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Smoking in pregnancy: from effects to solutions

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Smoking in pregnancy: from effects to solutions

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SMOKING IN PREGNANCY: FROM EFFECTS TO SOLUTIONS

By

Beth Leong Pineles
____________________________________________________________

A Dissertation presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(EPIDEMIOLOGY)

August 2013

Copyright 2013 Beth Pineles

ii

Dedication

This document is dedicated to my mother, who is always (pleasantly) surprised by the
achievements of her little troublemaker.

iii

Acknowledgements

I would like to thank my advisor, Jonathan Samet, for taking a chance on me when I was a
medical student who didn’t even really know what epidemiology was. He never failed to amaze
me with his insightful comments on my work despite his juggling of research, regulatory
committees, administration and travel. Each of my committee members (Lourdes Baezconde-
Garbanati, Kiros Berhane, Myles Cockburn, Sandy Eckel, and Sue Martin) also contributed
important advice and support for the research proposals that gradually morphed into several
projects not originally proposed. The work of several undergraduate students made the
systematic review and meta-analyses possible. Edward Park has worked with me for nearly two
years in completing these projects, and his hard work and persistence have been critical. Other
students who helped with parts of the meta-analyses and deserve recognition are Sarah Hsu,
Tiffany Chen, Rebecca Gao, and Jay Bhayani. Also valuable was advice and assistance from
several people who work in prenatal care or maternal and child health. The interviewees who
took time from their busy prenatal care schedules were very kind to answer all my questions,
though for most of them smoking was not an important priority.

My two lovely dogs, Osa and Quito, kept me company during the long hours of data analysis, re-
analysis, and writing. More useful are my amazing mother and older sister, who supported me
through the whole past year, did not complain as I worked while on vacation, and helped with
last-minute editing. My stomach thanks my younger sister for nourishing me with her cooking.
The rest of my body is grateful to my father and stepmother, who kept a cozy home where I
could lie in a hammock in the rare moments when I was not staring at my computer screen. My
little brother provided interesting (non) tobacco control updates from an unspecified prestigious
liberal arts college in the Northwest.

Lastly, I would like to acknowledge the cafés that I frequent with my laptop so often that I see
the employees and regulars more than any of my friends or family. I know the coffee shops over
iv

the whole of the Westside of Los Angeles so well that a friend suggested I write a guide. Good
coffee, pastries and the occasional glass of wine made working early, late, and long hours more
pleasure than pain.

v

Table of Contents

Dedication …………………………………………………………………………………. ii
Acknowledgements ……………………………………………………………………….. iii
List of Tables………………………………………………………………………………. vii
List of Figures…………………………………………………………………………........ viii
Abstract ....................…………………………………………………………………......... x
Chapter 1. Introduction ......................................................................................................... 1
1.1. Smoking among women ………………………………………………………... 1
1.2. Smoking during pregnancy …………………………………………………...... 5
1.3. Health consequences of smoking during pregnancy ………………………….... 6
1.4. Guidelines for smoking during pregnancy …………………………………....... 10
1.5. Overview of the dissertation ………………………………………………….... 11
Chapter 1 References ……………….......................................................................... 12

Chapter 2. Systematic review and meta-analysis of miscarriage and maternal exposure to
tobacco smoke during pregnancy ………………………………………………................. 17
2.1. Introduction ………………………………………………………….................. 17
2.2. Materials and methods …………………………………………………………. 18
2.3. Results ………………………………………………………………………...... 23
2.4. Discussion …………………………………………......….……………………. 35
Chapter 2 References................................................................................................... 41

Chapter 3. Systematic review and meta-analysis of perinatal death and maternal exposure
to tobacco smoke during pregnancy……………………………………………………….. 57
3.1. Introduction ……………………………………………….......…………........... 57
3.2. Materials and methods ……………………………………………………......... 58
3.3. Results ………………………………………………………………….............. 64
vi

3.4. Discussion …………………………………………………………………........ 84
Chapter 3 References .................................................................................................. 91

Chapter 4. Smoking cessation counseling among prenatal care providers .......................... 109
4.1. Introduction ………………………………………………….............................. 109
4.2. Materials and methods ……………………………………………………......... 110
4.3. Results ………………………………………………………….......................... 115
4.4. Discussion …………………………………………………………………….... 131
Chapter 4 References .................................................................................................. 138

Chapter 5. Discussion …………………………………………………………................... 141
5.1. Discussion of systematic reviews ……………………………............................. 141
5.2. Discussion of smoking cessation services by prenatal care providers ………..... 146
5.3. Overall discussion ………………………………………………………............ 153
Chapter 5 References .................................................................................................. 156

Appendix. The SAS %METADOSE Macro ........................................................................ 163
Bibliography ......................................................................................................................... 173

vii

List of Tables

Table 1. Summary of conclusions on the effects of smoking during pregnancy from the
Surgeon Generals’ Reports …………………………………………………….................. 9
Table 2. Characteristics of studies included in the systematic review on smoking and
miscarriage ........................................................................................................................... 25
Table 3. Heterogeneity and study quality analyses for smoking and miscarriage
…………………………….................................................................................................. 33
Table 4. Characteristics of studies included in the systematic review on smoking and
perinatal death ...................................................................................................................... 68
Table 5. Summary relative risks of perinatal death, stillbirth, and neonatal death in
smokers compared to nonsmokers ……………………………………………………....... 74
Table 6. Heterogeneity and study quality analyses for any active smoking and risk of
perinatal death ...................................................................................................................... 88
Table 7. Heterogeneity and study quality analyses for any active smoking and risk of
stillbirth ……….................................................................................................................... 89
Table 8. Heterogeneity and study quality analyses for any active smoking and risk of
neonatal death ....................................................................................................................... 90
Table 9. Factors associated with identification of tobacco use at visits by women of
reproductive age and pregnant women …………………………………………………..... 120
Table 10. Multivariate model of identification of tobacco use ………………………........
122
Table 11. Factors associated with provision of tobacco use/exposure counseling at visits
by all women of reproductive age and pregnant women who use tobacco .......................... 124
Table 12. Factors associated with tobacco use/exposure counseling at visits by women of
reproductive age and pregnant women who do not use tobacco ………………………...... 127
Table 13. Multivariate model of tobacco use/exposure counseling …………………….....
129
Table 14. Classification of reason for visit in NAMCS/NHAMCS .....................................
137

viii

List of Figures

Figure 1. Trends in cigarette smoking among persons aged >=18 years, by sex – United
States, 1955-1997 .……………………………………………………………….................. 2
Figure 2. Current smoking prevalence among female adults (aged 18 years or older) by
state, according to data from Current Population Survey, 2006-2007 ……………………... 3
Figure 3a. Adult cigarette smoking prevalence, Los Angeles County, 2007 ………………
4
Figure 3b. The percentage of the population whose median household income is $20,000
or less …................................................................................................................................. 4
Figure 4. Prevalence of cigarette smoking by five-year birth cohorts and calendar year for
white females ……………………………………………..................................................... 5
Figure 5. Smoking among women of reproductive age and pregnant women ……..............
7
Figure 6. Distribution of birth weights among infants born to smokers and nonsmokers,
United States, 1991 …………………………………………………………….................... 8
Figure 7. Flow chart of literature search and inclusion/exclusion status for systematic
review of smoking and miscarriage ……………………………………………………....... 24
Figure 8. Forest plot of the association between maternal smoking and miscarriage ...........
31
Figure 9. Dose-response curve of the association between maternal smoking and
miscarriage ............................................................................................................................. 32
Figure 10. Funnel plot of studies included in the comparison between any maternal
smoking and miscarriage ………………………………………………………………....... 34
Figure 11. Forest plot of cumulative meta-analyses of the association between maternal
smoking and miscarriage ……………………………………………………....................... 40
Figure 12. Flow chart of literature search and inclusion/exclusion status for systematic
review of smoking and perinatal death …………………………………….......................... 66
Figure 13. Forest plot of the association between maternal smoking and perinatal death …
75
Figure 14. Forest plot of the association between maternal smoking and stillbirth ..............
76
Figure 15. Forest plot of the association between maternal smoking and neonatal death .....
77
Figure 16. Dose-response curve of the association between maternal smoking and
perinatal death ........................................................................................................................ 79
ix

Figure 17. Dose-response curve of the association between maternal smoking and
stillbirth .................................................................................................................................. 80
Figure 18. Dose-response curve of the association between maternal smoking and
neonatal death ........................................................................................................................ 81
Figure 19. Funnel plot of studies included in the comparison between any maternal
smoking and perinatal death .................................................................................................. 82
Figure 20. Funnel plot of studies included in the comparison between any maternal
smoking and stillbirth ............................................................................................................ 83
Figure 21. Funnel plot of studies included in the comparison between any maternal
smoking and neonatal death ................................................................................................... 83
Figure 22. Overview of sampled NAMCS/NHAMCS visits and subpopulations for models
114
Figure 23. National smoking prevalence among all women of reproductive age and
pregnant women ..................................................................................................................... 116
Figure 24. Percent of NAMCS/NHAMCS visits by tobacco users among all women of
reproductive age and pregnant women of reproductive age by year ..................................... 117
Figure 25. Percentage of NAMCS/NHAMCS visits with tobacco use status identified and
percentage of tobacco users’ visits with tobacco use/exposure counseling among all
women of reproductive age and pregnant women of reproductive age ................................. 118
Figure 26. Los Angeles County Department of Public Health Comprehensive Perinatal
Services Program Prenatal Combined Assessment / Reassessment Tool .............................. 131

x

Abstract
This dissertation examines two aspects of smoking during pregnancy: health effects and
prevention of smoking. Miscarriage (loss of pregnancy) and perinatal mortality (death of the
fetus or newborn) are both associated with maternal smoking during pregnancy. The first two
studies in this dissertation were systematic reviews of the literature on the associations between
1) smoking and miscarriage and 2) smoking and perinatal death. Meta-analyses synthesized the
evidence and explored heterogeneity in the relative risks of miscarriage and perinatal death in
smokers compared to nonsmokers. The findings support the conclusion that smoking causes both
miscarriage and perinatal death. To prevent these complications, women need assistance in
quitting smoking. Counseling by health care providers is an important part of smoking cessation.
However, health care providers frequently do not follow best practices for addressing smoking
with a patient. The third study in this dissertation used a mixed quantitative and qualitative
approach to characterize health care providers who do not identify tobacco use among their
patients and who do not counsel patients about tobacco use. Data from the National Ambulatory
Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey
(NHAMCS) were analyzed to obtain estimates the frequencies of identification of tobacco use
and counseling of tobacco users among women of reproductive age. Qualitative interviews
further characterized prenatal care providers’ knowledge, behaviors, and attitudes regarding
smoking by pregnant patients. Since 2000, health care providers identified tobacco use in 73% of
visits by women of reproductive age and 67% of visits by pregnant women. The rate of tobacco
use identification in pregnant women decreased from 75% in 2001 to 69% in 2009. Counseling
on tobacco use was provided during only 21% of visits by pregnant tobacco users. Greater effort
xi

to combat smoking among pregnant women is needed, especially given the newly reinforced
evidence of its devastating consequences.

1

Chapter 1. Introduction

Beginning in the mid-20
th
century, American women of childbearing age began to smoke
in rapidly increasing numbers.
1
Research on the health effects of smoking during pregnancy
began decades ago, finding evidence that smoking adversely affects birth outcomes. While
smoking during pregnancy became less common as evidence on adverse health consequences
mounted, many women still smoke despite the accumulation of studies about the effects of
smoking on pregnancy.

1.1. Smoking among Women
Women began smoking cigarettes in increasing numbers several decades after cigarette
smoking became highly prevalent among men. By 1965, smoking by American women peaked
at 33.9% (Figure 1).
1
Since then, the prevalence of smoking in women has declined by more
than half to 16.5% in 2011.
2
The greatest reduction, 13% per decade, occurred prior to 1990,
when the rate of decline began to slow. From 1990 to 2000, the prevalence of smoking in U.S.
women decreased by only 8%, from 22.8% to 21.0%.
3
Smoking reduction increased again in the
first decade of the new century, with an 18% decline leading to a smoking prevalence of 17.3%
in American women in 2010.
4

2

Figure 1. Trends in cigarette smoking among persons aged >=18 years, by sex – United States, 1955-1997. Before
1992, current smokers were defined as persons who reported having smoked >=100 cigarettes and who currently
smoked. Since 1992, current smokers were defined as persons who reported having smoked >=100 cigarettes during
their lifetime and who reported now smoking every day or some days. Sources: 1955 Current Population Survey;
1965-1997 National Health Interview Survey. Reprinted from Office on Smoking and Health, National Center for
Chronic Disease Prevention and Health Promotion, CDC. Achievements in Public Health, 1900-1999: Tobacco Use
- United States, 1900-1999. MMWR. Morbidity and mortality weekly report. 1999;48(43):986-993
5

Smoking prevalence among women varies widely in different regions. In ten states, over
20% of adult women smoked in 2006-7, and only in California did fewer than 10% of women
smoke (Figure 2).
6
State laws and policies on tobacco taxation, tobacco control spending,
varying social norms, and differing intensities of bans on smoking in public places contribute to
between-state disparities in cigarette smoking.
7

3

Figure 2. Current smoking prevalence among female adults (aged 18 years or older) by state, according to data from
Current Population Survey, 2006-2007. Reprinted from Jemal A, Thun M, Yu XQ, et al. Changes in smoking
prevalence among U.S. adults by state and region: Estimates from the Tobacco Use Supplement to the Current
Population Survey, 1992-2007. BMC Public Health. 2011;11:512.
6

Smoking rates also vary within smaller geographic regions, like Los Angeles County,
reflecting racial/ethnic patterns and socioeconomic factors (Figure 3a). In Los Angeles, smoking
is less common than in the rest of the country, with a median prevalence of 12.7% among all
adults. Within smaller cities and neighborhoods, this ranges from 5.3% to 21.9%.
Socioeconomic status and race/ethnicity affect smoking status (Figure 3b). A multivariate
model from the 2000 National Health Interview Survey (NHIS) including age, gender, race
education and socioeconomic status found that smoking is far more prevalent among less
educated and poor women. Education had the strongest association with smoking. People with a
GED diploma were 6.7 times as likely to be current smokers as were those with college degrees.
4

Figure 3a. Adult cigarette smoking prevalence, Los
Angeles County, 2007. Reprinted from Cigarette
Smoking in Los Angeles County: Local Data to Inform
Tobacco Policy. Los Angeles 2010.
8

Figure 3b. The percentage of the population whose
median household income is $20,000 or less. Reprinted
from Mapping L.A.: Rankings: Income $20,000 or less.
9

Those living under the poverty line were 21% less likely to be current smokers as those living at
or above 300% of the poverty line. Smoking was more common among white women than Black
and Hispanic women, who were 0.34 and 0.61 times as likely to be current smokers than whites,
respectively.
10

Smoking varies by age group. In the United States, women of reproductive age smoke
more than women of any other age. From 1965-2000, the NHIS found that the highest rate of
smoking among women was in those aged 25-44.
1
Figure 4 shows that smoking prevalence rises
quickly through adolescence, peaks between the ages of 20-25 years, and declines slowly
through the remainder of the lifetime.
11

5

Figure 4. Prevalence of cigarette smoking by five-year birth cohorts and calendar year for white females. Reprinted
from Anderson CM, Burns DM, Dodd KW, Feuer EJ. Chapter 2: Birth-cohort-specific estimates of smoking
behaviors for the U.S. population. Risk Analysis : An official publication of the Society for Risk Analysis. Jul
2012;32 Suppl 1:S14-24.
11

1.2. Smoking during pregnancy
In the mid-20
th
century, women were smoking in large numbers, and few women quit
during pregnancy. The first large study to obtain the prevalence of smoking before and during
pregnancy was the British Perinatal Mortality Survey, which was conducted on all births in the
United Kingdom during a single week in 1958.
12
The Survey found that 41% of women were
smoking before pregnancy, and 27% of women continued to smoke after the fourth month of
pregnancy. Only 17% of the smokers completely abstained after the fourth month of pregnancy.
A repeat survey conducted in 1970 had almost identical findings.
13
In the United States, the
Collaborative Perinatal Project studied 55,908 pregnancies at selected institutions from 1959-
1965.
14
The Project found that 54% of white women and 42% of black women smoked in early
pregnancy, but did not specify how many women quit during their pregnancies.
6

The rates of smoking during pregnancy have declined substantially while the incidence of
quitting during pregnancy has risen. In a sample from 1988 weighted to reflect U.S. women who
had a live birth, 29% of women smoked in the 12 months before delivery. Of these smokers,
56% quit for at least a week during pregnancy.
15
In a selection of states and cities in 2000 and
2005, the self-reported prevalence of smoking during pregnancy was 15.2% and 13.8%,
respectively.
16
The Behavioral Risk Factor Surveillance Survey (BRFSS) has collected data on
smoking during pregnancy since 1985 (Figure 5; note that the sampling frame changed from
landline telephones to landlines and cellphones in 2011).
17
In the 2011 BRFSS, at least one in
four pregnant women reported current smoking in West Virginia, Tennessee, South Carolina and
Michigan. The only states with rates of smoking during pregnancy of less than 5% were
California, Colorado, Connecticut, Illinois, Texas and Utah.

1.3. Health Consequences of Smoking during Pregnancy
Studies examining the effects of smoking in pregnancy were started before studies were
undertaken to characterize the extent of smoking in the population. In 1927, the first human
study of smoking in pregnancy reported nicotine in the breast milk of a smoking mother.
18
For
the next twenty years, although a few physicians noted or suggested consequences of smoking
for the mother, fetus, and infant, few scientific studies were conducted and none found definitive
evidence of adverse effects. In 1957, the first epidemiological study on smoking in pregnancy
found that a birthweight less than or equal to 2,500 grams was more common among infants of
smoking mothers than those of nonsmokers.
19
This finding was quickly reproduced in seven
7

Figure 5. Smoking among women of reproductive age and pregnant women. Dashed lines are 95% confidence
intervals. Data from: Centers for Disease Control and Prevention (CDC). Behavioral Risk Factor Surveillance
System Survey Data. Atlanta, Georgia: U.S. Department of Health and Human Services, Centers for Disease Control
and Prevention, 1985-2011.
17

Studies up to 1964, when the landmark first report on tobacco from the Surgeon General
included a statement that, “Women who smoke cigarettes during pregnancy tend to have babies
of lower birth weight.”
20

In the 1960s, an association between smoking and perinatal mortality was established by
the findings of several large-scale, prospective studies of pregnancy in the U.S.,
14,21
Canada,
22

and Great Britain.
12
The causality of this relationship was challenged by some authors such as
Dr. Jacob Yerushalmy, who in 1971 noted, “Smoking mothers have relatively more low-
birthweight infants but these infants are much healthier than are low-birth-weight infants of
nonsmoking mothers - the low-birthweight infants of smoking mothers have lower neonatal
0%
5%
10%
15%
20%
25%
30%
35%
1985 1990 1995 2000 2005 2010
Women aged 18-44
Pregnant women
8

mortality rates and lower risks for severe congenital anomalies.”
21
He argued, “These
paradoxical findings raise doubts and argue against the proposition that cigarette smoking acts as
an exogenous factor which interferes with intrauterine development of the fetus.” Most authors
disagreed with Yerushalmy, who collaborated with tobacco industry studies of pregnancy.
23

Terrin and Meyer explained the statistical phenomenon of the “birthweight paradox” for the first
time ten years later: “These paradoxic results come from comparing perinatal mortality
separately for 2 birth weight subgroups when the hazard under scrutiny - maternal smoking -
forces the exposed (smokers' offspring) and the unexposed (nonsmokers' offspring) to have
different distributions of birth weights” (see Figure 6).
24,25

Figure 6. Distribution of birth weights among infants born to smokers and nonsmokers, United States, 1991
(national linked birth/infant-death data, National Center for Health Statistics). The line at 2,500 g indicates the cutoff
point used to define low birth weight. Reprinted from Hernandez-Diaz S, Schisterman EF, Hernan MA. The birth
weight "paradox" uncovered? Am J Epidemiol. Dec 1 2006;164(11):1115-1120.
25

9

The most recent Surgeon General’s conclusion on the topic, the 2001 report, says, “The
risk for perinatal mortality—both stillbirth and neonatal deaths—and the risk for sudden infant
death syndrome (SIDS) are increased among the offspring of women who smoke during
pregnancy.”
26
In addition to causing low birthweight and perinatal death, smoking has a variety
of other adverse effects during pregnancy that are summarized in Table 1. Notable is that a
conclusion has not been reached for the effect of smoking on spontaneous abortion (miscarriage),
which terminates up to ¼ of recognized pregnancies before viability of the fetus.
27

Table 1. Summary of conclusions on the effects of smoking during pregnancy from the Surgeon
Generals’ Reports
Effect
Surgeon General’s
conclusion*
Year of most
recent conclusion
Ectopic pregnancy
2004
Spontaneous abortion
2004
Premature rupture of the membranes
2004
Placenta previa
2004
Placental abruption
2004
Reduced risk for preeclampsia
2004
Preterm delivery and shortened gestation
2004
Fetal growth restriction and low birthweight
2004
Stillbirth
2001
Neonatal death
2001
* The evidence is sufficient to infer a causal relationship between maternal smoking and [effect] (2004
report)
28
or “risks are increased” (2001 report)
26

The evidence is suggestive but not sufficient to infer a causal relationship between maternal smoking and
[effect] (2004 report)
28

10

The contemporary evidence on adverse health effects was anticipated by physicians'
instincts and anecdotes about the effects of smoking during pregnancy. In 1935, with no other
evidence, one physician wrote, “It would probably be fanatical to state that all women should
abstain from smoking, but it is a responsibility of every physician to warn the young women of
this country of the dangers which attend excessive indulgence… One objection to excessive
smoking in women is the difficulty they experience in controlling the habit when they become
pregnant.”
29
Fifteen years later, with the knowledge that smoking increased the fetal heart rate,
30

another physician cautioned against “excessive cigarette smoking” during pregnancy.
31

1.4. Guidelines for Smoking during Pregnancy
As evidence has accumulated from more reliable studies, the recommendations for
smoking have changed from urging moderation to calling for abstention during pregnancy. The
U.S. Preventive Services Task Force was convened in 1984 and published its first report in 1989:
Guide To Clinical Preventive Services; An Assessment of the Effectiveness of 169
Interventions.
32
The report stated, “Tobacco cessation counseling should be offered on a regular
basis to all patients who smoke cigarettes, pipes, or cigars, and to those who use smokeless
tobacco.” Though redundant, this recommendation was endorsed as necessary for pregnant
women. With an updated version of the guideline published in 2008, the recommendations are
clear that health care providers need to advise and assist smokers to quit.
33
Effective steps to help
smokers quit are outlined in detail, and the document is available in several publications.
34,35

However, not all providers follow these guidelines for smoking cessation counseling.
36

11

1.5. Overview of the Dissertation
Miscarriage and perinatal death form a continuum of pregnancy loss. Because neither is
well understood, studying them together allows a broader view of these related pregnancy
outcomes. Despite numerous studies documenting the relationship between smoking and
miscarriage, the Surgeon Generals’ reports have not yet reached a causal conclusion. Chapter 2
of this dissertation examines the relationship between smoking and miscarriage with a systematic
review and meta-analysis. The Surgeon General did conclude that smoking causes perinatal
death, with conclusions gradually updated over the years and studies added to the reports.
28,37,38

However, a synthesis of this large and diffuse literature has not been conducted recently. Chapter
3 of this dissertation is a systematic review and meta-analyses of the known causal relationship
between smoking and perinatal death. The available evidence is consolidated and various
features of the relationship examined.
Health care providers are a major intermediate for women to access information and
advice about smoking, and improvements in provider adherence could result in fewer women
smoking during pregnancy. Chapter 4 of this dissertation is a study of prenatal care providers’
management of smoking in pregnancy. Based on national data, the study reports current
frequencies of identifying tobacco use and providing cessation counseling at health care visits by
women of reproductive age. Factors that are associated with tobacco use identification and
counseling are examined, and prenatal care providers’ views on the topic are presented from
qualitative interviews.

12

Chapter 1 References

1. Giovino GA. Epidemiology of tobacco use in the United States. Oncogene. Oct 21
2002;21(48):7326-7340.
2. Centers for Disease Control and Prevention. Current cigarette smoking among adults -
United States, 2011. MMWR. Morbidity and mortality weekly report. Nov 9
2012;61(44):889-894.
3. Trends in Tobacco Use. Washington, DC: American Lung Association Research and
Program Services Epidemiology and Statistics Unit;2011.
4. Centers for Disease Control and Prevention. Vital signs: current cigarette smoking
among adults aged >/=18 years--United States, 2005-2010. MMWR. Morbidity and
mortality weekly report. Sep 9 2011;60(35):1207-1212.
5. Office on Smoking and Health, National Center for Chronic Disease Prevention and
Health Promotion, CDC. Achievements in Public Health, 1900-1999: Tobacco Use -
United States, 1900-1999. MMWR. Morbidity and mortality weekly report.
1999;48(43):986-993.
6. Jemal A, Thun M, Yu XQ, et al. Changes in smoking prevalence among U.S. adults by
state and region: Estimates from the Tobacco Use Supplement to the Current Population
Survey, 1992-2007. BMC public health. 2011;11:512.
7. Rhoads JK. The effect of comprehensive state tobacco control programs on adult
cigarette smoking. Journal of health economics. Mar 2012;31(2):393-405.
8. Los Angeles County Department of Public Health, Office of Health Assessment and
Epidemiology. Cigarette Smoking in Los Angeles County: Local Data to Inform Tobacco
Policy. Los Angeles2010.
13

9. Mapping L.A.: Rankings: Income $20,000 or less. 2013;
http://projects.latimes.com/mapping-la/neighborhoods/income/20-or-
less/neighborhood/list/. Accessed March 6, 2013.
10. Barbeau EM, Krieger N, Soobader MJ. Working class matters: socioeconomic
disadvantage, race/ethnicity, gender, and smoking in NHIS 2000. Am J Public Health.
Feb 2004;94(2):269-278.
11. Anderson CM, Burns DM, Dodd KW, Feuer EJ. Chapter 2: Birth-cohort-specific
estimates of smoking behaviors for the U.S. population. Risk analysis : an official
publication of the Society for Risk Analysis. Jul 2012;32 Suppl 1:S14-24.
12. Butler NRB, D.G. Perinatal Mortality. Edinburgh: Livingstone; 1963.
13. Chamberlain GP, E.; Howlett, B.; and Masters, K. British Births 1970; a survey under
the joint auspices of the National Birthday Trust Fund and the Royal College of
Obstetricians and Gynaecologists. London: Heinemann Medical; 1978.
14. The Collaborative Perinatal Study of the National Institute of Neurological Diseases
and Stroke: The Women and Their Pregnancies. Philadelphia: Saunders; 1972.
15. Kahn RS, Certain L, Whitaker RC. A reexamination of smoking before, during, and after
pregnancy. Am J Public Health. Nov 2002;92(11):1801-1808.
16. Tong VT, Jones JR, Dietz PM, et al. Trends in smoking before, during, and after
pregnancy - Pregnancy Risk Assessment Monitoring System (PRAMS), United States, 31
sites, 2000-2005. MMWR.Surveillance summaries : Morbidity and mortality weekly
report.Surveillance summaries / CDC. 2009;58(4):1-29.
17. Centers for Disease Control and Prevention (CDC). Behavioral Risk Factor Surveillance
System Survey Data. Atlanta, Georgia: U.S. Department of Health and Human Services,
Centers for Disease Control and Prevention; 1985-2011.
18. Hatcher RA, Crosby H. Elimination of Nicotine in the Milk. Jounal of Pharmacology
and Experimental Therapeutics. 1927;32:1-6.
14

19. Simpson WJ. A preliminary report on cigarette smoking and the incidence of
prematurity. Am J Obstet Gynecol. Apr 1957;73(4):807-815.
20. Smoking and Health: Report of the Advisory Committee to the Surgeon General of the
Public Health Service. Washington, D.C.: U.S. Department of Health, Education, and
Welfare, Public Health Service; 1964.
21. Yerushalmy J. The relationship of parents' cigarette smoking to outcome of pregnancy--
implications as to the problem of inferring causation from observed associations. Am J
Epidemiol. Jun 1971;93(6):443-456.
22. Second Report of the Perinatal Mortality Study in Ten University Teaching Hospitals.
Toronto, Ontario, Canada: Maternal and Child Health Service, Special Health Services
Branch, Ontario Department of Health; 1967.
23. Furst A. Letter mentioning research grant. In: Yerushalmy J, ed1970.
24. Terrin M, Meyer MB. Birth weight-specific rates as a bias in the effects of smoking and
other perinatal hazards. Obstet Gynecol. Nov 1981;58(5):636-638.
25. Hernandez-Diaz S, Schisterman EF, Hernan MA. The birth weight "paradox" uncovered?
Am J Epidemiol. Dec 1 2006;164(11):1115-1120.
26. U. S. Department of Health and Human Services. Women and Smoking: A Report of the
Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers
for Disease Control and Prevention, Coordinating Center for Health Promotion, National
Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and
Health; 2001.
27. Abortion. In: Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY,
eds. Williams Obstetrics. Vol 23rd. United States of America: The McGraw-Hill
Companies, Inc.; 2010.
28. U. S. Department of Health and Human Services. The health consequences of smoking: a
report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human
15

Services, Centers for Disease Control and Prevention, Coordinating Center for Health
Promotion, National Center for Chronic Disease Prevention and Health Promotion,
Office on Smoking and Health; 2004.
29. Campbell AM. Excessive Cigarette Smoking in Women and Its Effect Upon Their
Reproductive Efficiency. Journal of the Michigan State Medical Society. March
1935;34:146.
30. Sontag LW, Wallace RF. Effect of Cigarette Smoking During Pregnancy Upon the Fetal
Heart Beat. American Journal of Obstetrics and Gynecology. 1935;29:77-83.
31. Clark JA. Smoking and the prenatal patient. The Mississippi doctor. Jan 1950;27(8):369-
371.
32. U.S. Preventive Services Task Force. Guide to Clinical Preventive Services: An
Assessment of the Effectiveness of 169 Interventions. Baltimore: Williams and Wilkins;
1989.
33. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008
Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and
Human Services. Public Health Service; 2008.
34. Lin KW, Tarantino DA. Counseling and interventions to prevent tobacco use and
tobacco-caused disease in adults and pregnant women: reaffirmation recommendation
statement. American family physician. Nov 15 2010;82(10):1266.
35. U. S. Preventive Services Task Force. Counseling and interventions to prevent tobacco
use and tobacco-caused disease in adults and pregnant women: U.S. Preventive Services
Task Force reaffirmation recommendation statement. Annals of Internal Medicine.
2009;150(8):551-555.
36. Jamal A, Dube SR, Malarcher AM, et al. Tobacco use screening and counseling during
physician office visits among adults--National Ambulatory Medical Care Survey and
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National Health Interview Survey, United States, 2005-2009. MMWR. Morbidity and
mortality weekly report. Jun 15 2012;61 Suppl:38-45.
37. The Health Consequences of Smoking: A Report of the Surgeon General. Washington,
D.C.: U.S. Department of Health, Education, and Welfare, Public Health Service; 1971.
38. U. S. Department of Health and Human Services. How Tobacco Smoke Causes Disease:
The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the
Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers
for Disease Control and Prevention, National Center for Chronic Disease Prevention and
Health Promotion, Office on Smoking and Health; 2010.

17

Chapter 2. Systematic review and meta-analysis of miscarriage and maternal
exposure to tobacco smoke during pregnancy

2.1. Introduction
Smoking during pregnancy causes low birthweight, placental abruption, and sudden
infant death syndrome (SIDS).
1,2
Nonetheless, 14% of pregnant women and 23% of women of
reproductive age report being smokers, with secondhand smoke (SHS) exposure even more
prevalent, at 37% of pregnant women.
3-5
Miscarriage, or loss of the fetus before it is viable, is the
most common complication of pregnancy, at 12-26% of recognized pregnancies. Although many
studies have addressed the association between miscarriage and smoking, the evidence has been
considered inconclusive. The Surgeon General’s most recent conclusion, from the 2004 report,
2

classified the evidence as suggestive but not sufficient to infer causation, and the authoritative
textbook, Williams Obstetrics, also described the lack of consistency.
6
Most miscarriages end
early in pregnancy, during an interval over which a woman might not have yet learned of being
pregnant or begun prenatal care. The benefits of quitting smoking early in pregnancy include
increased birthweight and a lower risk of preterm birth, but these effects would never manifest
for a woman who quits but also miscarries in the first trimester.
6
Thus, a more complete
understanding of the relationship between smoking and miscarriage is important for
preconception counseling and public health programs for women of reproductive age. This
systematic review and meta-analysis focuses on the association of smoking (active and passive)
with miscarriage.
7

18

2.2. Materials and methods
We carried out a systematic review and meta-analysis using the guidelines of the Meta-
Analysis of Observational Studies in Epidemiology (MOOSE) consensus statement and the
Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.
8,9

Inclusion criteria
Studies eligible for inclusion in the meta-analysis were original observational or
experimental studies. Eligible studies compared risk for miscarriage between women exposed
and unexposed to tobacco smoke from cigarettes. Relevant exposures were smoking of cigarettes
by the mother or SHS exposure in pregnant women. Articles in any language were eligible and
translated as necessary using Google Translate. We excluded duplicate publications and
publications with duplicated data (e.g., studies conducted on the same registry with overlapping
years). No quality measures were used to select studies for inclusion.

Literature search strategy
Two reviewers independently searched Pubmed (1956 – August 31, 2011) for articles
relevant to smoking and risk of adverse pregnancy outcomes (search terms: (smoking OR
tobacco) AND pregnancy). From the chosen articles, those relevant to miscarriage or perinatal
death were selected for inclusion and/or review of references. We then conducted manual
searches by checking references of the articles identified in the Pubmed searches. The articles
referenced by all relevant articles (original articles, reviews, and letters) were searched by at least
one reviewer, and the articles referenced by included articles and all Surgeon Generals’ Reports
19

regarding tobacco and smoking were searched by two reviewers. Disagreements on final
inclusion status were resolved by discussion.

Data abstraction
Study data were collected and managed using REDCap electronic data capture tools.
10

Two reviewers independently extracted data from all articles on study type, country, calendar
years of the pregnancies in the studies, population characteristics, participant inclusion and
exclusion criteria, recruitment method, participation and follow-up rates, exposure and outcome
definitions, features of data collection, numbers of participants, effect sizes, and statistical
significance tests. Differences in item coding were resolved through discussion between the
reviewers, and the kappa statistic was computed to assess agreement between reviewers. The
median Strout-Fleiss reliability statistic for continuous variables was 0.99, and the median kappa
statistic for covariates analyzed was 0.52.

Definition of outcomes
Miscarriage was defined in different ways including by gestational age ranges, karyotype,
and fetal weight. Common upper thresholds for gestational age were between 12 and 28 weeks.
Many authors did not provide a definition of miscarriage, and for these studies, any outcome
described as “miscarriage,” “spontaneous abortion,” or “pregnancy loss” without other
description was used and combined with other miscarriage outcomes. Reproductive lifetime
history of miscarriage (ever had at least one miscarriage over the lifetime) was analyzed
separately from miscarriage in an individual pregnancy.
20

Grouping of exposures
Any study that used as its exposure indicator “smoking,” “smoker,” “secondhand
smoke,” “environmental tobacco smoke,” “lives with a smoker,” or “partner/husband is a
smoker” was considered eligible. Studies were included that described the amount of smoking
exposure. Exposures were categorized by type (active/passive), timing in relation to pregnancy,
amount of exposure, and the source of exposure if given. Reference exposures included “0
cigarettes per day,” “nonsmoker,” “never-smoker,” “no SHS exposure,” and others indicating no
exposure to tobacco smoke. Studies that did not give a clear description of the timing of
exposure in relation to pregnancy were included. “Any active smoking” refers to definitions of
smoking as at least one cigarette per day and undefined terms of “smoker” and “smoking.”

Study analysis
The random-effects model of DerSimonian and Laird was chosen to account for
heterogeneity of study populations and designs.
11
The estimate of relative risk ratio (RRR) used
was the odds ratio (OR), risk ratio (RR), or hazard ratio (HR), as given in the original article. For
studies without an estimated RRR, the RR or OR was calculated from available data as
appropriate. A continuity correction
12
of 0.5 was applied to studies
13-15
with counts of zero in one
or more cells of the 2 x 2 table.
RRRs for “any active smoking” were combined, as were those for categories of 1-10, 11-
20, and 21+ cigarettes smoked per day.
16
All RRRs for the risk of miscarriage based on number
of cigarettes smoked per day, regardless of categorization scheme, were analyzed in a dose-
response meta-regression (Appendix).
17,18
Because too few studies that examined SHS or history
21

of miscarriage gave results by amount of exposure, no dose-response analysis was conducted for
these groups. Instead, studies that included RRRs for various categories of exposure were
included in “any exposure” analyses after combining the multiple RRRs into a single estimate for
each study.
19

Analyses were conducted using SAS 9.2.

Heterogeneity and study quality
Heterogeneity between studies was assessed using the I
2
statistic, which represents the
percent of total variation that is true between-studies heterogeneity.
20
Statistical significance of
the heterogeneity was analyzed with the Q statistic. When heterogeneity was statistically
significant and high, reasons for the heterogeneity were examined using random-effects meta-
regression for both continuous and dichotomous variables.
21,22
Subgroups were contrasted based
on exposure timing in relation to pregnancy (specified as during pregnancy versus not specified
or other). If unexplained heterogeneity remained, post hoc meta-regression and subgroup
analyses were conducted on other variables collected. Study quality assessment was undertaken
using indicators to address information bias, confounding, selection bias, and violation of
statistical assumptions.

Publication bias
Publication bias was analyzed for each comparison by visual analysis of funnel plots,
Egger Regression, Begg Rank Correlation, Funnel Plot regression, and trim-and-fill tests.
23

22

Sensitivity analyses were conducted by comparing results obtained after excluding studies with
very high RRRs.

Imputation
One study required the use of imputed data for variance estimation because the numbers
provided were miscarriage rates by categories of number of cigarettes per day, and only the total
number of smokers was given.
24
The distribution of cigarettes smoked per day was assumed to
be similar to that seen in other studies, and 50% of the smoking subjects were assigned to the 11-
20 cigarettes per day category and 25% each to the 1-10 and 21+ cigarettes per day categories.
Imputation of the covariates national smoking prevalence and national cigarettes per capita was
also performed for each study based on year and country. Both year of publication and midpoint
year of study pregnancies were used for the year value. Smoking prevalence data were mostly
obtained from the World Health Organization Global Infobase (complete reference list available
upon request).
25
Cigarettes per capita data were primarily obtained from one report,
26
with values
for the U.S. from the Centers for Disease Control and Prevention,
27
and a few other data points
from another source.
28

Sensitivity analysis
Because miscarriage is relatively common (10-20% of pregnancies), odds ratios were
converted to risk ratios and the results using these data were compared to those obtained with
odds ratios, risk ratios, and hazard ratios combined.
29

23

2.3. Results

Studies included in the systematic review and meta-analysis
From the initial 12,899 articles identified by keywords for tobacco and pregnancy, 109
articles were selected for inclusion in the systematic review and 97 in the meta-analyses (Figure
1, Table 1). Articles were excluded for being non-original (n=819), not studying miscarriage or
miscarriage alone (n=733), not analyzing smoking in relation to miscarriage (n=35), lacking a
control group or unexposed group (n=4), translation was not possible (n=4), or other reasons
(n=4). Twenty-six studies were placed into seven sets of overlapping data, with between two and
nine studies per set. These sets were identified based on the studies being conducted in the same
country, using the same registry or population, and during the same years. Often these were
duplicate publications by the same authors, though a few were registry studies with overlapping
years. The largest study appropriate for each analysis was chosen from each set. Of the 109
studies, 21 examined SHS exposure of the mother and 104 examined active maternal smoking.
Thirty-one percent of the studies were conducted in the U.S., and the remainder in 25 other
countries or sets of countries. Twenty-three studies used history of miscarriage as the outcome,
and 90 used miscarriage in an individual pregnancy. All results refer to miscarriage in an
individual pregnancy unless otherwise specified. Eleven duplicate studies were not used in any
analyses.
24

Figure 7. Flow chart of literature search and inclusion/exclusion status
25

Table 2. Characteristics of included studies
Study
a
Study design
Active/
Passive
Percent
Exposed
Outcome Location
Years of
study
Number of
subjects
Adolfsson 2006
30
* Cross-sectional Active 19.6% Miscarriage Sweden 1983-2003 2,503,605
Agnesi 1997
15
** Case-control Active 9.7% Miscarriage Italy 1987-1988 216
Agnesi 2011
31
**

Case-control Active 6.7% Miscarriage Italy 1987-1999 462
Ahlborg 1991
32
Prospective cohort
Active /
Passive
36% / 15% Miscarriage to 13 weeks Sweden 1980-1983 3,261
Ancel 2000
33
Case-control Active 12%
Miscarriage at 14-21
weeks
Multiple
European
1994-1997 4,507
Armstrong 1992
34
Retrospective cohort Active 33% Miscarriage to 28 weeks Canada 1953-1984 47,146
Axelsson 1984
35
Cross-sectional Active 27% Miscarriage Sweden 1950-1982 1,131
Baba 2011
36
Case-control
Active /
Passive
17% / 26% Miscarriage to 12 weeks Japan 2001-2005 1,290
Baird 1985
37
Cross-sectional Active 19% History of miscarriage U.S. 1954-1983 468
Baste 2008
38
Cross-sectional Active 63% History of miscarriage Norway 1965-1999 10,512
Bech 2005
39
Prospective cohort Active 17% Miscarriage to 28 weeks Denmark 1996-2002 88,482
Bernhard 1948
40
Cross-sectional Active 8% History of miscarriage Germany 1916-1947 5,548
Bernhard 1964
41
Retrospective cohort Active 8% Miscarriage to 25.5 weeks Germany 1943-1949 10,803
Bhattacharya 2010
42
† Retrospective cohort Active 34% Miscarriage to 28 weeks U.K. 1950-2005 49,272
Blanco-Munoz 2009
43
Nested case-control
Active /
Passive
42% / 46% Miscarriage to 20 weeks Mexico 2001-2004 107
Blohm 2008
44
Cross-sectional Active 25% History of miscarriage Sweden 1977-2001 733
Campbell 2011
45
Prospective cohort Active 70% Miscarriage to 20 weeks Australia 1999-2008 279
Cavedon 1987
46
Retrospective cohort Active 5% Miscarriage to 28 weeks Italy 1930-1982 3,332
Chatenoud 1998
47
Case-control
Active /
Passive
16% / 45% Miscarriage 4-12 weeks Italy 1990-1995 2,325
Cnattingius 2000
48
* Case-control Active 16% Miscarriage 6-12 weeks Sweden 1996-1998 1,515
Cone 1998
49
Retrospective cohort Active 13% Miscarriage 6-28 weeks U.S. 1990-1991 418
Cope 1973
50
Cross-sectional Active 25%
History of miscarriage to
20 weeks
Australia 1941-1971 4,992
Coste 1991
51
Case-control Active 28% Miscarriage France 1988-1988 558
de Weerd 2003
52
Prospective cohort Active 25% Miscarriage to 16 weeks Netherlands 1987-1990 240
Dominguez-Rojas
1994
53

Retrospective cohort Active 38% Miscarriage to 20 weeks Spain 1963-1991 691
26

Donovan 1977
54
Prospective cohort Active 65% Miscarriage to 28 weeks U.K. 1972-1973 1,274
Downing 1966
55
Prospective cohort Active 47% Miscarriage U.S. 1952-1958 5,659
Ericson 1986
56
Nested case-control
Active /
Passive
17% / 55% Miscarriage Sweden 1980-1981 1,142
Eskenazi 1995
14
Prospective cohort Active 15% Miscarriage U.S. 1965-1994 52
Fergusson 1979
24
Cross-sectional Active 40% History of miscarriage New Zealand 1948-1977 1,248
Fuentes 2010
57
Prospective cohort Passive 18% Miscarriage 2-8.5 weeks Chile 2004-2005 57
Gallicchio 2009
58
Cross-sectional Active 19% Miscarriage to 20 weeks U.S. 1965-2008 1,882
Farioli 2010
59
* Case-control
Active /
Passive
15% / 21% Miscarriage 6-12 weeks Sweden 1996-1998 1,327
George 2006
60
* Case-control
Active /
Passive
15% / 21% Miscarriage 6-12 weeks Sweden 1996-1998 1,327
Guerra-Shinohara
2010
61

Prospective cohort Active 13% Miscarriage to 20 weeks Brazil 2004-2005 100
Hafez 2001
62
Cross-sectional Passive 52% History of miscarriage Egypt 1963-2000 1,934
Hall 1992
63
† Prospective cohort Active 28% Miscarriage U.K. 1980-1989 1,261
Halmesmaki 1989
64
Case-control
Active /
Passive
26% / 36% Miscarriage 6-23 weeks Finland 1988-1988 161
Hansteen 1990
65
Case-control Active 39% Miscarriage to 26 weeks Norway 1985-1987 610
Hardy 1972
66
Prospective cohort Active 44% Miscarriage U.S. 1962-1963 1,329
Harlap 1980
67
Prospective cohort Active 25% Miscarriage 5-27 weeks U.S. 1974-1977 32,019
Harrison 1990
68
Prospective cohort Active 1% Miscarriage Australia 1988-1988 650
Hemminki 1983
69
Cross-sectional Active 15% Miscarriage Finland 1931-1981 2,714
Himmelberger 1978
70
Retrospective cohort Active NS Miscarriage to 20 weeks U.S. 1963-1972 12,914
Hruba 1997
71
Cross-sectional
Active /
Passive
45%
Miscarriage / history of
miscarriage
Czech Republic 1911-1993 7,397
Hudson 1945
72
Retrospective cohort Active 38% Miscarriage U.S. 1943-1945 645
Hughes 1994
13
Cross-sectional Active 48% Miscarriage Canada 1990-1992 48
Kharazmi 2010
73
Cross-sectional Active 21% History of miscarriage Finland 1916-2001 3,636
Khoury 2004
74
Prospective cohort Active 30%
Miscarriage to 20 weeks /
history of miscarriage
U.S. 1978-1993 191
Kizer 1967
75
Cross-sectional Active 39% Miscarriage Venezuela 1966-1967 6,566
Kline 1977
76
‡ Case-control Active 36% Miscarriage U.S. 1974-1976 883
Kline 1980a
77
‡ Case-control Active 34% Miscarriage U.S. 1974-1978 1,293
Kline 1980b
78
‡ Case-control Active 34% Miscarriage U.S. 1974-1978 1,295
Kline 1983
79
‡ Case-control Active 34%
Miscarriage of trisomic
fetus
U.S. 1974-1979 1,603
Kline 1995
80
‡ Case-control Active 34% Miscarriage to 28 weeks U.S. 1974-1986 3,911
27

Koller 1983
81
Prospective cohort Active 19% Miscarriage Germany 1964-1971 6,533
Kullander 1971
82
Prospective cohort Active 44% Miscarriage 8 to 30 weeks Sweden 1963-1964 6,195
Kyyronen 1989
83
Case-control Active 37% Miscarriage Finland 1973-1983 419
Lacuska 1968
84
Retrospective cohort Active 4% Miscarriage Czech Republic 1964-1967 3,670
Lemasters 1989
85
Retrospective cohort Active 20% Miscarriage to 20 weeks U.S. 1963-1985 2,909
Maconochie 2007
86
Case-control
Active /
Passive
24% Miscarriage to 13 weeks U.K. 1980-2001 6,709
Makay 1968
87
Cross-sectional Active 9% History of miscarriage Hungary 1935-1966 2,341
Martin 2000
88
† Retrospective cohort Active 34% Miscarriage to 27 weeks U.K. 1969-1997 3,150
Maximovich 1995
89
Retrospective cohort Active 19% Miscarriage U.S. 1992-1993 80
Medina 1990
90
Cross-sectional Active 55% History of miscarriage Chile 1943-1988 100
McKean 1978
91
‡ Case-control Active 36% Miscarriage U.S. 1974-1976 883
Meeker 2007a
92
†† Prospective cohort Passive 11% Miscarriage to 20 weeks U.S. 1994-2003 460
Meeker 2007b
93
†† Prospective cohort Passive 50% Miscarriage to 20 weeks U.S. 1994-1998 339
Mey 1967
94
Cross-sectional Active 14% History of miscarriage Germany 1906-1965 1,981
Mishra 2000
95
Cross-sectional Active 44% History of miscarriage Australia 1988-1996 2,617
Morales 1997
96
Cross-sectional Active 26% History of miscarriage U.K. 1950-1984 119
Murphy 1974
97
‡‡ Retrospective cohort Active 46% Miscarriage U.K. 1969-1973 12,013
Murphy 1978
98
‡‡ Retrospective cohort Active 46% Miscarriage U.K. 1969-1973 12,013
Nakamura 2004
99
Cross-sectional
Active /
Passive
24% / 45%
Miscarriage / history of
miscarriage
Brazil 2001-2001 596
Ness 1999
100

Case-control /
prospective cohort
Active 26% Miscarriage to 22 weeks U.S. 1995-1997 970
Nielsen 2006
101
§§ Nested case-control Active 45% Miscarriage to 28 weeks Denmark 1991-1995 1,921
No author 1995
102
Cross-sectional Active 33% History of miscarriage Denmark 1963-1992 68,065
O’Lane 1963
103
Cross-sectional Active 46% Miscarriage U.S. 1961-1962 1,914
Padron 1990
104
Retrospective cohort Active 44% Miscarriage Cuba 1986-1987 1,018
Palmgren 1971
105
§ Prospective cohort Active 48% Miscarriage 8-30 weeks Sweden 1964-1967 4,312
Palmgren 1973
106
§ Prospective cohort Active 48% Miscarriage Sweden 1964-1967 4,312
Pandya 1996
107
Cross-sectional Active 3% Miscarriage 10-13 weeks U.K. 1992-1995 16,806
Pattinson 1991
108
Prospective cohort
Active /
Passive
28% / 22% Miscarriage Canada 1984-1989 69
Raatikainen 2007
109
Cross-sectional Active 27% History of miscarriage Finland 1960-2001 25,591
Rasch 2003
110
Case-control Active 22% Miscarriage 6-16 weeks Denmark 1994-1996 1,486
Risch 1988
111
Cross-sectional Active 20% Miscarriage
U.S. and
Canada
1914-1981 6,282
28

Rumeau-Roquette
1972
112

Cross-sectional Active 10% History of miscarriage France 1934-1967 3,984
Sandahl 1989
113
* Case-control Active 49% Miscarriage 5-28 weeks Sweden 1980-1985 2,747
Scholl 1986
114
Prospective cohort Active 34% Miscarriage U.S. 1982-1984 775
Schwartz 1972
115
Prospective cohort Active 17% Miscarriage France 1963-1969 6,989
Selevan 1985
116
Case-control Active 13% Miscarriage Finland 1972-1980 445
Simoes 1985
117
Cross-sectional Active 25% History of miscarriage Brazil 1978-1979 6,179
Stein 1981a
118
‡ Case-control Active 30% Miscarriage U.S. 1974-1980 4,088
Stein 1981b
119
‡ Case-control Active 30% Miscarriage U.S. 1974-1980 4,088
Triopon 2006
120
Prospective cohort
Active /
Passive
21% / 43% Miscarriage France 2002-2005 63
Underwood 1965
121
Retrospective cohort Active 27% Miscarriage U.S. 1931-1961 16,158
van Ravenswaaij
2011
122

Retrospective cohort Active 7% Miscarriage to 16 weeks Netherlands 2002-2006 28,566
Venners 2004
123
Prospective cohort Passive 59% Miscarriage to 6 weeks China 1996-1998
526

Wallander 1970
124
§ Prospective cohort Active 50% Miscarriage Sweden 1967-1969 4,478
Warburton 1979
125
‡ Case-control Active 30% Miscarriage to 28 weeks U.S. 1974-1978 966
Wilcox 1990
126
Prospective cohort
Active /
Passive
5% / 8% Miscarriage 1-6 weeks U.S. 1982-1986 171
Windham 1992
127
Case-control
Active /
Passive
20% / 28% Miscarriage to 20 weeks U.S. 1986-1987 1,926
Windham 1999a
128
Prospective cohort
Active /
Passive
18% / 28% Miscarriage to 20 weeks U.S. 1990-1991 5,142
Windham 1999b
129
Cross-sectional Active 16% History of miscarriage U.S. 1966-1990 362
Winter 2002
130
Retrospective cohort Active 11% Miscarriage to 7 weeks Australia 1994-1999 1,196
Wisborg 2003
131
§§ Prospective cohort Active 29% Miscarriage 12-27 weeks Denmark 1989-1996 17,497
Wu 1998
132
Cross-sectional Active 24% History of miscarriage U.S. 1959-1988 12,465
Yuan 1994
133
Cross-sectional Active 19% History of miscarriage Japan 1961-1992 261
Zabriskie 1963
134
Cross-sectional Active 48% Miscarriage U.S. 1931-1961 5,619

a
Footnote markers, (*,**,†,††,‡,‡‡,§,§§) denote studies from the same “set” of definite or probable duplicated pregnancy data. Only one study from each set
was used in any given analysis.

29

Active maternal smoking

Results of the meta-analysis. The summary relative risk for miscarriage among smoking women
using only crude RRRs was 1.27 (95% confidence interval (CI): 1.18, 1.37, 35 studies), and that
using only adjusted RRRs was 1.17 (95% CI: 1.04, 1.31, 19 studies,). All further analyses used
adjusted and crude relative risks together because of the similarity of these estimates, which were
not significantly different (p=0.45). The summary relative risk of miscarriage with any active
smoking was 1.23 (95% CI: 1.16, 1.31, 50 studies, Figure 8). Women who quit smoking at
conception or early in pregnancy had a 25% lower risk of miscarriage than those who did not
smoke around the time of pregnancy at all, but the difference was not statistically significant
(summary RRR=0.75, 95% CI: 0.55, 1.02).

History of miscarriage. Any active smoking was associated with an increased risk of having a
history of miscarriage (at least one miscarriage in the woman’s lifetime; summary RRR=1.47,
95% CI: 1.26, 1.70, 22 studies). Ex-smokers had non-significantly increased risk of having a
history of miscarriage (summary RRR: 1.33, 95% CI: 0.96, 1.85, 2 studies).

Assessment of heterogeneity. Heterogeneity of the summary relative risk of miscarriage with any
active smoking was statistically significant and moderate (I
2
=60%, p<0.0001; see Table 3 for
detailed results). None of the following factors significantly affected the summary relative risk:
year of publication, midpoint year of the study pregnancies, the exposure prevalence in the study
population, or per-capita cigarette consumption (p values>0.25). Studies that defined miscarriage
30

as pregnancy loss with a maximum gestational age of 20 weeks or greater had a higher summary
relative risk of miscarriage than those that defined it with a maximum gestational age of less than
20 weeks (1.49 vs. 1.24, respectively, p <0.05). Cohort studies had higher summary relative risks
than studies with other designs (e.g., case-control or cross-sectional; 1.39 vs. 1.17, respectively,
p <0.05). Studies that specified that the smoking exposure they used was during the pregnancy in
which miscarriage risk was measured gave a summary relative risk that was higher but not
significantly different from those with exposures without a specified time or specified as
smoking before pregnancy, lifetime smoker, smoking during subsequent pregnancy, or at another
time (summary RRRs: 1.29 vs. 1.16, p for difference=0.09). Studies conducted in the U.S. had a
non-significantly higher summary relative risk than studies conducted in other countries (p for
difference=0.08).

Dose-response analysis. The relative risk increased with increasing numbers of cigarettes
smoked per day. For 1-10, 11-19, and 20+ cigarettes per day, the summary relative risks were
1.08 (95% CI: 0.96, 1.21, 16 studies), 1.25 (95% CI: 1.17, 1.34, 9 studies), and 1.42 (95% CI:
1.19, 1.70, 11 studies). Figure 9 shows the dose-response relationship with an estimated
increment per cigarette of relative risk by 1.01 (95% CI: 1.01, 1.02, 31 studies). The relationship
did not depart significantly from linearity based on the comparison of the log-likelihood for a
model with cubic spline variables to that for a model with only a linear term (p=0.59).
135

31

Figure 8. Forest plot of the association between maternal smoking and miscarriage, showing the relative risk and
95% confidence interval. RR/OR = Risk ratio/Odds ratio, LCL = Lower boundary of the 95% confidence interval
for the RR/OR, UCL = Upper boundary of the 95% confidence interval for the RR/OR, Weight = Random-effects
weight of the study.
32

Figure 9. Dose-response curve of the association between maternal smoking and miscarriage

Study quality. Studies that specified a gestational age range in their definitions of miscarriage
had higher RRRs than studies that did not (summary RRRs: 1.33 vs. 1.15, p for difference=0.02,
Table 3). Factors that did not impact the summary RRR were prospective or biochemical
measurement of smoking exposure, proper adjustment for confounders (adjustment for maternal
33

age but not prior miscarriage)
136
, analysis of only one pregnancy per woman, and high (>80%)
participation and follow-up rates (p values>0.35, Table 3).

Table 3. Heterogeneity and study quality analyses.
Number of
studies
OR 95% CI
Year of publication (per ten years) 50 0.98
a
0.94, 1.03
Midpoint year of study pregnancies (per 10 years) 50 0.99
a
0.95, 1.03
Exposure prevalence in the study population (per percent) 50 0.77
a
0.51, 1.17
Per-capita cigarette consumption (per thousand, imputed) 47 1.00
a
0.94, 1.06
Gestational age of miscarriages (per week, average of midpoints from
outcome definitions)
30 1.01
a
0.98, 1.03
Study design 50 0.87
b
0.77, 0.98
Cohort studies 28 1.39
c
1.22, 1.59
Other study designs (ref) 22 1.17
c
1.11, 1.24
Exposure definition timing 50 1.11
b
0.99, 1.25
Studies that specified that the smoking exposure they used was during
the pregnancy in which miscarriage risk was measured
24 1.29
c
1.19, 1.41
Studies with exposures without a specified time or specified as
smoking before pregnancy, lifetime smoker, smoking during a
subsequent pregnancy, or at another time (ref)
26 1.16
c
1.06, 1.28
Country of study 50 1.11
b
0.99, 1.25
Studies conducted in the U.S. 17 1.33
c
1.20, 1.48
Studies conducted in other countries (ref) 33 1.19
c
1.10, 1.28
Definition of miscarriage 50 1.14
b
1.02, 1.29
Studies that specified a gestational age range in their definitions of
miscarriage
30 1.33
c
1.21, 1.47
Studies that did not specify (ref) 20 1.15
c
1.06, 1.24
Biased self-report of smoking 50 1.07
b
0.93, 1.22
Prospective or biochemical measurement of smoking 20 1.31
c
1.13, 1.52
Retrospective, non-biochemical measurement (ref) 30 1.21
c
1.14, 1.30
Statistical adjustment 50 1.03
b
0.89, 1.21
Best statistical model (including at least maternal age and excluding
prior miscarriage)
11 1.28
c
1.15, 1.41
Other statistical models (ref) 39 1.23
c
1.15, 1.31
Independence of outcomes 50 0.96
b
0.85, 1.10
Analysis of only one pregnancy per woman or statistical adjustment
for non-independence of outcomes
19 1.20
c
1.01, 1.43
Not specified / more than one pregnancy per woman analyzed (ref) 31 1.24
c
1.16, 1.31
a
OR is for the change in the summary relative risk of miscarriage for smokers versus nonsmokers with each
increment of the continuous variable as specified.
b
OR is for the summary relative risk of miscarriage for smokers versus nonsmokers in the index group versus the
same summary relative risk in the reference group.
c
OR is the summary relative risk of miscarriage for smokers versus nonsmokers in the subgroup.
34
Assessment of publication bias. Formal statistical tests for publication bias (Egger OLS
regression, the Begg rank correlation, Funnel Plot WLS Regression, and the trim and fill tests)
did not demonstrate bias among studies that reported “any active smoking” analyses (p
values>0.35). The funnel plot was fairly symmetrical, suggesting no major impact of publication
bias (Figure 10).

Figure 10. Funnel plot of studies included in the comparison between any maternal smoking and miscarriage.
Sample size versus log RR/OR.

35
Sensitivity analyses. The summary RRR after converting odds ratios from 24 studies to risk
ratios was 1.22 (95% CI: 1.15, 1.29, 50 studies).

Maternal secondhand smoke exposure
Secondhand smoke exposure was not significantly associated with miscarriage (summary
RRR=1.11, 95% CI: 0.89, 1.39, I
2
=64%, 18 studies). Using studies that included nonsmokers
only or adjusted for active smoking did not change the summary RRR (95% CI: 0.91, 1.49, 13
studies). The only study that examined history of miscarriage found that secondhand smoke
exposure increased the risk of having a history of miscarriage by 21% (p<0.05).
62
The Egger test
for publication bias was statistically significant (p=0.05), but not the Begg rank correlation,
Funnel Plot WLS Regression, or the trim and fill tests (p values>0.5). Removal of three outliers
(log RRR less than -1 or greater than 1) eliminated the publication bias and increased the
summary RRR to 1.20 (95% CI: 1.02, 1.41, 14 studies).

2.4. Discussion
Most literature reviews published since the 1970s have emphasized inconsistency of the
evidence on smoking as a cause of miscarriage (see representative articles
137,138
) although several
have concluded that smoking causes miscarriage (see representative articles
139-141
). Two meta-
analyses published in 1984
142
and 1995
143
included only six and thirteen studies, respectively,
but found pooled relative risks very similar to the results in the present report (1.24 and 1.32,
respectively). This systematic review and meta-analysis confirmed an association of maternal
36
smoking during pregnancy with risk for miscarriage and also showed that risk increases with the
amount smoked.
Like other meta-analyses of observational data, our review has several limitations
reflecting the reliance on secondary data gathered from publications. First, we were unable to
fully investigate the effect of timing of smoke exposure across pregnancy on miscarriage risk.
Although we found that women who had quit smoking were not at increased risk of miscarriage
compared to never-smokers, whether a woman needs to quit months before pregnancy, weeks
into pregnancy, or at some other time to lower risk is currently unknown. Two studies gave
relative risks of miscarriage for women who quit at the time pregnancy was recognized, and
these showed a lowered risk of miscarriage compared to never smokers. This finding may reflect
a selection bias as women who quit upon learning of pregnancy are likely to be particularly
health-conscious. The relative risk of miscarriage for smokers was greater when miscarriage was
defined as pregnancy loss with a maximum gestational age of 20 weeks or greater. However, the
definition of miscarriage is only a proxy for the gestational ages at which women actually
miscarried, and more precise data on gestational age-specific risks would be useful.
Overall, the evidence in our systematic review supports a causal explanation for the
association between smoking and miscarriage. Applying the guidelines for assessing evidence
for causation,
144
we found: 1) consistency of findings across studies (Figure 8); 2) a biological
gradient (risk increased with amount smoked); 3) a temporal relationship between smoking and
miscarriage that is consistent with causation; and 4) semi-experimental evidence of causality
(quitters were not at increased risk). Not surprisingly, despite the general consistency of results,
there was significant overall heterogeneity of the relative risks, which ranged from 0.27 to 4.20.
The studies were carried out in 27 countries over a time period of observation that spanned more
37
than a century. Nonetheless, most studies showed an increased risk associated with maternal
smoking, with a tight interquartile range of 1.00 to 1.41. Meta-regression did not find covariates
that explained a significant portion of the heterogeneity. Smoking during pregnancy, and not
before or after, resulted in a greater risk of miscarriage. Studies specifying that they asked
women about smoking prospectively had a stronger association with miscarriage than
retrospective studies.
Cited in the literature are a variety of mechanisms for smoking to cause miscarriage, as
well as analogous relationships in which smoking causes other adverse pregnancy outcomes.
Carbon monoxide, nicotine, metals, and polycyclic aromatic hydrocarbons (PAHs), all
introduced into the body by cigarette smoking, are each implicated in mechanisms that could
cause miscarriage.
7
Elevated levels of carbon monoxide in the blood reduce oxygen delivery and
increase erythropoiesis. The resulting hyperviscosity from increased red blood cell mass can
reduce placental perfusion, which is associated with miscarriage.
145
Nicotine causes a dose-
dependent inhibition of progesterone synthesis in vitro, and recent studies have found that low
serum progesterone in early pregnancy predicts non-viable pregnancy.
146
PAHs and metals like
arsenic are associated with abortion and fetal mortality in animals models.
7
The relationship
between smoking and miscarriage is similar to the associations between smoking and other poor
reproductive outcomes. Smoking during pregnancy is known to cause low birthweight, preterm
birth, and perinatal death.
2
The risk for low birthweight increases in a dose-dependent manner
with amount smoked, consistent with our findings for miscarriage.
7
Additionally, explanations for the association other than causation are not likely. With
regard to information bias, differential recall or reporting of smoking between women with and
without miscarriages does not explain the increased risk because prospective cohort studies that
38
asked women about smoking before their pregnancy outcome was known also showed an
increased risk of miscarriage (Table 3). Indeed, the relative risk was higher among this group of
studies than among the retrospective studies which would have had greater likelihood of
information bias. Confounding of the relative risk by factors associated with both smoking and
miscarriage (e.g., maternal age) would not fully explain the increased risk, because results using
relative risks adjusted for important covariates are comparable to the results using only
unadjusted estimates. Selection bias also did not affect the relative risk found, because studies
with high participation and follow-up rates gave a summary RRR that was identical to that given
by the complete set of studies. Publication bias is also an unlikely explanation for the findings.
Statistical significance was not achieved with tests for publication bias, and because of the fairly
large number of studies (>30 in most analyses), the power of the Egger regression to detect
severe bias was substantial, at around 95%.
147
In addition, a sensitivity analysis performed by
excluding small studies with large relative risks gave a summary RRR that was very similar to
that found using all studies.
To examine why previous reviews did not generally conclude that the association
between smoking and miscarriage was consistent, we conducted cumulative meta-analyses of the
50 studies that assessed the risk of miscarriage with a report of “any active smoking” (Figure
11). We iteratively combined the estimates from the 50 studies, plotting the cumulative estimate
from the first two studies through the entire group. This analysis demonstrated that an increased
risk of miscarriage has been consistently documented since the publication of the first two
studies in 1963. The relative risk estimates in the cumulative meta-analysis were all statistically
significant and ranged from 1.22 to 1.43.
39
Thus, the consistency of the pooled estimate has not changed significantly over the last
50 years, so why has consensus not yet been reached? Comparison of this systematic review with
other reviews demonstrates that much of the relevant literature was not included in these reports.
For example, only 30 of the 105 articles included in this study were referenced by at least one of
the Surgeon Generals’ Reports on the health effects of smoking published from 1964 to 2010.
Many reviews of smoking and pregnancy, environmental exposures and reproduction, and causes
of miscarriage have stated that the evidence is inconsistent without conducting systematic
reviews. Multiple recent literature reviews we found cited only one or two original articles on
smoking and miscarriage,
148,149
and some limited their references to prior reviews.
139
Despite
reviews that found the evidence to be unconvincing, we demonstrated that the association
between smoking and miscarriage first documented by Zabriskie in 1963 has endured a half
century of research.

40

Figure 11. Forest plot of cumulative meta-analyses of the association between maternal smoking and miscarriage,
showing the relative risk and 95% confidence interval. Summary RR = summary relative risk ratio, LCL = Lower
boundary of the 95% confidence interval for the relative risk ratio, UCL = Upper boundary of the 95% confidence
interval for the relative risk ratio.

41

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57
Chapter 3. Systematic review and meta-analysis of perinatal death and
maternal exposure to tobacco smoke during pregnancy

3.1. Introduction
The relationship between smoking during pregnancy and the risk of perinatal death has
undergone extensive scrutiny since the 1960s.
1-3
Perinatal death includes two components:
stillbirth (death of the fetus in utero from around 20-28 weeks’ gestation) and neonatal death
(death within one month after birth at any gestational age). The scientific and medical
communities’ acceptance of smoking as a cause of perinatal death was hindered by the statistical
phenomenon of the “birthweight paradox.”
4
The paradox is that although babies of smokers are
less likely to survive than are babies of nonsmokers, low-birthweight babies of smokers are more
likely to survive than are low-birthweight babies of nonsmokers. This counterintuitive finding
was explained by the discovery that babies of smokers have a different birthweight distribution
of than babies of nonsmokers, invalidating birthweight-specific comparisons between the two
groups.
5
About 11% of smokers’ babies are considered “low birthweight” by the traditional
definition of less than 2,500 grams, compared to 6% of nonsmokers’ babies.
6
After decades of
controversy and resolution of the paradox,
5,6
smoking was gradually established as a cause of
perinatal death.
7

Several Surgeon General’s reports have cited an increased risk of perinatal mortality in
babies of smokers.
7-9
Most recently, the 2001 report, Women and Smoking, stated “The risk for
perinatal mortality—both stillbirth and neonatal deaths—and the risk for sudden infant death
syndrome (SIDS) are increased among the offspring of women who smoke during pregnancy.”
7

Despite this assessment, the complete literature on smoking and perinatal mortality has not been
58
consolidated into a single analytic paper. To update the conclusions, examine trends, and explore
heterogeneity and sources of bias, we conducted a systematic review and meta-analysis of the
effect of smoking on perinatal death.

3.2 Materials and methods
We carried out a systematic review and meta-analysis using the guidelines of the Meta-
Analysis of Observational Studies in Epidemiology (MOOSE) consensus statement and the
Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.
10,11

Inclusion criteria
Studies eligible for inclusion in the meta-analysis were original observational or
experimental studies. Eligible studies compared risk for perinatal death between women exposed
and unexposed to tobacco smoke from cigarettes. Relevant exposures were smoking of cigarettes
or secondhand smoke (SHS) exposure in pregnant women. Articles in any language were eligible
and translated as necessary using Google Translate. We excluded duplicate publications and
publications with duplicated data (e.g., studies conducted on the same registry with overlapping
years). No quality measures were used to select studies for inclusion.

59
Literature search strategy
Two reviewers independently searched Pubmed (1956 – August 31, 2011) for articles
relevant to smoking and risk of adverse pregnancy outcomes (search terms: (smoking OR
tobacco) AND pregnancy). From the chosen articles, those relevant to perinatal death were
selected for inclusion and/or review of references. We then conducted manual searches by
checking references of the articles identified in the Pubmed searches. The articles referenced by
all relevant articles (original articles, reviews, and letters) were searched by at least one reviewer,
and the articles referenced by included articles and all Surgeon Generals’ Reports regarding
tobacco and smoking were searched by two reviewers. Disagreements on final inclusion status
were resolved by discussion.

Data abstraction
Study data were collected and managed using REDCap electronic data capture tools.
12

Two reviewers independently extracted data from all articles on study type, country, calendar
years of the pregnancies in the studies, population characteristics, participant inclusion and
exclusion criteria, recruitment method, participation and follow-up rates, exposure and outcome
definitions, features of data collection, numbers of participants, effect sizes, and statistical
significance tests. Differences in item coding were resolved through discussion between the
reviewers, and the kappa statistic was computed to assess agreement between reviewers. The
median Strout-Fleiss reliability statistic for continuous variables was 1.00, and the median kappa
statistic for covariates analyzed was 0.68.

60
Definition of outcomes
Stillbirth, neonatal death, and perinatal death were analyzed separately. Stillbirth was
defined in various ways including by gestational age ranges and minimum birthweights.
Common lower thresholds for gestational age were between 20 and 28 weeks, and some studies
used minimum birthweights of 400-1,000 grams. Many authors did not provide a definition of
stillbirth, and for these studies, any outcome described as “stillbirth,” or “fetal death” without
other description was used and combined with other stillbirth outcomes. Some studies examined
antenatal and intrapartum stillbirth, or explained and unexplained stillbirth. These were
combined into the main analyses.
13
Neonatal death was usually defined as death after live birth
within 1, 7, 28, or 30 days. When no definition was provided, outcomes termed “neonatal death”
or “early neonatal death” were included. The broadest definition in each study was used for the
main analysis, and early neonatal death (within 6-8 days after birth) examined separately.
Perinatal death is the combination of stillbirth and neonatal death, and as in the other outcomes,
only some studies provided detailed definitions, but all were included. Reproductive lifetime
history of perinatal death (ever had at least one perinatal death over a woman’s lifetime) was
analyzed separately from perinatal death in an individual pregnancy. Outcomes stratified by
birthweight categories other than minima of <=1,000 grams were excluded.

Grouping of exposures
Any study that used as its exposure indicator “smoking,” “smoker,” “secondhand
smoke,” “environmental tobacco smoke,” “lives with a smoker,” or “partner/husband is a
smoker” was considered eligible. Studies were included that described the amount of smoking
61
exposure. Exposures were categorized by type (active/passive), timing in relation to pregnancy,
amount of exposure, and the source of exposure if given. Amount of exposure was given as
cigarettes or packs smoked per day by the mother or father, hours or general semi-quantitative
frequency of maternal secondhand smoke exposure, or maternal serum cotinine concentration.
Reference exposures included “0 cigarettes per day,” “nonsmoker,” “never-smoker,” “no SHS
exposure,” and others indicating no exposure to tobacco smoke. The timing of the smoking
exposure in relation to pregnancy was frequently given as during pregnancy, before or after a
specified gestational age, before pregnancy, or at the time of ascertainment. Studies that did not
give a clear description of the timing of exposure in relation to pregnancy were included.

Study analysis
The random-effects model of DerSimonian and Laird was chosen to account for
heterogeneity of study populations and designs.
14
The estimate of relative risk ratio (RRR) used
was the odds ratio (OR), risk ratio (RR), or hazard ratio (HR), as given in the original article. For
studies without an estimated RRR, the RR or OR was calculated from available data as
appropriate. A continuity correction
15
of 0.5 was applied to studies
16-18
with counts of zero in one
or more cells of the 2 x 2 table.
To analyze the association of active smoking with each outcome, RRRs for “any active
smoking” were combined, as were those for categories of 1-10, 11-20, and 21+ cigarettes
smoked per day.
19
Because too few studies that examined SHS or history of perinatal death gave
results by amount of exposure, no dose-response analysis was conducted for these groups.
Therefore, studies that included RRRs for various categories of exposure were included in “any
62
exposure” analyses after combining the multiple RRRs into a single estimate for each study.
13

Analyses were conducted using SAS 9.2.

Dose-response analysis
All RRRs given for the risk of stillbirth, neonatal death, or perinatal death based on
number of cigarettes smoked per day, regardless of categorization scheme, were analyzed in a
dose-response meta-regression, separately for each outcome. We used a SAS macro for meta-
analysis of linear and nonlinear dose-response relationships that combines studies of the same
relationship that have different exposure levels (Appendix).
20,21
The “dose” was calculated based
on the approximate mean number and categorical distribution of cigarettes smoked per day
among women in the National Health Interview Survey.
22
For closed-ended categories, the
midpoints were taken as the dose. For open-ended categories (those with minimum but not
maximum numbers of cigarettes per day such as “20 or more”), we imputed a maximum number
of cigarettes per day based on the category minimum, then took the midpoint of the minimum
and the imputed maximum as the dose. For categories with minima of 40 or more cigarettes per
day, the maximum was 45; for categories with minima of 30-39 cigarettes per day, the maximum
was 40; for categories with minima of 25-29 cigarettes per day, the maximum was 35; for
categories with minima of 20-24 cigarettes per day, the maximum was 30; for categories with
minima of 15-19 cigarettes per day, the maximum was 25; for categories with minima of 2-14
cigarettes per day, the maximum was 20.

63
Heterogeneity and study quality
Heterogeneity between studies was assessed using the I
2
statistic, which represents the
percent of total variation that is true between-studies heterogeneity.
23
Statistical significance of
the heterogeneity was analyzed with the Q statistic. When heterogeneity was statistically
significant, reasons for the heterogeneity, including bias, were examined using random-effects
meta-regression for both continuous and dichotomous variables determined a priori.
24,25
If
unexplained heterogeneity remained, post hoc meta-regression and subgroup analyses were
conducted on other variables collected. Study quality assessment was undertaken using
indicators to address information bias, confounding, selection bias, and violation of statistical
assumptions.

Publication bias
Publication bias was analyzed for each comparison by visual analysis of funnel plots,
Egger Regression, Begg Rank Correlation, Funnel Plot regression, and trim-and-fill tests.
26

Sensitivity analyses were conducted by comparing results obtained after excluding studies with
very high RRRs.

Imputation
Three studies required imputation of data for variance estimation. For two of these, the p-
value was specified as >0.05, and to use a conservative estimate, the mean of 0.05 and 1 was
imputed.
27,28
One other study required imputation of the numbers of subjects in subgroups of
64
boys and girls, for which we used the given number of subjects and approximated the sex ratio as
1.04.
29
This article was also missing the percent of subjects who were smokers, but we obtained
this percent from another article reporting the same study,
30
and assumed the prevalence of
smoking did not vary by sex of the baby. Imputation of the covariates national smoking
prevalence and national cigarettes per capita was also performed for each study based on year
and country. Both year of publication and midpoint year of study pregnancies were used for the
year value. Smoking prevalence data were mostly obtained from the World Health Organization
Global Infobase (complete reference list available upon request).
31
Cigarettes per capita data
were primarily obtained from one report,
32
with values for the U.S. from the Centers for Disease
Control and Prevention,
33
and a several data points from another source.
34

3.3. Results
Studies included in the systematic review and meta-analysis
From the initial 12,899 articles identified by keywords for tobacco and pregnancy, 196
articles were selected for inclusion in the systematic review and 139 in the meta-analyses (Figure
12, Table 4). Articles were excluded if not original (n=899), not studying stillbirth, neonatal
death, or perinatal death (n=442), not analyzing smoking in relation to stillbirth, neonatal death,
or perinatal death (n=139) lacking a control group or unexposed group (n=11), translation was
not possible (n=3), or other reasons (n=5). Articles included in the systematic review were
excluded from the meta analyses for having duplicated study data (n=37), not presenting data on
the association between smoking and perinatal death (n=7), lacking information for computation
of estimates or variance of the association (n=7), using a reference group not comparable to non-
smokers (n=2), or only presenting an analysis adjusted for birthweight (n=2). Among included
65
studies, the outcome analyzed in relation to smoking was stillbirth (n=93 articles), neonatal death
(n=39), and/or perinatal death (n=61). Of the 139 studies, 11 examined SHS exposure of the
mother and 134 examined active maternal smoking. Twenty-six percent of the studies were
conducted in the U.S., and the remainder in 28 other countries or sets of countries. Ten studies
used history of stillbirth as the outcome, and the remainder used stillbirth, neonatal death, and/or
perinatal death in an individual pregnancy. All results refer to stillbirth, neonatal death, or
perinatal death in an individual pregnancy unless otherwise specified.
In some instances, sources of data used by the studies were not unique to each publication. These
duplicated data were identified based on studies being conducted in the same country, using the
same registry, hospital, or city population, and during the same years. Some of these were
duplicate publications by the same authors and others were registry studies with overlapping
years, such as a set of articles all based on data from the Swedish Medical Birth Register. Forty-
four articles were placed into 19 sets of duplicated data with between two and six articles per set.
One article was separated into two studies with duplicated data due to using both cohort and
case-control designs. All studies remained in the analytic dataset to maximize the number of
studies per analysis, because even two studies with identical data sometimes presented it
differently (i.e. smoker/nonsmoker and categories of cigarettes per day). To prevent analysis of
duplicated data, only one study was chosen from each set for a single analysis.

66

Figure 12. Flow chart of literature search and inclusion/exclusion status

Active maternal smoking
Results of the meta-analysis. The summary relative risk for perinatal death among smoking
women was 1.35 (95% CI: 1.28, 1.44, 47 studies, Table 5, Figure 13). The relative risk was
greater for stillbirth than for neonatal death (1.45 vs. 1.20, p=0.008, Table 5, Figures 14 and 15).
67
Ex-smokers and those who quit during pregnancy had similar risks of perinatal death, stillbirth,
and neonatal death compared to never-smokers and those who did not smoke around the time of
pregnancy (summary RRRs: 1.05, 1.12, and 0.99, respectively, Table 5).

History of perinatal death. No studies examined the risks of having a history of perinatal death
or neonatal death based on smoking status (at least one death in the woman’s lifetime). Neither
being an active smoker nor being an ex-smoker was associated with an increased risk of having a
history of stillbirth (respectively - summary RRR=0.50, 95% CI: 0.11, 2.33, 7 studies and
summary RRR=1.22, 95% CI: 0.92, 1.63, 2 studies).
68
Table 4. Characteristics of included studies
Study
a
Study design
Active /
Passive
Percent
Exposed
Outcome Location
Years of
study
Number
of
subjects
Mohsin 2006
35
(a) Cohort Active 18% Stillbirth / Neonatal
death
Australia 1998-2002 433,227
Robson 2006
36
(a) Cohort Active 41% Stillbirth Australia 1998-2003 21,880
Mohsin 2008
37
(b) Cohort Active 17% Perinatal death Australia 1994-2004 244,840
Wong 1997
38
(b) Cohort Active 3% Perinatal death Australia 1994 684,034
Bell 1989
39
Cohort Active 22% Perinatal death Australia 1985 5,622
Cope 1973
40
Cohort Active 30% Stillbirth / Neonatal
death / Perinatal death
Australia 1970-1971 4,067
Lumley 1985
41
Cohort Active 38% Perinatal death Australia 1981-1982 10,889
Targett 1973
42
Cohort Active 39% Perinatal death Australia 1971-1972 1,000
Targett 1977
43
Cohort Active 34% Perinatal death Australia 1973-1975 3,000
Endler 1986
44
Cohort Active 26% Perinatal death Austria 1976-1982 6,688
Ferraz 1991
45
Nested case-
control
Active 34% Stillbirth Brazil 1984-1986 2,789
Gray 1991
46
Nested case-
control
Active 38% Neonatal death Brazil 1984-1986 3,588
Laurenti 1985
47
Cohort Active 32% Stillbirth / Neonatal
death / Perinatal death
Brazil 1981-1982 11,133
Dodds
48
(c) Case-control Both 19% /
21%
Stillbirth Canada 1991-2001 494
Goy 2008
49
(c) Case-control Active 15% Stillbirth Canada 1999-2001 510
Meyer 1976
50
Cohort Active 44% Perinatal death Canada 1960-1961 48,378
Fabia 1973
51
Cohort Active 43% Stillbirth / Neonatal
death / Perinatal death
Canada 1970-1971 6,879
Fabia 1980
52
Cohort Active 40% Stillbirth / Neonatal
death / Perinatal death
Canada 1972 377
Miller 2010
53
Cohort Active 11% Stillbirth Canada 2004-2006 303,977
Wood 2008
54
Cohort Active 17% Stillbirth Canada 1991-2004 157,929
Medina 1990
55
Cross-sectional Active 55% Stillbirth Chile 1943-1988 100
69
Cuk 2000
56
Cohort Active 26% Neonatal death Croatia 1987-1997 37,417
Frkovic 1990
57
Cohort Active 29% Stillbirth Croatia 1987-1988 716
Hruba 1997
58
Cross-sectional Both 42% Stillbirth Czech
Republic
1911-1993 3,180
Olsen 1999
59
(d) Cohort Active 32% Stillbirth / Perinatal
death
Denmark 1991-1992 113,814
No author 1995
60
(d) Cohort Active 33% Stillbirth Denmark 1992 68,065
Wisborg 2001
61
(e) Cohort Active 30% Stillbirth Denmark 1989-1996 25,102
Wisborg 2008
62
(e) Cohort Active 26% Stillbirth Denmark 1989-1998 19,282
Bech 2005
63
Cohort Active 17% Stillbirth Denmark 1996-2002 88,402
Helweg-Larsen 1996
64
Cohort Active NA Perinatal death Denmark 1991-1993 NA
Lauenborg 2003
65
Case-control Active 33% Stillbirth Denmark 1990-2000 1,361
Strandberg-Larsen
2008
66

Cohort Active 16% Stillbirth Denmark Not
available
87,032
Hafez 2001
28
Cross-sectional Passive 52% Stillbirth Egypt 1963-2000 1,934
Karro 1998
67
Cohort Active 5% Perinatal death Estonia 1992-1994 46,459
Rantakallio 1969
68
(f) Cohort Active 22% Perinatal death Finland 1965-1967 11,931
Xu 1998
29
(f) Cohort Active 22% Perinatal death Finland 1966-1986 20,873
Forssas 1999
69
Cohort Active 17% Perinatal death Finland 1991-1993 192,635
Hiltunen 2010
70
Case-control Active 11% Stillbirth Finland 1997-2009 820
Raatikainen 2007
71
Cohort Active 13% Stillbirth / Neonatal
death / Perinatal death
Finland 1989-2001 25,591
Kaminski 1978
72
(g) Cohort Active 12% Stillbirth France 1963-1969 9,136
Rumeau-Rouquette
1972
73
(g)
Cohort Active 12% Stillbirth / Neonatal
death
France 1963-1967 7,032
Rumeau-Rouquette
1974
74
(g)
Cohort Active 16% Stillbirth / Neonatal
death / Perinatal death
France 1963-1969 6,930
Bernhard 1948
75
(h) Cohort Active 8% Stillbirth Germany 1945-1947 1,470
Bernhard 1964
76
(h) Cohort Active 19% Stillbirth Germany 1943-1963 4,096
Knorr 1979
77
Cohort Passive 50% Stillbirth / Perinatal
death
Germany 1964-1972 5,183
Behrens 1987
78
Cohort Active 28% Stillbirth / Neonatal
death / Perinatal death
Germany 1980-1985 6,261
Beyerlein 2010
79
Cohort Active 11% Stillbirth Germany 1987-2007 2,292,053
70
Hammoud 2005
80
Cohort Active 23% Stillbirth / Neonatal
death
Germany 1991-1997 157,857
Hubner 1988
81
Cohort Active 48% Perinatal death Germany 1976-1986 1,148
Koller 1983
82
Cohort Active 17% Stillbirth / Perinatal
death
Germany 1964-1971 7,538
Makay 1968
83
Cross-sectional Active 9% Perinatal death Hungary 1935-1966 2,341
Mishra 2005
84
Cross-sectional Both 5% /
42%
Stillbirth India 1964-1999 19,189
Puri 1981
85
Cohort Active 1% Perinatal death India 1967-1978 1,497
Subramoney 2010
86
Cross-sectional Passive 30% History of stillbirth India 1973-2002 924
Tielsch 2009
87
Cohort Passive 40% Stillbirth / Neonatal
death
India 1998-2000 13,294
Rush 1988
88
Cohort Active 46% Perinatal death Israel 1974-1976 8,225
De Scrilli 1986
89
Cohort Active 18% Perinatal death Italy 1973-1979 36,544
Greenwood 1994
90
Case-control Active 7% Perinatal death Jamaica 1986-1987 11,507
Conde-Agudelo 2000
91
Cohort Active 11% Stillbirth Latin
America
1985-1997 420,298
Gaizauskiene 2007
92
Cohort Both 5% /
39%
Perinatal death Lithuania 2002 29,619
Maleckiene 2001
93
Case-control Active 20% Stillbirth Lithuania 1996-1998 174
Panduro Baron 2006
94
Case-control Active 7% Stillbirth Mexico 2001-2005 900
Romero Gutierrez
2004
95

Case-control Active 2% Stillbirth Mexico 1992-2002 500
Van der Velde 1985
96
Cohort Active 48% Perinatal death Netherlands 1978-1979 597
Verkerk 1994
97
Cohort Active 35% Stillbirth Netherlands 1978-1979 2,806
Bailey 1970
98
Cohort Active 39% Perinatal death New Zealand 1969 1,174
McCowan 2007
99
Case-control Active 17% Stillbirth New Zealand 1993-2000 59,975
Froen 2001
100
(i) Case-control Active 25% Stillbirth Norway 1986-1995 658
Froen 2004
101
(i) Case-control Active 25% Stillbirth Norway 1986-1995 597
Dalaker 1984
102
Cohort Active 37% Perinatal death Norway 1978-1979 2,408
Helgadottir 2011
103
Case-control Active 19% Stillbirth Norway 1990-2003 1,592
Tviet 2010
104
Cohort Active 78% Perinatal death Norway 2004-2005 2,168
Palmgren 1971
105
Cohort Active 47% Stillbirth / Perinatal
death
Sweden 1964-1967 4,312
71
Petersson 2002
106
(j) Cohort Active 9% Stillbirth Sweden 1998-1999 35,186
Wikstrom 2010
107
(j) Cohort Active 10% Stillbirth Sweden 1999-2006 562,829
Hogberg 2007
108
(k) Cohort Active 18% Stillbirth Sweden 1983-2001 495,788
Johansson 2009
109
(k) Cohort Active 17% Neonatal death Sweden 1983-2002 557,318
Kallen 2001
110
(k) Cohort Active 25% Stillbirth / Neonatal
death
Sweden 1983-1966 1,413,811
Rydhstroem 1996
111

(k)
Cohort Active 28% Stillbirth / Neonatal
death
Sweden 1983-1991 866,649
Winbo 2001
112
(k) Cohort Active 24% Stillbirth / Perinatal
death
Sweden 1983-1995 1,412,754
Ahlborg 1991
113
Cohort Both 36% /
15%
Stillbirth Sweden 1980-1983 3,884
Hogberg 1990
114
Case-control Active 24% Perinatal death Sweden 1980-1984 570
Kullander 1971
115
Cohort Active 44% Stillbirth / Neonatal
death / Perinatal death
Sweden 1963-1964 6,363
Sandahl 1989
116
Case-control Active 29% Stillbirth Sweden 1980-1985 2,747
Uncu 2005
117
Cohort Both 10% /
46%
Stillbirth Turkey 2004 499
Rush 1983
118
Cohort Active 41% Perinatal death U.K. 1970 16,688
Butler 1969
119
(l) Cohort / case
control
Active 28% Stillbirth / Neonatal
death / Perinatal death
U.K. 1958 16,774
Butler 1972
120
(l) Case-control Active 32% Stillbirth / Neonatal
death / Perinatal death
U.K. 1958 21,788
Tuthill 1999
121
Cohort Active 27% Stillbirth / Neonatal
death / Perinatal death
U.K. 1993-1995 16,250
Cardozo 1982
122
Cohort Active 32% Stillbirth / Neonatal
death
England 1981 2,000
Donovan 1977
123
Cohort Active 65% Perinatal death England 1972 1,274
Gardosi 1988
124
Case-control Active 27% Stillbirth England 1988-1995 46,765
Lowe 1959
125
Cohort Active 37% Perinatal death England 1958 1,823
Geary 1997
126
Case-control Active 57% Stillbirth Ireland 1989-1991 214
Murphy 2000
127
Cohort Active 46% Stillbirth / Neonatal
death
Ireland 1969-1973 12,013
Black 2008
128
(m) Cohort Active 38% History of stillbirth Scotland 1947-2002 34,079
Hall 1992
129
(m) Cohort Active 28% Stillbirth / Neonatal Scotland 1980-1989 1,261
72
death / Perinatal death
Smith 2007
130
(n) Cohort Active 29% Stillbirth Scotland 1992-2001 84,769
Sutan 2010
131
(n) Cohort Active 26% Stillbirth Scotland 1994-2003 543,263
Andrews 1972
132
(o) Cohort Active 43% Perinatal death Wales 1965-1968 17,746
Rush 1990
133
(o) Cohort Active 16% Perinatal death Wales 1965-1977 51,200
Salihu 2003
134
(p) Cohort Active 13% Neonatal death U.S. 1997 3,004,616
Salihu 2004
135
(p) Cohort Active 13% Stillbirth / Neonatal
death
U.S. 1995-1997 7,792,990
Gallicchio 2009
136
Cohort Active 19% Stillbirth U.S. 1965-2008 747
Hoyert 1996
137
Case-control Active 20% Stillbirth U.S. 1989-1990 3,651,470
Little 1993
138
Case-control Active 24% Stillbirth U.S. 1980 3,669
Reddy 2010
139
Cohort Active 6% Stillbirth U.S. 2002-2008 174,809
Niswander 1972
140
Cohort Active 47% Perinatal death U.S. 1959-1965 39,215
Faden 1997
141
Case-control Active 23% Stillbirth U.S. 1988 11,015
Copper 1994
142
Cohort Active 24% Stillbirth U.S. 1982-1986 34,350
English 1992
143
(q) Cohort Active 38% Perinatal death California 1959-1966 13,208
Yerushalmy 1964
144

(q)
Cohort Active 38% Neonatal death California 1959-1963 6,800
Yerushalmy 1971
4
(q) Cohort Active 37% Neonatal death California 1960-1967 13,083
Downing 1966
2
Cohort Active 46% Stillbirth / Neonatal
death / Perinatal death
California 1952-1958 5,659
Kharazzi 2004
145
Cohort Passive 80% Stillbirth California 1992 2,796
Pastore 1997
146
Case-control Active 22% Perinatal death California 1984 689
Raymond 1993
147
Cohort Active 35% Perinatal death California 1974-1977 307
Lynch 2007
148
Cohort Active 12% Perinatal death Colorado 1994-2001 1,100
Lubs 1973
149
Cohort Active 45% Neonatal death / history
of stillbirth
Connecticut 1942-1971 4,242
Kistin 1996
150
Cohort Active 20% Perinatal death Illinois 1988 16,252
Haddow 1988
151
Cohort Active 26% Stillbirth Maine 1979-1983 8,063
Comstock 1967
3
(r) Cohort Active 37% Stillbirth / Neonatal
death
Maryland 1953-1963 376
Comstock 1971
152
(r) Cohort Active 38% Neonatal death Maryland 1953-1963 12,505
Frazier 1961
153
Cohort Active 37% Stillbirth / Neonatal
death
Maryland 1959 2,736
73
Hardy 1972
154
Cohort Active 44% Stillbirth / Neonatal
death / Perinatal death
Maryland 1962-1963 1,329
Aliyu 2008
155
(s) Cohort Active 26% Stillbirth Missouri 1978-1997 1,436,628
Malloy 1988
156
(s) Cohort Active NA Neonatal death Missouri 1979-1983 305,730
Salihu 2008
157
(s) Cohort Active 25% Stillbirth Missouri 1978-1997 12,492
Schramm 1980
158
(s) Cohort Active 6% Stillbirth / Neonatal
death / Perinatal death
Missouri 1978 69,556
Schramm 1997
27
(s) Cohort Active 4% Stillbirth / Neonatal
death
Missouri 1978-1990 176,843
Wilcox 1993
159
(s) Cohort Active 16% Perinatal death Missouri 1980-1984 257,698
Ogunyemi 1998
160
Case-control Active 10% Stillbirth New Jersey 1985-1995 308
Savel 1962
161
Cohort Active 47% Stillbirth / Neonatal
death / Perinatal death
New Jersey 1961-1961 1,415
Scholl 1986
162
Cohort Active 34% Stillbirth / Perinatal
death
New Jersey 1982-1984 775
Rush 1972
163
Cohort Active 47% Stillbirth / Neonatal
death / Perinatal death
Massachusetts 1961-1962 3,276
Wang 1997
164
Cross-sectional Active 25% History of stillbirth Massachusetts 1957-1992 647
Underwood 1965
1
Cross-sectional Active 34% Stillbirth South
Carolina
1931-1961 4,441
Underwood 1967
165
Cohort Active 49% Stillbirth / Neonatal
death / Perinatal death
South
Carolina
1963-1965 48,494
Kizer 1967
166
Cohort Active 39% Perinatal death Venezuela 1966-1967 2,095

a
Footnote markers, (a) through (s) denote studies from the same “set” of definite or probable duplicated pregnancy data. Only one study from each set was used
in any given analysis.

74
Table 5. Summary relative risks of perinatal death, stillbirth, and neonatal death in smokers compared to nonsmokers
Perinatal death Stillbirth Neonatal death

Summary
RRR
95% CI N
Summary
RRR
95% CI N
Summary
RRR
95% CI N
Any active smoking
a
1.35 1.28, 1.44 47 1.45 1.37, 1.54 57 1.20 1.11, 1.27 28
1-10 cigarettes/day
a
1.20 1.03, 1.41 13 1.22 1.09, 1.38 15 1.13 1.05, 1.23 8
11-20 cigarettes/day
a
1.41 1.31, 1.51 6 1.29 1.21, 1.37 7 1.31 0.82, 2.09 2
>20 cigarettes/day
a
1.43 1.33, 1.54 11 1.16 0.89, 1.50 9 1.25 1.11, 1.40 4
Ex-smokers and those who quit
during pregnancy
a

1.05 0.91, 1.21 7 1.12 0.91, 1.37 6 0.99 0.81, 1.22 4
Evidence for publication bias
b
Medium Strong None/weak

a
Risk of perinatal death, stillbirth, or neonatal death per pregnancy
b
Using studies included in the comparison of any active smoking, excluding ex-smokers and those who quit during pregnancy, with
the risk of perinatal death, stillbirth, or neonatal death
75

Figure 13. Forest plot of the association between maternal smoking and perinatal death, showing the relative risk
and 95% confidence interval. RR/OR = Risk ratio/Odds ratio, LCL = Lower boundary of the 95% confidence
interval for the RR/OR, UCL = Upper boundary of the 95% confidence interval for the RR/OR, Weight = Random-
effects weight of the study.

76

Figure 14. Forest plot of the association between maternal smoking and stillbirth, showing the relative risk and 95%
confidence interval. RR/OR = Risk ratio/Odds ratio, LCL = Lower boundary of the 95% confidence interval for the
RR/OR, UCL = Upper boundary of the 95% confidence interval for the RR/OR, Weight = Random-effects weight of
the study.
77

Figure 15. Forest plot of the association between maternal smoking and neonatal death, showing the relative risk and
95% confidence interval. RR/OR = Risk ratio/Odds ratio, LCL = Lower boundary of the 95% confidence interval
for the RR/OR, UCL = Upper boundary of the 95% confidence interval for the RR/OR, Weight = Random-effects
weight of the study.

78

Assessment of heterogeneity. Among studies examining any active smoking, heterogeneity was
highest among those studying stillbirth (I
2
=68%, p<0.0001), moderate among those studying
perinatal death (I
2
=60%, p<0.0001), and lower for those studying neonatal death (I
2
=35%,
p<0.05; see Tables 6-8 for detailed results). Studies conducted in the U.S. had lower relative
risks for perinatal death than did studies conducted outside the U.S. (1.18 vs. 1.39), but the
difference was not statistically significant (p=0.08). No other covariates significantly affected the
summary relative risk of stillbirth, neonatal death, or perinatal death with any active smoking (p
values>0.05). Indicators of study quality were not associated with the summary relative risks (p
values>0.05).

Dose-response analysis. The relative risk of perinatal death in smokers compared to nonsmokers
increased with the number of cigarettes smoked per day (Figure 16). The relationship between
the relative risk of stillbirth and number of cigarettes smoked per day was similar up to about 13
cigarettes per day (Figure 17). The relationships were non-linear based on the comparison of the
log-likelihood for a model with cubic spline variables to that for a model with only a linear term
(p<0.0001).
167
The relationship between the relative risk of neonatal death with smoking and the
number of cigarettes smoked per day did not depart significantly from linearity (p=0.31). The
relative risk of neonatal death increased by a factor of 1.01 for each additional cigarette smoked
(95% CI: 1.01, 1.02, Figure 18). Using only the most common categories of 1-10, 11-20, and
>20 cigarettes per day, the summary relative risk of perinatal death increased as number of
cigarettes increased, but the summary RRRs for stillbirth and neonatal death did not continue to
increase above 11-20 cigarettes per day (Table 5).
79

Figure 16. Dose-response curve of the association between maternal smoking and perinatal death, including 23
studies with 60 data points.
80

Figure 17. Dose-response curve of the association between maternal smoking and stillbirth, including 23 studies
with 62 data points.
81

Figure 18. Dose-response curve of the association between maternal smoking and neonatal death including 10
studies with 38 data points.

Assessment of publication bias. Publication bias was demonstrated by several formal statistical
tests in analyses of any active smoking and perinatal death or stillbirth (p values <0.05 for Egger
regression, the Begg rank correlation, and the trim and fill tests). The same tests did not
demonstrate bias among studies used in analyses of any active smoking for neonatal death (p
82

values>0.1). Because the trim-and-fill tests for perinatal death and stillbirth found bias on the
right tails, a sensitivity analysis was conducted by removing outliers on the right tails after visual
inspection of the funnel plots. Studies with log relative risks greater than 1 were removed. With
four outliers removed, the p values increased to nonsignificance (>0.05) for the publication bias
tests on studies examining perinatal death, and the summary relative risk did not change
(summary RRR=1.33, 95% CI: 1.28, 1.39). For studies examining stillbirth, six outliers were
removed by the same criteria, and the funnel plot appeared symmetrical, but the Egger regression
and Begg rank correlation remained statistically significant (p values <0.05).

Figure 19. Funnel plot of studies included in the comparison between any maternal smoking and perinatal death.
Sample size versus log RR/OR.
83

Figure 20. Funnel plot of studies included in the comparison between any maternal smoking and stillbirth. Sample
size versus log RR/OR.

Figure 21. Funnel plot of studies included in the comparison between any maternal smoking and neonatal death.
Sample size versus log RR/OR.
84

Maternal secondhand smoke exposure
With only two studies, SHS was associated with a significantly increased risk of perinatal
death (summary RRR=1.58, 95% CI: 1.26, 1.97). Women who were exposed to SHS had a
similarly increased risk of stillbirth (summary RRR=1.61, 95% CI: 1.15, 1.24, 7 studies). The
only study to analyze SHS exposure in relation to risk of neonatal death found that, compared to
infants with nonsmoking parents, the adjusted relative risk of neonatal death was 1.16 when the
father smoked 1-10 cigarettes per day (95% CI: 0.93, 1.45), and 1.53 when the father smoked
>10 cigarettes per day (95% CI: 1.15, 2.04). Publication bias was found among the studies that
analyzed stillbirth in relation to SHS exposure (p values < 0.05 for Egger regression and Begg
rank correlation). Due to small numbers, publication bias was not examined among the studies
that analyzed perinatal death or neonatal death in relation to SHS exposure.

3.4. Discussion
The results of these meta-analyses are consistent with prior literature on the association
between maternal smoking and perinatal death.
7
New findings include the results of the meta-
regression showing the nonlinear relationship between the number of cigarettes smoked and the
relative risks of stillbirth, neonatal death, and perinatal death. In addition, the stronger impact of
smoking on stillbirth than on neonatal death has not previously been demonstrated.
Our review has several limitations reflecting the reliance on secondary data gathered
from publications. First, we were unable to fully investigate the effect of timing of smoke
exposure across pregnancy on perinatal death risk. In the small group of studies examined, ex-
smokers and women who quit in early pregnancy were not at increased risk, but when the
85

women quit in relation to pregnancy varied widely and was not always specified. Therefore, we
still do not know the optimal time for women to quit smoking and lower their risk of perinatal
death. Second, most articles only included a category of number of cigarettes smoked instead of
the actual number. The midpoints of these categories may not appropriately represent the number
of cigarettes smoked per day, and the imputation for open-ended categories may also have
created misclassified representations of the actual number of cigarettes smoked per day. This
source of bias may have contributed to the unexpected finding that the relative risk of stillbirth
increased with amount smoked only up to 14 cigarettes per day then decreased to the null.
Biases in study design are unlikely to fully account for the results. Grouping studies
based on design and analysis methods to study variation by risk of bias showed that of studies
with high and low risk for confounding and misclassification of smoking gave similar summary
relative risks. Studies with appropriate statistical considerations such as analysis of only one
pregnancy per woman and exclusion of twins gave similar results to studies with potential non-
independence of outcomes. Publication bias among studies examining perinatal death and
stillbirth are possible explanations for the findings on those outcomes. However, excluding small
studies with large relative risks gave summary RRRs that were very similar to those found using
all studies.
This study has several strengths. We compiled nearly 200 reports on the association
between smoking and perinatal death. Many covariates were analyzed to examine heterogeneity
and potential for biased results. Studies that had relative risks of perinatal death given for varied
categories of cigarettes smoked per day were combined, allowing a quantitative and visual
analysis of the dose-response relationships. Publication bias was analyzed for the first time on
86

this complete set of studies, allowing for stronger inference as to the causal effect of smoking on
perinatal death.
Overall, the evidence in our systematic review supports the established causal
explanation for the association between smoking and perinatal death. There was general
consistency of results despite significant overall heterogeneity of the relative risks that was not
explained by the examined covariates. The relative risks in the 19 subgroups for heterogeneity
and risk of bias analyses were consistent, never varying far from the main results of 35%, 45%,
and 20% increases among smokers in the risks for perinatal death, stillbirth, and neonatal death,
respectively. The studies were carried out in 28 countries over a period of observation that
spanned more than a half century. During this time, both the incidence of perinatal death and the
prevalence of smoking declined significantly based on both the included studies (data not shown)
and reports from the literature.
168
The rate of perinatal death per 1,000 births ranged from 0.4 to
44 deaths, and the prevalence of smoking during pregnancy varied between 0.7% and 52% of
women. Thus, the relative consistency of the results is remarkable given the variation in
populations, study designs, and the frequencies of perinatal death and smoking.
Smoking had a stronger impact on the risk of stillbirth than on the risk of neonatal death.
This was supported by the finding that the summary relative risk for perinatal death (1.35) was in
between the relative risks for stillbirth (1.45) and neonatal death (1.20). Postneonatal infant death
is largely caused by sudden infant death syndrome (SIDS), which has a stronger correlation with
maternal smoking during pregnancy than perinatal death (OR=2.25, 95% CI: 2.03, 2.50).
169

Thus, possibly because fetuses susceptible to the effects of maternal smoking die before birth,
the neonatal period is one in which the infant is the least vulnerable to smoking-related death.
87

Our findings for perinatal death are consistent with the dose-dependence of the well-
known increased risk of low birthweight with smoking.
170
Low birthweight is a major
intermediate between smoking and perinatal death because lower birthweight is strongly
associated with mortality.
171
The most likely mechanism for the effect of smoking on low
birthweight is the high dose of carbon monoxide that accompanies cigarette smoking. Both
clinical and animal studies show that carbon monoxide exposure causes low birthweight at levels
commensurate with cigarette smoking.
170
Another pathway through which smoking causes
perinatal death is placental abruption, an uncommon but serious condition in which the placenta
detaches from the uterus before delivery of the fetus, causing maternal hemorrhage and fetal
asphyxia.
172
Placentation abnormalities are thought to be responsible for abruption, but the
mechanism by which smoking causes abruption is unknown because the effects of smoking on
the placenta have been inconsistent.
170

Precise estimates of the effect of smoking on perinatal death are important for clinical
practice and public health policy. Patients increasingly ask practitioners for detailed information
about the risks of adverse health outcomes. The summary relative risks provided in this meta-
analysis allow practitioners and patients to make informed decisions about the consequences of
continued smoking during pregnancy. In addition, public health policymakers need to know the
magnitude of the effect of smoking during pregnancy to appropriately prioritize programs for
smoking prevention and cessation.
This report shows that the relationship between smoking and perinatal death is
statistically significant and consistent. Stillbirth is more closely associated with smoking than is
neonatal death. Prior conclusions that smoking causes perinatal death are supported by the
totality of the literature.
88

Table 6. Heterogeneity and study quality analyses for any active smoking and risk of perinatal death
Number of
studies
OR
a
95% CI
Year of publication (per 10 years) 47 1.02
b
0.98, 1.06
Midpoint year of study pregnancies (per 10 years) 45 1.02
b
0.98, 1.06
Smoking prevalence in the study population (per percent)
(prevalence in controls for case-control studies)
46 0.80
b
0.52, 1.23
Perinatal death rate among nonsmokers in cohort studies (per log
unit of the rate in thousands)
38 0.99
b
0.88, 1.11
Per-capita cigarette consumption (per thousand, imputed) 36 0.96
b
0.89, 1.02
Study design

Case-control studies 4 1.40 1.33, 1.48
Cohort studies 43 1.36 1.27, 1.46
Exposure definition timing
Studies that specified that the smoking exposure they used was
during the pregnancy in which perinatal death risk was measured
38 1.35 1.26, 1.43
Studies with exposures without a specified time or specified as
smoking before pregnancy, excluding former smoking
9 1.47 1.15, 1.87
Country of study
Studies conducted in the U.S. 10 1.18 1.07, 1.29
Studies conducted in other countries 37 1.39 1.30, 1.49
Definition of perinatal death
Studies that defined perinatal death as 20-23 weeks and up 12 1.39 1.28, 1.52
Studies that defined perinatal death as 24+ weeks and up 10 1.29 1.17, 1.41
Studies that did not specify 26 1.43 1.25, 1.64
Biased self-report of smoking
Prospective or biochemical measurement of smoking 22 1.37 1.24, 1.51
Retrospective, non-biochemical measurement 25 1.36 1.27, 1.46
Control for confounding
Control by statistical adjustment or matching 12 1.33 1.22, 1.45
No control for confounders (crude estimates) 36 1.36 1.26, 1.48
Odds ratios and risk ratios
Odds ratios 16 1.35 1.25, 1.45
Risk, rate, and hazard ratios 39 1.35 1.26, 1.45
Independence of outcomes
Analysis of only one pregnancy per woman or statistical
adjustment for non-independence of outcomes and among only
singleton births
8 1.36 1.22, 1.52
Not specified or more than one pregnancy per woman analyzed, or
twins included in analysis
41 1.34 1.25, 1.43
Overall risk of bias
Lowest risk: prospective, best statistical model, one pregnancy per
woman analyzed
2 1.24 1.18, 1.30
Highest risk: retrospective, no control for confounders, not
specified or more than one pregnancy per woman analyzed
19 1.33 1.22, 1.45

a
OR is the summary relative risk of perinatal death for smokers versus nonsmokers in the subgroup except where
specified.
b
OR is for the change in the summary relative risk of perinatal death for smokers versus nonsmokers with
each increment of the continuous variable as specified.

89

Table 7. Heterogeneity and study quality analyses for any active smoking and risk of stillbirth
Number of
studies
OR
a
95% CI
Year of publication (per 10 years) 57 1.02
b
0.97, 1.06
Midpoint year of study pregnancies (per 10 years) 55 1.01
b
0.97, 1.05
Exposure prevalence in the study population (per percent)
(prevalence in controls for case-control studies)
54 0.82
b
0.49, 1.37
Stillbirth rate among nonsmokers in cohort studies (per log unit of
the rate in thousands)
31 0.93
b
0.82, 1.05
Per-capita cigarette consumption (per thousand, imputed) 48 0.95
b
0.88, 1.02
Study design

Case-control studies 20 1.43 1.30, 1.58
Cohort studies 38 1.47 1.35, 1.60
Exposure definition timing
Studies that specified that the smoking exposure they used was
during the pregnancy in which stillbirth risk was measured
44 1.44 1.35, 1.53
Studies with exposures without a specified time or specified as
smoking before pregnancy, excluding former smoking
18 1.19 .88, 1.61
Country of study
Studies conducted in the U.S. 15 1.37 1.26, 1.48
Studies conducted in other countries 42 1.50 1.37, 1.63
Definition of stillbirth
Studies that defined stillbirth as 20-23 weeks and up 24 1.47 1.37, 1.58
Studies that defined stillbirth as 24+ weeks and up 15 1.62 1.35, 1.94
Studies that did not specify 19 1.40 1.19, 1.64
Biased self-report of smoking
Prospective or biochemical measurement of smoking 23 1.54 1.34, 1.78
Retrospective, non-biochemical measurement 35 1.45 1.36, 1.55
Control for confounding
Control by statistical adjustment or matching 25 1.47 1.35, 1.61
No control for confounders (crude estimates) 35 1.44 1.34, 1.55
Odds ratios and risk ratios
Odds ratios 36 1.42 1.34, 1.51
Risk, rate, and hazard ratios 33 1.51 1.38, 1.65
Independence of outcomes
Analysis of only one pregnancy per woman or statistical
adjustment for non-independence of outcomes and among only
singleton births
9 1.56 1.36, 1.78
Not specified or more than one pregnancy per woman analyzed, or
twins included in analysis
50 1.43 1.33, 1.52
Overall risk of bias
Lowest risk: prospective, best statistical model, one pregnancy per
woman analyzed
8 1.51 1.22, 1.87
Highest risk: retrospective, no control for confounders, not
specified or more than one pregnancy per woman analyzed
22 1.28 1.10, 1.48
Risk of stillbirth in second of two pregnancies with measured
smoking information

Smoking in first pregnancy only 2 1.06 0.88, 1.28
Smoking in second (index) pregnancy only 2 1.08 0.70, 1.68
Smoking in both first pregnancy and second (index) pregnancy 2 1.27 1.13, 1.44
a
OR is the summary relative risk of stillbirth for smokers versus nonsmokers in the subgroup except where
specified.
b
OR is for the change in the summary relative risk of stillbirth for smokers versus nonsmokers with each
increment of the continuous variable as specified.
90

Table 8. Heterogeneity and study quality analyses for any active smoking and risk of neonatal death
Number of
studies
OR
a
95% CI
Year of publication (per 10 years) 28 0.99
b
0.94, 1.03
Midpoint year of study pregnancies (per 10 years) 27 0.98
b
0.94, 1.02
Exposure prevalence in the study population (per percent)
(prevalence in controls for case-control studies)
28 1.23
b
0.69, 2.18
Neonatal death rate among nonsmokers in cohort studies (per log
unit of the rate in thousands)
24 1.01
b
0.92, 1.10
Per-capita cigarette consumption (per thousand, imputed) 27 0.98
b
0.92, 1.05
Study design

Case-control studies 3 1.23 0.98, 1.54
Cohort studies 26 1.19 1.10, 1.28
Exposure definition timing
Studies that specified that the smoking exposure they used was
during the pregnancy after which neonatal death risk was
measured
23 1.23 1.16, 1.32
Studies with exposures without a specified time or specified as
smoking before pregnancy, excluding former smoking
5 1.02 0.71, 1.47
Country of study
Studies conducted in the U.S. 10 1.13 1.06, 1.20
Studies conducted in other countries 18 1.20 1.08, 1.33
Definition of neonatal death
Studies that defined neonatal death as within 6-8 days of birth or
used the term “early neonatal death”
14 1.15 0.99, 1.32
Studies that defined neonatal death as within 28-31 days of birth
or did not specify
18 1.21 1.13, 1.29
Biased self-report of smoking
Prospective or biochemical measurement of smoking 13 1.20 1.09, 1.32
Retrospective, non-biochemical measurement 15 1.20 1.08, 1.33
Control for confounding
Control by statistical adjustment or matching 4 1.12 1.05, 1.19
No control for confounders (crude estimates) 26 1.24 1.14, 1.34
Odds ratios and risk ratios
Odds ratios 9 1.23 1.13, 1.34
Risk, rate, and hazard ratios 26 1.20 1.11, 1.30
Independence of outcomes
Analysis of only one pregnancy per woman or statistical
adjustment for non-independence of outcomes and among only
singleton births
8 1.22 1.13, 1.32
Not specified or more than one pregnancy per woman analyzed, or
twins included in analysis
24 1.17 1.09, 1.27
Overall risk of bias
Lowest risk: prospective, best statistical model, one pregnancy per
woman analyzed
1 1.20 1.01, 1.42
Highest risk: retrospective, no control for confounders, not
specified or more than one pregnancy per woman analyzed
14 1.21 0.07, 1.36

a
OR is the summary relative risk of neonatal death for smokers versus nonsmokers in the subgroup except where
specified.
b
OR is for the change in the summary relative risk of neonatal death for smokers versus nonsmokers with
each increment of the continuous variable as specified.

91

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109

Chapter 4. Smoking cessation counseling among prenatal care providers

4.1. Introduction
Smoking is one of the most common modifiable risk factors for poor pregnancy
outcomes like low birthweight, preterm birth, and stillbirth.
1
The average prevalence of self-
reported smoking during pregnancy in 2005 was 14.1%.
2
Among pregnant women in the 2003-
08 National Health and Nutrition Examination Survey (NHANES), 4.7% had serum cotinine
levels >10 ng/ml, indicating active smoking, and 36.7% had serum cotinine levels between 0.05
and 10 ng/mL, indicating light smoking or secondhand smoke exposure.
3
Thus, tobacco smoke
exposure during pregnancy is common and its rate of decline is lagging far behind expectations.
Evidence-based strategies for reducing tobacco smoke exposure in pregnancy are needed.
Smoking cessation is seen by experts as a key element in preventative health. Of 25
preventive health services ranked for health impact, smoking cessation advice and assistance was
one of only three interventions placed in the top tier.
4
The U.S. Public Health Service (PHS), the
U.S. Preventive Services Task Force (USPSTF) and the American College of Obstetrics and
Gynecology (ACOG) all recommend smoking cessation counseling for all tobacco users.
5,6

ACOG and the USPSTF specifically recommend counseling pregnant women about smoking
cessation. The steps recommended by the USPSTF for counseling about smoking cessation are:
1) Ask about tobacco use, 2) Advise to quit through clear personalized messages, 3) Assess
willingness to quit, 4) Assist to quit, and 5) Arrange follow-up and support.
6
These are termed
the “five A’s.” Most physicians identify tobacco use; however, fewer advise patients to quit, and
even fewer assist patients in quitting and follow up.
7

110

There is a major opportunity for public health agencies, clinicians, and health insurance
providers to improve maternal and child health through smoking cessation counseling.
Physicians who do not offer the complete five A’s of recommended tobacco counseling can be
targeted by strategies to improve compliance with PHS, USPSTF, and ACOG recommendations.
A needed step is to identify those providers whose counseling efforts could be improved
with targeted interventions by public health agencies and professional organizations. Moran et al.
used the National Ambulatory Medical Care Survey (NAMCS) to identify some preliminary
associations between physician characteristics and counseling behavior.
8
An important question
raised by their research was whether smoking prevalence in the population served influences
tobacco use identification and provision of counseling. Smoking prevalence could affect a
provider’s attitudes about smoking, as well as a patient’s openness to address her smoking status.
By identifying factors that affect provider counseling, public health agencies can target their
outreach efforts more effectively, helping to meet the public health goal of reducing tobacco
exposure in pregnant women, fetuses, and infants.
This study aimed to identify factors that affect provider counseling using data from two
national surveys of ambulatory care providers, one national population-based survey, and several
original qualitative interviews with prenatal care providers.

111

4.2. Materials and methods

Ambulatory care surveys
The United States National Center for Health Statistics (NCHS) conducts the NAMCS
and the National Hospital Ambulatory Medical Care Survey (NHAMCS).
9
These nationally-
representative surveys collect nearly identical information on samples of patient visits to
physician offices (NAMCS) and clinics within hospital outpatient departments (NHAMCS). The
NAMCS is a survey of non-federally employed office-based physicians who are primarily
engaged in direct patient care. The NHAMCS is based on a national sample of visits to
emergency and outpatient departments and to ambulatory surgery facilities in non-institutional
general and short-stay hospitals, exclusive of federal, military, and Veterans Administration
hospitals. Both NAMCS and NHAMCS use multi-stage sampling designs, first sampling from
geographically-defined primary sampling units (PSUs). The NAMCS design then samples
physician practices within the PSUs and patient visits at the practices. The NHAMCS design for
clinics includes probability samples of hospitals within the PSUs, clinics within the hospitals’
outpatient departments, and patient visits at the clinics. In both surveys, a systematic random
sample of visits is selected and the physician, office staff, or Census field representatives
complete the survey forms using patient records. Data are obtained on the physician or hospital,
patients’ symptoms, physicians’ diagnoses, and medications ordered or provided. The surveys
also provide statistics on the demographic characteristics of patients, diagnoses, and services
provided.
We used data from NAMCS and from the NHAMCS outpatient department file for the
years 2001-2009 and selected visits by women aged 15-44 for analysis. Between 1,191 and 1,477
112

physicians were included in NAMCS each year, with physician response rates between 58.9%
and 70.4%. Between 202 and 236 outpatient departments were included in NHAMCS each year,
with outpatient department response rates from 80.2% to 86.8%.
10
Except where specified, all
analyses include visits from both NAMCS and NHAMCS for 2001-2009.
Two sections of the NAMCS/NHAMCS patient record form refer to tobacco smoking.
The first question asks, “Does patient use tobacco?” and allows the answer choices, “Yes,” “No,”
or “Unknown.” The second question is a check box under the subheading of
“Counseling/Education/Therapy,” that instructs the respondent to “Mark (X) all ordered or
provided at this visit. Exclude medications.” Some of the choices are, “None,” “Asthma
education,” “Diet/Nutrition,” and “Psychotherapy.” The relevant choice for our analysis was
“Tobacco use/exposure.”
A dichotomous smoking status identification variable was coded from the question on the
patient record form, “Does patient use tobacco?” by collapsing the answers “Yes” and “No” into
an “identified” category and recoding “Unknown,” “Blank,” and “Missing” into a “not
identified” category. We used only visits by women aged 15-44, and conducted all analyses on
either this total population or all pregnant women within this group. Reasons for visit were
categorized by reason for visit and diagnosis codes into the following categories: routine,
uncomplicated prenatal visits, prenatal visits for complicated pregnancy, non-pregnant visits for
respiratory disease, non-pregnant visits for hypertension, non-pregnant visits for routine
gynecological exams, and all other reasons (Table 14).
11

The two dependent variables were identification of tobacco use and provision of tobacco
use/exposure counseling (Figure 22). Tobacco use status identification was examined among all
113

women and among pregnant women. Tobacco use/exposure counseling was studied among the
same two groups subdivided into tobacco users and tobacco nonusers (Figure 22).
Bivariate associations between the dependent and independent variables were examined
in the target population and subpopulations. All variables with statistically significant bivariate
associations were included in multiple logistic regression models. Independent variables were
selected a priori, and interaction terms were created post hoc based on plausibility of interaction
and single variable associations. Estimates based on fewer than 30 records or with a relative
standard error of >30% are considered unreliable; and thus, variables with too few visits per
category were recoded by collapsing several categories to allow appropriate estimation.
12
All
unreliable estimates presented in the results are identified, and none were used as referent
categories for multivariate models. To protect the confidentiality of respondents, tabulations
involving cells with fewer than six visits are not presented.
The Behavioral Risk Factor Surveillance Survey (BRFSS)
13
is conducted each year in all
states and territories to estimate the prevalence of healthy and unhealthy behaviors. The BRFSS
was used to compute two independent variables: state- and year-specific smoking prevalence
among women aged 18-44 and the state-specific change in smoking prevalence from 2001-
2009.
14
These were based on the state in which each physician/outpatient department was
located. The prevalence of smoking among all women of reproductive age was used as a proxy
for the prevalence of smoking among pregnant women because the numbers of pregnant women
in each state and year were too small for stable estimates. A correlation of 0.49 was found
between the rate of smoking in pregnant women and the rate of smoking in all women of
reproductive age (p<0.001). Tests of statistical significance were two-tailed and used a
114

significance level of 0.05. To account for the multistage sampling, analyses were conducted
using SAS-callable SUDAAN versions 10.0 and 11.0 with SAS versions 9.2 and 9.3.

Figure 22. Overview of sampled visits and subpopulations for models

Prenatal care provider interviews
Prenatal care providers were interviewed to better understand their opinions and practices
regarding pregnant patients who smoke. Interviews were sought with a convenience sample of
prenatal care providers of a variety of educational levels and practicing in different settings. The
115

interviews were conducted by telephone or in person by BP. Providers were asked about their
patient populations, procedures for addressing smoking and secondhand smoke in pregnant
patients, and knowledge of the effects of smoking during pregnancy. We addressed methods for
identifying tobacco use, the frequency of encountering pregnant tobacco users, and the rate at
which these women quit or cut down during pregnancy. Providers were asked about their typical
course of action when faced with a pregnant smoker, and reasons for not following guidelines
were assessed. The Health Sciences Institutional Review Board of the University of Southern
California approved the study.

4.3. Results

Ambulatory Care Surveys
There were 130,363 visits by women of reproductive age sampled from 2001-2009,
representing 1,865,742,345 visits in the population. Of these, 15% were visits by pregnant
women. The prevalence of smoking in women of reproductive age decreased from 25% to 18%
between 2001 and 2009 while the prevalence of smoking in pregnant women remained steady at
an average of 11% (Figure 23). The rate of smoking in all visits by women of reproductive age
was 12% and in visits by pregnant women 8% (Figure 24). Tobacco use was identified in 67% of
all visits and 73% of visits by pregnant women (Figure 25).

116

Figure 23. National smoking prevalence among all women of reproductive age (squares) and pregnant women of
reproductive age (diamonds) from BRFSS. Dashed lines are 95% confidence intervals.

0%
10%
20%
30%
2001 2002 2003 2004 2005 2006 2007 2008 2009
Pregnant women All women aged 18-44 95% CI
117

Figure 24. Percent of visits by tobacco users among all women of reproductive age and pregnant women of
reproductive age by year

0%
2%
4%
6%
8%
10%
12%
14%
2001 2002 2003 2004 2005 2006 2007 2008 2009
Percent of tobacco users in visits by women aged 15-44
Percent of tobacco users in visits by pregnant women
118

Figure 25. Percentage of visits with tobacco use status identified (black lines) and percentage of tobacco users’ visits
with tobacco use/exposure counseling (gray lines) among all women of reproductive age (squares) and pregnant
women of reproductive age (diamonds).

Identification of tobacco use. Survey (NAMCS vs. NHAMCS), year, region, metropolitan status,
smoking prevalence, physician specialty and age, medical school affiliation, pregnancy status,
reason for visit, and patient race were associated with identification of tobacco use (Table 9).
Pregnant women were 43% more likely to have tobacco use status identified than were non-
pregnant women (odds ratio (OR)=1.43, 95% CI: 1.25, 1.65). Office-based physicians (NAMCS)
were 1.56 times as likely to identify tobacco use status in all women as were providers working
at outpatient departments (NHAMCS; OR=1.56, 95% CI: 1.37, 1.78). In visits by all women,
clinics affiliated with medical schools identified tobacco use status in only 54% of visits,
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
2001 2002 2003 2004 2005 2006 2007 2008 2009
Tobacco use identified Tobacco use/exposure counseling provided
All women aged 15-44 Pregnant women
119

compared to 66% for non-affiliated clinics [OR=0.61 (95% CI: 0.45, 0.82)]. In visits by all
women and visits by pregnant women, higher smoking prevalence in the state was associated
with a higher probability of identification of tobacco use (p values for trend <0.05). From 2001
to 2009, the rate of tobacco use identification declined in visits by all women and pregnant
women (p values for trend < 0.005). Patient age had no significant impact on identification of
tobacco use in either all women or pregnant women (p values >0.05). Independent predictors of
identification of tobacco use were survey, year, metropolitan area status, physician specialty,
physician age, pregnancy status, patient race, and new patient status (Table 10). Associations in
pregnant women generally reflected those seen in all women of reproductive age (Table 9).
However, among pregnant women and not among all women, new patients were less likely to
have tobacco use identified than were established patients (OR=0.76, 95% CI: 0.60, 0.98).
Identification of tobacco use in pregnant women was independently associated with survey,
physician age, patient race, and year of survey (Table 10).

120

Table 9. Factors associated with identification of tobacco use at visits by women of reproductive
age and pregnant women
Visits by all women Visits by pregnant women

Sampled
visits
Tobacco use identified
Sampled
visits
Tobacco use identified
% OR 95% CI % OR 95% CI
Total 130,363 67%

24,374 73%

Survey

NAMCS 47,356 68% 1.56 1.37, 1.78 5,214 76% 2.24 1.72, 2.91
NHAMCS-OPD 83,007 57% 1.00 ref 19,160 58% 1.00 ref
Year

2001 13,919 66% 1.00 ref 2,747 75% 1.00 ref

2002 15,953 70% 1.21 0.97, 1.51 3,128 81% 1.41 0.83, 2.41

2003 14,314 70% 1.21 0.93, 1.58 2,707 79% 1.25 0.66, 2.37

2004 13,766 68% 1.07 0.85, 1.36 2,665 75% 0.99 0.50, 1.97

2005 12,330 69% 1.11 0.90, 1.37 1,996 73% 0.90 0.51, 1.58

2006 15,297 65% 0.96 0.77, 1.20 2,637 71% 0.82 0.49, 1.38

2007 15,707 59% 0.75 0.60, 0.92 2,856 62% 0.53 0.33, 0.86

2008 14,383 65% 0.95 0.75, 1.20 2,788 71% 0.82 0.44, 1.53
2009 14,694 67% 1.02 0.82, 1.27 2,850 69% 0.74 0.44, 1.26
Region of the U.S.

Northeast 37,161 65% 1.00 ref 7,119 76% 1.00 ref

Midwest 33,519 72% 1.35 1.12, 1.61 6,939 74% 0.92 0.58, 1.43

South 35,103 67% 1.10 0.89, 1.35 5,416 73% 0.84 0.56, 1.25
West 24,580 62% 0.86 0.71, 1.06 4,900 70% 0.70 0.45, 1.10
Classification of patient’s ZIP code
a

Large metro 33,556 63% 1.00 ref 6,841 69% 1.00 ref

Medium/small metro 17,553 67% 1.19 1.01, 1.40 3,024 72% 1.18 0.78, 1.78

Non-metro 6,958 69% 1.30 1.06, 1.59 940 71% 1.10 0.72, 1.69

Missing
b
2,104 47% 0.52 0.36, 0.77 326 43%
h
0.34 0.12, 0.98
Prevalence of smoking among women aged 18-44 in the state where the physician practice / hospital is located and year of visit
c

<15% 12,641 61% 0.80 0.63, 1.01 2,888 68% 0.81 0.47, 1.40

15% - <20% 31,735 65% 0.95 0.81, 1.12 5,891 71% 0.91 0.60, 1.37

20% - <25% 46,824 66% 1.00 ref 8,082 73% 1.00 ref

25% - <30% 26,631 71% 1.24 1.04, 1.48 4,775 79% 1.43 0.88, 2.33
>=30% 12,320 72% 1.32 1.02, 1.71 2,689 76% 1.20 0.68, 2.12
Change in smoking prevalence from 2001 to 2009 in the state where the physician / hospital is located
c

>=25% decrease 29,000 64% 0.85 0.72, 1.01 6,555 71% 0.79 0.53, 1.18

15-25% decrease 77,860 68% 1.00 ref 14,041 75% 1.00 ref
<15% decrease 23,291 67% 0.99 0.83, 1.19 3,729 71% 0.80 0.58, 1.09
Medical school affiliation
d

Not/unknown 22,766 66% 1.00 ref 4,393 68% 1.00 ref
Affiliated 60,241 54% 0.61 0.45, 0.82 14,767 56% 0.59 0.32, 1.08
Physician specialty
e

Obstetrics and gynecology 11,609 73% 1.00 ref 4,465 76% 1.00 ref

Family/general/ internal
medicine
14,112 68% 0.81 0.68, 0.95 652 71% 0.77 0.53, 1.14

Pediatrics 1,311 69% 0.84 0.65, 1.08 <=5

Other 20,324 62% 0.62 0.52, 0.73 82 70%
h
0.74 0.40, 1.40
Physician medical school
e

U.S. school 34,451 69% 1.00 ref 4,126 77% 1.00 ref

Foreign school 8,583 64% 0.81 0.69, 0.94 703 66% 0.59 0.35, 0.99
Missing 4,322 70% 1.09 0.88, 1.37 385 81% 1.28 0.71, 2.30
121

Table 9 (continued). Factors associated with identification of tobacco use at visits by women of
reproductive age and pregnant women
Visits by all women Visits by pregnant women

Sampled
visits
Tobacco use identified
Sampled
visits
Tobacco use identified
% OR 95% CI % OR 95% CI
Physician age
e

<40 9,000 72% 1.11 0.91, 1.35 1,252 76% 0.89 0.56, 1.42

40-54 24,089 70% 1.00 ref 2,679 78% 1.00 ref

55+ 13,961 62% 0.70 0.61, 0.81 1,246 70% 0.64 0.42, 0.98
Missing 306 64% 0.79 0.35, 1.79 37 46%
h
0.23 0.09, 0.59
Physician sex
e,f

Female 14,626 72% 1.30 1.14, 1.49 2,386 78% 1.20 0.85, 1.71
Male 32,707 66% 1.00 ref 3,342 74% 1.00 ref
Physician race
e

Non-Hispanic White 20,193 69% 1.00 ref 2,209 78% 1.00 ref

Non-White 6,032 65% 0.88 0.73, 1.05 657 70% 0.66 0.42, 1.03
Missing 21,131 67% 0.91 0.79, 1.05 2,348 74% 0.82 0.55, 1.21
Pregnancy status

Nonpregnant 105,989 66% 1.00 ref ---- ---- ---- ----
Pregnant 24,374 73% 1.43 1.25, 1.65 ---- ---- ---- ----
Reason for visit

Routine prenatal care 16,594 74% 0.95 0.77, 1.17 16,594 74% 1.00 ref

Complicated pregnancy 7,780 71% 0.85 0.67, 1.09 7,780 72% 0.90 0.73, 1.11

Routine gynecological exam 5,374 71% 1.00 ref ---- ---- ---- ----

Hypertension 2,246 68% 0.71 0.55, 0.91 ---- ---- ---- ----

Respiratory disease 10,610 70% 0.79 0.64, 0.97 ---- ---- ---- ----
Other or missing
g
87,758 64% 0.60 0.50, 0.72 ---- ---- ---- ----
Patient age

15-19 18,302 65% 0.92 0.83, 1.01 3,506 69% 0.84 0.69, 1.02

20-24 22,341 67% 1.00 ref 7,356 72% 1.00 ref

25-34 44,873 67% 1.01 0.93, 1.09 10,931 74% 1.08 0.90, 1.30
35-44 44,847 66% 0.96 0.88, 1.04 2,581 75% 1.13 0.88, 1.47
Patient race

Non-Hispanic White 94,875 68% 1.00 ref 16,116 75% 1.00 ref
Non-White 35,488 62% 0.79 0.73, 0.86 8,258 67% 0.67 0.54, 0.84
Patient type

Established patient 107,069 67% 1.00 ref 21,691 74% 1.00 ref

New patient 22,780 68% 1.05 0.98, 1.13 2,600 68% 0.76 0.60, 0.98
Missing 514 37% 0.30 0.15, 0.58 83 66%
h
0.71 0.19, 2.60

a
Years 2005-2009 only
b
Missing or unclassifiable ZIP code
c
Numbers do not sum to total because one state was missing smoking prevalence data for one year
d
NHAMCS only
e
NAMCS only
f
Numbers do not sum to total because one physician was missing data on sex; no estimates presented to protect confidentiality
g
Missing category was too small for stable estimates and was combined with visits for any other reason
h
Unstable estimate with relative standard error >30% or <30 visits

122

Table 10. Multivariate model of identification of tobacco use
Visits by all women Visits by pregnant women
aOR 95% CI aOR 95% CI
Survey

NAMCS 2.04 1.69, 2.46 2.46 1.81, 3.32
NHAMCS-OPD 1.00 ref 1.00 ref
Year

2001 1.00 ref 1.00 ref

2002 1.20 0.96, 1.50 1.54 0.88, 2.69

2003 1.22 0.94, 1.59 1.40 0.74, 2.65

2004 1.07 0.84, 1.35 1.09 0.55, 2.16

2005 1.12 0.90, 1.39 1.02 0.57, 1.82

2006 1.00 0.81, 1.24 0.94 0.55, 1.62

2007 0.77 0.64, 0.93 0.60 0.37, 0.96

2008 1.00 1.00, 1.00 0.97 0.51, 1.83
2009 1.07 0.85, 1.34 0.82 0.46, 1.47
Classification of patient’s ZIP code
a

Large metropolitan 1.00 ref --- ---

Medium/small metro 1.20 1.02, 1.42 --- ---

Non-metropolitan 1.32 1.07, 1.63 --- ---
Missing
b
0.52 0.35, 0.78
Physician specialty
e

Obstetrics and gynecology 1.00 ref --- ---

Family/general/ internal
medicine
0.84 0.71, 1.00 --- ---

Pediatrics 0.93 0.71, 1.21 --- ---
Other 0.66 0.56, 0.79 --- ---
Physician age
e

<40 1.09 0.89, 1.32 0.87 0.54, 1.41

40-54 1.00 ref 1.00 ref

55+ 0.73 0.63, 0.83 0.64 0.42, 0.98
Missing 0.81 0.31, 2.12 0.26 0.10, 0.67
Pregnancy status

Nonpregnant 1.00 ref --- ---
Pregnant 1.24 1.09, 1.41 --- ---
Patient race

Non-Hispanic White 1.00 ref 1.00 ref
Non-White 0.83 0.77, 0.90 0.78 0.63, 0.95
Patient type

Established patient 1.00 ref --- ---

New patient 1.15 1.08, 1.23 --- ---
Missing 0.31 0.15, 0.62 --- ---

a
Years 2005-2009 only
b
Missing or unclassifiable ZIP code
e
NAMCS only

123

Provision of counseling to tobacco users. Tobacco use/exposure counseling was provided or
ordered in only 19% of visits by tobacco users and 21% of visits by pregnant tobacco users
(Figure 25). The factors associated with tobacco use/exposure counseling among tobacco users
were region, year, medical school affiliation, physician specialty, physician sex, physician sex
and patient age (Table 11). There were no linear trends in counseling by year or patient age
(p>0.1). Visits in the South and West regions were 0.60 and 0.59 times as likely to have tobacco
use/exposure counseling, respectively, as were visits in the Northeast (p <0.05). In multivariate
analyses of all women of reproductive age, those aged 25-34 were 0.78 times as likely as those
aged 20-24 to receive tobacco use/exposure counseling (p <0.05, Table 13). Women in the South
were 0.58 times as likely to receive tobacco use/exposure counseling than women in the
Northeast, after adjusting for age, medical school affiliation, and physician specialty (95% CI:
0.43, 0.78). In pregnant women, as age increased, provision of tobacco use/exposure counseling
decreased from 26% in the younger age groups to 15% in the older age groups (p for
trend=0.0016, Table 11). The number of pregnant tobacco users in the sample was small, and for
many variables estimates did not reach the threshold for reliability, so a multivariate model was
not fit.

124

Table 11. Factors associated with provision of tobacco use/exposure counseling at visits by all
women of reproductive age and pregnant women who use tobacco
Visits by all women who use tobacco Visits by pregnant women who use tobacco

Sampled
visits
Counseling provided
Sampled
visits
Counseling provided
% OR 95% CI % OR 95% CI
Total 17,947 19%

2,656 21%

Survey

NAMCS 5,929 19% 0.98 0.79, 1.21 461 20% 0.71 0.48, 1.05
NHAMCS-OPD 12,018 19% 1.00 ref 2,195 26% 1.00 ref
Year

2001 1,914 17% 1.00 ref 354 6%
h
1.00 ref

2002 2,168 22% 1.36 0.91, 2.03 365 25% 5.42 1.83, 16.05

2003 2,089 23% 1.41 0.89, 2.23 330 43% 12.46 4.43, 35.05

2004 1,957 13% 0.69 0.44, 1.09 314 13%
h
2.47 0.81, 7.48

2005 1,823 24% 1.49 0.98, 2.25 267 25% 5.56 1.77, 17.42

2006 2,143 15% 0.85 0.56, 1.27 284 17% 3.42 1.16, 10.05

2007 2,138 20% 1.19 0.76, 1.87 255 17%
h
3.36 1.06, 10.65

2008 1,880 17% 0.96 0.64, 1.44 248 21% 4.41 1.37, 14.20
2009 1,835 18% 1.04 0.71, 1.53 239 11%
h
1.96 0.52, 7.42
Region of the U.S.

Northeast 5,068 24% 1.00 ref 805 22% 1.00 ref

Midwest 5,829 21% 0.84 0.65, 1.10 1,089 26% 1.06 0.53, 211

South 4,694 16% 0.60 0.47, 0.75 489 16% 0.72 0.35, 1.46
West 2,356 16% 0.59 0.44, 0.79 273 17% 0.58 0.26, 1.27
Classification of patient’s ZIP code
a

Large metro 3,554 16% 1.00 ref 504 15% 1.00 ref

Medium/small metro 2,908 19% 1.16 0.84, 1.60 369 23% 1.79 0.93, 3.45

Non-metro 1,319 18% 1.09 0.79, 1.50 125 14%
h
0.93 0.40, 2.16

Missing
b
215 19% 1.20 0.65, 2.22 NA
i

Prevalence of smoking among women aged 18-44 in the state where the physician practice / hospital is located and year of visit
c

<15% 920 14% 0.76 0.48, 1.19 119 6%
h
0.26 0.05, 1.41

15% - <20% 3,487 18% 0.98 0.76, 1.27 392 24% 1.36 0.69, 2.70

20% - <25% 6,334 18% 1.00 ref 812 19% 1.00 ref

25% - <30% 4,685 21% 1.20 0.91, 1.57 786 21% 1.17 0.50, 2.74
>=30% 2,491 20% 1.14 0.82, 1.58 541 25% 1.42 0.67, 2.99
Change in smoking prevalence from 2001 to 2009 in the state where the physician / hospital is located
c

>=25% decrease 3,027 19% 1.01 0.79, 1.30 410 18% 0.88 0.43, 1.79

15-25% decrease 11,301 19% 1.00 ref 1,732 20% 1.00 ref
<15% decrease 3,589 19% 1.04 0.80, 1.35 508 23% 1.16 0.64, 2.12
Medical school affiliation
d

Not/unknown 4,390 16% 1.00 ref 649 24% 1.00 ref
Affiliated 7,628 19% 1.51 1.05, 2.17 1,546 26% 1.13 0.69, 1.84
Physician specialty
e

Obstetrics and gynecology 1,249 23% 1.00 ref 388 20% 1.00 ref

Family/general/ internal
medicine
2,241 39% 1.29 0.94, 1.77 66 24%
h
1.29 0.54, 3.05

Pediatrics 54 19%
h
2.73 1.42, 5.25 NA
i

Other 2,385 11% 0.52 0.37, 0.74 NA
i

Physician medical school
e

U.S. school 4,180 18% 1.00 ref 355 18% 1.00 ref

Foreign school 1,070 22% 1.27 0.93, 1.75 50 38%
h
2.70 1.03, 7.03
Missing 679 18% 0.97 0.71, 1.31 56

125

Table 11 (continued). Factors associated with provision of tobacco use/exposure counseling at
visits by all women of reproductive age and pregnant women who use tobacco
Visits by all women who use tobacco Visits by pregnant women who use tobacco

Sampled
visits
Counseling provided
Sampled
visits
Counseling provided
% OR 95% CI % OR 95% CI
Physician age
e

<40 1,257 22% 1.28 0.96, 1.70 107 24%
h
1.27 0.74, 2.18

40-54 3,025 18% 1.00 ref 257 20% 1.00 ref

55+ 1,587 18% 1.01 0.78, 1.32 92 16%
h
0.77 0.32, 1.85
Missing 60 15%
h
0.78 0.16, 3.78 NA
i

Physician sex
e,f

Female 1,726 22% 1.35 1.04, 1.75 168 25% 1.66 0.83, 3.32
Male 4,196 18% 1.00 ref 291 17% 1.00 ref
Physician race
e

Non-Hispanic White 2,546 20% 1.00 ref 214 21% 1.00 ref

Non-White 770 18% 0.85 0.59, 1.23 51 20% 0.97 0.30, 3.13
Missing 60 15% 0.90 0.71, 1.14 196 18%
h
0.83 0.44, 1.58
Pregnancy status

Nonpregnant 15,291 19% 1.00 ref ---- ---- ---- ----
Pregnant 2,656 21% 1.14 0.85, 1.53 ---- ---- ---- ----
Reason for visit

Routine prenatal care 1,737 20% 0.65 0.41, 1.03 1,737 20% 1.00 ref

Complicated pregnancy 919 22% 0.71 0.42, 1.21 919 22% 1.09 0.65, 1.85

Routine gynecological exam 714 28% 1.00 ref ---- ---- ---- ----

Hypertension 399 35% 1.35 0.76, 2.39 ---- ---- ---- ----

Respiratory disease 1,715 32% 1.19 0.80, 1.76 ---- ---- ---- ----
Other or missing
g
12,463 15% 0.45 0.32, 0.62 ---- ---- ---- ----
Patient age

15-19 1,535 26% 1.37 0.98, 1.91 444 26% 0.94 0.51, 1.71

20-24 3,291 20% 1.00 ref 960 27% 1.00 ref

25-34 6,101 16% 0.76 0.60, 0.98 1,065 15% 0.48 0.31, 0.73
35-44 7,020 20% 0.97 0.76, 1.23 187 15%
h
0.47 0.19, 1.15
Patient race

Non-Hispanic White 13,881 19% 1.00 ref 1,945 20% 1.00 ref
Non-White 4,066 19% 1.02 0.83, 1.27 711 25% 1.33 0.79, 2.23
Patient type

Established patient 14,551 19% 1.00 ref 2,384 20% 1.00 ref

New patient 3,348 19% 1.04 0.84, 1.29 270 29% 1.49 0.78, 2.85
Missing 48 14%
h
0.73 0.14, 3.71 NA
i

a
Years 2005-2009 only
b
Missing or unclassifiable ZIP code
c
Numbers do not sum to total because one state was missing smoking prevalence data for one year
d
NHAMCS only
e
NAMCS only
f
Numbers do not sum to total because one physician was missing data on sex; no estimates presented to protect confidentiality
g
Missing category was too small for stable estimates and was combined with visits for any other reason
h
Unstable estimate with relative standard error >30% or <30 visits
i
Data not shown to protect confidentiality due to small numbers of <=5 visits

126

Provision of counseling to tobacco nonusers. Among nonusers, tobacco use/exposure counseling
was provided or ordered in 0.72% of visits by women of reproductive age and 0.47% of visits by
pregnant women. Visits to NAMCS physicians, in the South and West regions, by pregnant
patients, and older patients had lower rates of counseling in this group (Table 12). In addition,
visits paid by Medicaid were more likely to have counseling than visits paid by private insurance
(1.09% versus 0.66% of visits, OR=1.67, 95% CI: 1.12, 2.49). In a multivariate model, visits in
the South, visits by pregnant women, and visits by older patients were less likely to have tobacco
use/exposure counseling (Table 13).

Prenatal care provider interviews
Three obstetrician-gynecologists, one certified nurse-midwife, one medical assistant, and
one care coordinator were interviewed. All interviewees were females between the ages of 28
and 54, and five of the six were practicing in public or low-cost clinics, with one OB/GYN who
worked in private practice.

Identification of tobacco use. All physicians stated that they did not ask patients directly about
smoking unless the prenatal intake questionnaire completed by a lower-level care provider or by
the patient herself specified that the patient was a smoker. The midwife said she always asked
directly about smoking. The medical assistant and care

127

Table 12. Factors associated with tobacco use/exposure counseling at visits by women of
reproductive age and pregnant women who do not use tobacco
Visits by

all women who

do not use tobacco
Visits by

pregnant women who

do not use
tobacco

Sampled
visits
Counseling provided
Sampled
visits
Counseling provided
% OR 95% CI % OR 95% CI
Total 59,915 0.72%

13,098 0.47%

Survey

NAMCS 25,442 0.68% 0.59 0.42, 0.84 3,289 0.24%
h
0.10 0.04, 0.24
NHAMCS-OPD 34,473 1.14% 1.00 ref 9,809 2.39% 1.00 ref
Year

2001 5,729 0.28%
h
1.00 ref 1,396 0.21%
h
1.00 ref

2002 6,933 0.78% 2.83 1.27, 6.34 1,615 0.63%
h
2.99 0.49, 18.12

2003 6,673 0.43%
h
1.57 0.57, 4.31 1,545 0.25%
h
1.19 0.33, 4.28

2004 6,309 0.58%
h
2.10 0.66, 6.63 1,459 0.49%
h
2.30 0.50, 10.70

2005 5,703 0.88% 3.23 1.28, 8.14 1,013 0.94%
h
4.45 1.06, 18.70

2006 7,231 1.09% 4.01 1.49, 10.77 1,494 1.01%
h
4.79 1.30, 17.70

2007 6,812 1.05% 3.86 1.54, 9.64 1,448 0.66%
h
3.11 0.61, 15.82

2008 7,236 0.75% 2.75 1.10, 6.87 1,568 0.14%
h
0.66 0.19, 2.38
2009 7,289 0.71% 2.59 1.01, 6.62 1,560 0.13%
h
0.63 0.14, 2.82
Region of the U.S.

Northeast 16,254 1.14% 1.00 ref 3,916 0.95%
h
1.00 ref

Midwest 16,112 0.72% 0.63 0.39, 1.02 3,747 0.62%
h
0.59 0.22, 1.58

South 16,835 0.57% 0.50 0.31, 0.78 3,004 0.46%
h
0.4 0.14, 1.19
West 10,714 0.61% 0.53 0.28, 1.00 2,431 0.07%
h
.06 0.02, 0.18
Classification of patient’s ZIP

code
a

Large metro 15,627 1.05% 1.00 ref 3,504 0.78%
h
1.00 ref

Medium/small metro 8,811 0.72% 0.69 0.39, 1.20 2,419 0.14%
h
0.16 0.05, 0.49

Non-metro 3,344 0.65% 0.62 0.35, 1.11 NA
i

Missing
b
786 1.00%
h

NA
i

Prevalence of smoking among women aged 18-44 in the state where the physician practice / hospital is located and year of visit
c

<15% 5,900 0.75%
h
0.95 0.43, 2.06 1,576 0.12%
h
0.19 0.05, 0.71

15% - <20% 14,551 0.65% 0.81 0.50, 1.33 3,057 0.67%
h
1.05 0.35, 3.16

20% - <25% 21,114 0.80% 1.00 ref 4,414 0.64%
h
1.00 ref

25% - <30% 12,435 0.68% 0.86 0.52, 1.41 2,570 0.33%
h
0.52 0.19, 1.46
>=30% 5,826 0.67%
h
0.83 0.37, 1.86 NA
i

Change in smoking prevalence from 2001 to 2009 in the state where the physician / hospital is located
c

>=25%

decrease 13,154 0.75% 1.05 0.64, 1.71 3,476 0.47%
h
7.01 3.93, 12.52

15-25%

decrease 36,071 0.72% 1.00 ref 7,644 0.52% 1.00 ref
<15%

decrease 10,601 0.68% 0.94 0.57, 1.56 1,954 0.31%
h
0.58 0.17, 2.02
Medical school

affiliation
d

Not/unknown 9,819 1.29% 1.00 ref 2,367 4.72%
h
1.00 ref
Affiliated 24,654 1.08% 0.84 0.46, 1.52 7,442 1.81% 0.37 0.17, 0.83
Physician specialty
e

Obstetrics

and

gynecology 6,971 0.29%
h
1.00 ref NA
i

Family/general/

internal
medicine
7,306 0.87% 3.03 1.71, 5.38 NA
i

Pediatrics 838 5.27% ###
10.25,
36.30
NA
i

Other NA
i

NA
i

Physician medical school
e

U.S. school 18,899 0.66% 1.00 ref NA
i

Foreign school 4,169 0.89% 1.35 0.81, 2.23

Missing 2,374 0.36%
h
0.54 0.25, 1.16

128

Table 12 (continued). Factors associated with tobacco use/exposure counseling at visits by
women of reproductive age and pregnant women who do not use tobacco
Visits by

all women who

do not use tobacco
Visits by

pregnant women who

do not use
tobacco

Sampled
visits
Counseling provided
Sampled
visits
Counseling provided
% OR 95% CI % OR 95% CI
Physician

age
e

<40 4,996 0.57% 0.79 0.44, 1.40 NA
i

40-54 13,439 0.73% 1.00 ref NA
i

55+ 6,890 0.66% 0.91 0.57, 1.46 NA
i

Missing NA
i

NA
i

Physician sex
e,f

Female 8,382 0.91% 1.62 1.04, 2.51 NA
i

Male 17,047 0.56% 1.00 ref NA
i

Physician race
e

Non-Hispanic White 11,031 0.65% 1.00 ref NA
i

Non-White 3,047 1.01% 1.56 0.79, 3.09 NA
i

Missing 11,364 0.61% 0.93 0.58, 1.50 NA
i

Pregnancy status

Nonpregnant 46,817 0.77% 1.00 ref ---- ---- ---- ----
Pregnant 13,098 0.47% 0.60 0.38, 0.97 ---- ---- ---- ----
Reason

for visit

Routine prenatal

care 9,062 0.46% 0.34 0.16, 0.72 NA
i

Complicated pregnancy 4,036 0.49%
h
0.36 0.15, 0.89 NA
i

Routine

gynecological

exam 2,909 1.35% 1.00 ref ---- ---- ---- ----

Hypertension 1,057 0.26%
h
0.19 0.06, 0.64 ---- ---- ---- ----

Respiratory

disease NA
i

---- ---- ---- ----
Other or missing
g
42,851 0.74% 0.53 0.28, 0.99 ---- ---- ---- ----
Patient

age

15-19 9,418 2.07% 3.04 1.81, 5.11 1,862 1.05%
h
2.06 0.76, 5.63

20-24 10,165 0.69% 1.00 ref 3,841 0.51%
h
1.00 ref

25-34 20,813 0.46% 0.67 0.39, 1.15 5,949 0.39%
h
0.77 0.32, 1.87
35-44 19,519 0.48% 0.70 0.39, 1.26 1,446 0.30%
h
0.59 0.18, 1.91
Patient race

Non-Hispanic White 43,968 0.68% 1.00 ref 8,664 0.47% 1.00 ref
Non-White 15,947 0.90% 1.34 0.89, 2.03 4,434 0.47% 1.00 0.54, 1.84
Patient type

Established patient 49,339 0.74% 1.00 ref 11,731 0.35% 1.00 ref

New patient 10,465 0.60% 0.81 0.51, 1.27 1,347 2.20%
h
6.33 2.74, 14.62
Missing NA
i

NA
i

a
Years 2005-2009 only
b
Missing or unclassifiable ZIP code
c
Numbers do not sum to total because one state was missing smoking prevalence data for one year
d
NHAMCS only
e
NAMCS only
f
Numbers do not sum to total because one physician was missing data on sex; no estimates presented to protect confidentiality
g
Missing category was too small for stable estimates and was combined with visits for any other reason
h
Unstable estimate with relative standard error >30% or <30 visits
i
Data not shown to protect confidentiality due to small numbers of <=5 visits

129

Table 13. Multivariate model of tobacco use/exposure counseling

Visits by all women who use
tobacco
Visits by all women who do
not use tobacco
aOR 95% CI aOR 95% CI
Region of the U.S.

Northeast 1.00 ref 1.00 ref

Midwest 0.81 0.63, 1.04 0.63 0.39, 1.03

South 0.61 0.49, 0.77 0.39 0.24, 0.62
West 0.58 0.43, 0.78 0.56 0.29, 1.09
Medical school affiliation
d

Not/unknown 1.00 ref --- ---
Affiliated 1.49 1.10, 2.02 --- ---
Physician specialty
e

Obstetrics and gynecology 1.00 ref --- ---

Family/general/ internal medicine 1.23 0.91, 1.68 --- ---

Pediatrics 2.34 1.20, 4.59 --- ---
Other 0.50 0.36, 0.70 --- ---
Reason for visit

Routine prenatal care --- --- 0.32 0.14, 0.69

Complicated pregnancy --- --- 0.33
h
0.13, 0.82

Routine gynecological exam --- --- 1.00 ref

Hypertension --- --- 0.23
h
0.07, 0.77

Respiratory disease --- --- NA
i

Other/missing --- --- 0.41
h
0.22, 0.77
Patient age

15-19 1.32 0.94, 1.85 3.02 1.78, 5.10

20-24 1.00 ref 1.00 ref

25-34 0.78 0.61, 0.99 0.49 0.29, 0.85
35-44 1.04 0.83, 1.30 0.60 0.33, 1.11

d
NHAMCS only
e
NAMCS only
h
Unstable estimate with relative standard error >30% or <30 visits
i
Data not shown to protect confidentiality due to small numbers of <=5 visits

coordinator worked for two clinics that participate in the California Department of Public Health
Comprehensive Perinatal Services Program (CPSP). CPSP is a statewide program for Medi-Cal
eligible pregnant women in California that provides a wide range of services, including standard
obstetric services and enhanced nutritional, psychosocial, and health education services. To
participate, providers must become certified and follow the guidelines of the program, including
use of forms approved by the local public health departments. Figure 26 shows the tobacco use
130

section of the Prenatal Combined Assessment / Reassessment Tool that CPSP providers use on
intake and follow-up in Los Angeles County. Tobacco use should be identified in each trimester,
but the CPSP care coordinator interviewed said that she does not ask women about smoking on
follow-up visits. .” A 37-year-old OB/GYN physician in private practice in Pasadena, California,
with a PPO-insured or cash-payment patient population, said that all of her smoking patients
report quitting upon discovery of the pregnancy. She could not remember the last time she
encountered a smoking pregnant patient.

Counseling and referral to cessation services. Half of the providers advised patients to quit
smoking, and the other half recommended that patients “quit or cut down. A 54-year-old
OB/GYN in Fairfax, Virginia who works at a public clinic that serves uninsured patients who are
not eligible for Medicaid said she advises patients to cut down to less than half a pack a day,
because she believed that was the safe and recommended level of smoking. The information
providers gave about the risks of smoking during pregnancy was similar, with most listing low
birthweight or preterm birth as more likely in smoking mothers. None of the providers recorded
smoking cessation counseling or billed for it, but most had cessation programs where they
referred smoking patients. One physician was certain that she could not be reimbursed for
tobacco cessation counseling without the entire visit focusing on tobacco use. Excepting the
CPSP providers, the Virginia OB/GYN physician was the only provider to ask patients about
secondhand smoke (SHS) exposure. She explained that she discusses the increased risk of
sudden infant death syndrome (SIDS) caused by SHS exposure.

131

Figure 26. Los Angeles County Department of Public Health Comprehensive Perinatal Services Program Prenatal
Combined Assessment / Reassessment Tool

4.4. Discussion
We found that physicians are not identifying tobacco use status in all women of
reproductive age, and are following through with counseling in very few tobacco users.
Pregnancy, a time when a woman and her fetus are both at risk from smoking, did not increase
the frequency of tobacco use/exposure counseling, though pregnancy was associated with higher
rate of identification of tobacco use.

Identification of tobacco use
Identification of tobacco use in visits by pregnant women decreased from 75% in 2001 to
69% in 2009. This trend is consistent with a gradual decline beginning as early as 1991, when
Moran et al. found that identification of tobacco use among visits by pregnant women in
NAMCS decreased from 80% to 76% in 1996.
8
Though the national prevalence of smoking
among women of reproductive age declined during the 2000s, the prevalence among pregnant
women did not change. Thus, the number of unidentified pregnant tobacco users may actually
have increased.

132

Provision of tobacco use/exposure counseling
Tobacco use/exposure counseling was provided or ordered for only one in five visits by
pregnant women. Because the sampling unit is women, and nearly all women have multiple
visits for prenatal care, this does not translate to one in five pregnant tobacco users receiving
counseling during her pregnancy. However, smoking should be addressed at every visit. ACOG
recommends, “For current and former smokers, smoking status should be monitored and
recorded throughout pregnancy, providing opportunities to congratulate and support success,
reinforce steps taken towards quitting, and advise those still considering a cessation attempt.”
5

Health care providers are important sources of information and influence. A recent study found
that of smoking pregnant women who contacted a smoking cessation helpline, 50% had heard of
the quitline through a health care provider.
15

Predictors of tobacco use identification and provision of counseling

Smoking prevalence. State- and year-specific smoking prevalence among women of reproductive
age was a predictor of both identification of tobacco use and provision of counseling. This was
the only factor to significantly affect both identification and counseling. As prevalence increased,
identification and counseling increased. Such associations have not been reported in the
literature, and could be due to a heightened awareness of smoking as a problem in areas where it
is more prevalent. However, after adjusting for other factors, smoking prevalence was not
independently associated with either identification or counseling. Statewide smoking prevalence
is only loosely tied to local smoking prevalence, which is more relevant and is associated with
age, race, and socioeconomic status.
16

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Geographic variation. Tobacco use status identification and tobacco use/exposure counseling
had different patterns across the regions of the country but similar associations with metropolitan
area status. Compared to the Northwest, identification of tobacco use was more likely in the
Midwest and similar in the West and South, but tobacco use/exposure counseling was less likely
in the West and South and similar in the Midwest. Both identification and counseling were more
common among patients living in smaller metropolitan or non-metropolitan areas compared to
large metropolitan areas. Smoking prevalence is generally higher in rural areas,
17
and thus
metropolitan area status may be acting as a proxy for smoking prevalence in geographic regions
more finely delineated than state.

Patient demographics. Patient age was not significantly associated with tobacco use
identification, but was strongly associated with tobacco use/exposure counseling. In both all
women and pregnant women who use tobacco, those aged 25-34 were much less likely as
women aged 20-24 to receive tobacco use/exposure counseling. Women aged 25-34 form a
critical group in which counseling should be improved, because they typically account for more
than half of all births to American women (51% of 4.1 million births in 2009).
18
Nonwhite
women were less likely to have a documented tobacco use status. Though the majority of the
sampled visits were made by white women, this group accounted for only 54% of births in 2010,
and this percentage is quickly declining.
18
Providers may feel less need to identify tobacco use in
nonwhite women, because they are less likely to smoke than white women. However, as new
immigrants acculturate, they adapt to American behaviors such as smoking.
19

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Prenatal care provider interviews
The provider interviews highlighted lack of awareness of appropriate guidelines as a
major problem. Several providers did not know to always advise complete cessation, and one
thought that some smoking was safe. The knowledge of health care providers needs significant
improvement, and they are willing to learn. In a survey of Ohio obstetricians, 77% reported no
formal training in smoking cessation and 87% wanted to learn more about how to advise women
to quit.
20

Strengths
The strengths of this study are that it is nationally-representative and utilizes a large
number of visits to analyze the important subgroup of health care visits by pregnant women. The
data included comprise all recent, consecutive years in which the tobacco use and counseling
questions were asked in a similar format. The included visits represent nearly all visits by women
of reproductive age to physician offices or outpatient departments. Visit, patient, physician, and
geographically defined demographic variables provide insight into a variety of factors that affect
identification of tobacco use and provision of counseling. Provider interviews allowed for the
integration of survey data with informative personal anecdotes.

Limitations
One limitation of the study is that because the sampling unit is a visit, estimates for
individual women are not possible. Because pregnant women have multiple visits over the course
of the pregnancy, the rates of tobacco use identification and provision of counseling per woman
135

could be much higher than the per-visit estimates. However, only 68% of new pregnant patients
had tobacco use identified compared to 74% of established patients. Visits by new patients
provide a measure of the rate of tobacco use identification per patient, thus a substantial number
of pregnant women do not have tobacco use identified at their first visit to a new provider. A
second limitation is that the data for some variables, like physician age and physician race, were
missing for a large proportion of visits. A third limitation is that documentation of services does
not correspond directly to provision of these services, and services may not be documented.
Despite the lack of universal identification of tobacco use in NAMCS/NHAMCS, all providers
directly interviewed said they or their office always asks patients whether they smoke. Most of
the interviewees also said they counsel all patients about smoking, but none recorded this as a
procedure or billed for it. This problem was found by a study of 84 family practices in Ohio that
compared direct observation of patient care by research nurses to NAMCS reports.
21
Smoking
counseling was observed in 12.2% of visits, but reported to NAMCS in only 7.3% of visits,
giving NAMCS a sensitivity of 52% for tobacco use counseling.

Future work
This study characterized situations in which identification of tobacco use and provision of
counseling are not occurring at the appropriate rate. The next step is to improve both the
frequency and quality of provider counseling, which can be more efficient using targeted
approaches. Medical school-affiliated outpatient departments are an obvious target for increased
identification of tobacco use. ACOG or other organizations could reach out to older male
physicians, or those in the West or South. The key group of women aged 25-34 could be targeted
136

by a public health campaign outside the health care system, or physicians could be alerted to the
age disparity in counseling.

Conclusions
The rates of identification of tobacco use and tobacco use/exposure counseling in women
of reproductive age are far below adequate. The declining rate of identification of tobacco use in
pregnant women is concerning, because unidentified pregnant tobacco users cannot be counseled
to quit. Targeted education and outreach efforts to improve counseling are needed.
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Table 14. Classification of reason for visit in NAMCS/NHAMCS
Reason for visit* ICD-9 codes Reason for visit codes
Pregnant

Complicated pregnancy 640-49 Complications mainly related to pregnancy 1790 Problems of pregnancy

V23 Supervision of high-risk pregnancy 2735
Diagnosed complications of pregnancy and
puerperium

Normal pregnancy V22 Supervision of normal pregnancy 3205 Prenatal exam
Nonpregnant

Respiratory disease 460-519 Diseases of the respiratory system 2600-2649 Diseases of the respiratory system

1400-1499 Symptoms referable to the respiratory system

Hypertension 401-405 Hypertensive disease 2505 Hypertension with involvement of target organs

2510 Hypertension, hypertensive
Routine gynecological
examination
V72.31 Routine gynecological examination 3225 Gynecological exam

Other

All other nonmissing codes

All other nonmissing codes
* NAMCS and NHAMCS provide three ICD-9 codes and three reason for visit codes for each visit. Reason for visit was re-categorized using these codes based
on any of the six codes falling into the categories listed above. Reasons were classified as pregnant by the ICD-9 codes specified only if the fifth digit was not
1,2, or 4, which are codes for “delivered” and “postpartum.” The order in the table gives the hierarchy. For example, classification of a visit for normal
pregnancy would preclude classification for respiratory disease, and classification of a visit for hypertension would preclude classification for routine
gynecological exam.

138

Chapter 4 References

1. U. S. Department of Health and Human Services. The health consequences of smoking: a
report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human
Services, Centers for Disease Control and Prevention, Coordinating Center for Health
Promotion, National Center for Chronic Disease Prevention and Health Promotion,
Office on Smoking and Health; 2004.
2. Tong VT, Jones JR, Dietz PM, et al. Trends in smoking before, during, and after
pregnancy - Pregnancy Risk Assessment Monitoring System (PRAMS), United States, 31
sites, 2000-2005. MMWR.Surveillance summaries : Morbidity and mortality weekly
report.Surveillance summaries / CDC. 2009;58(4):1-29.
3. Centers for Disease C, Prevention . National Center for Health Statistics . National H,
Nutrition Examination Survey D. Vol 2010. Hyattsville, MD: U.S. Department of Health
and Human Services, Centers for Disease Control and Prevention.
4. Preventive Care: A National Profile on Use, Disparities, and Health Benefits.
Washington, DC: Partnership for Prevention;2007.
5. Committee opinion no. 471: Smoking cessation during pregnancy. Obstetrics and
gynecology. 2010;116(5):1241-1244.
6. U. S. Preventive Services Task Force. Counseling and interventions to prevent tobacco
use and tobacco-caused disease in adults and pregnant women: U.S. Preventive Services
Task Force reaffirmation recommendation statement. Annals of Internal Medicine.
2009;150(8):551-555.
7. Okoli CT, Greaves L, Bottorff JL, Marcellus LM. Health care providers' engagement in
smoking cessation with pregnant smokers. Journal of obstetric, gynecologic, and
neonatal nursing : JOGNN / NAACOG. 2010;39(1):64-77.
139

8. Moran S, Thorndike AN, Armstrong K, Rigotti NA. Physicians' missed opportunities to
address tobacco use during prenatal care. Nicotine & tobacco research : official journal
of the Society for Research on Nicotine and Tobacco. 2003;5(3):363-368.
9. CDC/National Center for Health Statistics. About the Ambulatory Health Care Surveys.
2009; http://www.cdc.gov/nchs/ahcd/about_ahcd.htm. Accessed Feb. 20, 2013.
10. CDC/National Center for Health Statistics. NAMCS and NHAMCS Downloadable
Documentation, 2001-9. 2012;
http://www.cdc.gov/nchs/ahcd/ahcd_questionnaires.htm. Accessed April 4, 2012.
11. Schneider D, Appleton L. Reason for visit classification system for patient records in the
ambulatory care setting. An ambulatory care classification system offers applications to
quality assurance. QRB.Quality review bulletin. 1977;3(1):20-26.
12. CDC/National Center for Health Statistics. Ambulatory Health Care Data: Reliability of
Estimates. 2010; http://www.cdc.gov/nchs/ahcd/ahcd_estimation_reliability.htm.
Accessed March 6, 2013.
13. About the BRFSS. Vol 2011: United States Department of Health and Human Services
Centers for Disease Control and Prevention Office of Surveillance, Epidemiology, and
Laboratory Services Public Health Surveillance Program Office; 2008.
14. BRFSS Annual Survey Data: Survey Data and Documentation. In: United States
Department of Health and Human Services Centers for Disease Control and Prevention
Office of Surveillance E, and Laboratory Services Public Health Surveillance Program
Office, ed. Vol 2011. Atlanta, GA2011.
15. Bombard JM, Farr SL, Dietz PM, Tong VT, Zhang L, Rabius V. Telephone Smoking
Cessation Quitline Use Among Pregnant and Non-pregnant Women. Matern Child
Health J. Jul 15 2012.
140

16. Cui Y, Baldwin SB, Lightstone AS, Shih M, Yu H, Teutsch S. Small area estimates reveal
high cigarette smoking prevalence in low-income cities of Los Angeles county. Journal of
urban health : bulletin of the New York Academy of Medicine. Jun 2012;89(3):397-406.
17. Vander Weg MW, Cunningham CL, Howren MB, Cai X. Tobacco use and exposure in
rural areas: Findings from the Behavioral Risk Factor Surveillance System. Addictive
behaviors. Mar 2011;36(3):231-236.
18. Statistics. CfDCaPNCfH. VitalStats. Accessed March 16, 2013.
19. Lorenzo-Blanco EI, Unger JB, Ritt-Olson A, Soto D, Baezconde-Garbanati L. A
Longitudinal Analysis of Hispanic Youth Acculturation and Cigarette Smoking: The
Roles of Gender, Culture, Family, and Discrimination. Nicotine Tob Res. Oct 29 2012.
20. Chapin J, Root W, American College of O, Gynecologists. Improving obstetrician-
gynecologist implementation of smoking cessation guidelines for pregnant women: an
interim report of the American College of Obstetricians and Gynecologists. Nicotine &
tobacco research : official journal of the Society for Research on Nicotine and Tobacco.
2004;6 Suppl 2:S253-257.
21. Gilchrist VJ, Stange KC, Flocke SA, McCord G, Bourguet CC. A comparison of the
National Ambulatory Medical Care Survey (NAMCS) measurement approach with direct
observation of outpatient visits. Med Care. Mar 2004;42(3):276-280.

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Chapter 5. Discussion

This research addressed an ongoing public health problem - smoking by women during
pregnancy - in spite of clear evidence showing the harms to the fetus. The findings reinforce that
there are severe consequences to smoking during pregnancy and document the current
inadequacy of smoking-related counseling. Women, doctors, and policymakers, using the
information on the effects of smoking during pregnancy presented here, can proceed with
enhanced decision-making and prioritization.

5.1. Discussion of Systematic Reviews
Chapters 2 and 3 of the dissertation synthesized, for the first time, hundreds of studies on
smoking and pregnancy loss that were published from 1934 to 2011. The synthesis of the
evidence in these papers found that active maternal smoking is associated with increased risks of
miscarriage, stillbirth, neonatal death, and perinatal death. Despite publication bias among
studies of stillbirth and perinatal death, the findings of the analyses were remarkably consistent,
leading to the conclusion that smoking during pregnancy causes each of these severe
consequences. Other biases that did not significantly affect the results include confounding,
misclassification, and selection of participants. Important potential confounders that were
controlled for in many studies included maternal age, race/ethnicity, and socioeconomic status.
The size and diversity of this body of literature limited prior syntheses of this evidence and some
studies were apparently overlooked in comparison to the set of studies identified in the present
search. Nonetheless, the prior reviews led to conclusions comparable to those reached here.

142

Dozens of articles have reported on systematic reviews and/or meta-analyses of smoking
and pregnancy outcome. The associations between smoking and miscarriage and between
smoking and perinatal death were addressed in only three and six of these, respectively. The
results of the previously published meta-analyses are generally similar to contemporaneous
results of the cumulative meta-analyses conducted for this dissertation, as discussed below.

Active smoking and miscarriage
In 1984, Dr. Ian McIntosh wrote the first systematic review addressing smoking and
miscarriage, and he included seven of the 26 relevant studies published to date.
1
This review
found a combined relative risk of 1.12 (95% CI: 1.05, 1.20) and a combined odds ratio of 1.29
(p<0.0001, CIs not available). These results are concordant with the cumulative meta-analysis
presented in this dissertation, which combined odds ratios and risk ratios in studies up to 1983 to
give a summary relative risk of 1.22 (95% CI: 1.17, 1.28; 12 studies, Figure 11). Ten years later,
the next and most recent systematic analysis, by DiFranza and Lew, reviewed 15 studies of the
48 then available.
2
They found a pooled odds ratio of 1.32 (95% CI: 1.18, 1.48; 6 studies) and a
pooled risk ratio of 1.24 (95% CI: 1.19, 1.30; 7 studies). In comparison, the cumulative meta-
analysis gives a summary relative risk of 1.25 for studies published through 1994 (95% CI: 1.15,
1.35; 27 studies, Figure 11). The striking consistency of these analyses despite relying on
significantly different sets of studies suggests that the selection of publications did not influence
the results. This consistency lessens, but does not exclude, the possibility that publication bias
substantially contributes to the positive associations.

143

Secondhand smoke exposure and miscarriage
Two systematic reviews of the associations between secondhand smoke exposure and
adverse pregnancy outcomes including miscarriage were published in 2010
3
and 2011.
4
These
included nine and seven studies, respectively, of the 16 published before 2010. Despite including
different studies, these analyses found identical non-significant 17% increases in the risk of
miscarriage with maternal exposure to secondhand smoke (2010 95% CI: 0.97, 1.41; 9 studies
and 2011 95% CI: 0.88, 1.54; 6 studies). These are similar to the results of the meta-analysis in
this dissertation that found a summary relative risk of 1.11 (95% CI: 0.89, 1.39; 17 studies).

Active smoking and perinatal death
Rush and Kass wrote the first large-scale review of maternal smoking and perinatal death
in 1972.
5
Including 21 studies, they found a “weighted excess” of perinatal death of 34.4%,
combining studies of abortion, stillbirth, neonatal death, and perinatal death. This cannot be
directly compared to the outcome-specific analyses conducted here, but the cumulative meta-
analysis found a relative risk of 1.10 for perinatal death in eight studies published through 1971
(95% CI: 0.99, 1.23). The Rush and Kass study was published before resolution of the
birthweight paradox, around the same time that Dr. Jacob Yerushalmy, who did not believe in
the harm of smoking during pregnancy, published articles titled, “The relationship of parents’
cigarette smoking to the outcome of pregnancy – implications as to the problem of inferring
causation from observed associations,”
6
and “Infants with low birth weight born before their
mothers started to smoke cigarettes.”
7
In this polarized environment, with sparse data, Rush and
Kass remarkably arrived at the same 35% increased risk found by the complete set of 48 studies

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on perinatal death analyzed in this dissertation (95% CI: 1.27, 1.44). Including only seven
studies, in 1984 McIntosh found a nearly identical relative risk of perinatal death in smoking
mothers of 1.34 (p<0.001).
8
By that time, the relative risk in the cumulative meta-analysis had
risen to 1.31 (95% CI: 1.18, 1.46; 24 studies).

Active smoking and stillbirth
In more recent years, authors have tended to separate perinatal death into stillbirth and
neonatal death. The median publication year for studies of perinatal death was 1986 (interquartile
range 1976-1996), compared to 1999 for studies of stillbirth (interquartile range 1987-2006).
Possibly due to this trend, the first meta-analysis of smoking and stillbirth was the 1984 study by
McIntosh, which found a combined odds ratio of 1.25 in 15 articles (p<0.0001).
8
At this time, the
cumulative meta-analysis gives a relative risk of 1.45 (95% CI: 1.24, 1.68; 15 studies). The next
meta-analysis of smoking and stillbirth was published in 2011 and found that smoking increased
the risk of stillbirth by 40% (95% CI: 1.27, 1.46).
9
Including only studies published between
1998 and 2009 and conducted in high-income countries, this estimate is very similar to the
relative risk of 1.45 found in the meta-analysis of studies in this dissertation without restriction
by time or place (95% CI: 1.37, 1.54; 57 studies).

Active smoking and neonatal death
The only systematic review and meta-analysis of active smoking and neonatal death was
the study by McIntosh in 1984. This review found an odds ratio of 1.22 for total neonatal death

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(p<0.0001, 11 studies), compared to 1.23 for the 17 studies included in the cumulative meta-
analysis up to 1984 (95% CI: 1.16, 1.31). Again, despite different study inclusions, both analyses
arrived at the same quantitative result.

Secondhand smoke exposure and stillbirth, neonatal death, and perinatal death
The studies by Salmasi et al.
3
and Leonardi-Bee et al.
4
were the only systematic reviews
to assess SHS exposure and any type of perinatal death. Salmasi et al. did not find any studies on
stillbirth or perinatal mortality. Leonardi-Bee et al. reviewed five studies on stillbirth and one
each on neonatal and perinatal mortality. They found that SHS exposure increased the risk of
stillbirth by 23% (95% CI: 1.09, 1.38, 4 studies). This is substantially lower than the summary
relative risk of 1.63 found in six studies in this meta-analysis (95% CI: 1.16, 2.29). However,
Leonardi-Bee et al. included only two studies analyzed here and two studies not included in the
current analysis. One of these combined stillbirth and miscarriage into a “fetal loss” indicator,
10

and the other gave an odds ratio for each unit increase in log cotinine level.
11

Interdependency of pregnancy loss outcomes
The study of pregnancy loss is complicated by the lack of an ideal denominator of the full
set of pregnancies beginning at the earliest point. One-fifth of implantations end in early losses
that are unrecognized by the mother or her clinician and thus cannot be included in research.
12

Other early pregnancy losses may also be excluded from research due to the mother's uncertainty
about being pregnant or lack of documentation by health care providers if the mother did not

146

seek medical care. Two studies by Wilcox et al. and Winter et al. give the best possible
approximation of the number of conceptions because they measured the risk of smoking on early
pregnancy loss among women with natural conception during daily biochemical pregnancy
testing
13
or embryo transfer with a positive pregnancy test at 16 days of gestation.
14
Combining
the two studies, smokers had an 87% increased risk of early pregnancy loss (95% CI: 1.24, 2.83).
Most of these losses would be excluded from traditional studies of miscarriage because they
were so early in gestation that even the mother generally had not yet recognized the pregnancy.
These exclusions would cause underestimation of the risk of smoking on the set of all
conceptions because the denominator (the number of recognized pregnancies) has already been
reduced by smoking. The meta-analyses presented in this dissertation found that smoking
increased the risk of miscarriage by 23%, the risk of stillbirth among remaining pregnancies by
44%, and the risk of neonatal death among those that survived to live birth by 18%. The total risk
of smoking on pregnancy loss is greater than the sum of these effects, because of the
underestimated effect on miscarriage and because a pregnancy that ends in miscarriage has no
chance for the fetus/infant to overcome the risk of smoking on stillbirth and neonatal death.

5.2. Discussion of smoking cessation services among prenatal care providers
Chapter 4 of this dissertation found that not all smoking women of reproductive age are
identified during doctor’s visits, and that those smokers who are identified are frequently not
counseled about smoking cessation. Many pregnant women want to quit, and a number of
barriers exist to quitting, including nicotine addiction, stress, living with a smoking partner,

147

incomplete knowledge of the health effects of smoking, and inadequate counseling by healthcare
providers.

Patients want to quit
The majority of smokers want to quit. In the 2010 National Health Interview Survey,
71% of female smokers said they were interested in quitting.
15
Among pregnant women surveyed
in the 1990s, 82% agreed with the statement, “If I stop smoking, it is likely that my baby will be
healthier.”
16
Among a national sample of smoking women, 38% reported quitting for at least one
week during pregnancy.
17
Women who quit smoking during pregnancies in 1981 were twice as
likely to know there was a danger to the fetus (86% versus 40%) compared to women who
continued smoking throughout pregnancy.
18
Despite the desire to quit and motivation of
concerns for the baby’s health, heavy smokers have trouble quitting. In a randomized trial to
evaluate the efficacy of a smoking cessation intervention consisting of personalized feedback
during ultrasound plus motivational interviewing-based counseling sessions, major differences in
response were found based on the daily number of cigarettes smoked at baseline. Heavy smokers
(>10 cigarettes/day) did not respond to the intervention, but among light smokers (<=10
cigarettes/day) the intervention more than doubled the end-of-pregnancy quit rate compared to
the “best practices” control group (34% versus 16%).
19
Selby et al. found that there may be a
pharmacokinetic predisposition to a high rate of nicotine metabolism for some heavily smoking
women who are unable to quit.
20

Patients are not receiving smoking cessation services

148

Patients are not receiving advice to quit smoking. Only 52% of female smokers surveyed
in 2010 said they had received a health professional’s advice to quit within the past year.
15
Sixty-
five percent of those women who tried to quit did so without medicine or counseling. Two
studies reported results from the Pregnancy Risk Assessment Monitoring System (PRAMS), a
surveillance project of the CDC and state health departments. PRAMS collects state-specific,
population-based data on maternal attitudes and experiences before, during, and shortly after
pregnancy. Among women surveyed from 2004-2007 in South Carolina and Oklahoma,
respectively, 7.4% and 12.6% of pregnant women stated a need for help to quit smoking during
pregnancy; of those, only 29.1% and 30.4% reported receiving that help.
21
Tran et al. studied
PRAMS data from 2000-2001 in Oregon and found that only 42.2% of pregnant smokers were
asked about smoking, advised to quit, and assisted with quitting.
22
Substantial racial/ethnic
disparities were found: only 28% of Hispanic and 31% of Non-Hispanic American Indian/Alaska
Native smokers received all three interventions, compared to 61% of Non-Hispanic Blacks and
43% of Non-Hispanic Whites. Of the total number of smokers surveyed, 47% were Non-
Hispanic White, 25% were Non-Hispanic American Indian/Alaska Native, 15% were Non-
Hispanic Black, and 8% were Hispanic. Elimination of the disparity in care without other
improvement (serving all women at the 61% rate of black women) would improve the rate of
service by 50%. Pregnant women are not receiving appropriate smoking cessation services, and
disparities in care contrast with the population’s real and perceived needs.

149

Providers are not identifying tobacco use or providing counseling
The findings from the present NAMCS/NHAMCS analysis and prenatal care provider
interviews are in line with a recent review of the literature on health care providers’ practices
regarding pregnant patients who smoke.
23
The review of 28 articles in Alabama, North Carolina,
Michigan, Ohio, Texas, Massachusetts, Germany, England, and Australia that addressed
practices among family practitioners, obstetrician-gynecologists, pediatricians, nurses and nurse-
midwives, and other clinic staff. The percentage of providers who always asked about tobacco
use ranged from 73% of 194 nurse-midwives in Ohio
24
to 100% of 276 obstetricians in Ohio.
25

Assistance with quitting was rarer and less consistent, with a median of 56% in the U.S. that
ranged from 28% of obstetricians in Alabama
26
to 99% of maternity care providers in
Milwaukee, Wisconsin.
27

Secondhand and thirdhand smoke exposure
Secondhand smoke exposure was only addressed by one of the six interviewees in the
present study, which is consistent with the literature. Bailey et al. addressed Tennessee
obstetricians’ behavior and attitudes regarding SHS exposure during pregnancy.
28
They found
that 82% of respondents were not regularly asking their patients about SHS exposure during
pregnancy. This is nearly the same result as the only 16.7% of respondents in the Argentinean
survey who always discuss the risks of SHS exposure with pregnant patients.
29
Thirdhand smoke
refers to the particulate matter and gases in tobacco smoke that may remain long after any smoke
is noticeable by sight or smell. Thirdhand smoke contain carcinogens, some resulting from
chemical reactions that take place after surface deposition of smoke components.
30
It is

150

particularly relevant to pregnancy because infants and small children crawl on the ground,
allowing for materials to be absorbed dermally, and put their mouths on old carpets and
furniture. The concept of thirdhand smoke is relatively new, and was not acknowledged by any
of the interviewees or the literature on prenatal care providers’ knowledge of the effects of
tobacco.

Providers’ attitudes regarding tobacco use
Health care providers may not perceive smoking cessation as a topic they should address
or need to address. Interviews with midwives in Camden, England found that they reported a fear
of judging and putting pressure on pregnant smokers.
31
One midwife said, “I normally assume
they don’t want to [quit]. If they said, ‘I’m a smoker,’ then that itself sort of statement implies
that they intend to continue to be a smoker, do you know what I mean?” Physicians in the U.S.
also reported perceived barriers to counseling, such the perception that pregnant smokers are not
responsive to physicians’ advice about cessation.
32

Education of providers is inadequate
Only 40% of primary care physicians surveyed in 2003-2004 were aware of the Public
Health Service clinical guideline on tobacco use and dependence.
33
Physicians in other
specialties and non-physician health professionals had lower rates of knowledge. In 2004, most
(64%) surveyed fourth-year students from six medical schools in New York City rated their
preparation to assist patients to quit smoking as less than adequate.
34
A survey of 79 physician

151

assistant training programs in 2008-9 found that an average of 14 hours was devoted to tobacco
dependence education curriculum, but only 42 minutes of this time was spent on cessation
counseling, with much more time devoted to the health effects of tobacco use.
35
Among
specialized programs that provided postgraduate tobacco cessation education to physicians, only
60% covered the topic of pregnant women.
36

Providers’ knowledge regarding tobacco use
The discovery that prenatal care providers are not all familiar with current guidelines for
addressing tobacco use is consistent with other reports. Applegate et al. surveyed primary care
providers in Mississippi and found that only 33.7% of physicians, dentists, and nurse
practitioners were familiar with the Public Health Service clinical practice guideline.
37,38
In a
survey of Argentinean physicians, 64.6% of respondents said they would recommend that
pregnant patients smoke up to six cigarettes per day if they were unable to stop.
29
Thus, the
interviewee in the current study who recommends that patients smoke no more than ½ pack per
day may not be unusual.

Effectiveness of smoking cessation interventions
Pregnant women need counseling on smoking from their providers. The Cochrane
Collaboration has addressed the effectiveness of simple advice to quit among all patients
39
and
more intensive smoking cessation interventions among pregnant patients.
40
Pooled data from 17
randomized controlled trials found that a medical practitioner’s brief advice to quit smoking

152

increased the quit rate by 66% compared to no advice or usual care (RR=1.66, 95% CI: 1.42,
1.94).
39
The authors concluded that given an unassisted quit rate of 2-3%, brief advice could
increase the quit rates by a further 1 to 3%. Lumley et al. analyzed 56 randomized controlled
trials and nine cluster-randomized trials of the effect of smoking cessation interventions on
cessation during pregnancy.
40
They found that interventions improved cessation rates and
pregnancy outcomes. Smoking cessation interventions reduced the rate of smoking in late
pregnancy (RR=0.94, 95% CI: 0.93, 0.96), low birthweight (RR=0.83, 95% CI: 0.73, 0.95) and
preterm birth (RR=0.86, 95% CI: 0.74, 0.98). Methods to support smoking cessation in
pregnancy that are currently being studied in ongoing or recently completed trials include
physical activity,
41
financial incentives,
42,43
and a high-intensity intervention with counseling,
cognitive behavior therapy, and education.
44

Effectiveness of provider training
Healthcare provider knowledge and training in tobacco use and dependence significantly
increase cessation counseling.
23,45,46
A Cochrane review analyzed randomized controlled trials of
training of health care professionals in smoking cessation. Meta-analyses found that health care
professional training increased the point prevalence of quitting (OR=1.36, 95% CI: 1.20, 1.55)
and the rate of continuous abstinence (OR=1.60, 95% CI: 1.26, 2.03). Training also increased the
frequency of healthcare providers asking patients to set a quit date, make follow-up
appointments, counseling of smokers, provision of self-help material and prescription of a quit
date.
47
An example of provider training is Pennsylvania’s continuum of tobacco education pilot
project.
48
In this program, third-year medical students attended a five-hour didactic seminar in

153

which myths and misconceptions were dispelled and Public Health Service guidelines and
effective techniques introduced. After the program, the percentage of students obtaining tobacco
histories and counseling patients increased. In the antenatal care setting, a provider training
program resulted in a 12-month quit rate of 13%, compared to the 6.7% unassisted quit rate in
the community.
49
Thus, education of healthcare providers is effective and practical.

5.3. Overall discussion
Chapters 2 and 3 of this dissertation have shown that smoking during pregnancy causes
miscarriage, stillbirth, and neonatal death. In addition, elimination of all active maternal smoking
could prevent one in twenty preterm deliveries and preterm-related deaths and up to one-third of
all SIDS deaths.
50
Both low birthweight and SIDS are also caused by secondhand smoke
exposure.
51

Overall women’s health could also be improved by reducing smoking during pregnancy.
A recent analysis found that in 2005, smoking was by far the leading cause of death for women
under 70, accounting for 25% of deaths.
52,53
Pregnancy is an opportune time for tobacco smoke
exposure reduction both because of maternal concerns for the fetus and because many women
seek prenatal care when they become pregnant, but would otherwise remain outside the
healthcare system. Women typically see their obstetrician repeatedly during pregnancy, which
strengthens the doctor-patient relationship and allows built-in follow-up visits for addressing
progress in smoking cessation.

154

Implications
The increased risks of miscarriage, stillbirth, and neonatal death associated with cigarette
smoking are completely avoidable, at least theoretically, by smoking cessation and prevention of
smoking initiation. The systematic reviews and meta-analyses presented here strengthen the
evidence for the harms of smoking during pregnancy, reinforcing the need for physicians and
other health care providers to counsel smokers to quit. However, Chapter 4 of this dissertation
found that counseling is inadequate, and that education of physicians is needed. Thus, despite the
growing evidence that smoking during pregnancy is harmful, solutions are not being
implemented.

Future work
Further epidemiological research is not needed to establish that maternal smoking causes
miscarriage, stillbirth, and neonatal death. However, research on successful smoking cessation
strategies and action are needed to effectively encourage women not to smoke or to quit
smoking. A good system to prevent pregnant women from smoking would include information
that is easy to find and understand, smoking cessation counseling services, and healthcare
providers who are well-informed and supportive of quitting. Information tailored to women is
available at women.smokefree.gov, and this website also provides access to the National Cancer
Institute’s quitline and instant-messaging-based counseling, and a single phone number that
connects smokers to their state quitlines.
54
Lacking from the system are healthcare providers who
are informed and equipped to help women quit smoking with advice, counseling, and referrals.
Of pregnant smokers who called the American Cancer Society quitline in 2006-8, the majority

155

(50.4%) were referred by a healthcare provider.
55
Medical schools, clinics, medical groups,
public health departments and any other entities that employ healthcare providers can
immediately begin training on tobacco use counseling. Special attention to the problem by
prenatal care providers is needed given that many women quit smoking upon discovering their
pregnancies, and those who are still smoking during prenatal care may be more heavily addicted.
Concurrent with these programs, investigators can study effective, efficient educational methods,
but action should not wait for more research.

156

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Asset Metadata

Creator Pineles, Beth Leong (author)

Core Title Smoking in pregnancy: from effects to solutions

School Keck School of Medicine

Degree Doctor of Philosophy

Degree Program Epidemiology

Publication Date 01/27/2015

Defense Date 04/29/2013

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag miscarriage,OAI-PMH Harvest,perinatal death,Pregnancy,smoking,smoking cessation counseling,stillbirth,tobacco

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Samet, Jonathan M. (committee chair), Baezconde-Garbanati, Lourdes (committee member), Berhane, Kiros T. (committee member), Cockburn, Myles (committee member), Eckel, Sandrah (committee member), Martin, Sue Ellen (committee member)

Creator Email bpineles@gmail.com,pineles@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-301548

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Legacy Identifier etd-PinelesBet-1856.pdf

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