NINCDS, stated: "The gestations that produced the SIDS vic-
tims were characterized by a greater frequency of mothers who
smoked cigarettes and had anemia" than was true for the whole
population of 53,721 infants or for a set of 375 controls matched
for important factors (96). Rhead, commenting on studies pub-
lished to date which demonstrate an increased incidence of
maternal cigarette smoking in SIDS, states: "It is now . . . clear
that maternal cigarette smoking contributes to an infant's risk
of dying from SIDS" (123).
Analysis of data from the prospective study of 19,047 births to
members of the Kaiser Foundation Health Plan (1960-1967)
also showed a strong association of SIDS with maternal smok-
ing. In the SIDS group, 70.6 percent of mothers smoked during
pregnancy, compared with only 35.3 percent of mothers of
babies who did not die of SIDS (p < .OOl>. The relative risk of
SIDS for smokers versus nonsmokers was 4.4 (67).

Clues to the mechanisms by which smoking may increase the
risk of pregnancy complications are available from pathological
and physiological studies of placentas, membranes, blood ves-
sels, circulatory patterns, and serum levels of substances im-
portant for cell and tissue integrity. For example, it is possible
that placental changes in smokers that serve as adaptations to
the hypoxic effects of carbon monoxide may also increase the
risk of placental complications.

Christianson has reported findings from carefully stand-
ardized gross examinations of 7,651 placentas from smokers and
nonsmokers. These examinations revealed that smokers'
placentas were thinner and larger in their minimum diameter
than those of nonsmokers. This significant change effectively
increased the surface area of the smokers' placentas and must,
therefore, have increased their area of attachment to the
uterine wall. The distance from the edge of membrane rupture
to the placental margin was also less for smokers, and signifi-
cantly more smokers than nonsmokers had zero distance, which
is consistent with the diagnosis of placenta previa (19). These
findings suggest a possible mechanism to account for the signif-
icant dose-related increase in the frequency of the clinical diag-
nosis of placenta previa that accompanies maternal smoking
(86). A similar increase in this condition occurs with increasing
altitude (75).

Christianson's study also revealed that smokers had signifi-
cantly more placental calcification, primarily of the maternal
surface, and patchy subchorionic fibrin, as shown in Table 11.
226


TABLE Il.--Selected results of gross examinations of placentas from smokers and nonsmokers

        Percent of Placentas with Stated Condition

         White                      Black
Nonsmoker    Smoker         Nonsmoker Smoker
N=3,461    N=2,239      P    N= 1,300   N=652      P

Calcification                                  49.5        60.8      < .OOOl     43.5      59.0      < .0001
Patchy Subchorionic Fibrin                       26.2        35.3      < .OOOl     30.8      37.0      < .Ol
Infarcts                                     24.6        22.3      -c .05      14.4      14.5      NS

Thickness (mean cm)                             2.16        2.12     < .OOl      2.11      2.06     c.01
Ratio of smallest diameter to thickness                  8.19        8.40     < .OOl      8.39      8.68     < .Ol
Shortest distance, edge of rupture of
membranes to placental margin (mean cm)              4.32        4.09     < .025      5.08      4.83      NS
Percent with zero distance                         26.6        27.9      NS      18.6      20.3     < .05

SOURCE: Christianson, R.E. (19).


These changes are characteristic of maturation and aging of the
placenta and occur as normal gestation proceeds; however, they
occurred earlier in smokers than in nonsmokers (19). This find-
ingis compatible with other manifestations of accelerated aging
reported to be associated with cigarette smoking (28,108).
Asmussen compared placental vessels in smoking and
nonsmoking mothers by electron microscopy. In the smoking
group these vessels were characterized by subintimal edema
with destruction of the intimal elastic membranes, a marked
decrease in collagen content, and proliferation of myocytes.
Asmussen postulated that similar damage may occur in the
fetal and infant vascular system. To what extent such changes
may predispose to the subsequent development of vascular dis-
ease remains unknown. The author regarded most of the
changes observed in smokers' vessels as degenerative, but men-
tioned the possibility that the thickening of the basement mem-
brane observed in smokers might be an attempt at repair (4,5).
Naeye (93) has described an increased frequency of placental
microscopic lesions associated with smoking. These include:
cytotrophoblastic hyperplasia, obliterative endarteritis,
stromal fibrosis, and small villous infarction. Smokers also
demonstrated an increased frequency of necrosis and inflam-
mation in the decidua capsularis and in the decidua basalis at
the placental margin. Placental features observed less fre-
quently in smokers' placentas were excessive syncytial knots
and various thrombotic phenomena.
Naeye found increasing placental enlargement with smoking
level, accompanied by decreasing birth weight and a consequent
increase in the placental ratio. The author stated that "as smok-
ing increased, placentas developed microscopic lesions charac-
teristic of underperfusion of the uterus." Naeye's data showed
positive trends with maternal smoking level for some findings
and negative trends for others (93). Many of the changes cited
were of low frequency in all groups, and no clear pattern of
possible mechanisms of action emerged.
Other studies that may shed light on these complex interrela-
tionships include the report by Goujard and colleagues that
heavy alcohol consumption as well as smoking contributes to
the risk of stillbirth caused by abruptio placentae. In a prospec-
tive survey of 9,169 women, the risk of stillbirth was 21 per 1,000
in smokers who were light or nondrinkers, 20 per 1,000 in
nonsmoking drinkers of 45 ml equivalents or more of absolute
alcohol per day, and 8.5 per thousand for nonsmokers who drank
less than 45 ml per day. The small number of smokers who were
also heavy drinkers had stillbirth rates of 50.5 per 1,000 (95
women with 5 stillbirths). The proportions of these deaths that
228


were attributable to abruptio placentae increased with smoking
and with drinking, based on data unadjusted for the effects of
age, parity, and other factors (122):

More research is needed to define possible pathways of action
by which the active components of cigarette smoke affect preg-
nancy complications that may lead, in turn, to fetal death or to
preterm birth with or without survival.

Experimental Studies

TOBACCO SMOKE

Tobacco smoke contains more than 2,000 compounds includ-
ing: carbon monoxide, oxides of nitrogen, ammonia, polycyclic
aromatic hydrocarbons, hydrogen cyanide, vinyl chloride, and
nicotine. For the pregnant woman and fetus the most important
of these appear to be nicotine, carbon monoxide, and the
polycyclic aromatic hydrocarbons.

NICOTINE

The effect of nicotine on sympathetic and parasympathetic
ganglia, skeletal muscles, and the central nervous system is
similar to that of acetylcholine. At all three sites it first stimu-
lates, then depresses. Minute doses of nicotine stimulate the
chemoreceptors of the carotid and aortic bodies, causing reflex
hypertension. Nicotine also releases epinephrine from the ad-
renal medulla, thereby producing cardiovascular changes.
Thus, it can produce widely differing effects depending upon the
dosage and the particular site that is most sensitive to stimula-
tion.

Nicotine rapidly crosses the placenta to affect the fetus (142).
Relatively mature rhesus monkey fetuses respond to nicotine
infusion with a rise in blood pressure, bradycardia, acidosis,
hypercarbia, and hypoxia (141). Maternal nicotine administra-
tion in rats also has been shown to affect the fetal central ner-
vous system and its response to electrical stimulation during
the newborn period (56,78).

Quigley, et al. noted that in moderate to heavy smokers, after
34 weeks gestation, smoking two cigarettes in 10 minutes was
associated with a 60 percent increase in maternal plasma
norepinephrine and epinephrine and a 20 percent increase in
serum cortisol concentrations (118). These changes also were
associated with an increase in maternal pulse and blood
pressure. Lehtovirta and Forss measured changes in placental
intervillous blood flow using the 133 xenon method (66). Im-
mediately after smoking, intervillous flow decreased 22 percent.

229


These data correlate with the studies of Resnik, et al. (122),
showing nicotine-induced increases in catecholamines and de-
creased uterine blood flow in sheep, and of Haberman, demon-
strating decreased uteroplacental blood flow in women, using
thermography (48).
Sastry and his colleagues have carried out a series of studies
on the effect of nicotine on the human placenta. Nicotine added
to a calcium-containing medium caused a 33 percent increase in
the rate of acetylcholine release from isolated placental villi
(131). The authors postulated that this effect could account for
the decrease in placental amino acid transport (125,154) pro-
duced by nicotine-mediated cholinergic blockade (105). Rowe11
and Sastry also demonstrated that nicotine caused a 41 percent
decrease in uptake of alpha amino isobutyric acid in an experi-
mental placental system (126). Their studies indicate that under
normal circumstances acetylcholine exhibits a muscarinic ef-
fect facilitating placental amino acid uptake. Nicotine blockade
of the facilitating effects of acetylcholine on amino acid uptake
may result in fetal growth retardation (126). These data agree
with the 1977 work of Crosby, et al. in humans (26).
Nicotine injection in rats results in prolonged gestation with
lower than normal newborn weights. A possible cause of this
prolonged gestation is nicotine-induced delay in ovum implan-
tation. Yoshinaga, et al. tested this hypothesis, administering
7.5 mg nicotine tartrate twice daily from the morning of proes-
trus until the day of sacrifice on days 1 to 5 of pregnancy (161).
The nicotine-injected animals demonstrated a delay of about 12
hours in ovum cleavage from the two- to the four-cell stage, and
each step of development after the four-cell stage was thereby
delayed. In addition, ovum entry into the uterus, blastocyst
formation, shedding of the zona pellucida, and implantation
were delayed. Nicotine injection also was associated with a
"crowding" of implantation sites toward the tubal ends of the
uterine horns.
During the preimplantation period the serum concentrations
of progesterone, luteinizing hormone, and prolactin were lower,
while the concentrations of estrogen and follicle stimulating
hormone were higher than in control animals. These workers
suggested that the delayed ovum implanation followed a de-
layed increase in progesterone secretion required to prepare
the uterus for the implanting blastocyst, and that the delayed
progesterone secretion results in part from nicotine-induced
disturbed hypothalamus pituitary balance.
Hamosh, et al. observed that, while administration of 100 mg
kg-`day-* nicotine to pregnant rats from day 14 gestation onward
failed to affect the mother or fetus, administration of 1 mg kg-`day-l
230


(a dose "comparable" to that of a 20 cigarette-per-day smoker) re-
sulted in a decrease in litter size and an increase in stillbirth rate.
Although administration of 100 mg kg-`day-' nicotine failed to affect
newborn birth weight by 12 days of age continued maternal nicotine
administration resulted in a 9 percent decrease in body weight and a
40 percent decrease in weight of the stomach contents. These de-
creases presumably resulted from lower milk production by the
nicotine-treated animals (51).
CARBON MONOXIDE (CO)
Carboxyhemoglobin concentrations of 4 to 5 percent are as-
sociated with numerous physiologic alterations in adults.
Cigarette smoking raises the carboxyhemoglobin concentration
4 to 5 percent per pack smoked per day. Although CO diffuses
across the placenta relatively slowly [ the half time equals 1.5 to
2 hr (72)], fetal carboxyhemoglobin concentrations reflect those
of the mother, and under steady state conditions are 10 to 15
percent higher than maternal levels (71). Elevated car-
boxyhemoglobin concentrations in the fetus are associated with
decreased fetal blood oxygen tensions. These decreased oxygen
tensions are associated with a redistribution of fetal blood flow
to the brain, heart, and adrenal glands (146).
Carboxyhemoglobin concentrations have been described
under several conditions of pregnancy. Davies, et al. (31) com-
pared earboxyhemoglobin concentrations and "available oxy-
gen" (a function of 0, content in ml dl blood-`) in women who
stopped smoking for 48 hours during the last trimester of preg-
nancy, with women who did not stop smoking, and with
nonsmoking women. In those women who stopped smoking, car-
boxyhemoglobin concentrations decreased. "Available oxygen"
increased about 8 percent due both to an increase in functioning
hemoglobin and a shift in the oxyhemoglobin saturation curve;
this increase in "available oxygen" should contribute to im-
proved fetal oxygenation.
Exposure of rabbits (6) and rats (39) to CO during gestation
resulted in decreased fetal weights and increased perinatal
mortality. Such CO-exposed newborn animals showed less activ-
ity as well as decreased lung weights and decreased concentra-
tions of brain protein, DNA, and the neurotransmitters
norepinephrine and serotonin (45). Cellular hypoxia is the final
common pathway mediating the adverse effect of CO on the
developing fetus.
Recent experimental studies have explored various aspects of
CO-induced biochemical changes in the fetus and the newborn.
Newby, et al. demonstrated a persistent effect of CO exposure in
8- and 13-day-old rats following a single 5-hour exposure to 1,500
                                          231


120 r -co~n=a

c *=*COc3+n=15
   010 CONT $?n=9
100  c-o=o CONTdn=9       T

I      I              I              I          I
     1           2           4           16

Intensity (CandlepowerI9.4 x 104)

FIGURE 12.-Effect of prenatal CO upon peak-to-peak
       amplitudes of the first positiive to the first
       negative component of the flash evoked potential
        recorded from the rat visual cortex. Vertical bars
       represent * standard error of the means

SOURCE: Dyer, R.S. (36).

parts per million (0.15 percent CO) (100). In these animals alpha
methyl-p-tyrosine, a potent inhibitor of the enzyme tyrosine
hydroxylase, was injected 1 hour before the CO exposure, and
the extent of catecholamine depletion was taken as an index of
the rate of catecholamine turnover. CO-treated rats showed in-
creased steady state dopamine concentrations with decreased
rates of dopamine turnover. In addition, the CO effect on
dopamine turnover persisted for at least 3 to 6 weeks after a
single exposure of 8-day-old rats. There was no CO effect on
norepinephrine concentrations or turnover rates, and the effect
was not produced in rats exposed to 8 percent oxygen instead of
carbon monoxide. This is consistent with the data of Coyle and
Campochiaro, which indicates that a maturational event occurs
in the striatum of the 8-day-old rat (25). Whether this event
represents the age of functional maturity, initiation of
232


dopaminergic transmission, or maturation of cholinergic inter-
neurons is unclear.

Prenatal CO exposure may have long-term consequences on
central nervous system function. For instance, Dyer, et al. ex-
posed female Long-Evans hooded rats to 150 ppm CO through-
out pregnancy (36). At birth the litters and mothers were placed
in room air without CO. On day 65 electrodes were placed in the
young rats' skulls, and 2 weeks later visually evoked potentials
were recorded. Figure 12 illustrates the effect of such prenatal
exposure on the peak-to-peak amplitudes of the Pl-Nl (first pos-
itive to first negative) component of the visual evoked potential
from the cortex. Females showed a significant increase in Pl-Nl
amplitude at each of four flash intensities. Although the exact
nature of this amplitude increase could not be determined, it
suggests altered cell populations at the retinal, geniculate, and
cortical levels, and may represent impaired inhibitory mecha-
nisms, rendering other neurons more excitable.

The question of the posible teratogenicity of CO has never
been resolved. Schwetz, et al. exposed mice to 250 ppm CO for 7
or 24 hours per day, from days 6 through 15 of gestation, and
rabbits to the same concentration from days 6 through 18 (137).
Blood carboxyhemoglobin concentration ranged from 10 to 15
percent. The fetuses of mice exposed to CO for 7 and 24 hours
per day were slightly heavier and lighter, respectively, than
those of the control animals. The only increase in teratogenic
effects were minor skeletal variants such as extra lumbar ribs
and spurs.

POLYCYCLIC AROMATIC HYDROCARBONS

The polycyclic aromatic hydrocarbons (PAH), such as ben-
zo(a)pyrene, are widely distributed mutagens and carcinogens.
These substances, produced by incomplete combustion of or-
ganic material, are important constituents of tobacco smoke.
Exposure of cells to PAH induces the enzyme, aryl hydrocarbon
hydroxylase. The inducibility of this enzyme system has been
used by some workers to demonstrate, indirectly, that ben-
zo(a)pyrene and other polycyclic hydrocarbons reach the
placenta and fetus.
The placental concentration of benzo(a)pyrene is highly corre-
lated with the amount which a pregnant woman smokes (97,
111). In pregnant rats exposed to this substance higher doses
were required to induce enzyme activity in the fetus as com-
pared with the dose required to stimulate placental enzyme ac-
tivity (153), suggesting that the placenta may protect the fetus
from these substances. However, the placenta is not imperme-
                                       233


able to benzo(a)pyrene (134). The placenta is involved in com-
plex hormonal interrelations between mother and fetus, and
oxidative enzyme pathways in the placenta are important in
maintaining hormonal and nutrient balance for normal fetal
development. The hydroxylation of polycyclic hydrocarbons and
the active transport of various compounds by trophoblast cells
may share common enzyme systems. Thus, the induction of var-
ious enzymes by polycyclic hydrocarbons may interfere with
normal transport systems.

Another unanswered question concerns the carcinogenic risk
for progeny exposed in utero to polycyclic aromatic hydrocar-
bons. The offspring of mice that were injected with ben-
zo(a)pyrene late in gestation showed an increased incidence of
neoplasms of the lungs, liver, and mammary glands (101). Pel-
konen, et al. determined that placental aryl hydrocarbon hyd-
roxylase activity correlated closely with both the amount the
mother smoked and newborn weight (112). These authors
suggested that the placental concentration of this enzyme may
be used as a measure of fetal exposure to maternal cigarette
smoking. Vaught, et al. also reported much higher aryl hyd-
rocarbon hydroxylase activity in the placental microsomes of
smokers compared with nonsmokers (148),

Although currently available data do not allow a quantitative
assessment of the genetic risk to man from cigarette smoking,
such risk may occur since so many components of cigarette
smoke are mutagens (as well as carcinogens) (11). Male
cigarette smokers may have an increased number of abnormal
spermatozoa (150). Paternal and maternal chromosomal aber-
rations (103) and sister chromatid exchanges may be increased
in smokers (62). Because the proportion of smokers in the popu-
lation is so high (between 30 and 50 percent), even a relatively
weak mutagenic effect could have a significant effect on the
gene p00i (11).

OTHER COMPONENTS

Cyanide, another constituent of cigarette smoke, may con-
tribute to retarded infant growth and increased perinatal mor-
tality. Smokers have increas-ed levels of cyanide and thiocyan-
ate in body fluids. Serum concentrations of vitamin Blz, used in
cyanide metabolism, are decreased as well. Several workers
have recorded increased thiocyanate concentrations in both
women who smoke and in their fetuses (2,140,154). Pettigrew, et
al. compared cyanide and thiocyanate concentrations in smok-
ers and nonsmokers,. matched for age, height, parity, and
socioeconomic status (116). Cyanide and thiocyanate concentra-
234


tions were two to four times greater in the blood and urine of
smokers and in the urine of smokers' infants as compared with
controls. Meberg, et al. reported that thiocyanate concentra-
tions were correlated with cigarette consumption and inversely
correlated with birth weight (81).

Cadmium, another constituent of tobacco smoke, is concen-
trated in the placenta of smokers (124). Webster exposed preg-
nant mice to 10 to 40 ppm cadmium and noted an inverse corre-
lation between cadmium concentration and fetal weight (152).

Lauwerys, et al. examined the effects of epidemiology factors
on heavy metal and CO concentrations in the blood, placenta,
and fetus of smoking women (65). Cadmium concentrations in
maternal blood were twofold greater than concentrations in
fetal blood, suggesting that the placenta acts as a barrier to this
metal. They reported a correlation between maternal cadmium
and carboxyhemoglobin concentrations (13,65). They also found
that the cadmium concentration of smokers' placentas was
about 25 percent greater than in a control group and that the
placental cadmium concentration exceeded that of maternal
blood about tenfold (124).

Fertility

Fertility results from the successful completion of a complex
step-wise process beginning with gametogenesis (sperm and egg
production), continuing through gamete release (ejaculation
and ovaluation), gamete interaction (fertilization), conceptus
transport through the fallopian tube into the uterus, and end-
ing with implantation of the embyro into the endometrial wall.
An adverse effect of smoking on any of these steps may impair
fertility.

SMOKING AND REPRODUCTION IN WOMEN

Several epidemiologic studies have suggested that smoking
decreases fertility in women (50,115,143,149). The retrospective
study of Tokuhata demonstrated that 21 percent of women who
regularly smoked cigarettes were infertile while only 14 percent
of those who never used tobacco regularly were infertile (143).
After several characteristics (cause of death, age at and year of
death, education, occupation and frequency of marriage as well
as husbands' smoking habits, education and occupation) were
controlled, a 46 percent excess of infertility was found in women
who smoked.

In a study on the return of fertility after discontinuing con-
traception, Vessey, et al. found a suggested reduction in fertility
among women smoking 15 or more cigarettes per day (149). Pet-
                                           235


tersson, et al. found a tendency toward a greater prevalence of
secondary amenorrhea among smokers (4.8/100 women) than
among nonsmokers (3.7/100 women) (115). Hammond found that
49 percent of the nonsmoking women between 40 and 49 years
had regular menses while only 40 percent of those smoking
more than one pack a day had a regular menses (50). Conversely
only 18 percent of nonsmokers had irregular menses while 24
percent of those smoking one or more packs of cigarettes per
day said they had irregular menses. Smoking women were also
more likely to have an unusual vaginal discharge and vaginal
bleeding than nonsmokers. Experimental studies have demon-
strated alterations in luteinizing hormone release and a de-
creased ovulatory response in rats exposed to tobacco smoke (76).

The effect of smoking on ovulation may result from direct
effects of nicotine on the hypothalamus or pituitary. This would
alter the release of gonadotropin releasing hormones from the
hypothalamus or impair the pituitary response to releasing
hormones.

SMOKING AND AGE OF MENOPAUSE

Substantial data demonstrate that smoking lowers the age of
spontaneous menopause (7,9,27,58,68,69). The recent study by
Jick, et al. revealed a dose dependent decrease in the age of
menopause in smoking women who live in Sweden and the
United States (58). The median age of menopause in nonsmok-
ers was 50; among those smoking one-half pack/day it was 49; in
those smoking 1 or more pack/day, it was 48. Similar studies
have been published indicating an earlier onset of menopause in
smoking women in the United States (29), in England (7), in
Germany (9), and in Sweden (68,69). The mechanism of early
menopause in smokers may be related to ovotoxins in cigarette
smoke (37) or to toxic alterations in the hormonal regulatory
mechanisms controlling the hypothalamic-pituitary-ovarian
axis (76). One group of ovotoxins may be polycyclic aromatic
hydrocarbons which have been demonstrated to be metabolized
by ovarian enzymes to toxic products which destroy oocytes in
rat and mouse ovaries (47,79).

Evidence collected by Daniel1 (29) and Lindquist (68) suggest
that the earlier menopause of smokers is not related to weight
differences between smokers and nonsmokers but is a direct
result of some component of cigarette smoke.

SMOKING AND REPRODUCTION IN MEN

Spermatogenesis, sperm morphology, sperm motility
(17,64,133,150) and androgen secretion (12,113) appear to be al-
236


tered in men who smoke. Viczian (150) has demonstrated de-
creased sperm density, a cigarette-dose-dependent decrease in
sperm motility, and a cigarette-dose-dependent increased ab-
normal sperm morphology among smokers.

In metabolic studies of alcoholic men admitted to a clinical
research center, an inverse relationship between number of
cigarettes smoked and reduction of testosterone levels was seen
(113). Briggs (12) has reported lower plasma testosterone among
smoking men compared to matched nonsmoking controls and
has shown that cessation of smoking resulted in increased tes-
tosterone levels in these men. Wintermitz and Quillen (158) in a
study on the acute effects of smoking in men demonstrated in-
creases in plasma cortisol and growth hormone during the
smoking period. Growth hormone returned to the presmoking
level shortly after the smoking period, and cortisol fell gradu-
ally to the presmoking level by 90 minutes after cessation of
smoking. Urinary catecholamines were higher on the smoking
day than the nonsmoking day. No acute changes were observed
in gonadotropins or testosterone in these men. These studies
demonstrate stimulatory effects of smoking on growth hormone
and cortisol.

Studies in experimental animals have also shown that to-
bacco smoke impairs spermatogenesis (37,151). Smoking also
lowers sexual activity in male rats (18).

These data suggest two possible mechanisms of action of
smoking on male reproduction. A component of cigarette smoke
may have a direct action on the testes, disrupting gamete pro-
duction. This would be consistent with the suggested effect of
cigarette smoke on the ovary. In addition, cigarette smoke is
known to contain compounds which are mutagenic (59). Alter-
natively, cigarette smoke may interfere with the regulatory
mechanisms controlling the hypothalamic-pituitary-testicular
axis.

FERTILIZATION AND CONCEPTUS TRANSPORT

The effect of smoking on sperm-egg interaction (fertilization)
has not been studied in mammalian species. Evidence from
sub-mammalian species demonstrates that nicotine promotes
polyspermy (the entrance of more than one sperm into the oo-
cyte) (73). Polyspermy would result in abnormal embryonic de-
velopment and early abortion, which is one known effect of
smoking (60).

The effect of smoking on conceptus transport in the fallopian
tube or entry into the uterus is unknown; however, some evi-
dence suggests that smoking can alter the amplitude and tone
                                       237


of contractions measured during the Rubin uterotubal insuffla-
tion test (a combined measure of uterotubal junction and tubal
patency) (98), suggestive that smoking may alter conceptus
transport in the fallopian tube or its entrance into the uterus.
In summary, cigarette smoking appears to exert an adverse
effect on fertility. Further studies are needed to quantify the
effects, identify etiologic agent(s), and define the mechanism(s)
of action.
Summary
1. Babies born to women who smoke during pregnancy are, on
the average, 200 grams lighter than babies born to comparable
nonsmoking women.
2. The relationship between maternal smoking and reduced
birth weight is independent of all other factors that influence
birth weight including race, parity, maternal size,
socioeconomic status, and sex of child; it is also independent of
gestational age.
3. There is a dose-response relationship between maternal
smoking and reduced birth weight; the more the woman smokes
during pregnancy, the greater the reduction in birth weight.
4. If a woman gives up smoking early during pregnancy, her
risk of delivering a low-birth-weight baby approaches that of a
nonsmoker.
5. The ratio of placental weight to birth weight increases with
increasing levels of maternal smoking, reflecting a considerable
decrease in mean birth weight and a slight increase in mean
placental mass; this may represent an adaptation to relative
fetal hypoxia.
6. The pattern of fetal growth retardation that occurs with
maternal smoking is a decrease in all dimensions including body
length, chest circumference, and head circumference.
7. Maternal smoking during pregnancy may adversely affect
the child's long-term growth, intellectual development, and be-
havioral characteristics.
8. Maternal smoking during pregnancy exerts a direct
growth-retarding effect on the fetus; this effect does not appear
to be mediated by reduced maternal appetite, eating or weight
gain.
9. The risk of spontaneous abortion, fetal death, and neonatal
death increases directly with increasing levels of maternal
smoking during pregnancy; interaction of maternal smoking
with other factors which increase perinatal mortality may re-
sult in an even greater risk.
10. Excess deaths of smokers' infants are found mainly in the
coded cause categories of "unknown" and "anoxia" for fetal
238


deaths, and the categories of "prematurity alone" and "respira-
tory difficulty" for neonatal deaths; this suggests that the ex-
cess deaths are due to problems of the pregnancy, rather than
to abnormalities of the fetus or neonate.
11. Increasing levels of maternal smoking result in a highly
significant increase in the risk of abruptio placentae, placenta
previa, bleeding early or late in pregnancy, premature and pro-
longed rupture of membranes, and preterm delivery-all of
which carry high risks of perinatal loss.
12. Although there is little effect of maternal smcking 01.
mean gesl;ation, the proportion of fetal deaths and li\c births
that occur before term increases directly with matern;; smok-
ing level. Up to 14 percent of all preterm deliveries in the United
States may be attributable to maternal smoking.
13. The incidence of preeclamgsia is decreased amunr women
who smoke during pregnancy; however, if preeclampsia devel-
ops in a smoking woman, the risk of perinatal mortality is
markedly increased compared to preeclamptic nonsmokers.
14. An infant's risk of developing the "sudden infant death
syndrome" is increased by maternal smoking during pregnancy.
15. There are insufficient data to support a judgement on
whether maternal and/or paternal cigarette smoking increases
the risk of congenital malformations.

16. Infants and children born to smoking mothers may expe-
rience more long-term morbidity than those born to nonsmok-
ing mothers; however, studies usually cannot distinguish be-
tween the effects of smoking during pregflancy and the effects
of the infant's or child's passive exposure to cigarette smoke
after birth.

17. Studies in women and men suggest that cigarette smok-
ing may impair fertility.

18. Experimental studies on tobacco smoke, nicotine, carbon
monoxide, polynuclear aromatic hydrocarbons, and other con-
stituents of smoke help define pathways by which maternal
smoking during pregnancy may exert its aforementioned ef-
fects.

References

(1) ALBERMAN, E., CREASY, M., ELLIOTT, M., SPICE& C. Maternal
  factors associated with fetal chromosal anomalies in spontaneous
   abortions. British Journal of Obstetrics and Gynecology 83: 621-627,
   August 1976.
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