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366
CHAPTER 8
SMOKING CESSATION AND
REPRODUCTION

367
CONTENTS

 

 

 

Part]. Female .... 2... eee een eben evens 37]
Pregnancy and Pregnancy Outcome .............0 000000000 cece eee 37]
Introduction 2.02... n eee ee 371
Pathophysiologic Framework ......00.0000 000000 c cece eee eee. 371
Nonexperimental Studies ...... 00.00.00 cece eens 374
Fertility and Infertility 0.2.0... cee eee eee 374
Ectopic Pregnancy and Spontaneous Abortion ...................... 375
Fetal, Neonatal, and Perinatal Mortality .........0000.0....00000000.. 376
Birthweight and Gestational Duration ..................0.00000000. 379
Introduction 20... ec cee ee ee eevee es 379
Continued Smoking ..............2 eee eee 38]
Cessation Before Conception ............ 0000 c ec ee ee eee eee eee. 382
Cessation After Conception ..........0...0 000000000 eee eee. 383
Birthweight . 2.0.0.2... eee eee 383
Preterm Delivery ..... 00... c ec eee eee ee 386
Complications of Pregnancy ...........0 000 ccc cece eee eee 387
Randomized Trials of Smoking Cessation During Pregnancy ............ 387
Prevalence of Smoking and Smoking Cessation During Pregnancy and Time
Trends in Prevalence and Cessation ........0..0.0.0.0.000 0000 e cece 390
Introduction . 0.0... cee eee e eee e nes 390
Prevalence of Smoking and Smoking Cessation...................0. 390
Time Trends in Smoking and Smoking Cessation ................... 393
Estimates of Attributable Risk Percent ...............00.00200002.... 393
Age at Natural Menopause ............00000 000 cece cece eee cece es 396
Introduction 2... cence tee e eens 396
Pathophysiologic Framework .........00.. 00000 ccc eee eee eeees 396
Studies of Former Smokers .........0..00000 0000 cc cece ee eeeeeeeeeeee 398
Part I. Male... 00... e cee e eee eeteveeeees ree . 400
Introduction 2.0... 2 cece ccc cece eee eeeeees 400
Pathophysiologic Framework ......0.00.00000 00 ccc cece cece eee eee eees 400
Sexual Activity and Performance ........00.0000 0.000 ccc cece eee eeeue 401
Sperm Density and Quality ......0000.000000 0000. c cece e eee e ee 404
Conclusions 0. c cece cece eee e ete eteaerreenes 410
References ........... bbe been t tb tet eb vette eneeeerened veeeee ee 4H

369
PART I. FEMALE
Pregnancy and Pregnancy Outcome

Introduction

Since the late 1940s, cigarette smoking during pregnancy has been linked with poor
pregnancy outcome (Bermhard 1949; Athayde 1948). Adverse effects of smoking on
pregnancy began to receive considerable attention after publication of the results of a
study of 7,499 pregnant women in San Bernardino County. CA, in which the rate of
prematurity, defined as birthweight less than 2,500 g, was found to be about twice as
high among smokers as among nonsmokers during pregnancy (Simpson 1957).

Early reports of the Surgeon General (US DHEW 1971, 1973, 1978) concluded that
maternal smoking during pregnancy retards fetal growth and is a probable cause of late
fetal and infant mortality (US DHEW 1973). The 1977 Report of the Surgeon General
(US DHEW 1978) concluded that smoking during pregnancy has dose-response
relationships with abruptio placentae. placenta previa, bleeding during pregnancy.
premature and prolonged rupture of the membranes, and preterm delivery. The 1979
and 1980 Reports of the Surgeon General (US DHEW 1979, US DHHS 1980)
comprehensively reviewed information on the association of maternal smoking with
pregnancy outcome and further concluded that the risk of spontaneous abortion in-
creases with the amount of smoking and that the risk of sudden infant death syndrome
(SIDS) is increased by maternal smoking during pregnancy. The 1980 Report (US
DHHS 1980) also indicated the possibility of a link between cigarette smoking and
impaired fertility.

Two earlier reports of the Surgeon General (US DHEW 1979; US DHHS 1980)
concluded that mean gestational duration is not affected by maternal smoking and that
data are not sufficient to support a conclusion that maternal smoking increases,
decreases, or has no association with risk of congenital malformations.

This Section reviews observational studies of smoking cessation and the following
reproductive outcomes: fertility and infertility; ectopic pregnancy and spontaneous
abortion; fetal, neonatal, and perinatal mortality; birthweight and gestational duration:
and complications of pregnancy. Three randomized trials of smoking cessation and
pregnancy outcome are described and discussed in detail. Information on the
prevalence of smoking during pregnancy and time trends in prevalence is presented,
along with estimates of the attributable risk of several pregnancy outcomes. SIDS and
congenital malformations are not considered because of the limited information on
smoking cessation.

Pathophysiologic Framework

The effects of smoking that might mediate adverse effects on the developing fetus
and on fertility, fetal loss. and pregnancy complications have been reviewed in other
publications (Longo 1982; Mattison 1982; US DHHS 1980). These reviews are
summarized with attention to the temporal course of the relation between exposure to

37]
cigarette smoking and pregnancy outcome as well as the distinction between reversible
and irreversible effects of smoking. Reversible effects would be expected to result in
similar risks for never smokers and former smokers, whereas irreversible effects would
be expected to lead to different risks in both current and former smokers compared with
never smokers.

Several pathways have been postulated by which tobacco smoke might adversely
affect fertility (Mattison 1982) (Table |). These include disturbance of hypothalamic—
pituitary function, interference with motility in the female reproductive tract (Chow et
al. 1988), and impairment of implantation, all of which are thought to be reversible
consequences of exposure to absorbed chemicals in tobacco smoke (principally
nicotine). It has also been suggested that smoking results in oocyte depletion through
direct toxicity (Mattison 1980), which would have irreversible consequences for
fertility. Chow and colleagues (1988) postulated that altered immune function (Hersey,
Prendergast, Edwards 1983) may predispose smokers to pelvic inflammatory disease.
which in turn can result in permanent scarring and occlusion of the fallopian tubes.
Alterations in the neuroendocrine control of ovulation have been suggested to account
for increased amenorrhea reported among smokers (Pettersson. Fries, Nillius 1973):
this mechanism, as an effect of smoking on fertility. would be reversible.

TABLE 1.—Possible mechanisms for the effect of smoking on pregnancy
and pregnancy outcome

 

Outcome Possible mechanism

 

Reduced fertility Hormonal effects
Impaired tubal motility
Impaired implantation
Oocyte depletion
Altered immunity leading to pelvic
inflammatory disease

Spontaneous abortion Nicotine toxicity

Reduced birthweight Impaired weight gain
Nicotine toxicity
CO toxicity
Increased cyanide teading to impaired vitamin
Bi2 metabolism
Hy poxia due to increased levels of CO or to
vasoconstriction of umbilical artery

 

NOTE: CO=carbon monoxide.

Mechanisms for an effect of cigarette smoking on spontaneous abortion have not been
clearly defined, partly because so little is known about the pathophysiologic basis for
spontaneous abortion. The causes of spontaneous abortion are broadly divided into
genetic and nongenetic causes (Kline 1984). Because smoking seems to have its
primary impact on chromosomally normal spontaneous abortions (Kline 1984: Alber-
man et al. 1976). nongenetic pathways are implicated for smoking (Table |).

372
Most attention has been focused on the mechanisms mediating a reduction of fetal
growth among smokers (Table 1). An indirect, nutritionally based mechanism in which
smokers are postulated to eat less and gain less weight during pregnancy. thus delivering
smaller infants, has been prominent in discussions of fetal growth retardation in smokers
(Papoz et al. 1982: Rush 1974; Meyer 1978: Davies and Abernethy 1976). This subject
has been reviewed in depth in previous reports of the Surgeon General (US DHEW
1979: US DHHS 1980) and more recently by other researchers (Werler, Pober, Holmes
1985). Differences in weight gain do not entirely explain fetal growth retardation in
smokers because differences in weight gain during pregnancy between smokers and
nonsmokers are very small and have not been observed consistently and because a
relationship between growth retardation and smoking persists after adjusting for mater-
nal weight gain.

In this context, however, the studies of weight gain in women who quit smoking
during pregnancy are of interest. Pulkkinen (1985) found that women who quit
smoking during the first trimester gained more weight than nonsmokers or continuing
smokers (1.0 vs. 1.3 kg average difference, respectively). Kuzma and Kissinger (1981)
also found that women who quit smoking during pregnancy gained more weight
compared with women who did not smoke during pregnancy (average difference of 4.7
kg) and women who smoked throughout pregnancy (average difference of 5.6 kg).
Also, women who quit smoking before the onset of pregnancy were reported to gain
more weight during pregnancy than nonsmokers or smokers (1.3 kg and 0.9 kg average
difference, respectively) (Anderson et al. 1984). Rush (1974) reported a reduction in
weight gain of 0.12 pounds per week among continuing smokers compared with those
who quit. This pattern may reflect the well-established tendency to gain weight
following smoking cessation (Manley and Boland 1983: Rabkin 1984), as discussed
further in Chapter 11.

There are several hypotheses that attempt to explain the mechanism by which fetal
growth is affected by cigarette smoking (Table 1), but cigarette smoking is believed to
impact on fetal growth through intrauterine hypoxia (Longo 1977). Carbon monoxide,
a component of cigarette smoke, has the ability to cross the placenta and bind with the
hemoglobin in both the mother and the fetus producing carboxyhemoglobin. Car-
boxyhemoglobin reduces the ability of the blood to carry adequate levels of oxygen to
the fetus. Smoking is also believed to cause vasoconstriction of the umbilical arteries.
and therefore, impact on placental blood flow (Lehtovirta and Forss 1978: Naeye and
Tafari 1983; Longo 1982). Cigarette smoking during pregnancy decreases the
availability of oxygen to the fetus by both mechanisms.

These mechanisms imply a reversible effect of cigarette smoking for fetal growth
because normal function would resume shortly after nicotine or CO is cleared from the
system. Support for the suggestion that these effects are reversible is derived from
several sources. Davies and coworkers (1979) found that 48 hours of smokin g cessation
late in pregnancy increased oxygen availability to the fetus. ViSnjevac and Mikov
(1986) found similarly low levels of carboxyhemoglobin (COHb) in mothers and
newborns when the mother was a former smoker or never smoker: mothers who smoked
during pregnancy and their newbors had high levels of COHb.

373
Mechanisms for the effects of smoking on neonatal. perinatal, and infant mortality
are poorly understood. although the reduction in birthweight is often considered to be
the mediating process. However, smoking appears to cause a shift in the distribution
of birthweight without having much effect on mean gestational age (US DHEW 1979,
US DHHS 1980), and shifts in birthweight distribution across different populations do
not always produce corresponding shifts in mortality (Wilcox 1983; Wilcox and Russell
1983a.b).

That gestational age is little affected by smoking, whereas birthweight is reduced at
every gestational age. explains why small infants of smokers have a better prognosis
than small infants of nonsmokers (Yerushalmy 1971; MacMahon. Alpert, Salber 1966).
Increases in perinatal mortality among smokers may result not from the reduction in
birthweight, but rather from the modest increases in preterm delivery, very low
birthweight, and specific pathologic conditions such as placenta previa and abruptio
placentae. However, this has not been addressed explicitly in any study. Because the
smaller smoking-related increases in less frequent, more severe outcomes parallel the
pronounced smoking-related reduction in birthweight. birthweight serves as a useful
empirical marker of smoking’s harmful consequences, even if it is not the direct
mediator of those effects.

Nonexperimental Studies

Fertility and Infertility

Consistent evidence indicates that smokers have lower fertility than nonsmokers
(Daling et al. 1987: Howe et al. 1985: Baird and Wilcox 1985: Hartz et al. 1987), as
noted in the 1989 Report of the Surgeon General (US DHHS 1989). The studies that
have assessed indicators of fertility in former smokers are summarized in Table 2.

Pettersson. Fries. and Nillius (1973) studied secondary amenorrhea, one mechanism
for reduced fertility, and found an increased prevalence among smokers. However,
prevalence among former smokers was even higher than among continuing smokers.
Hammond (1961) found that irregular menstrual cycles were more common among
smokers than never smokers and that former smokers were at slightly lower risk than
never smokers.

Howe and colleagues (1985) analyzed data on more than 4.000 women in a British
cohort study. which assessed the safety of oral contraceptives. Compared with never
smokers, women who smoked 20 cigarettes or more at entry into the study were twice
as likely to be undelivered 5 years after ceasing contraceptive use with the intention of
becoming pregnant. whereas former smokers had the same likelihood of being un-
delivered as never smokers. Baird and Wilcox (1985) reported that the time period until
pregnancy was the same for 31 women who quit smoking in the year prior to attempting
to conceive as it was for never smokers.

Daling and coworkers (1987) conducted a large case-control study in Washington
State and found that, compared with never smokers, the relative risk of primary tubal
infertility was 2.7 among current smokers and 1.1 among former smokers. Information

374
TABLE 2.—Summary of studies of fertility among smokers and former smokers

 

Relative risk of measure of fertility”

 

Measure of

 

Reference Location fertility Smokers Former smokers
Pettersson, Fries, Sweden Secondary amenorrhea 13 1.6
Nillius (1973)

Howe et al. England Not pregnant S yr after 2.0" 1.0
(1985) ceasing contraceptive use

Baird and Wilcox Minnesota Time to pregnancy >I yr 3.4 1.0
(1985)

Daling et al. Seattle Primary tubal infertility 2.7 1.0
(1987)

Daling et al. Seattle Secondary tubal infertility 1.6 1.3
(1985)

 

“Compared with never smokers.

h .
Smokers of >20 cig/day .

on secondary tubal infertility from the same study (Daling et al. 1985) revealed a smaller
difference between current and former smokers. Although the study focused on prior
induced abortion, data are presented that allow computation of crude odds ratios for
current and former cigarette smokers. Current smokers had a 1.6-fold increase in the
risk of secondary tubal infertility, and former smokers had a 1.3-fold increase in risk.
It is difficult to assess the causal effect of smoking on tubal infertility independent of
the effects of sexually transmitted diseases (STDs) known to co-vary with smoking in
many populations.

In summary, the data suggest that impairment of fertility measured as delay in time
to conception is related to smoking near the time of attempting to conceive and that
smoking cessation prior to conception returns fertility to that of never smokers.
Conclusions about smoking and the risk of tubal infertility cannot be drawn because of
concern about uncontrolled confounding.

Ectopic Pregnancy and Spontaneous Abortion

Tubal (ectopic) pregnancy occurs at about the same time in the reproductive process
as fetal loss. However, the mechanisms are thought to be similar to those operating in
tubal infertility and largely concern tubal motility and patency. Several reports indicate
an increased risk of ectopic pregnancy in smokers (Campbell and Gray 1987: Mat-
sunaga and Shiota 1980), but only Chow and associates (1988) examined the associa-
tion with prior smoking in detail. In a case-control study in western Washington State.
155 cases of tubal pregnancy were compared with 456 controls who had given birth.
Current smokers had an estimated 2.2-fold increased risk of ectopic pregnancy com-

375