Late Fetal nn.47 .Ileonatal Death8

Considerable variation has occurred in the definition of the study
population among the studies in which the relationship of cigarette
smoking to fetal mortality (other than abortion) and early infant
mort.ality was examined. The most commonly identified st,udy popula.
tions have been perinatal deaths, neonatal deat'hs, and late fetal phIs
ntwnat:~l deaths. Pcrinatal deaths are a combination of late fetal deaths
(i.e., stillborn infants) and deaths occurring within the first week of
life. Neonatal deaths include all deaths of liveborn infants wit,hin the
first 28 days of life.

EPIDEMIOLOGICAL STUDIES

Most, of the earlier epidemiological studies of the association between
cigarette smoking and late fetal plus neonatal mortality were revieffed
in the 1971 and 1972 reports on the health consequences of smoking
(101, Z&Y). h review of previously unreported studies (67? 763, as weI1
as reexamination of previously cited studies. forms the basis of the
following statements :

The results of several prospective and retrospective studies indicate
a statistically significant higher late fetal and/or neonatal mortality
for the infants of smokers compared to those of nonsmokers (14, li.
25, 43). The results of other prospective and retrospective studies iden-
tified no significant tliffcrmce in the mortality rates between the in-
fants of smokers and nonsmokers (20.6.5. 72.85, 1013. 115).

If mortality rates were compared for those infants of smokers and
nonsmokers weighing less than S..`,OO prams. the infants of nonsmokers
apparently had a consitlrrably !lipher risk than did those of smokers.
The results of recent studies, coupled with a critical review of thp
design and analysis of previous studies, and a reexamination of exist-
ing data, may provide at least a partial explanation of discrepancies
between the results of previous studies.

Comparisons of the 3Iortality Risks of r,o~v-Rii~ll-~T'eiF]lt Infants
          Born to Smokers and ;?;onsniokers

The perinatal mortality risk for infants weighing less than 2.5M
grams appears to bc lower for those infants born to women wlln
smoke during pregnancy than for those born to nonsmokers (tablr

126


3). I-Ton-ever, available evidenre shows that cigarette smokers' infants
tend t,o be small-for-gestat,iorlal age rather than gestationally pre-
mature. Hence, within a given birth w-eight group, the infants of
smokers are, on the average, gestationally more nlature than those of
nonsmokers. Data collected by the Kational Center for Health Sta-
tistics (IO./) demonstrate that within a given birth weight group? the
snore gestationally mature an infant, the lower is its mortality risk
(fig. 6). Thus, the difference in perinatal mortality risks experienced
Iy the infants of cigarette smokers and nonsmokers, within comparable
hirtll n-right classes, reflects the facts that the two sets of infants are
not of the same average gestational age, and that gestational age is
:I major factor influencing late fetal and neonatal mortality. An accu-
rate estimate of comparative mortality risks for the infants of cig-
arette smokers and nonsmokers requires adjustment for gestational
age.

For infants of comparable gestational age. lower birth weight is as-
sociated with higher mortality (fig. 6). Since infants of cigarette
smokers have, on the awrage, loner birth weights than the infants of
[lousmokers. within groups of comparable gestational age, cigarette
wakers' infants should experience higher mortality rates than non-
slnokers' infants of similar gestational ages. In a recent review, Meyer
nnd Comstock (51) provided a more extensive discussion of these
points.

TABLE 3.- Comparison qf the perinata.1 mortality -for infants u$eighing
   less than 2,500 grams, qf smokers and nonsmokers

Authcr, reference

Perinatal mortality rate (deaths per 1,CWJ
        live births)

   Smokers      Nonsmokers

rnderwood, et al. (l00)-~-_--_----_-_------.-
(`ntario Department of Health (67)------.-----
Kullander and Kiillen (4s)._----_-~-------_---
l~antdmio (76)__-.__--_-__-_-_----~~- ____ -_
YfmhaImy 1 (IIS) :
Blackwomen-_-_--__-_-_- __._ -__- .___ -.
White women---_----_-_--~--.---------~
Rrltlerand Alberman (14)------~-------------

187          269
232          300
129          139
288          344


114          202
114          218
269          284

' %"Xted neonatal mortality rates only.

127


In
ii   100

`E   80
f
.-   60


   40                      1,
rl

     JANUARY 1 TO MARCH 31, 1950
400                                  7
  .\
     \

Figure &-Neonatal mortalify rates amoyg single white births in h,ospitals (by
    detailed birth weight and speckfled gestation groups: United States),

28-31 weeks

BIRTH WEIGHT (in grams)

SOURCE: U.S. Public He&h Service, National Center for Health Statistics (103).

Recent Studies

The Ont.ario Perinat.al Mortality Study (66: 67) eras conduct4
among 10 teaching llospitals (Iuriug 1%X and 1961. In this retrospw
tivr study of 51.190 1"~~
          `~wi;~li(~irs. a statistically siguificant increa~c~
in the prinatal mortality rate was dcmonstratecl for sniokers' in-
fants as conipar~d with those of nonsmokers; the infants of sulolters
csperienwd an 0~crall relative risk of 1.27 (I'< 0.001). Moreover, tlw
inr-rstigators found a statistically significant (low-response relationsllip
b&Keen t.hc amount of cigarettes smoked and the prinatal mortality
rate (P<O.OOl) (fig. `i).

128


Figure 7.-Perinatal mortality rate per 1,000 total births by cigarette smoking
     category.

          Nonsmoker



Number of
Perinatal deaths:   659

Total births:    28,368

<I pack of
cigarettes     z,l pack of
           clga rettes
per day       per day



  425            220

15,328         6,581

(P <O.ool)

SOURCE: Ontario Department of Health (66).

Recently Butler, et al. (15) further analyzed the British Perinatal
IIortality Study. They found a highly significant association between
niaternal smoking after the fourth month of pregnancy and both
Iate fetal and neonatal deat,hs. Infants of smokers had an increase in
Ilie late fetal mortality rate of 30 percent, and an increase in the neo-
W%l mortality rate of 26 percent, compared to the infants of non-
smokers. The overall mortality ratio of late fetal plus neonatal deaths
`yas 1.28 (P<O.OOl). Given t,he large number of women in the study,
:llld the significant changes in smoking behavior which occurred,
nkcy found it possible to consider the effect. of a change in smoking

129


behavior bctxecn the beginning of pregnancy and the fourth month
on late fetal and neonatal mortality. ,I statist,ically significant alld
dose-related increase in mortality occurred among the infants et
mothers who continued to smoke after the fourth month of pregnanrY,
as compared wit,h the infants of nonsmokers and those of women I&,
smoked prior to the pregnancy but gave up smoking by the fourth
month of gestation.

Nislvandtr and Gordon (63) reported data from the prospectne
Collaborative Perinatal Study of the National Institute of Xeurologi.
cal Disease and Stroke. The :39,215 pregnancies registered at 12 uni-
versity hospitals in the I-nited States were almost equally divided
between black and white w-omen. They found a nonsignificant. increase
in perinatal mortality among t.he infants of white smokers as Compared
to those of white nonsmokers; the overall mortality ratio was 1.1:3
(P>O.l). The infants of black smokers, however, had a significant]!
higher mortality risk than did those of black nonsmokers; the mar-
tality ratio was 1.18 (P<O.O2). Moreover, a definite dose-response r-e-
lationship bet.ween cigarettes smoked by pregnant mothers and
mortality risk was shown for black infants. Black women were noted to
smoke significantly fewer cigarettes, on the average? than white
women.

Rush and Knss (83) found, in a prospective study of 3.2'76 preg-
nancies followed at Boston City Hospital. a nonsignificant increase
in late fe'tal plus neonatal mortality rate among the infants of white
n-omen who smoked as compared to those of white nonsmokers. Holy-
ever, the infants of black women who smoked had a statistically sig-
nificant increase in mortality rate compared to the infants of blacb
nonsmokers (P<O.Ol) . The overall mortality ratio for black women
who smoked was 1.86. The difference in frequency of stillbirth among
the infants of smokers and nonsmokers was the primary factor w-hick
contribrltcd to the signifcancc of the difference in mortality rates.

-1nalysis of Previously Re.ported Studies

Previously reported studies can be divided into two groups : A proq
in which the late fetal plus neonatal mortality rates for infants born
to cigarette Fmokers were significantly higher than those for thp
infants born to nonsmokers, and a group in which no significant
ditl'crrnces were detected in the mortality rates for the infants born
to smokers and nonsnrokers. The results of several studies (I.$. 17. ,OC
49, $3, 55, Sj. 92) yielded mortality ratios ranging from 1.38 to 1.X
The results of other studies ($0. 65/r: 76. X,5, I/XI. 215) yielded mortalit!
ratios ranging from 1.01 to 1.06. Roth groups contained retrospective
and prospective studies of comparable size. The two groups did differ

130


~~~iiificantly, however. with regard to control of wriables other t,han
,ig;wctte smoking which influence perinatal mortality.

Fwtors V7~ich Influence Pcrinatal Mortality Other Than Smoking

13utler and Mberman (I.)), on data from the British Perinatal
Ywtality Study, employed a logit tl.:~nuforlllatio~l analysis of vari:mceY
.1t1(1 demonstrated that nlaternal height, agr, l)aritJ? social class, and
wwre preeclampsia all had a dignificant indelwndent ctlect On late
itatal and neonatal mortality. Rumeau-Roquette (81) provided evi-
~lcwe that a 1)rerious stillbirth or low-birth-\vcight infant significantly
it~rrrnsc~d the risk of a future stillbirth. Meyer and C'omstock ~~51)
lwvided examples of 110~ the diflerrntial distribution of smoking and
1~t11rr factors which are related to perinntnl mortality, in a population
of women, can bias data (e.g., black w01ne~i have higher perinatal
lllortnlity rates than do white women, but black women smoke, less
t11an white women do. Hence. nonsmokers Iv-ill tend to include more
`~lwk women, and smokers more white women. This I\-ill tend to
r&ice any differences between the groups in mortality rates.) Meyer
~l1t1 Comstock conc~luded, Comparisons of mortality rates of smokers
~1 nonsmokers' babies Aould be made within subgroups according
to parity, socioeconomir status. and other appropriate risk factors:
M not separated by birth weight."
In three of the studies in which a significantly higher mortality risk
aas demonstrated for the infants of smokers, adjustment for other
rnriables was performed. The resu1t.s indicated that, after such ad-
jtistment, a significant independent association between cigaret,te
smoking and infant mortality persisted (13 and 15. 17, 81). Of the
studies which revealed no significant increase in mortality risks for
smokers' infants, one (11.5) cont,rolled for race alone. Hence, at least
l)art of the discrepancy in results between the two groups of studies
1iia.r be explained by a lack of control of variablw other than smoking.
-inother possible, at, least partial, explanation of the discrepancy
iii results obtained by the tn-o sets of studies is that cigaret'te smoke
may be more harmful to the fet,uses of certain women- than others.
Several developing lines of evidence suggest that. this may be the case:
1. Cigarette smoking and socioeconomic background.
Butler, et al. (15) noted t.hat when data from the British Perinatal
JIertality Study are grouped by social class of the mother's husband,
the late fetal plus neonatal moG.ality ratio for infants of smokers and
tiensrnokers in the upper social classes I and II is 1.10: t.he mortality
ratio for the entire sample was 1.28. Rush and Kass (82) reviewed the
%tish Perinatal JIortality Study, along with several other studies,
and noted that all have sho\rn the strongest, association betwwr excess
infant mortality and cigarette smoking among the infants of those

405-028 o--7B----Jo                                      131


mothers with lower socioeconomic status. Comstock and Lundin (16)
found excess mortality among smokers' infants almost entirely eon.
fined to those whose fathers had a grammar school education or 1%.
Several of the studies which revealed no significant difference in mopA
tality among the infants of smokers and nonsmokers were conducted
in predominately middle class populations ($0, 100,115).

2. Cigarette smoking and previous obstetrical experienc;e.
Peterson, et al. (72) had rigid criteria for entry into his stu$

population of 7,740 women, He*included only those women who pre.
viously had healthy infants with a birth weight greater than 2,500
grams. He found a significant decrease in birth weight among smokers,
infants, but no significant increase in mortality rates. Rumeau.
Roquette (81) found that among women who previously had delivered
only healthy infants weighing more than 2,500 grams, cigarette smok.
ing was not associated with an increased risk of stillbirth ; among those
women with a previous stillbirth, smoking was significantly associated
with increased risk of a future stillbirth.

3. Cigarette smoking and gBnetic differences.

The consistent finding that the mortality risk for the infants of black
smokers is higher than t,he risk for the infants of white smokers, even
when the socioeconomic background for both is ostensibly similar.
suggests that genetic factors also may interact with smoking to pro-
duce enhanced risk (82, 99, 115).

Availa,ble evidence suggests that. if those women, who are already
likely to have small infants for reasons other than smoking, smokp
during pregnancy, t.heir infants will be most unfavorably affected,
This means that the women in the United States Those infants will
be most affected by cigarette smoking are those who have an unfavor-
able socioeconomic sit,uation, have a history of previously unsuccessful
pregnancies, and are black.

Studies in Animals

Studies previously reviewed in the 1971 and 1972 reports on the
health consequences of smoking (101,102) demonstrate that exposure
of rabbits and rats to tobacco smoke and to injections of large doses
of nicotine resulted in significantly increased late fetal and neonatal
mortality. Astrup ($?) has recently studied the e.ffect of continuous
exposure of pregnant rabbits to carbon monoxide on stillbirth rates.
He found a significantly higher, dose-related incidence of stillbirtllF
and deaths within the first 21 hours of life among the offspring of the
experimental rabbits (table 4).

132


TABLE 4.-ELff~cf ?f carbon monoxide exposure of pwgnant rabbits on
        birth weight and neonad mortality

Group 1,     Group 2,      Oroup 3,
0 psrrnt   8 to 10 Percent  16 to 18 percent
COHb      COHb       COHb

(P<O.OOl)

' 1 percent.
? 10 percent.
$36 yerccnt.
Source: Astrue, I'. (a)

Studies in Humans

Some investigators have examined the causes of death among the
infants of smokers as compared nith those of nonsmokers. Comstock,
et al. (17) found that infants of smokers died more frequently of as-
])hyxia, atelectasis, and immaturity. Kullander and Kallen (.&!I) found
ilhruptio placentae significantly increased as a cause of death among
smokers' infants. Butler and Xlherman (14) found little difference in
the death rat.es for the infants of smokers and nonsmokers from iso-
immunization and malformations. but higher rates mere found for
smokers' infants in t.he groups in which death occurred before or dur-
ing labor, or in which death resulted from massive pulmonary hemor-
rhage, or pulmonary infection. As t,he authors noted. "The lat,ter three
are conditions knoLn to be associated 4t.h small-for-dates babies."
Tlley pointed out that distribution of causes of deat.11 in the smoking
~enp could be accounted for almost, entirely by the excess of low-birth-
~~~~ipht babies. This supports the conclusion that the mechanism which
Lltfects birth weight also influences mortalit,y.

$hGNIFICAXE OF TIIl? ~k3SOCIhTION

The following calculation is offered to piw some idea of the order of
r~9?nitude of increased late fetal and neonatal mortality associated
"yitll Cig:lty$ttl srljokill f (Illl.iIIg 1)1ygtl:lllc\-. If \voi11t~ii \\I10 snloked dltr-

133


inp pregnancy in the United States had an elevation in risk of 28 per.
cent for late fetal and neonatal mortality. as demonstrated by Butler.
ct, al. (l/j) for I3ritain, Srotlancl, and Wales, and if 20 percent ef
pregnant women smoked throughout the pregnancy,l the higher risk
of stillbirth and neonatal death for the infants of mothers who smoke
cigarettes during pregnancy would account, for approximately 4,606 of
the 87,263 stillbirth and neonatal deaths in the rnited States in 1Dfjfj.

LATE FETAL AND NEONATAL DEATH SUMMARY

A strong, probably causal association between cigarette smoking
and higher late fetal and infant mortality among smokers' infants is
supported by the following evidence :

1. Twelve retrospective and prospective studies have revealed a sh-
tistically significant relat.ionship between cigarette smoking ant1
an elevated mortality risk among the infants of smokers. In t,hree
of these studies, of sufficient size to permit adjustment for other
risk factors, a highly significant independent association betweet!
smokng and mortality was established. Part of the discrepancy in
results between these studies and those in which a sign&ant
association between smoking and infant mortality was not dem-
onstrated may be explained by a lack of adjustment for risk fac-
tors other than smoking.

2. Evidence is converging to suggest that cigarette smoking may be
more harmful to the infants of some women than others; this may
also, in part, explain the discrepancies between the results of the
studies in which a significantly higher mortality risk was shown
for the infants of smokers compared to those of nonsmokers and
the results of those studies in which significant differences in
mortality risk were not, found.

3. Within groups of similar birth weight, the infants of nonsmokers
appear to have a higher mortality risk t,han do the infants of ciga-
rette smokers. This results from the fact that the infants of non-
smokers within such similar birth weight groups are on the
average gestationally less mature than the infants of cigarette
smokers. Available evidence indicates that within groups of sim-
ilar gestational age, infant,s of lower birth weight experience a
higher mortality risk. Since the infants of cigarette smokers an

`Based on extrapolation of data on smoking behavior change during pregnancy from
the British Perinatal Mortality Studs. which probably Fields a conservatire estimnte.

134


small-for-gestational age, one. should expect, that if the infants of
cigarette smokers and nonsmokers are compared within similar
gestational age classes, the infants of cigarette smokers would
have the higher mortality rat,e.

4. The results of recent studies have documented a statist.ically sig-
nificant dose-response relationship between the number or amount
of cigarettes smoked and late fetal and neonatal mortality.
5. Kew data suggest that if a woman gives up smoking by the fourth
month of pregnancy, she will bnve the same risk of incurring a
fetal or neonatal loss as a nonsmoker.
6. Available evidence strongly supports cigarette smoking as one
cause of fetal growth retardation. The causes of excess deaths
among the infants of smokers are those associated with small-
for-dates babies.

i'. Data from experiments in animals ha1.e demonstrated that expo-
sure to tobacco smoke or some of its ingredients, such as nicotine
or cnrboii monoxide. rwults in it significant increase in late fetal
and or neonatal deaths.

8. The results of studies in humans have shown that the fetus of
a smoking mother may be directly csl~owtl to agents such as
carbon monoxitlc nitllin tobacco smoke, at ha\-els comparable to
those n-hicall llal-e heen shown to produce stillbirth in experimental
animals.

Sex Ratio

-4lthough a number of small studies have found a slight, usually
statistically nonsignificant. increase in tlic prot)ortion of female infants
born to smokers, the three lill'gest studies of Ivndrrwood. ct al. (48.505
pregnancies), Butler (15,791 l~regnancies)7 and NacMahon (12,155
pregnancies) have found similar infant sex ratios among bot.h smok-
ing and nonsmoking mothers. with tlw espwtetl slight excess of males
among each (table 5).

Available cviderlre strongly indicates thnt matt~rnnl c*igarette smok-
irlg does not influenc~e the sex ratio of ncwl~~rn infants.

135


TABLE 5.-Proportion qf male in,fants delivered to smoking and non-.
           smoking mothers

Author, reference

    Propo;;C$;f male
Pregnancies               Statistical

       Smokers    NOW   significance
              smokers

Underwood, et al. (IOO)-_. .--_-__--._-- 48, 505
Butler and Alherman (f.$- _ .__. _..___.. 15, `791
MacMahon, et al. (49)-_~--~-~-----~--- 12, 135
Kullander and Klillen (43)- __-_-_ . . . . . .  6,363
Reinke and Henderson `(78) - - _-. . _.. .__  3, 156
Frazier, et al.' @?b) -___. . _ _. _ _ _. . . . . . . - _  2, 915

518    519
,518    .516
513    .512
515    501
498    .517
472   505

502
492
501
532
513

493
. 517
,533
529
. 512

Kizer (@)-.- . . . . - ._.. ~_~ . .._ . . . . ..__  2,095
Herriott, et al. (35)..-- ._.... ~.----_---  2, 745
Ravenholt, et al (77) ____.-.__...__.____  2, 052
Lowe (46)-_-_..--..---_-~_..----~.--- 2,042
Russell, et al. (85) _._._ -. . .___-_..___ ._  2, 002

' Black women.

Congenital Malformations

Previous epidemiological studies which examined the relationship
between cigarette smoking and congenital malformations mere E-
viewed in the 1971 and 1972 reports on the health consequences of
smoking (101, 10.2). Recently, the authors of the Ontario Perinatal
Mortality Study (Ml 67): a retrospective study of 51,490 births, re-
ported no difference in malformation rate for the infants of smokers
and nonsmokers. The various studies of the. association b&aeen ciga-
rette smoking and congenital malformation have differed signific.antly
with regard to stud>- design. the type of population sampled. sample
size and number of infants with malformations, the definition of mal-
formation, and resu1t.s (table 6).

Previous experimental vork was reviewed in the 1971 and 1972
reports on the health consequences of smoking (102, 102). The chick
embryo has been employed in recent studies. The direct application of
nicotine to the embryo results in cephalic hematomas (26). malforma-
tions of the cervical vertebrae (99). and anomalies of the heart (27).
depending upon dose of nicotine and period of incubation in which
exposure occurs. Anomalies of the limbs of chicken embryos can also
be induced by exposure of the e gg to high levels of carbon monox-
                                   _
ide (4).

None.
Do.
Do.
Do.
Do.
(fl:od.OS)
None.
DO.
P<O.O5
None.
DO.

136


TABLE 6.-Relatire risk qf congenital ma(;formation .for in:fants of
cigarette smokers and nonsmokers, comparzng available studies with,
regard to study design, study population, sample size) number of
infants with malformaiions, and cl&ition qf malformation

Author.
reference

Study design

                 Infants Relative
Study population   Sample   with    risk    Definition of
             size   malfor-  SM/SS  malformations
                 mations

Cornstock, et al.
(17).
Yerushalmy (112)

Ontario Depart-
ment of Health
(i;Y).
htlur and hl-
berman C/4).

Gullender and
Gallen l&3).

Retrospective. Stillborn plus 24.hour
          deaths.

.__._ do __.__.... Neonatal deaths __.___

Prospective.. Infants less than
         2,500 g.
RetrGspectlve. Stillborn plus lst-
         week deaths plus
          surviving infants.
_..._ do _...... Stillborn plus neo-
          natal deaths.
   I (8) Stfllborn plus neo-
             natal deaths

rrospectise.. .

plus remainder
of deaths to age
1.

I (b) Surviving infants
   to age 1.
(4 ' Stillborn plus
   neonatal deaths 1
   and deaths to

Fedrick, et al.
(14).

Retrospective.

age 7.'sur-
vlvors 2 to age
7.

I (b) Neonatal deaths '
   (3-month
   study).

2,042

236

695


51,490



7,123

137

4,903

17,418

7,822

23

3i

59

1, 744

1.382

43

7cn

86







201

1.36 Jlajor.

.31 xajor, cause of
    death.
.6i Major.

.9?

1.19 JlRjOT, CallSB of

1.25



   8


1.06

death.

bfajor and minor
malfomlations.

1.55 (1).







1.07 (2).

' hutopsy-proron congenital cardiac malformation.
' Clinically determined congenital heart disease.

Given the considerable variation in study design, study population,
sample size, number of affected infants, definition of malformation,
and results, no conclusions can bc drawn about, any relationship
between maternal cigarette smoking and congenital malformation at
the present t,ime.

137


Lactation

Introduction

The following section is a review of available evidence which bears
upon any interaction bet.ween cigarette smoking and lactation. Emphn.
sis is placed upon the relationship of cigarette smoking to the quantity
of milk produced, to the presence of constituents of cigarette smoke
within the milk, and to effects upon the nursing infant mediated
through changes in either the quantity of milk available or the sub-
stances within the milk.

Epidem.ioZogica.Z Studies

Underwood, et. al. (99)? in a study of 2,000 women from various
social and economic strata, observed a definite but statistically insig
nificant trend toward more frequent inadequacy of breast milk pro-
duction among those smoking mothers who attempted to nurs,e
compared to nonsmokers.

Mills (5a), in a study of 520 women, found that among women who
indicated either a desire to nurse or no desire to nurse yet continued
to nurse beyond 10 days, and who had delivered their first live-born
infant, the average period of nursing for mothers who smoked was
significantly shorter than for nonsmokers. Moreover, among t.he 24
mothers who had given up smoking during at least the final 3 months
of their pregnancies, the average length of nursing was identical to
t,hat, of the nonsmokers. There was no significant difference between
smokers and nonsmokers with regard to complete inability to nurse
their offspring. This study is difficult to interpret because the author
did not determine the reason(s) for the discontinuation of nursing
among the women.

Experimental Studies

STEDIES IS ~~IAI,S

Nicotine

         Influence on the Lac.tation Process
BIake and Sawyer (11) studied the influence of subcutaneousl!
injected nic,otine (4 mg. total over a 5-minute period) upon lactatioll
in the rat,. They found that nicotine inhibited the suckling-inducrll

138


rise in prolact,in. So effect, of injected nicotine was demonstrated for
qtocin secretion since milk release was not' blocked.
1vilson (110) examined the effects of nicotine supplied through
,lrinking water (0.5, 1.0, and 2.0 mg. daily) on the weight gain of
nrirsing rats. Apparently. the nicotine had been available throughout
gestation as well. because the author commented on a reduction in litter
size among the experimental groups. more, or less proportionate to t.he
close of nicotine; hence, a prenatal effect could not have been dis-
tinguished from a postnatal one. Average birt,h weight was similar for
rspcrimental and control groups. So difference in weight. gain was seen
for any of the, groups. The lack of impact on birth \veight suggests
that close was lower t,han that used in other studies.

Presence of Nicotine in the Milk

Hatcher and Crosby (3.2): using a frog bioassay, reported traces of
nicotine in cow's milk 24 hours after the intramuscular injection of
5.0 mg./kg. and 5 hours aft,er the injection of 0.5 mg./kg.

Evidence for an Effect Upon the Nursing Offspring

Hatcher and Crosby (3.2). found that 0.5 mg./kg. nicotine injected
into nursing cats had no apparent harmful effect upon the kit,tens.
dpparently 4.0 mg./kg. suppressed lactation. Kittens fed the milk
from the cow which had been injected with 5.0 mg./kg. nicotine were
also apparently unaffected.

Kitrosamines

Bohr (53) found that diethylnitrosamine and dibutylnitrosamine,
Then administered to lactating hamsters? lvere associat,ed with the
(ierelopment of typical tracheal papillary tumors in the young? sug-
gesting passage of these compounds in.the milk. Although diet,hyl-
aitrosamine and dibutylnitrosamine have not been identified in ciga-
rette smoke,, many N-nitrosamines are potent carcinogens, and some
of them are present in cigarette smoke (37, 79).

STUDIES IX HCMANS

Nicotine and/or Tobacco Smoke

        Influence on the Lactation Process
Emanuel (~2') noted no reduction in milk production among 10 wet
nurse who were encouraged to smoke seven to 15 cigarettes daily ;

139


some were observed to inhale the smoke. Hatcher and Crosby (32)
noted that after a mother smoked seven cigarettes within 2 hours, it
was difficult to obtain a specimen of breast milk. Perlman, et al. (71)
found that of 55 women smokers wit.h an adequate milk supply at the
beginning of his st,udy, 11 (20 percent) of the women had an inade-
quate supply at the time of discharge from the hospital. No relat,iou-
ship was reported between the number of cigarettes smoked and the
likelihood of developing an inadequate milk supply. The authors' im-
pression was that there was no greater proportion with an inadequate
milk supply among smokers than among nonsmokers, but no car-
roborat.ing data were supplied.

Presence of Nicotine in the Milk

Hatcher and Crosby (32) f ound, using a frog bioassay, that the
milk of a woman collected after she had smoked seven cigarettes in 2
hours contained approximately 0.6 mg./liter nicotine. Emanuel (.ss),
using a leech bioassay, studied excretion of nicotine in the milk of wet
nurses who were encouraged to smoke for the experiment. After the
subjects had smoked six to 15 cigarettes over a l- to e-hour period, the
author found nicotine in their milk 4 to 5 hours after smoking, with a
maximum concentration of 0.03 mg./liter. Bisdom (10) demonstrated
nicotine in t,he milk of a mother who smoked 20 cigarettes a day.
Thompson (97) found approximately 0.1 mg./liter of nicotine in the
milk of a mother who smoked nine cigarettes a day (plus three pipe-
fuls). Perlman, et al. (71)) using a Daphnia bioassay, demonstrated
nicotine in the milk of all women who smoked in their study. Moreover,
they found a direct dose-relat.ionship between concentration of nicotine
and the number of cigarettes smoked. No comment is made by the
authors on the possible inaccuracy introduced by examining only the
residual milk following nursing, but it, is well known that the composi-
tion of the fore milk and hind milk is different and perhaps the
concentration of nicotine also differs.

Evidence for a Clinical Effect Upon the Offspring

Emanuel (22) noted that among t,he infants in his study, loose stools
were observed only in the one whose wet nurse had smoked 20 c&a-
rettes in the previous 4 hours. Bisdom (10) observed a case of "nico-
tine poisoning" in a 6-meek-old infant whose mother smoked 20 cig:l-
rettes a day. The symptoms included : restlessness. vomit,ing, diarrh~~:l.
and tachycardia. Nicotine was demonstrated in the milk, and tl~
symptoms abated when smoking was stopped. Greiner (JO) also &-
scribed a case of possible nicot,ine poisoning in a 3-week-old nurslil+'

140


~llose mother smoked 33 to 10 cigarettes a day. The symptoms included
vomiting and loose stools. Following the curtailment of smoking. the
+wptoms gradually abated over a 3-day period. I'erlman2 et. al. (71)
noted no effect of smoking on the weight gain of the infants of the
smokers in their study. Furthermore, no untoward symptoms were
observed. They therefore doubted an effect of smoking on lactat,ion.
Thy noted that, the dose received by the infants was beneath the toxic
level as computed from adult experience, and this accorded wi-ith their
clinical observations. The fact that they admit.ted to the study only
\vomen with an apparently adequate milk supply may have affected
tlteir results. The authors suggested that perhaps t.he lack of effect of
smoking upon lactation might represent the development of tolerance
to nicot,ine! as both the mother and the oRspring had been exposed
throughout the pregnancy.

VITAMIN C

Venulet (105, 106, 107). in a series of studies, demonstrated that
the level of vitamin C was reduced in the milk of smoking mothers as
compared with nonsmokers. The clinical significance of this observit-
tlon has not been evaluated.

Lzctndion Xu.mmary

1. The two pertinent epidemiological studies suggest. a possible in-
fluence of smoking upon the adequacy of milk sul~ply However,
with only limited numbers of women and without control of other
potentially significant variables, no conclusions can be drawn.
2. Studies in rats have clrmonstrxted that nicotine can interfere with
suckling-induced rise in prolac~tin. The rele\-ancc for humans
is uncertain.

3. Evidence csists that nicotine passes into breast milk. Xo clear
evidence for an acute efTect upon the nursing infant is arailable.
Potential chronic effects Ilaw not been studied.
4. Sew eviticncc froni c~slwrinwilts with niicc suggests that nitros-
amines. lillO\V11 cnrcino,~ws, 1~ass tllrorlgtl tlle milk to suckling
yonnp.

141


Preeclampsia

Previous epidemiological studies of the relationship between ci,g.
arette smokimg and preeclampsia were revierved in the 1971 and 197~
reports on the health consequences of smoking (101,102) and form the
basis of the follo\ving statements :

The results of several large prospective and retrospective studies
indicate a statistically significant lower incidence of preeclampsia
among smoking women (1& 43,100). The results of one large retre.
spective study demonstrated a significant inverse relationship betlreen
the incidence of preeclampsia and the number of cigarettes smoked
(100). When other risk fact,ors, such as parity, social class, maternal
weight before the pregnancy, and maternal weight gain during the
pregnancy were controlled, smoking women retained a significanth
decreased risk of preeclampsia (22). The lower risk of preeclam&
for cigarette smoking women has been demonstrated in Britain and
Scotland (14. 21. 46, 83)) The IJnited States (100, 118)? Venezu&
(@), and Sweden (43). If a maternal smoker does develop preeclamp.
sia, however, available data suggest that her infant has a higher mar.
tality risk than does the infant of a nonsmoker with preeclampsi~
(.21,83).

1. Available evidence indicates that maternal cigarette srnok?b
have a significantly lower risk of developing preeclampsia a>
compared to nonsmokers.

2. If a woman who smokes cigarettes during pregnancy does derelnl,
preeclampsia, her infant has a higher mortality risk than the
infant of a nonsmoker with preeclampsia.

Pregnancy References

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142


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`I$) D~MAQALA, J., DO~I~~GALA, L. Zachowanie sie wagi urodzeniowej oraz
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143


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( 7-s )


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