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7-25


8. PREGNANCY AND INFANT HEALTH.

National Institute of Child Health and Human
        Development


CONTENTS

Introduction .............................................................. 9
Biomedical Aspects of Smoking .............................. 9
  Historical Considerations ........................................ 9

Smoking, Birth Weight, and Fetal Growth.. .................. 11
  Birth Weight ...................................................... 11
  Placental Ratios .................................................. 14
  Gestation ........................................................... 17
  Fetal Growth ................ .._ ................................... 19
Long-Term Growth and Development .................... .21
Role of Maternal Weight Gain .............................. 24
Evidence for Indirect Associations Between Smoking
   and Birth Weight.. .......................................... .26
Summary ........................................................... 27

Cigarette Smoking and Fetal and Infant Mortality.. ...... .28
  Overview ........................................................... 28
Spontaneous Abortion ........................................... 30
Perinatal Mortality .............................................. 32
  Cause of Death.. ................................................ .36
Complications of Pregnancy and Labor.. ................ .39
Preeclampsia ...................................................... .41
  Preterm Delivery ................................................ .42
Pregnancy Complications and Perinatal Mortality by
   Gestation. ........................................................ 43
  Sudden Infant Death Syndrome ............................. 44
Summary .......................................................... .46

Lactation and Breast Feeding ..................................... 48
  Introduction ........................................................ 43
Epidemiological Studies ....................................... .43
Experimental Studies ........................................... 49
    Studies in Animals ....................................... 49
      Nicotine ................................................... 49
     Studies in Humans ....................................... 50
       Nicotine and Tobacco Smoke.. .................... .50

Physiologic-Experimental Studies ................................. 52
  Studies in Animals .............................................. 52

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  Tobacco Smoke ............................................. 52
   Nico:il>e ...................................................... 53
   Carbon Monoside.. ....................................... .57
   Carbon Monositie Cptake and Elimination .... .58
   Effec;s on Fetal Growth and Development .. .60
    Carbon MMoiloside Effects on Tissue
    Oxygenation ......................................... .61
    Effects on Newborn -4nimais . ...................... 65
  Polycyclic Hyclroc;lrbons ................................. 65
Studies in Humans. ............................................. 67
   Tobacco Smoke., .......................................... .67
  Carbon Monoxide .......................................... 70
   Vitamin Blz and Cyanide Detoxification.. ......... .73
   Vitamin C..                        74   .
               .................................................

Research Issues ......................................................... .74
  Fetal Death ........................................................ 75
  Neonatal Death ................................................... 76
Spontaneous Abortion .......................................... .77
  Preeclampsia ....................................................... 77
Sudden Infant Death S.yndrome ............................. 7i
Long-Term Follow-Up .......................................... 77   .
  Birth Weight and Placenta.. ................................ .78
Experimental S'.udies .......................................... .78
  Lactation and Breast Feeding ...... ..-*r
                           ....................... 78
  Tobacco Smoke ................................................... .79
  Nicotine ............................................................. 79
  Carbon 11onoside ................................................. 80
  Polycxclic Hydrocarbons ........................................ 81

References ..................................................... .......... i;i!
                                                  _

LIST OF FIGURES

Fipre 1. --Perccntqc cia:riiwtioll hy birth weight of
infants of mot&rs \vho (ii11 not smoke &ring pregntrnq
and of those whc, sm&tul r>ne l)ack or I:~~)I*L' of cigarettes
per day . . . . . . . . . .._..._................................................ li

                                     -

Figure 2.--Ratio of IJhXctid weight to uirth weight by
length of gestation and maternal smoking category.. . . . 18


Figure 3.-Mean birth weight for week of gestation
according to maternal smoking habit: control week
singletons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Figure $.-Percentage of birth weights under 2.500 grams
by maternal smoking level for early, average, and late-
term births . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20

Figure 5.-Theoretical cumulative mortality risk according
to smoking habit, in mothers of different age, parity,
and social class groups . . . . . . . . . . . . . . . . . . . . .._..................... 31

Figure 6.-Percentage distribution by weks of gestation
of births to nonsmokers, smokers of less than one pack
per day, and smokers of one pack per day or more.. . . . 43

Figure 7.-Probability of perinatsl death for smoking and
nonsmoking mothers, by period of gestational age.......45

Figure &-Risks of selected pregnancy complications for
smoking and nonsmoking mothers, by period of
gestational age at delivery.. . . . . . . . . . . . . . . . . Y . . . . . . . . . . . . . . . . . . . 46

Figure O.-Time course of carbon monoxide uptake in
maternal and fetal sheep exposed to varying carbon
monoxide concentrations.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Figure lO.-Human maternal and fetal oxyhemoglobin
saturation curves showing carbon monoxide effect.. . . . . .62

Figure Il.-The partial pressure at which the
oxyhemoglobin saturation is 50 percent, P59, for human
maternal and fetal blood as a function of blood
carboxyhemoglobin concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Figure 12-Fetal values of oxygen partial pressure as a
function of carboxyhemoglobin concentrations during
pm&steady-state conditions.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64

Figure I3.-Thermogram from a near-term pregnant
patient before and after smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Pigme 14.-Percent carboxyhemoglobin in maternal and
fetal blood as a function of car!mn monosidc partial

8-5


pressure and concentration (parts per million) in inspired
air..............................................................,..,.....71

Figure 15.-The degree of compensation necessary to
offset the effects of elevated fetal carboxyhemoglobin
concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..*.............. 73

LIST OF TABLES

Table l.-Birth weight under 2,500 grams by maternal
smoking habit, relative and attributable risks derived
from published studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .,. . . . . . . . . . 13

Table 2.-Mean birth weight of infants of smoking and
nonsmoking mothers, by other biologic and socioeconomic
factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Table 3.-Birth weight under 2,500 grams by maternal
smoking and other factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

Table 4.-Spontaneous abortions by maternal smoking
habit and desideration of pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Table 5.-Perinatal mortality rates per 1,900 live births to
smoking and nonsmoking mothers, and relative risks for
infants of smokers by maternal age, parity, and years of
school . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Table 6.-Examples of perinatal mortality by maternal
smoking status related to other subgroup
characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Table `7.-Cause of stillbirth related to smoking habit.. . . . 36

Table %-Cause of neonatal death related to smoking
habit.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Table 9.-Stillbirths according to cause in relation to
maternal smoking during pregnancy.. . . . . . . . . . . . . . . . . . . . . . . . . 3'7

Table lO.-Fetal and neonatal deaths by coded cause and
maternal smoking habit.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

8-6


Table Il.-Perinatal mortality and selected pregnancy
complications by maternal smoking levels.. . . . . . . . . . . . . . . . . .40

Table 12.-Fetal and neonatal deaths by maternal smoking
and other coded conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Table 13.-Preterm births by maternal smoking habit,
relative and attributable risks, derived from published
studies.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Table 14.-The relation of the concentrations of fetal to
maternal carboxyhemoglobin in mothers who smoke
during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . `72

8-7


Introduction

Biomedical Aspects of Smoking

Data accumulating in the scientific literature during the past decade
strongly corroborate findings reported in the 1960's that cigarette
smoking during pregnancy has a significant and adverse effect upon
the well-being of the fetus, the health of the newborn baby, and the
future development of the infant am! child. Adverse effects on
pregnancy range from increased risk for reproductive loss, fetal
mortality, preterm birth, and neonatal tltath, to retardation in fetal
growth as reflected in birth mcasuremtants of lo\\er mean body weight,
shortened body length, and smaller head circumference, as well as to a
number of problems of adaptation ir, the neonatal period. In addition,
there is suggestive evidence of long-term impairments in physica!
growth, diminished intellectual function, and deficiencies in behavioral
development for those babies who survive the first 4 weeks of life. It
appears that children of smoking mothers do not catch up with the
offspring of nonsmoking mothers in various phases of development.

The present chapter highlights previously reported and recent
studies on the relationships between cigarette smoking and pregnancy
outcome, including sections on historical considerations, birth weight
and fetal growth, feta! and infant mortality, lactation and breast
feeding, and physiologic-experimental studies. The concluding section
of this chapter, entitled Research Issues, identifies questions and areas
of concern that need clarification and further investigation.

Historical Considerations

In 1957, Simpson (1~) reported that infants born to women who
smoked during their pregnancies were of significantly lower birth
weight relative to babies born to nonsmokers. During the intervening
20 years, there has been increasing concern, coupled with the conduct
of a large number of related studies, about the effect of smoking
during pregnancy upon the well-being t)f the developing fetus and
infant.

Concern about the effects of exposure to tobacco and cigarette
smoking during pregnancy upon reproductive loss, maternal health,
Pregnancy outcome, and infant well-being dates back a century. In
1902, Ballantyne (9) questioned what might be the effect of tobacco
Poisoning upon antenatal life. While he did not specifically mention
maternal smoking during pregnancy, he summarized the opinions of a
number of authors writing during the latter part of the 19th century
about the risks of spontaneous abortion for women who worked in
tobacco factories. He referred specifically to an 1879 paper by Decaisne
from France and to an 1868 report by Kostial from Austria about
female tobacco workers. Ballantyne wrote that both of these authors
"were quite convinced that abortion was very frequent in women

8-9


workers in tobacco [factories]...." Ballantyne concluded by stating,
"While there is much doubt, therefore, regarding the evil effect of
nicotism in cutting short antenatal life, there seems to be no shadow of
doubt that there is a very large infantile mortality in postnatal life
among the offspring of women workers in tobacco. Possibly this may
be due in part to the influence of the milk, but it is more probable that
it is on account of congenital debility."

Discussion of the problem of smoking during pregnancy at the turn
of the century appears to have been based on empirical evidence and
anecdotal reports. Until the end of the 1920's, there was a sparsity of
reports on this topic in the scientific literature. Thereafter, several
articles were published reporting the results of animal studies and
clinical investigations pertinent to the effects of nicotine and smoking
during pregnancy upon reproductive loss, maternal health, and
pregnancy outcome.

In 1935, Sontag and Wallace (175) investigated the effects of
cigarette smoking during pregnancy upon fetal heart rate. Their
observations were made during the last 2 months of pregnancy on
eight mothers and their fetuses. Their data revealed that the smoking
of one cigarette by the pregnant woman generally produoed an
increase in the rate of the fetal heart beat, and sometimes a decrease.
They concluded that there was "a definite and real" increase in the
fetal heart rate after the mother began to smoke a cigarette and that
this was probably due to transplacental transfer of nicotine into the
fetal circulation.

In 1935 and again in 1936, Campbell (23, 2.4) reported that heavy
cigarette smoking was prejudicial to efficient childbearing as a result
of chronic nicotine poisoning. Campbell warned that excessive smoking
in certain cases was detrimental to maternal health. He noted that, in
general, a woman who smoked during pregnancy was likely to have
more difficulty during the course of pregnancy, parturition, and
lactation than a woman who did not smoke.
In 1940, Elssenberg and associates (46), in a well-designed study,
investigated the effects of nicotine and cigarette smoke on pregnant
female albino rats and their offspring. The three groups of subjects
included a group of animals that received intraperitoneal or subcuta-
neous injections of solutions of chemically pure nicotine, a second
group of animals that were exposed to tobacco smoke that approximatr
ed human smoking of one pack of cigarettes a day, and a third group of
animals that were untreated.

The immediate effects on the animals in the two treated groups
were similar, although more severe in the injected group. It was
reported that:

1. Two-thirds of all the young of treated mothers were underweight;
the young from nicotine-injected mothers were more underweight
than those from mothers exposed to tobacco smoke.

8-10


2, The underweight group remained underweight during the entire
period of observation; many of the young of this group were
undersized and died early.

3. Of the females injected, 63.0 percent lost one or more young
before weaning, and 33.3 Percent lost all of their young.
4. Of the mothers exposed to tobacco smoke, 23 percent lost one or
more of their young before weaning, and 25 percent were
underweight.

5. Of the mothers exposed to smoke prior to mating, 23.3 percent lost
one or more of their young before weaning, and 25 percent were
underweight.
6. In both groups of treated mothers, temporary sterility, resorption
of young in utero, and abortions were noted.
7. Alteration of maternal behavior was observed, consisting of
cannibalism and neglect of the young as to care and feeding.
The findings of &se&erg, et al. (46), reported in 1940, raised
important questions regarding the effects of smoking on pregnancy
outcome that were not investigated in depth until some 29 years later
when Simpson reported her findings (I 72).
Results of epidemiological surveys and experimental studies appear-
ing in the literature over the past two decades owe much to
improvements in research technology which contributed to more
accurate and reproducible measurements in the laboratory. For
example, nicotine concentrations in minute amounts can be determined
with gas chromatography, and the degree of carbon monoxide
displacement of oxygen from hemoglobin can be  assessed with
Considerable precision by biophysical methodology. Use of new
technology has often permitted scientists to confirm earlier impres-
sions obtained with the use of crude but ingenious bioassays. Such
Wnfirmation is a tribute to the perception and the dedication of these
Pioneering investigators and astute clinicians.

Smoking, Birth Weight, and Fetal Growth
Birth Weight

Babies born to women who smoke during pregnancy are, on the
average, 269 grams lighter than babies born to comparable women who
do not smoke. Since 195'7, when Simpson reported this finding from her
original study (172), it has been confirmed by over 45 studies of more
than half a million births (1, 2, 7, 20, 22, 29-31, 37, 41, 47, 54, 61, 62, 71,
% 86, 89,90,101-103, 115, 118,119,123-127, 137,141-143,144 147,151,
l55-157, 161, 163-166, 168, 169, 185, 188, 189, 190-192, 208, 212). Reds
of these studies are expressed as mean birth weights of smokers' and
nonsmokers' babies, or alternatively, as the percentage of babies who
Weigh less than a specified amount, usually 2,500 grams. The methods
and results of 28 studies carried out between 1957 and 1970 were

8-11


summarized in the chapter on smoking and pregnancy in The Health
bt.sequ~n~~~~ of Snwkirlg, A R~por? of the Surgeon General: 1971, which
concluded: "Maternal smoking during pregnancy exerts a retarding
influence on fetal growth as manifested by decreased infant birth
weight and an increased incidence .)f prematurity, defined by weight
alone" (:Yo). The same conclusion has been drawn from subsequent
studies.

In the chapter on pregnancy in Thu He&h Cmseguewes of Smoking
in 1973, a detailed, critical review is given of studies published to that
date. The chapter summary of the evidence that the association
between maternal smoking and reduced birth weight is one of cause
and effect includes the following (192):

1. Results are consistent in all studies, retrospective and prospective,
from many different countries, races, cultures, and geographic settings
(2, 7, 20, 22, 30, 31. 61, $7. 54, 62, 72, 81, 86, 89, 109, 115, 118, 119, 125-
127, 137. 141-l&7, 147, l.il, 1.52, 1.57, 161, 163, 164, 166, 169, 172, 185, 189,
192, 193, 206, 212).

2. The relationship between smoking and reduced birth weight is
independent of all other factors that influence birth weight, such as
race, parity, maternal size, socioeconomic status, sex of child, and other
factors that have been studied (1 ) 2, 7, 20, 22, 31, 47, 54, 71, 101, 102,
115, ll?, 119, 142, 145, 1.52, 1.57. 164, 169, 192, 193). It is also
independent of gestational age (2, 19, 20, 22, 54, 72, 115, 141, 157, 163,
166,169,193,206).

3. The more the woman smoke:; during pregnancy, the greater the
reduction in birth weight; this is a dose-response relationship (2, 22, 31,
47, 54, 83, 101, 102, 103, 115, 118, 119, 137, 142, 143, 169, 189, 192, 193,
206).

4. If a woman gives up smoking during pregnancy, her risk of
delivering a low-birth-weight baby is similar to that of a nonsmoker
(22, 54, 101, 103, NC~).

To iliustrate typical results of studies showing the association
between maternal smoking and an increased proportion of low-birth-
weight infants, five published studies with an aggregated total of
almost 113,000 births in Wales, the United States, and Canada are
summarized in Table 1. In these populations, 34 to 54 percent of the
mothers smoked during pregnancy and on the average had twice as
many low-birth-weight babies as the nonsmokers. Under these
conditions, from 21 to 39 percent of the low-birth-weight incidence in
the total population could be attributed to maternal smoking (2,20,47,
115,137,1iz, 143).

An outstanding feature of the relationship between maternal
smoking and birth weight is its dependence on the level of maternal
smoking and its independence of the large variety of other factors that
influence birth weight, such as maternal size, maternal weight gain,
age, parity, socioeconomic status, and sex of child (1, 2, 20, 22, 31, 47,

8-12


TABLE I.-Birth weight under 2,500 grams by maternal smoking habit, relative and attributable risks derived
     from published studies
                                        Smokers          Births <p gm(9        Relative      Attribut

       Study            Nonsmokers             Propor-        Non-                   risk         able
                      (No.)         NO.          tion        smoker       Smoker       smoker:        risk*
                                                                           nonsmoker      6)

chdiff                     7,176       6238         ,465          4.1          8.1         1.96         31

US Collaborative
White

Bl8Ck
California, Kaiser
Permanente
White
Black
MOlltlX?d
Ontario

6,466        9.731         536          4.3          9.5         2.21          39
11252       7m         A09         10.7         17.5         1.64          21



3,139       2,145         402          3.5          6.4         1.83          25
934          479         ,333          6.4          13.4         209          27
3,964       3,004         ,432          5.2         11.4         2.19          34
27,316       21,062         ,435          4.5          9.1         262          31

*Percentage of tot.4 birth weighta <S,E40 gm attributable to mtemal smoking. Attributable rink in population - IT+1) divided by b(r-1) + 1 where b - prop&ion of mothera who smoke and I -
relative rink of low birth-weight - smoker rate/nonsmoker rate
SOURCE: Meyer. M.B. (116).


,

71, 101, 102, 115, 118, 119, 137, 152, 157, 163, 164, 169, 192, 193). This
feature is illustrated in Tables 2 and 3. Table 2 shows mean birth
weights for babies of smokers and nonsmokers in selected subdivisions
by biologic and socioeconomic factors, using data from the approxi-
mately 10,900 white births studied from 1960 to 1967 by the Berkeley
Child Health and Development Studies whose subjects were members
of the Kaiser Foundation Health Plan. Mean birth weights vary with
maternal age, parity, height, weight, and socioeconomic status, from a
low of 2,912 grams for babies of smoking mothers who had given birth
to previous low-birth-weight infants, to a high of 3,573 grams for
babies of nonsmoking mothers of high parity. Nevertheless, within
each subgroup the effect of maternal smoking on mean birth weight is
clearly seen, with smokers' infants weighing from 193 to 236 grams
less than nonsmokers' infants in the subgroups shown (193). Table 3,
using data from the 50,097 births of the Ontario Perinatal Mortality
Study, shows the incidence of low birth weight (percent under 2,500
grams) for three levels of maternal smoking and for subcategories of
hospital pay status, mother's height and weight, and the sex of the
child. Despite percentages of births under 2,560 grams that vary from
2.7 percent for nonsmokers who were 68 inches or taller to 15.8 percent
for smokers of more than a pack per day who weighed less than l20
pounds before pregnancy, the increased risk of having a baby weighing
less than 2,500 grams is remarkably stable-about 70 percent for
women who smoke less than a pack of cigarettes per day and about 166
percent for smokers of a pack or more per day-compared with the risk
for nonsmokers (119).

The picture that emerges from these findings is that birth weight is
affected by maternal smoking independently and to a uniform extent,
regardless of other determinants of birth weight. Comparisons of the
percentage distributions of birth weights for smokers' and nonsmokers'
babies show a downward shift of the whole set of weights of smokers'
babies by about 200 grams, as illustrated in Figure 1 (103). In other
words, the data displayed in Figure 1 corroborate the impression that
all births are affected similarly by maternal smoking and negate the
possibility that changes in mean birth weight are due to extreme
effects in a few cases with other cases unchanged.

Placental Ratios

Authors of a few earlier studies in which placental weights were
analyzed by maternal smoking habits noted that these weights were
either not affected or were less affected by maternal smoking than
were birth weights (81, 89, 125, 141, 202). As a result, because of the
dose-related reduction in birth weights with increasing number of
cigarettes smoked, the ratio of placental weight to birth weight, or
placental ratio, tended to be larger for smokers than for nonsmokers.

S-14


TABLE Z.-Mean birth weight of infants of smoking and
     nonsmoking mothers, by other biologic and
      socioeconomic factors

Prepregnsncy factam

Mean birth       Mean difference
weight (pm)    Nonsmokers-SmokeR(gm)

Cravida's age <20 years
Smoker8
Nonsmokera

Parity > 4 previous pmgnancie3
Smokem
Nonsmokers

Previous birth <2.500 grams
Smoker3
Nonmolten

Gnvida's height <60 inches
Smokers
Nonsmoken

Gnrvida's prepwgnancy weight <lo0 Ibs.
Smoken
Nonsmokera

Gravida's education: leas than high school graduate
Smokers
Nonsmoker

Husband's education: leas than high school graduate
Smoker3
Nonsmokers

Huabsndk cap&ion: unskilled laborer, service
worker
Smokers
Nonsmokers

3219
3.412

3b7
3,573

2,912
3,120

3.058
3.259

2918
3,164

3,196
3.446

3.196
3,452

3,224
3.471

193





a36





208





201





246





25.3





256

247

SOURCE: van den Berg. BJ. (195).

Kullander and Kaellen reported placental ratios of 0.171, 0.175, 0.176,
and 0.188, respectively, for nonsmokers, smokers of less than 10
cigarettes a day, those smoking 10 to 20 a day, and those smoking more
than 20 cigarettes per day, based on a prospective study of 6,376
Pregnancies in Malmo, Sweden (89). Wilson compared the ratios of
untrimmed, fresh placenta weights to birth weights for 1,895 deliveries
in Sheffield, England, finding a significantly higher ratio for babies
born to smokers than to nonsmokers. He suggested that the increase
might signify a response by the placenta to chronic hypoxia in the
fetus (202).
Wingerd, et al. have now published a definitive study of this
relationship, using data from a prospective study of 7,000 pregnancies
among members of the Kaiser Foundation Health Plan in Oakland,

8-15


TABLE 3.-Birth weight under 2,500 grams by maternal smoking
     and other factors (Ontario data)

Factor and class

Births under 2,5CQ grams
(per hundred total births)
Matemal smoking: packs per day

Smoker:
nonsmoker
Relative risk
Packs per day

Hcepital status
Private
Public

Mother's height
< 62 inches
62-64 inches
65-67 inches
68+ inches
Prepregnant weight
< 120 pounds
l2&134 powlda
135+ pounds

Sex of child
Male
Female

SOURCE: Meyer. M.B. (115).

5.9       10.8       15.1        1.8        26
4.7        7.9       Lt.8        1.7        2.7
3.9        6.2       10.1        1.6        2.6
2.7        6.0        9.3        2.2        3.5


6.1       10.2       15.8        1.7        26
4.2        6.3        9.5        1.5        22
3.3        5.1        a.7        1.5        26



4.2        7.3       11.5        1.7        27
5.2        8.3       12.7        1.6        24

California (203). At an interview early in pregnancy, information was
obtained about numerous factors related to the pregnancy, including
the woman's smoking habits. Placentas were weighed by specially
trained personnel after the cord and attached membranes had been
trimmed off according to Benirschke's protocol, an extremely impor-
tant procedure to reduce variability of measurement. The study was
confined to black or white women who delivered single, live infants
without severe anomalies between 37 and 43 weeks' gestation and for
whom at least one hemoglobin value during gestation had been
reported. Because placental ratios change with gestational age, it is
important to compare values specific for weeks of gestation at the time
of delivery. Results of this study are shown in Figure 2. At each
gestational age from 37 through 43 weeks, the more the mother
smoked during pregnancy the higher is the placental ratio. Comparison
of the observed mean weights by smoking level showed that, as
expected, birth weights decreased as smoking level increased. Further-
more, mean placental weights were the same or slightly lower for light
smokers and slightly higher for heavy smokers (over 20 cigarettes per
day) than for nonsmokers. Ratios were higher for black than for white
women and tended to increase as maternal hemoglobin level decreased.
This trend was most marked in black women who smoked (203).

8-16


10

INFANT WEIGHT AND PARENTAL SMOKING HABITS
  I"`I"""`l"`I""""""  I

- - Iuonsmokefs

  - - - - - Smokers   A
             I'.,#          I

     4     5    6    7    8    9    10    11
BIRTH WEIGHT (SCALE IN POUNDS. INTERVALS OF 4 OZ.)

FIGURE l.-Percentage distribution by birth weight of infants of
mothers who did not smoke during pregnancy and of those who
smoked one pack or more of cigarettes per day
SOURCE: MacM~oo. B. (IOS).

As described in another section of this chapter, the carbon monoxide
present in cigarette smoke combines with maternal and fetal
hemoglobin and results in a reduced carrying capacity of the blood for
oxygen and also a reduction of the pressure at which oxygen is
delivered to the fetal tissues. Somewhat similar reductions of oxygen
availability for the fetus mur at high altitude and in cases of
maternal anemia. Under these conditions, increases in placental ratios
have also been observed that are in proportion to the elevation or to
the degree of anemia (1.4, 88, 108). The possibility that these changes
may represent physiological responses to relative fetal hypoxia, with
increased oxygen delivery by a larger placenta and decreased oxygen
demand by a smaller fetus, has been considered (I&88, 108,202,203).
If this is the case, it is important to know whether a mechanism that
might increase the possibility of survival at a lower birth weight is
accompanied by any long-term costs in later growth and development.

Gestation

The consistent finding that mean birth weights were lower and the
frequency of low-weight babies higher for women who smoked during
Pregnancy than for similar nonsmokers raised the obvious question of

8-17


I       I       I       I       I       I      I
37     38     39     40      41     42     43

          WWkalgessabion

FIGURE 2.-Ratio of placental weight to birth weight by length of
gestation and maternal smoking category

SOURCE: Wingwd. J. (ZOSJ.

whether this might be due to a corresponding reduction in the duration
of gestation if the mother smoked. In his study of 2,042 women in
Birmingham, England, published in 1959, Lowe noted that the infants
of smoking mothers were delivered only 1.4 days earlier on the average
than those of nonsmokers, not enough to account for the mean birth
weight reduction of 170 grams (101). Subsequent studies of mean
gestation have shown similarly small differences between mean
durations of pregnancy for smokers and nonsmokers (2, 19,20, 67, 72,
141, 157, 166, 206). For example, Buncher, in an analysis of the 49,897
births to U.S. Navy wives studied by Underwood, et al. (189), found
that the mean duration of pregnancy was only 0.25 weeks shorter for
male babies and 0.18 weeks shorter for female babies if the mother
smoked during pregnancy (19).

The finding that maternal smoking does not cause an overall
downward shift in the distribution of gestational ages, such as was
shown for birth weights, leads to the conclusion that the lower birth
weight of smokers' infants must be due to a direct retardation of fetal
growth. In other words, these infants are small-for-dates rather than
preterm. The truth of this conclusion has been demonstrated by studies
in which mean birth weights or percentages of low-birth-weight babies

8-18


35    37     38    39    40    41     42     43+
       Gestatim in cotnphd weeks

FIGURE 3.-Mean birth weight for week of gestation according to
maternal smoking habit: control week singletons
SOURCE: Butler, N.R (SO).

were compared within units of gestational age. Butler and Alberman,
in an analysis of data from the British Perinatal Mortslity Study of
17,000 births in Great Britain in March, 1958, found lower mean birth
weights for smokers' than for nonsmokers' babies at each week of
gestation from 36 through 43, as shown in Figure 3 (20). Evidence of
the same birth weight relationship is presented in Figure 4 (113), taken
from Meyer's analysis of data from the Ontario Perinatal Mortality
Study (1.42, 14.~). This Figure shows that, as one would expect, the
proportion of births under 2,566 grams decreases as gestation
increases. It also shows, within each gestational age group, the effect
of maternal smoking on birth weight, as the frequency of low-weight
births increases directly with smoking level for term births of early,
average, and late time of delivery.

As the 10~ birth weight associated with maternal smoking is
independent of gestational age and is not due to a significant reduction
in mean gestation, it must therefore be due to a reduction in the rate of
fetal growth. In several studies the relationship between maternal
smoking and other body measurements besides birth weight has been
examined. Kullander and Kaellen, in a prospective study of 6,376 births
in Malmo, Sweden, found that, as the level of maternal smoking
increased, the body length, head circumference, and shoulder circum-
ference decreased consistently for both male and female babies (89).

8-19


I

Private Hospital Status

Cl NON -SMOKER
0 < I PACK/DAY
m I + PACK/DAY

UY --
"5 IO
5g
zg
3-  5

I
&
z    0     38-39   40-41    42+

WEEKS of GESTATION

Public Hospital Status

ni i=
z
5; IO
clg
z-  5
z
6
    0     38-39  40-41    42)

      WEEKS of GESTATION

FIGURE I.-Percentage of birth weights under 2,500 grams by
maternal smoking level for early, average, and late-term births.
Private hospital status and public hospital status (Bars show 95
percent confidence intervals)
SOURCE: Meyer, M.B. (118).

Other studies have corroborated these findings (34, 67, 81,141). Hardy
and Mellits compared the birth measurements and subsequent growth
of 33 pairs of neonates from the population of the Collaborative
Perinatal Study of the National Institute of Neurological and
Communicative Disorders and Stroke (NINCDS) (137). Women who
reported smoking 10 or more cigarettes a day and whose children had
survived and been examined at age `7 were matched by race, age,
educational background, sex of child, and delivery date with women
who did not smoke any cigarettes during pregnancy and whose
children were examined at age 7. At birth, the smokers' babies weighed
an average of 250 grams less (p~O.OOl), were 1.34 centimeters shorter
(p<O.OOl), and had head circumferences 0.32 centimeters smaller than
babies of nonsmoking mothers (67'). In a study of 1,159 infants whose
mothers' smoking habits were ascertained early in pregnancy, Davies

8-20


and coworkers found the familiar gradient of decreasing mean birth
weights with increasing smoking level. When these infants were
measured at 7 to 14 days of age, a similar gradient was found for body
length and, head circumference of both male and female babies (34).
These and other studies (33, 67, 204) indicate that maternal smoking
leads to an overall retardation of fetal growth.

Miller, Hassanein, and coworkers have described two- types of fetal
growth retardation in term babies. One `is chara;dterized by an
abnormally low ratio of birth weight to crown-heel length, the thin
baby with a low ponderal index but with normal length. The other is
characterized by abnormally short crown-heel length for fetal age, the
baby who is generally smaller than expected in all measurements (118).
A study of 1,112 uncomplicated term pregnancies indicated that
mothers who smoked cigarettes during pregnancy were more likely to
have infants with short body lengths for dates, whereas mothers who

had abnormally low weight gain in the last two trimesters were more
likely to have babies-with low ponderal indices (I 19).

Long-Term Growth and Development

Whether or not there are long-term consequences of the fetal growth
retardation associated with maternal smoking during pregnancy is of
much greater concern than are measurements at the time of birth.
There is evidence that children of smoking mothers have measurable
deficiencies in physical growth, intellectual development, and emotion-
al development that are independent of other known predisposing
factors.
The matched-pair study of Hardy and Mellits compared physical
measurements and intellectual function in children of smokers and
nonsmokers through age 7. Among 88 pairs, although the babies of
smokers were 250 grams lighter and 1 to 2 cm shorter at birth and still
shorter than their counterparts at one year, the authors reported that
there was no significant difference in either physical measurements or
intellectual function at 4 and 7 years (67'). It should be noted, however,
that to achieve statistical significance from such numbers of cases, the
difference between them must be very strong. In Hardy and Mellits'
study of the 88 pairs of children matched for race, date of delivery,
maternal age and education, and sex of child, mean values for the
children of nonsmokers were larger than those of smokers at all ages
for all measurements through age 7, including body weight, body
length, and head circumference. At age 1 year, 96 percent of
nonsmokers' babies and 90 percent of smokers' babies had normal
neurological status. At age 4, nonsmokers' babies had slightly higher
Scores on the Stanford-Binet intelligence test, and at age 7 they tested
higher on all of the tests reported except for the Wide Range
Achievement Test subtest for arithmetic. An additional set of 55 pairs
of children of smokers and nonsmokers who were matched on birth

8-21


weight as well as on the other factors listed also showed fewer
smokers' children with normal neurological status and lower scores for
smokers' children on 6 out of 8 tests of intellectual function. The fact
that few of these differences reached "statistical significance" does not
rule out the possibility that harmful long-term effects may exist (38,
43).

In the California study by Wingerd and Schoen (204), the net effect
of various factors on length at birth and height at 5 years was
determined in 3,707 single-born, white, California children. Children of
smoking mothers were found to be shorter (p<O.OOl) at birth and at 5
years than children of nonsmoking mothers. (Intellectual development
was not measured in this study.)

In a prospective study of children of low birth weight, Dunn and
coworkers analyzed growth with respect to maternal smoking habits of
81 who were "small-for-dates," 99 "truly premature," and 146 controls
of full birth weight. At 6112 years of age, the children of nonsmoking
mothers had a slightly greater mean height and weight in all three
categories. The mean social class of the smoking mothers was lower
than that of the nonsmokers, but within the two lowest social classes,
IV and V (77 percent of all subjects), the nonsmokers' children had a
greater mean height and weight than their counterparts whose
mothers smoked. Statistically significant differences in favor of
nonsmokers' children were demonstrable with regard to weight gain
and growth in length/weight at 1 to 4 years and with regard to actual
height at 4 and 6% years and weight at 6% years in the full birth
weight controls (43). There was no evidence that the children of
smoking women "caught up" in growth with the nonsmokers' children,
a concept postulated by Russell, et al. (164) but not corroborated by
other studies.

Dunn also evaluated the neurological, intellectual, and behavioral
status of these children at age 7 and analyzed the results according to
the mothers'. smoking habits during pregnancy. Neurological abnor-
malities, including minimal cerebral dysfunction and abnormal or
borderline encephalograms, were slightly more common among
children of smoking women, although this difference was not quite
statistically significant. In a battery of psychological tests, the mean
scores of children of nonsmoking mothers were better than those of
smokers' children in 45 out of 48 correlations, and the difference was
significant in 14 of these. Factorial analysis of variance suggested that
these differences could be only partially attributed to the slightly
lower social status of smokers' children. Some significant differences in
favor of nonsmokers' children were also demonstrated with respect to
behavior ratings and school placement (44). These results are very
similar to those of Hardy and Mellits in that the direction of the
differences is almost always in favor of the nonsmokers' child. Perhaps
more attention should be paid to these patterns and less to the question

8-B


of "statistical significance," which is difficult to achieve with such
small numbers. Dunn concludes that "some slight direct damaging
effect on foetal brain development and subsequent intelligence and
behaviour cannot be excluded" (44).
Small numbers and population selection factors are not a problem in
the longitudinal follow-up of the population originally included in the
British Perinatal Mortality Study, comprising approximately 17,000
births, an estimated 98 percent of all births in England, Scotland, and
Wales during the week of March 3 to 9,1958. These children have been
traced and studied again at age 7 and at age 11, to describe their
behavior, their health, their physical development, their educational
standards, and their home environment. At ages 7 and 11 years,
physical and mental retardation due to smoking in pregnancy were
found, and this deficit increased with the number of cigarettes smoked
during pregnancy. Children whose mothers smoked 10 or more
cigarettes a day during pregnancy were on average 1.0 centimeters
shorter and between 3 to 5 months retarded in reading, mathematics,
and general ability, as compared with the offspring of nonsmokers.
After allowing for associated social and biological factors, all of these
differences are highly significant (p<0.001)(33,38,43,204).
Recently an association has been reported between maternal
smoking and hyperkinesis in children. Denson and colleagues matched
each of 20 consecutive methyl-phenidate-sensitive cases with a
nonhyperkinetic dyslexic child and also with a normal control by sex,
age within six months, and social class. Mean birth weights were
similar for the three groups. Mothers of hyperkinetic children tended
to be younger, and significantly more of their children were firstborn.
Outstanding and highly significant differences were found in maternal
cigarette consumption. Mothers of hyperkinetic children consumed
more cigarettes during the study pregnancy (p<O.O5), had higher
maximum consumption during that pregnancy (p<O.Ol), and con-
sumed more at the time of questioning (p<O.OOl). The present mean
consumption by mothers of hyperkinetic children was 33.3 cigarettes
per day, more than three times the average for the two control groups.
Only four mothers of hyperkinetic children had not smoked during
pregnancy, and all of these reported complicated deliveries. Of
smokers, 11 with complicated pregnancies had a mean consumption of
13.4 cigarettes daily, and 5 with various complications smoked an
average of 28 cigarettes daily throughout pregnancy. The role of
anoxia as a possible cause of hyperkinetic disease and the hypoxic
effects of carbon monoxide and of smoking-related complications of
Pregnancy and labor are discussed in the study. The authors conclude:
"These findings are consistent with the hypothesis that smoking
during pregnancy is an important cause of the hyperkinetic syndrome"
(36).