List of Figures

Figure 1.—Mean birth weight for week of gestation according
to maternal smoking habit: control week singletons__.______
Figure 2.—Percentage distribution by birth weight of infants of
mothers who did not smoke during pregnancy and of those
who smoked 1 pack of cigarettes or more per day...
Figure 3.—Percentage of pregnancies with infant weighing less
than 2,500 grams, by cigarette smoking categorv__..______-
Figure +.—-Average birth weight by maternal smoking habit
(a) before current pregnancy and (b) during current preg-
nancy
Figure 5.—Percent of low birth weight white infants by smok-
ing status of their mothers_.-----------.-..
Figure 6.—Neonatal mortality rates among single white births
in hospitals (by detailed birth weight and specified gestation
groups: United States).00
Figure 7.-Perinatal mortality rate per 1,000 total births by
cigarette smoking category

List of Tables

Table 1.—Infant birth weight by maternal and paternal smok-
ing habits.-_- 22-08
Table 2.—Effect of carbon monoxide exposure of pregnant
rabbits on birth weight.--.-0.---0 0
Table 3.—Comparison of the perinatal mortality for infants
weighing less than 2,500 grams, of smokers and nonsmokers.
Table 4.—Effect of carbon monoxide exposure of pregnant rab-
bits on birth weight and neonatal mortality_..---.2 22288,
Table 5.—Proportion of male infants delivered to smoking and
nonsmoking mothers_-._-...2- 22-8
Table 6.—Relative risk of congenital malformation for infants
of cigarette smokers and nonsmokers, comparing available
studies with regard to study design, study population, sample
size, number of infants with malformations, and definition of
malformation

Page

104

110

113

128

129

111

117

127

133

136

137

101
Introduction

Cigarette smoking is a common habit among women of child-bearing
age in the United States. In 1970, approximately one-third of Amer-
ican women of child-bearing age were cigarette smokers. The percent-
age of U.S. women who smoked throughout pregnancy is not definitely
known, but is presumably lower, probably in the neighborhood of 20
to 25 percent. With a large fetal population at potential. but prevent-
able, risk, the relationship between cigarette smoking and the out-
come of pregnancy has been the focus of considerable and continuing
research.

Every investigator who has examined the relationship has confirmed
that the infants of women who smoke during pregnancy have a lower
average birth weight than the infants of women who do not smoke
during pregnancy. Much evidence indicates that cigarette smoking
during pregnancy causes this reduction in infant birth weight. Several
investigators have demonstrated that the fetal and neonatal niortality
rate 1s significantly higher for the infants of smokers than for the
infants of nonsmokers: other investigators have not found higher mor-
tality for smokers’ infants. Studies of the association bet ween maternal
cigarette smoking and congenital malformations have produced con-
flicting results,

The following is a review of work previously reported and recent
studies which bear on the relationships between cigarette smoking and
different outcomes of pregnancy. In addition, the chapter includes a

review of the relationship between cigarette smoking and lactation.

Smoking and Birth Weight

Epidemiological Studies

Cigarette SmoKixne anp THE Low-Brrtu-Weient INrant

In 1957, Simpson (99), using a retrospective study desion. deter-
juined that among 7.499 women in San Bernardino County. Calif.. the
delivery of infants weighing less than 2.500 grams was nearly twice as

103
frequent among cigarette smokers as among nonsmokers. Subsequently,
Lowe (46) studied 2,042 women in Birmingham, England, and dem-
onstrated in his retrospective study that the infants of smoking
mothers were delivered only slightly earlier (1.4 days on the average)
than those of nonsmokers. He further noted that for gestations of 260
days and over, the infants of smokers were consistently lighter in
weight during each week of gestation than those of the nonsmokers,
This finding has been confirmed since, and figure 1 from the British
Perinatal Mortality Study (73) provides illustration of this
relationship.

Given the nearly constant disparity present between the birth
weights of the infants of smokers and nonsmokers for gestations of 260
days and over, but absent prior to that time, and given the similar
birth weights of infants of nonsmokers and of women who gave up
smoking early in pregnancy and did not begin to smoke again, Lowe
inferred that the influence of smoking upon birth weight might lie
mainly in the later months of pregnancy. He emphasized the tentative
nature of this conclusion, since the number of infants with a gestation
of less than 260 days and the number of women who gave up smoking
early in the pregnancy and did not begin to smoke again were both
small.

Figure 1.—Mean birth weight for week of gestation according to maternal smok-
ing habit: control week singletons.’

 

 

; 3650

» _—* eer 3400
o oT” n
gS) Non: or 3150 s
3 smokers -7 4 ha
= 105 ee s
oo P 7 ~
= 4 2D Smokers 4 2900 &
oi &
$ ” $
3 95 Le | 2650 §
= " =

85 F + 2400

75 be . F ‘ n . 2150

 

 

36 37 38 39 40 41 42 43+

Gestation in completed weeks

*This term refers to singleton births in England, Scotiand, and Wales occurring during the
week of March 3-9, 1958, which are included in the Perinatal Mortality Survey. These
comprise 97 percent of ali births notified in England and Wales or registered in Scotland
during this week.

SOURCE: Butler, N. R., Alberman, E. D. (13).

104
Lowe found that the infants whose mothers smoked throughout
pregnancy weighed, on the average, 170 grams less than those whose
mothers did not smoke. In addition, he noted that the entire distribu-
tion of weights of infants of smokers was shifted to the left (toward
lower weights) relative to that for the infants of nonsmokers. This
finding, too, has been confirmed by other investigators, Figure 2 offers
an illustration fron: MacMahon, et al. (49).

Given that the infants of smokers and nonsmokers differed only
slightly with respect to the duration of gestation. Lowe concluded that
the lower birth weight of smokers’ infants must be attributed to a
direct retardation of fetal growth. In other words, on the basis of his
data, the infants of smokers were small-for-dates rather than truly
premature.

Many investigators have subsequently confirmed this point (12, 14,
“5, 35,09, 78, 85, 113). Buncher (12), in a study of 49,897 births among
U.S. naval wives, in the same population studied by Underwood, et al.
(100), found that the infants of smokers were, on the average, de-
livered only 1 day earlier than those of nonsmokers. This finding
accounted for only 10 percent of the discrepancy in birth weight be-
tween the two groups of infants. The remainder of the studies resulted
in the detection of either similar variations in gestational length or
no average difference. In a recent study, Mulcahy and Murphy (56),

Figure 2.—Percentage distribution by birth weight of infants of mothers who did
not smoke during pregnancy and of those who smoked 1 pack of
cigarettes or more per day.

INFANT WEIGHT AND PARENTAL SMOKING HABITS

i ee ee

 

— ¥
10 —~ Nonsmokers

aati Smokers ip
é

Percent

 

 

 

4 5 6 7 8 9 10 11

BIRTH WEIGHT (SCALE IN POUNDS; INTERVALS OF 4 02Z.)
SOURCE: MacMahon, et al. (49).

105
in a sample of 5,099 Irish mothers, concluded that although the babies
born to cigarette smokers were delivered slightly earlier than those
of nonsmokers, independent of age and parity, the direct effect of
smoking in retarding fetal growth was more significant.

The following points, based upon the results from many different
studies, can be made about the relationship between cigarette smoking
during pregnancy and lower infant birth weight:

1. Women who smoke cigarettes during pregnancy have a higher
proportion of low-birth-weight infants than do nonsmokers. This
excess of low-birth-weight infants among cigarette smokers pre-
dominantly consists of infants who are small-for-gestational age
rather than gestationally premature.

2. The entire distribution of birth weights of the infants of ciga-
rette smokers is shifted toward lower weights compared to the
birth weights of the infants of nonsmokers,

3. The birth weights of the infants of cigarette smokers are con-
sistently lighter than those of the infants of nonsmokers when
the birth weights of the two sets of infants are compared within
groups of similar gestational age beyond the 36th week of
gestation.

The results of the studies which have been considered so far identify
a relationship between cigarette smoking and lower infant birth
weight and illustrate some aspects of that relationship, but do not
indicate whether the association is causal or indirect. The succeeding
two sections of this chapter contain evaluations of the available evi-
dence which bears upon the nature of the association between cigar-
ette smoking during pregnancy and the incidence of small-for-dates
infants.

Eviwence For a Cavsan Association BeTwren CIGARETTE SMOKING
AND SMALL-FoR-Dates INFANTS

Evidence previously reviewed in the 1971 and 1972 reports on the
health consequences of smoking (/02, 102) suggests that cigarette
smoking is causally associated with the delivery of small-for-dates
infants. The following is a summary of this evidence:

1. The results from all 80 studies in which the relationship between
smoking and birth weight was examined have demonstrated a strong
association between maternal cigarette smoking and delivery of low-
birth-weight infants. On the average. the smoker has nearly twice the
risk of delivering a low-birth-weight infant as that of a nonsmoker

106
(3, 13, 17, 20, 25, 29, 35, 42, 43, 46, 47, 49, 57, 58, 59, 65, 70, 72, 73,
77,78, 80, 83, 85, 90,95, 99, 100, 113,118).

2. The strong association between cigarette smoking and the de-
livery of small-for-dates infants first demonstrated with results from
studies of retrospective design (3, 13, 17, 35, 46, 47, 49, 57, 58, 59, 65,
70,72, 73, 77, 80, 85, 90, 95, 99, 100, 118) has been repeatedly confirmed
subsequently by data from studies of prospective design (20, 25, 29, 42,
43,78, 83,113).

3. A strong dose-response relationship has been established between
cigarette smoking and the incidence of low-birth-weight infants (25,
43, 46, 49, 100, 113).

4. When a variety of known or suspected factors which also exert an
influence upon birth weight have been controlled for, cigarette smok-
ing has always been shown to be independently related to low birth
weight (1, 13, 25, 43, 46,73, 78,83).

0. The association has been demonstrated in many different coun-
tries, among different races and cultures, and in different geographical
settings (13, 17,25, 29, 36, 42. 43,59, 73, 78, 80, 113).

6. Previous smoking does not appear to influence birth weight if
the mother gives up the habit prior to the start of her pregnancy (25.
46,49, 113).

7. The infants of smokers experience an accelerated growth rate
during the first 6 months after delivery, compared to infants of
nonsmokers. This finding is compatible with viewing birth as the re-
moval of the smoker's infant from a toxic influence (83).

8. Data from experiments in animals have documented that ex-
posure to tobacco smoke or some of its ingredients results in the
delivery of low-birth-weight offspring (7, 8, 9, 23, 40, 87, 117).

Several recently published studies have provided additional sup-
porting evidence for a causal relationship between cigarette smoking
and small-for-dates infants. The Ontario Perinatal Mortality Study
(66) was conducted among 10 teaching hospitals during 1960 and
1961. The authors of this retrospective study of 50,267 births demon-
strated a significant excess of infants weighing less than 2,500 grams
among cigarette smokers as compared with nonsmokers (P<0.001).
Smoking was significantly dose-related to the percentage of preg-
nancies terminating in the delivery of a low-birth-weight infant
(fig. 3).

Niswander and Gordon (63) have recently reported data from the
Collaborative Perinatal Study of the National Institute of Neuro-
logical Diseases and Stroke. In this prospective study of 39,200 preg-
nancies, which were nearly equally divided among black and white
Women, the authors found a significant dose-related excess of low-
birth-weight infants among smokers of both groups, compared to
nonsmokers of the same race.

107
Figure 3.—Percentage of pregnancies with infant weighing less than 2,500
grams, by cigarette smoking category.

 

-_
nD
°

12.0 F

 

11.0 F

10.0 fF

9.0 F

@

Oo
“I
N

 

 

 

 

 

 

 

 

 

 

 

 

U;
2 7.0 fF YY) Vz
2 6.0 + Z V7
3.0 | Y “7 V2
2.0 + Y Y V2
0.0 LZ Y) LZ
Nonsmoker <1 pack =1 pack
per day per day
Number of

infants weighing
<2,500 grams: 1,322 1,186 793
Total births: 28,358 15,328 6,581

(P <0.001)

SOURCE: Ontario Department of Health (66).

108
Rantakallio (76) carried out a prospective study of 11,905 single
births in Finland. Cigarette smoking mothers had significantly more
infants weighing less than 2,500 grams than did nonsmokers
(P<0.00L).

Rush and Kass (82), in a prospective study of 1,040 pregnancies in
Boston, Massachusetts; Domagala. ct al. (19), in a retrospective study
of 1,832 pregnancies in Poland; and Mukherjee and Mukherjee (54),
in a retrospective study of 2,886 pregnancies in India, each found a
significantly higher incidence of low-birth-weight infants among
cigarette smokers,

Butler, et al. (25) have further analyzed the British Perinatal Mor-
tality Study data. Analysis of the 16,994 questionnaires revealed that
40.8 percent of the women were cigarette smokers before pregnancy,
After the fourth month, this percentage hal decreased to 27.4 per-
cent. Given the large number of women in the study, and the sig-
nificant changes in smoking behavior which occurred, Butler, et al.
found it possible to consider the effect of a change in smoking be-
havior on birth weight between the beginning of the pregnancy and
the fourth month (after which smoking behavior was reportedly
stable), The authors stated, “If smoking itself (rather than the
type of woman who smokes) has a deleterious effect on the fetus,
it would be reasonable to expect the mothers who gave up smoking
during pregnancy to show differences in the birth weight and peri-
natal mortality of their offspring compared with those who continued
tosmoke.” Their results are presented in figure 4. The birth weights
by smoking categories were estimated by using a main effect model
without mediating variables, However, the anthors reported that when
the mediating variables (social class, maternal age, parity, maternal
height, sex of infant, gestational age, and perinatal mortality) were
allowed for, the results of the analysis were very similar. The effect
of cigarette smoking before pregnancy was insignificant compared to
that of smoking regularly after the fourth month of gestation. The
authors concluded, “The finding that a change in maternal smoking
habits during pregnancy had the effect of putting the baby into a
birth weight and perinatal mortality category associated with the new
smoking habits points toward some kind of cause-effect. relationship.
*** This finding is further strengthened by the birth weight analysis
which shows that the diminution in birth weight of the offspring of
smoking mothers persists and is indeed little changed when allowance
7 been made for a number of other social and obstetric mediating
actors.”

109
Figure 4.—Average birth weight by maternal smoking habit (a) before Current
Pregnancy and (b) during current pregnancy.

Number of Cigarettes /day
in current pregnancy,
after the fourth month

3,400 F of gestation
NN 3

 

 

 

 

”
£
£3,300 }
£
2 1-4
=
t
6B 3,200+
oo
2
2
3,100 +
lL 1 ] l
0 1-4 5-9 10-19 20-30 Total
Number of cigarettes /day before current pregnancy pis
1,67]

SOURCE: Adapted from Butler, et al. (15).

EvinEncE ror AN INpIRECT AssocraTion Between CIGARETTE SMOKING
AND SMALL-For-Datzs Inrants

Yerushalmy (1/3, 114, 115 ) has suggested that smoking is an index
to a particular type of reproductive outcome and thus does not play a
causal role in the production of small-for-dates infants. He has de-
veloped several lines of support for this hypothesis, from an analysis
of data from the prospective investigation of 13,083 mothers in the
Oakland Child Health and Development Study. He has emphasized
that ineffective randomization and the phenomenon of self-selection
complicate the development of appropriate inferences with regard
to causality. Such difficulties do not prevent the identification of
causal associations, but they demand careful and critical analysis of
the data. Yerushalmy has questioned the causal nature of the relation-
ship between cigarette smoking and small-for-dates infants because
of: (a) The relationship between the smoking habit of the father
and low birth weight of the infant, (b) behavioral differences between
smokers and nonsmokers, and (c) comparison of the birth weights

110
of a woman’s infants born during the periods when she smoked ciga-
rettes and when she did not.

Yerushalmy (//4) has stated that the smoking habit of the father
could not reasonably be related to the birth weight of the infant. From
preliminary data derived from the study, however, he determined
that there was an increased incidence of low-birth-weight infants
when the fathers smoked and, moreover, there was an apparent dose-
tesponse relationship as found for maternal smoking. However, he
noted that only when both the husband and the wife smoked was the
incidence of low-birth-weight babies increased. He felt that these
findings supported the conclusion that smoking was a marker of
types of individuals and not a eausal factor for low birth weight.
Other investigators have since examined this relationship (49, 100),
but none has confirmed an independent association for paternal
smoking. The association hetween paternal smoking and birth weight
appears to be an indirect one. Paternal and maternal smoking be-
havior are highly correlated and maternal smoking is strongly related
to infant birth weight. Underwood. et al. (707) studied 48.505 women,
their husbands* smoking behavior, and the relation with birth weight
(table 1). If the mother was a nonsmoker. then the father's smoking
had no influence on the birth weight of the infant.

Tape 1.—Jnfant birth weight by maternal and paternal smoking habits

 

Fathers (nonsmoking mothers)

  

 

Cigarettes per day rans! ‘Birthweight (grams) _

Number -- Sse Number 9 ---—- -—--—--~-—~-~

Meu Ditferepce Mean Difference?

None_- 24, 865 3,595 0 9, 547 3, 396 0

Ito 10-02 7,609 3, 286 109° 3,493 3, 389 7

M to 380.0222 14,450 3,196 199 10,403 3, 891 5

?30. 1, 570 3, 182 213 1, 330 3, 393 3
ee

 

' Nonstnoker niinus smoker.
a -
Source: Underwood, et al. (199),

Yerushalmy (7/5) pointed out that other investigators had found
marked differences between smokers and nonsmokers. In his own
‘tudy, he found that nonsmokers sed contraceptives significantly
More frequently than did smokers. Moreover, a significantly higher
Proportion of smokers drank coffee, beer, ail whiskey. However, he
id not adjust for these variables in his analysis of the association
het ween cigarette smoking and Jower infant birth weight. Other in-
“estigators have also found differences between smokers and non-
“Hokers, For example, Frazier. et al, (25) found significant differences
n the distribution of parity, work history, education, and psycho-

WY
somatic complaint score between smokers and nonsmokers. However,
when smokers were compared with nonsmokers of the same parity,
education, work history, and psychosomatic complaint score, cigarette
smokers still had a significantly higher proportion of small infants
than did nonsmokers, As previously mentioned, whenever other factors
known or suspected to influence birth weight have been controlled,
cigarette smoking has always been demonstrated to have an inde.
pendent and significant effect.

Ounsted (69) offered evidence that the best predictor of the birth
weight of a mother’s future offspring was the birth weight of her
previous children. Herriott, et al. (35) found prematurity rates for
previous pregnancies among smokers to be markedly higher than
among nonsmokers, independent of parity, height, and social class,
Evidently a woman whose previous infants have been small tends to
continue to have relatively smaller than average infants in subsequent
pregnancies. The question is, will those infants be even smaller than
expected if she smokes?

Goldstein, et al. (28), in a comprehensive review, proposed a research
design in which a woman would serve as her own control to compare
outcomes of pregnancies during which she smoked with those during
which she did not with consideration of the effect of parity on the
outcome. Yerushalmy (2/2) has recently tested this type of research
design, using data from his Oakland Growth Study. With information
on the age at which a woman began to smoke cigarettes, her smoking
status during the pregnancy actually studied, her prior reproductive
experience, and the outcome of her present pregnancy, the author
compared the outcomes of pregnancy during periods of smoking and
nonsmoking using the woman as her own control. As the author noted,
“If smoking causes the increase in low-birth-weight infants, then the
incidence of low birth weight for infants born to smoking mothers
during the period before they acquired the smoking habit, should be
relatively low. If, on the other hand, the high incidence of low birth
weight is due to the smoker, then it should be high for infants of future
smokers also when they were born before their mothers started to
smoke.”

Yerushalmy then proceeded to compare the reproductive experiences
of four groups of women: (a) Those who smoked in none of their
pregnancies, (b) those who smoked in all of their pregnancies, (c)
those who were smoking now but previously had not smoked during
some pregnancies (future smokers), and (d) those who were ex-
smokers now but had previously smoked during some pregnancies.
These outcomes are shown in figure 5. The incidence of low-birth-
weight infants in the pregnancies of the future smokers, before they
started to smoke, was similar to that for women who smoked in every
pregnancy, which was significantly higher than that of infants from

112
mothers who had never smoked. He also noted that ex-smokers, during
the period before they quit, gave birth to relatively few low-birth-
weight infants; the incidence was significantly lower than for mothers
who smoked during all of their pregnancies. He concluded that the
findings cannot be easily reconciled with a cause-effect basis for smok-
ingand birth weight. He said, “Rather the evidence appears to support
the hypothesis that the higher incidence of low-birth-weight infants is
due to the smoker. not the smoking.”

There are several considerations which limit the interpretations
which can be drawn from this study. The information on smoking
lehavior of the women during past pregnancies was apparently de-
rived from the woman's age when she began to smoke, her smoking
behavior early in the study pregnancy, and the age at which she had
her prior pregnancies. Thus, if the woman reported that. she began
wnoking at a certain age, and that she was still smoking at the time of
the study, it was apparently inferred that she had smoked during all of
her pregnancies. Since no questions were specifically asked about actual
smoking behavior during each previous pregnancy, it is possible that
the woman indeed had not smoked during every pregnancy or that
the amount. or way she smoked had differed from current smoking

Figure 5.——Percent of low birth weight white infants by smoking status of their
mothers.

Gravidas’ smoking habits Percent low birth weight infants
in previous pregnancies

 

Nonsmoker *
(during all pregnancies) 5.3 2,529

Nonsmoker *

(future smoker) ss S—i«d 210
Smoker 8, }** 2,076

(during all pregnancies) 8.9 ,
Smoker “"

(future ex-smoker) | 651

2 4 6 8 10
Percent

Difference is statistically significant (P <0.01).
Difference is Statistically significant (P <0.02).

SOURCE: Adapted from Yerushalmy, J. (112).

 

 

 
habits. This would be important to know given the strong dose.
response relationship which has been established between cigarette
smoking and low birth weight, and would tend to make the reproduc.
tive outcomes for ex-smokers similar to those of nonsmokers, and
different from those of women who smoked in all pregnancies.

For ex-smokers, the age at which smoking began was not elicited,
Hence, some of the infants of ex-smokers may have been born before
their mothers acquired the smoking habit. This would also tend to
make the reproductive experiences of ex-smokers more like those of
nonsmokers and different from those of women who smoked in al]
pregnancies.

No direct adjustment for age, parity, and other variables was
reported, although Yerushalmy stated that the study population was
limited to the births that occurred to women at age 25 years or legs,
He noted that, “In order to adjust for parity, the same comparisons
were performed for firstborn infants only. The numbers were reduced
considerably, but the same tendencies as found above were noted.”
However, no data were presented. Primiparous births and births in
teenagers are strongly associated with the delivery of low-birth-weight
infants. If the pregnancies which occurred among future smokers
included a predominance of very young women and primiparous
births, the reproductive experiences of future smokers would tend to
be similar to those of women who smoked during all pregnancies, and
different from those of nonsmokers. In the absence of more precise
information on actual smoking behavior during pregnancy and more
rigorous adjustment for maternal age, this study does not provide
a critical test of the hypothesis that it is the smoking during pregnancy
which is responsible for the high proportion of small-for-dates in.
fants born to women who smoke.

Experimental Studies
Srupres 1y ANIMALS

‘Tobacco Smoke

Several investigators have demonstrated that exposure of pregnant
rats or rabbits to tobacco smoke leads to a reduction of birth weight
in the offspring, as compared to controls (23, 87, 117). Younoszai, et al.
(117) reported data from studies in rats which indicated that some
agent present in cigarette smoke other than nicotine was responsible
for the reduction in birth weight observed. The authors suggested that
carbon monoxide might also not be responsible for the retardation of

V4
fetal growth; however, the evidence presented was inadequate to
support a firm conclusion.

Haworth and Ford (33) recently extended the experiments of
Younoszai. A group of pregnant rats was exposed to cigarette tobacco
smoke for 6 to 8 minutes, five times a day, from days 3 to 20 of ges-
tation. These rats were compared with another group whose food
intake was restricted to the amount actually consumed by the tobacco-
exposed rats, and both were compared to a well-fed control group.
The animals in both experiments were killed on the 2ist day of
gestation, and weights of the entire body, the liver, and the kidney
of each fetus were recorded. The total average fetal weight of the
group exposed to tobacco smoke was significantly lower than that of
both the food-restricted and control groups. The fetal weights of the
latter two groups were quite similar. Protein and DNA analyses were
performed separately on the entire forebrains and hindbrains of the
fetuses and on the entire carcass. Both DNA and protein were sig-
ulficantly and proportionately reduced in the carcass and hindbrains
uf the animals exposed to tobacco smoke. This implies that cell number
was reduced and cell size was normal, and suggests that the exposure
to tobacco smoke either inhibited cellular proliferation or accelerated
cellular destruction.

Nicotine

Several workers have demonstrated that chronic injections of large
loses of nicotine into pregnant rats resulted in a reduction of birth
weight of the offspring (7, 8, 9, 23, 40). Other investigators have de-
'ermined that tritium-labelled nicotine injected into pregnant rabbits
ind C-labelled nicotine injected into pregnant mice crossed the
placenta to the developing embryo and fetus (89, 98). Kirschbaum,
ttal. (47) found no significant acute effects of small doses of nicotine,
‘hjected intravenously into near-term sheep, on blood gas composition,
pH, blood pressure, or heart rate in either the ewes or their fetuses.
The authors concluded that the influence of maternal smoking upon
the fetus must result from chronic effects or through the effects of
‘ther variables which they did not study.

_ Recently, Suzuki, et al. (94) evaluated the short-term effects of in-
lected nicotine on the cardiovascular performance, acid-base status,
‘nd oxygenation of pregnant female Rhesus monkeys and their infants
“Wing the second half of gestation using the mothers as their own
“ntrols, Nicotine was administered either as a single intravenous

dos . . . .
8e of 0.5 to 1.0 mg. or as a continuous infusion of 100 yug./kg. over
495-028 O—73 9

 

115
a 20-minute period. The injection of nicotine in the larger, single dose
into the mother produced a rise in maternal blood pressure and a
fall in maternal heart rate, and an immediate fall in both fetal blood
pressure and fetal heart rate followed by persistent hypotension and
tachycardia in the fetus. Subsequent to the injection of 1.0 mg./kg. of
nicotine into pregnant monkeys, in a single dose, significant changes
in the arterial blood of the older fetuses included a fall in pH, a rise
in base deficit, and a fall in oxygen tension. Carbon dioxide tension
remained unchanged. Nicotine injected directly into the fetus prompted
an immediate rise in fetal blood pressure and a fall in fetal heart
rate. These responses were similar to those previously seen in the
mothers following a direct injection of nicotine. The changes were more
prominent in older rather than in younger fetuses. The authors sum-
marized their findings by stating that: (a) fetuses in different ges-
tational stages are differentially responsive to a given dose of nico-
tine, probably because of the different stages of development of the
autonomic nervous system; (b) diminished intervillous space per-
fusion resulting from vasoconstriction in the uterine circulation ap-
pears to be mainly responsible for the fetal asphyxia following the
injection into the mother, because fetal hypotension and bradycardia
were not preceded by the transient hypertension seen following the
direct administration of nicotine to the fetus; (c) the differences be-
tween the results obtained by Kirschbaum and by Suzuki, et al. may
reflect either the considerable dosage differences or species differences;
and (d) the doses which the authors employed were much larger than
those which a human mother would absorb from usual cigarette smok-
ing, but that differences in tolerance to nicotine between the Rhesus
monkey and humans would imply that the dosages were, in fact, com-
parable and that, “Hence, it can be envisaged that the concentration
of nicotine which could be reached in the organism of a smoking
mother would reduce oxygen availability to the fetus.”

Carbon Monoxide

Longo (45) has reviewed the work of several investigators which
has demonstrated the transplacental passage of carbon monoxide from
mother to fetus in animals. A recent study which related CO to birth
weight was published by Astrup (?). He found that continuous ex-
posure throughout gestation of pregnant rabbits to different levels
of ambient carbon monoxide resulted in a statistically significant dose-
related reduction in birth weight (table 2). The actual significance
level was not reported.

116
TABLE 2.—Fiffect of carbon monoxide exposure of pregnant rabbits
on birth weight

 

 

Group 1, Group 2, Group 3,
0 percent 8tol0 percent 16 to 18 percent
COHb COHb COHDb
Number of pregnant rabbits.._.______ 17 14 17
Total number of babies__-_-__...____ 116 81 123
Average weight of babies in grams_____ 53. 7 51.0 44.7

 

Source: Astrup, P. (2).

Polycyclic Hydrocarbons

Polycyclic aromatic hydrocarbons (PAH) such as benzo(a)pyrene
(BAP) are constituents of cigarette smoke which have been impli-
cated in the generation of cancers in many animal species (1/7). No
studies presently available relate benzo(a)pyrene to a reduction in
birth weight of exposed offspring. Evidence suggests, however, that
BAP does reach and cross the placenta. Aryl hydrocarbon hydroxylase
(AHH) is a part of the cytochrome P-450- containing microsomal
enzyme system, present in many tissues of different species. This
enzyme system is induced to hydroxylate polycyclic aromatic hydro-
carbons after exposure of cells to PAH. Several investigators have
utilized the inducibility of the enzyme system to demonstrate indirectly
that benzo(a)pyrene and other polycyclic hydrocarbons reach the
placenta and fetus.

Welch, et al. (108) extended this work by administering the poly-
cyclic hydrocarbon, 3-methylcholanthrene (8-MC), to rats during late
gestation. The metabolism of benzo(a)pyrene was studied in vivo (us-
ing tritium-labelled benzo(a)pyrene) and in vitro. AHH activity was
increased in fetal livers to adult levels by pretreatment with 3-MC
Since a relatively high dose of polyeyelic hydrocarbon was required
to stimulate enzyme activity in the fetus, compared to the dose which
stimulated placental enzyme activity, the authors suggested that the
placenta may protect the fetus from exposure to polycyclic hydro-
carbons. However, immaturity of the fetal enzyme system might also
account for its apparent relative insensitivity to polyevelic hydro-
carbons. Therefore, an exposure of the fetus to levels of poly-
cyclic hydrocarbon similar to those experienced by the mother cannot
be ruled out by the available data.
Schlede and Merker (86) have studied the effect of benzo(a)pyrene
administration on aryl hydrocarbon hydroxylase activity in the mater-
nal liver, placenta, and fetus of the rat during the latter half of
gestation. The pregnant animals were treated with large oral doses
of benzo(a)pyrene 24 hours prior to sacrifice. Control rats had no
detectable levels of aryl hydrocarbon hydroxylase in their placentas,
Treatment. with benzo(a)pyrene resulted in barely detectable placental
levels on gestation day 13, but steadily rising values until day 15, and
then constant levels thereafter. No activity was detected in the fetuses
of untreated controls. In the treated animals, the fetal enzyme activity
rose steadily from the 13th to the 18th day of gestation. The authors
concluded that the stimulatory effect of benzo(a)pyrene treatment on
aryl hydrocarbon hydroxylase activity in the fetus demonstrates that
benzo (a) pyrene readily crosses the rat placenta.

STwDIEs In Hvuasrans

Carbon Monoxide

Smokers and their newborn infants have significantly elevated levels
of carbon monoxide as compared with nonsmokers and their infants
(31, 34, 88, 116). Recently, Baribaud, et al. (5) studied 50 nonsmokers
and 27 cigarette smokers and their newborns. All smokers inhaled. The
authors found that the mean level of CO content in the blood of non-
smokers was 0.211 volumes percent compared with 0.672 volumes per-
cent in the blood of smokers. The values for blood samples from the
umbilical cords of their newborns were 0.352 and 0.949 volumes per-
cent, respectively. Moreover, a definite dose relationship was found
bet ween CO levels and number of cigarettes smoked.

Younoszai, et al. (776) found, in addition to elevated carboxyhemo-
globin levels among the infants of smoking mothers, significant
elevation of mean capillary hemotocrits and signifieant reduction of
standard bicarbonate levels, as compared to the infants of nonsmoking
mothers. Since no evidence for nicotine effects upon blood glucose,
serum FFA levels, or urinary catecholamines, or for hypoxia was
present, they concluded that the higher hematocrit levels in the infants
of smoking mothers may have represented a compensatory response
to the decreased oxygen-carrying capacity of the blood due to the
presence of carboxyhemoglobin.,

Longo (45) pointed out that a level of 9 percent carboxyhemoglobin
in the fetus is the equivalent of a 41 percent decrease in fetal blood
flow or fetal hemoglobin concentration. In reviewing the studies of
CO levels in human mothers and their newborns, he made the follow-

118
ing comments: “These samples were obtained at the time of vaginal
delivery or Cesarean section and may not accurately reflect the normal
values of (COHb)y for several reasons. The number of cigarettes
smoked by the mothers during labor may be less than their normal
consumption and was not specified in these studies. The blood sam-
ples were collected at varying time periods following the cessation
of smoking. In addition, many of the samples were probably taken
early in the day before COHb levels had built up to the levels reached
after prolonged periods of smoking. Thus actual levels of (COHb) x
and (COHb)» may be higher than the reported values.”

Polycyclic Hydrocarbons

The results of several studies concur that cigarette smoking is
strongly associated with the induction of aryl hydrocarbon hydrox-
ylase in the human placenta (18, 38, 61, 99, 109). This finding imphes
that benzo(a)pyrene or other polycyclic hydrocarbons reach the
placenta. To date, evidence to support the passage of polycyclic hydro-
carbons through the placenta to the human fetus has not been
published.

Vitamin B,, and Cyanide Detoxification

McGarry and Andrews (48) determined serum vitamin B,, levels
in 826 women at their first prenatal clinic visit, They found that the
serum levels for smokers were significantly lower than for nonsmokers.
After adjustment for gestational age, parity, social class, hemoglobin
level, hypertension, and maternal weight, smokers still had signifi-
cantly lower levels of B,>. They also found a direct, statistically sig-
nificant dose-response relationship between cigarettes smoked and
serum vitamin B,, level. They again confirmed the relationship be-
tween smoking and low birth weight. The authors suggested that the
lowered vitamin B,, levels reflect a disorder of cyanide detoxification.
Cyanide is a demonstrable ingredient in cigarette smoke (39, 60, 62,
54,68,74,91).

Vitamin C
Venulet (105, 106, 107) has demonstrated that the vitamin C level
is significantly lower in the serum of women who smoke cigarettes

during pregnancy, compared to values for their nonsmoking counter-
parts.

Possible Mechanisms

The following mechanisms have been proposed for the production
of low birth weight and other unfavorable outcomes of pregnancy
following exposure to cigarette smoke:
1. A direct toxic influence of constituents of cigarette smoke upon
the fetus (2, 45, 50, 51, 117).

2. Decreased placental perfusion (94).

- Decreased maternal appetite and diminished maternal Weight
gain with secondary effects upon the fetus (6, 33, 36, 65, 75, 99.
117).

. A direct effect upon the placenta (36, 57, 65, 110).

. An oxytocic effect on uterine activity (44).

- A disturbance of vitamin B,, metabolism ( 48).

. A disturbance of vitamin C metabolism (105, 106, 107).

oo

ID oR

Of the potential mechanisms, available evidence suggests that
neither decreased maternal appetite and decreased maternal weight
gain nor a direct effect upon the placenta are responsible for a sig.
nificant reduction in birth weight. Existing evidence does not permit
firm conclusions concerning the relative significance of the remaining
mechanisms.

Timing of the Influence of Cigarette Smoking on Birth Weight

Several investigators have published results which bear on the time
period during which exposure to cigarette smoke most affects fetal
growth. Lowe (46) and Zabriskie (778) have offered evidence which
suggests that cigarette smoking influences fetal growth most during
the second half of pregnancy. Butler, et al. (15) found that the birth
weights of infants of women who did not smoke after the fourth
month of pregnancy were essentially the same as those of the infants of
nonsmokers. This implies that the influence is most probably exerted
after the fourth month of pregnancy. Herriott, et al. (35), however,
found that women in lower socioeconomic classes who gave up smoking
early in pregnancy tended to have intermediate weight babies as com-
pared with nonsmokers and persistent smokers, but his numbers of
women were small and the results were not statistically significant.
Underwood, et al. (00) found that cigarette smoking in any single
trimester was associated with a lower birth weight of the infant,
although the difference between the birth weights of infants of
women who smoked only during a single trimester and infants of non-
smokers was not statistically significant because of small numbers.
Several investigators have detected a nearly constant difference be-
tween the birth weights of the infants of smokers and nonsmokers.
delivered during the last month of pregnancy. following gestations
of comparable length [fig. 1, (77)]. Although this observation is

120
compatible with the suggestion that the influence of cigarette smoking
upon the fetus occurs prior to the last month of pregnancy, it is based
upon data derived from cross-sectional rather than longitudinal
studies. The results of many human epidemiological studies suggest
that maternal smoking prior to pregnancy does not influence fetal
weight gain (15, 25, 46, 49, 113).

Site of Action at the Tissue and Cellular Level

The use of labelled nicotine (98) and the preparations of autoradio-
grams have permitted the localization of nicotine within the tissues
of the fetus and mother. Tjalve, et al. (98) found high levels of nico-
tine in the respiratory tract, adrenal, kidney, and intestine of 16- to 18-
day mice fetuses. The use of other labelled constituents during various
parts of gestation might further the understanding of how certain
ingredients in cigarette smoke produce an impact upon birth weight.
Haworth and Ford (33) have reported data which suggest that the
reduction of birth weight of rat fetuses caused by the action of the
ingredient (s) of tobacco smoke results from a reduction in cell number,
but not in cell size.

Significance of the Association

Among all women in the United States, cigarette smokers are
nearly twice as likely to deliver low-birth-weight infants as are non-
smokers. Assuming that 20 percent of pregnant women in the United
States smoked cigarettes through the entire pregnancy (extrapolated
from data on changes in smoking behavior during pregnancy collected
for the British Perinatal Mortality Study), taking into account the
apparently different risks of delivering a small-for-dates infant for
Caucasian and non-Caucasian women who smoke during pregnancy,
and considering the number of infants with a birth weight less than
2,500 grams born to Caucasian and non-Caucasian women, an excess
of nearly 43,000 occurred in the 286,000 low-birth-weight infants
among the 3,500,000 infants born in the United States in 1968, because
of the increased risk among women who smoke of having small-for-
dates infants.

Since neonatal mortality is higher for low-birth-weigth infants.
with gestational age held constant, the excess of small-for-dates infants
‘mong smoking mothers would imply a significant excess mortality
risk as well.

121
Birth Weight Summary

A causal association between cigarette smoking and fetal growth
retardation is supported by the following evidence:

1.

7.

122

The results of all 42 studies in which the relationship between
smoking and birth weight was examined have demonstrated a
strong association between cigarette smoking and delivery of
small-for-dates infants. On the average, the smoker has nearly
twice the risk of delivering a low-birth-weight infant as that of
a nonsmoker.

. This association has been confirmed by both retrospective and

prospective study designs.

. A strong dose-response relationship has been established between

cigarette smoking and the incidence of low-birth-weight infants,
Available evidence suggests that the effect of smoking upon fetal
growth reflects the number of cigarettes smoked daily during a
pregnancy, and not the cumulative effect of cigarette smoking
which occurred before the pregnancy began.

- When a variety of known or suspected factors which also exert

an influence upon birth weight have been controlled for, cigarette
smoking has consistently been shown to be independently related
to low birth weight.

. The association has been found in many different countries,

among different populations, and in a variety of geographical
settings.

- New evidence suggests that if a woman gives up smoking by the

fourth month of pregnancy, her risk of delivering a low-birth-
weight infant is similar to that of a nonsmoker.

The infants of smokers experience a transient acceleration of
growth rate during the first 6 months after delivery, compared
to infants of nonsmokers. This finding is compatible with viewing
birth as the removal of the smoker’s infant from a toxic influence.

. The results of experiments in animals have shown that exposure

to tobacco smoke or some of its ingredients results in the delivery
of low-birth-weight offspring. New evidence demonstrates that
chronic exposure of rabbits to carbon monoxide during gestation
results in a dose-related reduction in the birth weight of their

offspring.

. Data from studies in humans have demonstrated that smokers’

fetuses are exposed directly to agents within tobacco smoke, such
as carbon monoxide, at levels comparable to those which have
been shown to produce low-birth-weight offspring in animals.
Cigarette Smoking and Fetal and Infant Mortality

Introduction

Several previous studies of the relationship between cigarette smok-
ing and higher fetal and infant mortality among the infants of smokers
have been reviewed in the 1971 and 1972 reports on the health con-
sequences of smoking (101, 102). In many of these studies, the authors
combined two or more categories of fetal and infant mortality. Differ-
ent mortality outcomes, such as spontaneous abortion, stillbirth, and
neonatal death, are influenced by different sets of factors. Among
other factors, the frequency of abortion is influenced by congenital
infections, hormonal deficiencies, and cervical incompetency. In addi-
tion to other factors, the frequency of stillbirth is influenced by pre-
mature separation of the placenta, uterine inertia, and dystocia. Along
with other factors, the frequency of neonatal death is influenced by
gestational maturity, birth injuries, and delivery room and nursery
care, Separate analysis of the relationship of cigarette smoking to
tach different mortality outcome, with control of the unique set of
factors which influences it, may facilitate understanding of the
relationship.

Spontaneous Abortion

Previous epidemiological and experimental studies of the relation-
ship between spontaneous abortion and cigarette smoking reviewed in
the 1971 and 1972 reports on the health consequences of smoking (101,
102) form the basis of the following statements:

The results of several studies, both retrospective and prospective,
have demonstrated a statistically significant association between ma-
ternal cigarette smoking and spontaneous abortion (43, 65. 70, 99,
118). Data from some of these studies have documented a strong dose-
response relationship between the number of cigarettes smoked and
the incidence of spontaneous abortions (70, 99, 118). In general, vari-
ables other than cigarette smoking (e.g., maternal age, parity, health,
desire for the pregnancy, and use of medication), which may influence
the incidence of spontaneous abortions, have not been controlled. The
Tesults of the one study, in which adjustment for the woman’s desire
for the pregnancy was performed, indicated that after such adjust-
ment cigarette smoking during the pregnancy retained an association
ith spontaneous abortion of borderline significance (43). The time
Period during which cigarette smoking might exert an influence on
the incidence of spontaneous abortions has not been determined. Abor-

123
tions have been produced in animals only with large doses of Nicotine
(23, 96, 104) ; the relevance of these studies for humans is uncertain

Spontaneous Aportion SumMMARY

Although several investigators have found a significantly higher
dose-related incidence of spontaneous abortion among cigarette
smokers as compared to nonsmokers, the lack of control of significant
variables other than cigarette smoking does not permit a firm con.
clusion to be drawn about the nature of the relationship.

Stillbirth

Epidemiological studies of the association between cigarette smok.-
ing and stillbirth previously reviewed in the 1971 and 1972 reports on
the health consequences of smoking (101, 102) form the basis for the
following statements :

In one group of retrospective and prospective studies, a higher still.
birth rate was found for the infants of smokers as compared to those
of nonsmokers (14, 25, 43). In another group of retrospective and
prospective studies, no significant difference was detected in the still-
birth rate among the infants of smokers and nonsmokers (16, 20, 85,99,
100). Differences in study size, numbers of cigarettes smoked, or the
presence or absence of control of variables, such as age and parity,
which may influence stillbirth rates, were probably not sufficient to
explain the differences in results obtained.

Several recent epidemiological studies have added to our under-
standing of the relationship between cigarette smoking and stillbirth.
Niswander and Gordon (63) have reported data from 39,215 preg-
nancies followed prospectively and collected between 1959 and 1966
at 12 university hospitals in the United States. A random sample of
women who presented to hospital prenatal clinics were enrolled in the
study. The authors reported no increase in stillbirths among white
smokers as compared with white nonsmokers. A higher incidence of
stillbirths was found among black women who smoked than among
nonsmoking black women. and a dose-response relationship with
cigarettes smoked was suggested, although the findings did not attain
statistical significance. The results were not adjusted for other vari-
ables, Rush and Kass (82) found, in a prospective study of 3,296
pregnancies at Boston City Hospital, a nonsignificant increase in

124
stillbirths among white women who smoked, but a statistically signifi-
cant increase in stillbirths among black women who smoked (P<0.02).
These findings are consistent with those previously outlined by
Frazier, et al. (25) and Underwood, et al. (99).

Rumeau-Roquette (87), in a prospective study of 4,824 pregnancies
in Paris, demonstrated that the risk of stillbirth was significantly
higher for cigarette smokers than for nonsmokers (P<0.001). The
authors also presented evidence that a woman with either a previous
stillbirth or at least one prior infant weighing less than 2,500 grams
at birth was significantly more likely to have a future stillborn infant
than a woman without such an obstetrical history. After previous
obstetrical history was controlled, smokers still retained a statistically
significant increased risk of subsequent stillbirth as compared to non-
smokers (P<0.01). Of further interest. was the finding that among
women who previously had delivered only living infants, weighing
over 2,500 grams, cigarette smoking had no influence on the stillbirth
rate.

Previous experimental studies were reviewed in the 1971 and 1972
reports on the health consequences of smoking (/0/, 102). The authors
demonstrated that exposure of pregnant rabbits to tobacco smoke and
pregnant rats te large doses of injected nicotine resulted in a signifi-
cant increase in stillbirths (7, 8, 23, 87).

STILLBIRTH SUMMARY

1. The results of recent studies suggest that cigarette smoking is
most strongly associated with a higher stillbirth rate among
women who possess less favorable socioeconomic surroundings or
an unfavorable previous obstetrical history. In the United States,
black women have higher stillbirth rates than white women. The
finding that cigarette smoking is associated with an even greater
difference between the stillbirth rates of the two groups merits
special attention. These findings may provide at least a partial
explanation for the lack of a significant difference in stillbirth
rates between smokers and nonsmokers, which some investigators
have found.

2. The results of experiments in animals demonstrate that exposure
to tobacco smoke and some of its ingredients, such as nicotine,
can result in a significant increase in stillbirth rate.