum
et al.,
1970,
U.S.A. (18).

Rat.

Pregnant rsts were exposed to smoke from
regular tobacco cigarettes. non-nicotine cig-
erettes mede with Iettnw leaves nnd 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
X percent by exposing the animals to smoke
5 times s day st Z-hour intervals. Other
groups of rats were fed restricted diets,
receiving from 65 to 80 percent of the
food consumed by control rats.

Sheep.

Intravenous injection of fresh solutions of
nicotine, and simulated smoking of eiga-
ret&,  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.

(a) Fetuses of all smoked rats were growth   Control rats were
retarded compared to control animals, those    handled in the ssme
exuosed to tobacco smoke (cigarette) being    wny except that
most severely affected.                they were not ex-
(b) The amount of food consumed by rats    posed to cigarette
exposed to cigarette smoke wss reduced.     smoke.
(e) There wss B 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.

-

No significant changes were observed as a   Eath experiment in-
result of either nicotine administration or    eluded s control
smoke inhalation.                  period during which
                              attainment of a
                              steady state was
                              the aim.


isotope studies in mice (18) 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.

(3) BECKER, R. F., LITTLE, C. R. D., KING, 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 lOO(7) :
   957-968, April 1, 1968.

(4) BUNCHER, C. R. Cigarette smoking and duration of pregnancy. American
   Journal of Obstetrics and Gynecology 103 (7) : 942-946, April 1, 1969.
(5) BUTLER, 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 12-181970, 11 pp.

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

415


(8) DUFFUS, G. M., MACGILL:.VRAY, I. The incidence of pre-eclamptic
  toxaemia in smokers and nonsmokers. Lancet l(7550) : 994-995, May
   11, 1968.
(9) ENGEL, R. R., RODKEY, F. I;., O'NEAL, J. I)., COLLISON, H. A. Relative
   affinity of human fetal hemoglobin for carbon monoxide and oxygen.
   Blood 33(l) : 37-45, January 1969.

(10) ESSENBERG, J. RI., SCHWIND, J. V., PATRAS, A. R. The effects of nicotine
   and cigarette smoke on pregnant female albino rats and their ofi-
   springs. Journal of Laboratory and Clinical Medicine 25: `708-717,
    1940.

(1j) FABRO, S., SIEBER, S. M. Cafleine and nicotine penetrate the pre-implan-
   tation blastocyst. Nature 223(5204) : 410-411, July 26, 1969.
(12) FRAZIER, T. M., DAVIS, G. H., GOLDSTEIN, H., GOLDBERG, I. D. Cigarette
   smoking and prematurity A prospective study. American Journal of
   Obstetrics and Gynecology U(5) : 988-996, May 1961.
(13) GATLIEG, R. R. Effect of nicotine on chick embryo. Archives of Pathology
   W(6) : 652-657, December 1964.

(24) HADDON, W., JR., NESBITT, R. E. L., GARCIA, R. Smoking and pregnancy:
   Carbon monoxide in blood during gestation and at term. Obstetrics
   and Gynecology 18(S) : 261-267, September 1961.
(15) HERON, H. J. The effects of smoking during pregnancy: A review with a
   preview. New Zealand Me,dical Journal 61:545-548, November 1962,
(16) HERRIOTT, A., BILLEWICZ, M'. Z., HYTTEN, F. E. Cigarette smoking in
   pregnancy. Lancet 1: 771-773, April 14, 1962.
(17) KING, J. E., BECKER, R. F. Studies on nicot.ine absorption during preg-
   nancy. I. LI);,: for pregnant and nonpregnant rats. American
   Journal of Obstetrics and Gynecology 95(4) : 508-514, June 15, 1966.
(18) KIRSCHBAUM, T. H., DILTS, I'. V., JR., BRINKMAN, C. R., III. Some acute
   effects of smoking in sheer1 and their fetuses. Obstetrics and Gynecol-
   ogy 35(4) : 527-536, April 1970.
(19) KIZER, S. Influencia de1 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) :
    595-643, 1967.

(20) KU&TAR, D., ZOURLAS, P. A. Studies on human premature births. II. In
    viva 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.

(21) LASZLO, V. A dohanyzas karls hatasai a gestatios folyamatokra. (The
   deleterious effects of smoking on the sequences of gestation.) Magyar
   Noorvosok Lapja 32(2) : 16;3-167, March 1969.
(2~) LONGO, 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(l) : 313-341, October 5, 1970.
(23) LOWE, C. R. Effect of mothers' smoking habits on birth weight of their
    children. British Medical Journal 2: 673-676, October 10, 1959.
(24) MACMAHOX, B., ALPERT, M., SUBER, E. J. Infant weight and parental
   smoking habits. American Journal of Epidemiology 82(3) : 247-261,
    November 1963.

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

416


(26) MCDONALD, R. L., LANFORD, C. F. Effects of smoking on selected clinical
   obstetric factors. Obstetrics and Gynecology 26 (4) : 470-4'75, October
     1965.
(27) MOSER, 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.
(28) MULCAHY, R., KNAGGS, J. F. Effect of age, parity, and cigarette smoking
   on outcome of pregnancy. American Journal of Obstetrics and Gyne-
   cology lOl(6) : 844-849, July 15, 1968.
(29) MULCAHY, R., MURPHY, J., MARTIN, F. Placental changes and maternal
   weight in smoking and nonsmoking mothers. American Journal of Cb-
    stetrics and Gynecology 106(5) : 703-704, March 1, 1970.
(JO) MURDOCH, D. E. Birth weight and smoking. Nebraska State Medical
    Journal 48(11) : 604-606, November 1963.
(31) 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) : 1763-1769, October 1969.
(32) NISHIMURA, H., NAKAI, K. Developmental anomalies in offspring of
    pregnant mice treated with nicotine. Science 127(3303) : 877-878,
    April 18, 1958.
(33) O'LANE, J. M. Some fetal effects of maternal cigarette smoking. Obstet-
   rics and Gynecology 22(2) : 181-184, August 1963.
(34) 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.
(35) 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.
(36) 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.
(37) ROBINSON, P. `Yshwn nshym Bwrmmywt vzmn 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): 37-39,1965.
(38) RUSSELL, C. S. Another hazard of smoking. New Scientist 41(631) : 64-
    65, January 9, 1969.
(59) 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.
(40) RUSSELL, C. S., TAYLOR, R., MADDISON, R. N. Some effects of smoking ifi
   pregnancy. Journal of Obstetrics and Gynecology of the British Com-
   monwealth 73 : 742-746, October 1966.
(41) SAVEL, L. E., ROTH, E. Effects of smoking in pregnancy: -4 continuing
   retrospective study. Obstetrics and Gynecology 20 (3) : 313-316,
    September 1962.
(42) SCHOENECK, F. J. Cigarette smoking in pregnancy. New York State
   Journal of Medicine 41: 1945-1948, October 1, 1941.
(4.3) SCOPPETTA, V. Sul contenuto di ossido di carbonio nel sangue circolante
   di gestanti fumatrici. (C  b
                        ar on monoxide content in the blood circu-


(44)

(4`5)

(46)

(47)

(48)

(49)

(50)

(51)



(52)

(53)



(54)



(55)



(56)

(57)

(58)

lating in pregnant smckers.) Archivio di Ostetricia e Ginecologia
`73 (3) : 369-375, 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.

SONTAG, 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., LANGWORTH, J. T. The relationship of antenatal and post-
natal factors to sudden unexpected death in infancy. Canadian Medi-
cal Association Journal !)4: 1165-1171, May 28, 1966.
TERRIS, M., GOLD, E. M. Ar epidemiologic study of prematurity. I. Rela-
tion to smoking, heart volume, employment, and physique. American
Journal of Obstetrics and Gynecology 103 (3) : 358-370, February 1,
1969.

TJALVE, H., HANSSON, E., SCNMITERLOW, C. G. Passage of `"C-nicotine
and its metabolites into mice foetuses and placentae. Acta Pharma-
cologica et Toxicologica 26(6) : 539-555, 1968.
TOKUHATA, G. K. Smoking in relation to infertility and fetal loss.
Archives of Environmental Health 17 (3) : 353-359, September 1968.
UNDERWOOD, P. B., HESTEI:, L. L., LAFII-~E, 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.

UNDERWOOD, P. B., KESLER, K. F., O'LANE, J. M., CALLAGAN, D. -4.
Parental smoking empirically related to pregnancy outcome. Obstet-
rics and Gynecology 29 (3 ) : 1-8, January 1967.
WELCH, R. M., HARRISON, E'. E., GOMMI, B. W., POPPERS, P. J., FINSTER,
M., CONNEY, A. H. Stimulatory effect of cigarette smoking on the
hydroxyiation 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 : Jamcss, G., Rosenthal, T. (Editors). Tobacco 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, I. M., PUGH, L. G. C. E. The carbon monoxide content of foetal
and maternal blood. Journal of Obstetrics and Gynecology of the
British Commonwealth 7C (4) : 681-684, 1963.
YOUNOSZAI, M. Ii., KACIC, A., HAWORTH, J. C. Cigarette smoking during
pregnancy: The effect upem the hematocrit and acid-base balance of
the newborn infant. Canadian Medical Association Journal 99(5) :
197-200, August 3, 1968.

YOUNOSZAI, M. K., PELOSO, J., HAWORTH, 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
2,090 cases. Obstetrics and Gynecology 21(4) : 405-411, April 1963.

418


CHAPTER 6

Peptic Ulcer


                                     Page
Summary  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   423

References  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   429

LIST OF TABLES

1. Smoking and peptic ulcer disease morta1it.y . . . . . . . . . . .   424
2. Summary of results of retrospective and cross sectional
studies of peptic ulcer and smoking . . . . . . . . . . . . . . . . . .   425
3. Methods used in retrospective and cross sectional studies
of peptic ulcer and smoking . . . . . . . . . . . . . . . . . . . . . . . .   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
ulcer 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


TABLE L-Smoking and peptic ulcer disease mortality
(Numbers in parentheses represent actual number of deaths)
SM L Smokers   NS = Nonsmokers   G = Gastric   D = Duodenal

Author,
ye*=,
country.
reference

Number and
type of
population

Doll and   41,000 male
Hill,      British
1964,     physicians.
Great
Britain
(5.6).

    Data
  collection


Questionnaire
and follow-up
of death
certificate.

                              Mortality ratios
Actual
deaths                Cigarettes/day       Pipe         Cigar         comments
SM     NS             Gastric Duodenal Gastric Duodenal Gastric Duodenal

  54                   tPeptic             Pipe/cigar         t Tots1 number of
         NS              1.00                 4.00             deaths were too
         All cigarette        7.00                               small to allow
         l-14 gs. per day     2.33                              separate examin-
         15-24           10.33                               ations.
         >25             7.33

Hammond, 440.658      Interviews by   G-83 11 NS 1.00 (11) 1.00 (22)
,966.      males 35-     ACS volunteers D-93 .22 SM (aae 45-64) 2.95)  -.. 2.861 ^I.
U.S.A.    84 years of             SM (age65-79) 4.061 ""' 1.50]`=
(11).     age in 26
        states.

Kahn,     U.S. male     Questionnaire   678  . ,. .12 NS . 1.00(12) l.OO(26) l.OO(12) 1.00(26) l.OO(12) 1.00(26)
1966,     veterans      and follow-up  D-119 . . ...26 SM                    2.84 (4) 1.59 (5) 2.90 (7) 1.58 (8)
U.S.A.    2.265.674     of death               Allcigarette 4.13(39) 2.98(57)
(Id).     person years.   certificate.               l-9  __._. 3.96 (6) 2.30 (6)
                                    lo-20 __________ 2.77(13) 2.74(26)
                                      21-39  . :. 6.46(X) 3.98(22)
                                      >39  . . . . . . . ..11.6? (6) 2.89 (3)

Weir and   68,163 males   Questionnaire       44      NS  .    1.00                            No deaths from
Dunn. in various     and follow-up            All cigarette      0.53                             gastric ulcer oc-
1970.     occupations    of death               210  1.00    0.40                             curred in "on-
U.S.A.    in California.   certificate.              -c20  . 1.67    0.69                             smokers and risk
(IS).                                 230 _. 2.38    0.32                            of those smoking
                                                                           z?lO/day wss set
                                                                           at 1.00. NS in-
                                                                           cluded pipe.
                                                                           cigar, and
                                                                           .x-smokers.


Author,
Year,
e"u"trY,
reference

SW   Number

CZWes
  Method of selection

Numhrr

              

C"ntr"ls                     C"mme"ts
Method of selection

Barn&t,       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. Ulcer diagnosis prob-
                                                                           ably well established.

Trowell,
1934,
England
(31).

M      50 Duodenal   Not stated

Allibone and
Flint,
195%
England
(I).

MandF 107

Consecutive admissions to hospital
of patients with gastric and du-
odenal hemorrhage or perforation.

Doll et al.,
1958,
England
(7).

M and F  327 Gastric.    Ulcer patients in Doll and Hill Lung
      33X Duodenal.    Cancer Study plus additional pa-
                tients in Central Middlesex Hospi-
                 tal.

Edwards et al.,   M      1,137        Men aged 60 and over on 11 General
1959,                         Practioners' lists were examined
England                       and interviewed by these practi-
(8).                        tioners. Represents about 84 per-
                            cent of all such me" on these
                            lists.

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

400   Selected at random from wards of   1. Interviewed by inves-
     a general hospital.             tigator.
                          2. Ulcer diagnosis con-
                           firmed by X-ray and/or
                             S"Tgery.

107   Matched by we, sex. and time of   Patients and controls in-
     admission from acute general sur-    twviewed by same
     pical emergency admissions.       observer.

                     -~-.___~ ~~
1.143   Patients with non-ulcer diseases.   1. Same interviewers and
      Each case matched with 2 co"-    questionnaire in cases
      trol patients of same sex, B-year    and controls.
      am ProuP,  and 5llr"c type of   2. Ulcer diagnosis proh-
      place of residence. Male patients    ably well established.
      matched by social class.

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