Research

www.AJOG .org

OBSTETRICS

Plasma cotinine indicates an increased risk of preeclampsia

in previous and passive smokers
Zhong-Cheng Luo, PhD; Pierre Julien, PhD; Shu-Qin Wei, PhD; Francois Audibert, MD, MSc;
Graeme N. Smith, MD; William D. Fraser, MD; and the MIROS study group
OBJECTIVE: Self-reported tobacco smoking in pregnancy has been
consistently associated with a decreased risk of developing preeclampsia, but the evidence has been limited and inconsistent for previous and
passive smokers. Misclassifications and inaccuracies of self-reported
tobacco exposure may disguise the true relationship. This study aimed
to assess the association of gestational hypertension and preeclampsia
with maternal smoking status as ascertained by plasma cotinine.

RESULTS: Compared to nonsmokers, the risk of developing preeclampsia did not change significantly for current smokers, but
increased significantly (adjusted odds ratio, 6.06; 95% confidence
interval, 2.32e15.85; P < .001) for previous and passive smokers.
There were no significant differences in the risk of developing
gestational hypertension only.

STUDY DESIGN: This was a prospective study of 605 pregnant women

preeclampsia. Avoidance of exposure to environmental tobacco smoke

in pregnancy may decrease the risk of preeclampsia.

without chronic hypertension. Maternal smoking status at 24-26 weeks

gestation was defined by plasma cotinine: >3.0 ng/mL current
smokers, 0.20-3.00 ng/mL previous and passive smokers, and
<0.20 ng/mL nonsmokers.

CONCLUSION: Previous and passive smoking may increase the risk of

Key words: cotinine, gestational hypertension, passive smoker,

preeclampsia, previous smoker

Cite this article as: Luo Z-C, Julien P, Wei S-Q, et al. Plasma cotinine indicates an increased risk of preeclampsia in previous and passive smokers. Am J Obstet Gynecol
2014;210:232.e1-5.

obacco smoking, or in short

smoking, is a well-known risk
factor for a number of adverse pregnancy
outcomes including fetal growth restriction, preterm delivery, and placental
abruption.1,2 Paradoxically, self-reported

From the Department of Obstetrics and

Gynecology, Sainte-Justine Hospital, University
of Montreal, Montreal (Drs Luo, Wei, Audibert,
and Fraser), and Department of Endocrinology
and Nephrology, Quebec Hospital Research
Center, Laval University, Quebec City
(Dr Julien), Quebec, and Department of
Obstetrics and Gynecology, Kingston General
Hospital, Queens University, Kingston, Ontario
(Dr Smith), Canada; and Ministry of EducationShanghai Key Laboratory of Childrens
Environmental Health, Xinhua Hospital,
Shanghai Jiao-Tong University School of
Medicine, Shanghai, China (Dr Luo).
Received June 27, 2013; revised Sept. 9, 2013;
accepted Sept. 30, 2013.
This work was supported by a research grant
from the Canadian Institutes of Health Research
(grant number 78879).
The authors report no conict of interest.
Reprints not available from the authors.
0002-9378/$36.00
2014 Mosby, Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2013.09.041

smoking during pregnancy has been

consistently associated with a reduced
risk of preeclampsia3-6ea serious pregnancy complication characterized by the
de novo onset of hypertension and proteinuria occurring >20 weeks gestation
in women without known chronic hypertension or protenuria.7 The potential
protective effect of active smoking against
preeclampsia could be due to the gaseous
tobacco combustion molecule carbon
monoxide, which has cytoprotective effects on endothelial cells and antiapoptotic
properties in the human placenta.8,9 It
remains controversial whether there is a
protective effect for previous smokers,10-12
and the evidence has been scanty for
passive smokers or exposure to environmental tobacco smoke. The current body
of evidence largely comes from studies
based on self-reported smoking status.
Misclassications and inaccuracies of
exposure according to self-reports may
distort the true relationship, especially for
passive smokers notoriously vulnerable to
reporting errors.13 Whether there is any
biologically meaningful current exposure
burden in previous smokers is uncertain
without a biomarker measurement. These
limitations can be resolved if we use

232.e1 American Journal of Obstetrics & Gynecology MARCH 2014

a biomarker-based smoking exposure

measure. However, there have been very
few and limited studies on biomarkerbased smoking exposure and the risk
of gestational hypertension and preeclampsia. We could identify only 2 such
original studies; both addressed the risk
of preeclampsia in current smokers
only.14,15 The present study sought to
assess the risk of gestational hypertension and preeclampsia in current, previous, and passive smokers according
to plasma cotinine levels. We hypothesized that previous and passive smoking
may be associated with an increased
risk of gestational hypertension and
preeclampsia due to the deleterious
placental effects of previous or current
exposure to numerous tobacco chemicals in the absence of signicant current
exposure to carbon monoxide that may
explain the reduced risk of preeclampsia
in current smokers.

M ATERIALS

AND

M ETHODS

Study design
This was a prospective pregnancy cohort study using the plasma specimen
bank constituted in the International
Trial of Antioxidant Supplementation

Obstetrics

www.AJOG.org
(vitamins C and E) for the Prevention of
Preeclampsia (INTAPP). The trial was
conducted in Canada and Mexico from
2004 through 2006, and found no association between antioxidant supplementation (from 12-18 weeks gestation
onwards) and the risk of developing
preeclampsia.16 Canadian INTAPP subjects were reconsented to participate in a
biobank (n 733) for further research
on pregnancy complications. Excluding
46 subjects with chronic hypertension
and 82 subjects without maternal plasma
specimen available at 24-26 weeks gestation for the measurement of plasma
cotinine, the nal study cohort included
605 subjects. During INTAPP, participants were requested to donate a 14-mL
blood specimen at 24-26 weeks gestation into 2 7-mL EDTA-containing
tubes. Patients were aware in advance
that they would be giving a blood sample. The study was approved by the
University of Montreal Sainte-Justine
Hospital Research Ethics Board. Maternal characteristics and clinical outcomes were similar and not signicantly
different between Canadian subjects
who consented to contribute to the
biobank versus those who did not.
Mexican subjects did not participate as
it was not feasible to reconsent INTAPP
Mexican participants. In INTAPP, women were stratied according to the
presence or absence of risk factors for
preeclampsia. Women were in the highrisk stratum for preeclampsia if they
met at least 1 of the 4 criteria: prepregnancy chronic hypertension, prepregnancy diabetes, a multiple pregnancy, or
a history of preeclampsia; the remaining
subjects were in the low-risk stratum.
Women with chronic hypertension were
excluded in the present study because
the diagnosis of gestational hypertension
is not applicable to such patients. The
study denitions of gestational hypertension and preeclampsia were according to the criteria of the Society of
Obstetricians and Gynecologists of
Canada: gestational hypertension was
dened as de novo hypertension (2
readings of diastolic blood pressure
90 mm Hg taken 4 hours apart)
occurring at 20 weeks gestation; preeclampsia was dened as gestational

hypertension with de novo proteinuria

(urine protein dipstick test 2 or urinary excretion of 0.3 g in 24-hour
urine collection).7 Sensitivity analyses
were conducted to assess whether the
main ndings remained valid if alternatively, gestational hypertension was
dened as diastolic blood pressure
90 mm Hg and/or systolic blood
pressure 140 mm Hg (the Canadian
denition considered diastolic blood
pressure only).

Plasma cotinine assays

Plasma specimens were stored at e80 C
until assays. Maternal plasma cotinine
(ng/mL) at 24-26 weeks gestation was
measured using an enzyme-linked immunosorbent assay kit (Calbiotech,
Spring Valley, CA). Based on measurements using standard cotinine concentrations and blank controls provided by
the kit, the detection limit was 0.20 ng/
mL; intraassay and interassay coefcients
of variation were 6.0% and 10.1% (at
5.0 ng/mL), respectively.
Smoking status according to plasma
cotinine
Because only limited information on
smoking status was obtained in INTAPPe
the question for capturing smoking status
was only a limited part of the INTAPP
baseline questionnaire (did you ever
smoke in this pregnancy?)ewithout information on smoking cessation during
pregnancy in subsequent visits, the number of cigarettes smoked, or exposure to
environmental tobacco smoke, the present study dened smoking status according to plasma cotinine. Maternal
smoking status at 24-26 weeks gestation
was dened according to plasma cotinine:
>3.00 ng/mL current smokers, 0.203.00 ng/mL previous or passive smokers
(impossible to distinguish between the
two), and <0.20 ng/mL nonsmokers
(reference group). The use of the relatively
lower circulating cotinine concentration
cutoff of 3.0 ng/mL to dene current
smokers has been recommended recently
in contrast to the previously commonly
used 14-ng/mL cutoff in studies of early
years, considering the decreasing numbers
of smokers and the ban of smoking in
most public facilities and consequently

Research

lower background exposure to environmental tobacco smoke in recent decades

in North America.17 The 0.20-ng/mL
cutoff in plasma cotinine to detect even
light passive exposure to tobacco smoke
is similar to the 0.21-ng/mL cutoff reported in a recent study.18
Sensitivity analyses were conducted
to examine whether the main ndings
remained valid if alternatively, plasma
cotinine >4.85 ng/mL was used to dene current smokersea recently recommended cutoff for Caucasians,17 the
majority ethnic group in the study populationeor the previously commonly
used 14.0-ng/mL cutoff was applied to
dene current smokers.

Statistic analysis
Logistic regression was used to estimate
the crude and adjusted odds ratios
(OR) with 95% condence intervals (CI)
of developing gestational hypertension
only, preeclampsia, or either condition
in association with current, previous,
and passive smoking. The adjusted ORs
were controlled for prespecied potential confounding factors including risk
stratum (low risk, high risk), maternal
ethnicity (Caucasian, others), age (35
years, yes/no), primiparity (yes/no),
prepregnancy obesity (body mass index
30 kg/m2, yes/no), education (university, yes/no), employment (yes/no), and
treatment group (antioxidant supplementation, yes/no). The risk stratum
was used rather than individual risk
conditions in multivariate logistic regression to reduce the number of covariables and improve the stability of the
regression models. Two-sided P values
< .05 were considered statistically signicant. All analyses were performed
using SAS software (version 9.2; SAS
Institute Inc, Cary, NC). Ad hoc power
calculations indicated a power of
80.5% to detect an OR of 4.0 association of previous and secondhand
smoking with gestational hypertension
and preeclampsia.

R ESULTS
According to plasma cotinine at 24-26
weeks gestation, 47 pregnant women
were smokers, 42 were previous or passive smokers, and 516 were nonsmokers

MARCH 2014 American Journal of Obstetrics & Gynecology

232.e2

Research

Obstetrics

in the study cohort. Table 1 presents

maternal characteristics according to
smoking status. There were no signicant differences by maternal smoking
status in the proportions of women of
non-Caucasian ethnicity, age 35 years,
nulliparity, prepregnancy obesity, highrisk stratum, or antioxidant treatment
group. There was a higher proportion
of women unemployed or with completed education lower than university
among current smokers than among
previous and passive smokers or among
nonsmokers.
A total of 30 subjects (5.0%) developed preeclampsia, and 67 subjects
(11.1%) developed gestational hypertension only (without proteinuria). As
compared to nonsmokers, there was a
substantially increased risk of preeclampsia among previous and passive
smokers (crude OR, 5.84; 95% CI,
2.40e14.22; P < .001), and the risk
elevation changed little and remained
statistically signicant after adjusting for
risk stratum, obesity, and other potential
confounders (adjusted OR, 6.06; 95%
CI, 2.32e15.85; P < .001) (Table 2).
There were no signicant changes in
the risks of gestational hypertension,
preeclampsia, or either condition among
current smokers, although there was a
nonsignicant trend of lower risk of
developing either condition (adjusted
OR, 0.64; 95% CI, 0.24e1.76; P .38).
Identical results were observed for
preeclampsia when alternatively, gestational hypertension was dened as diastolic blood pressure 90 mm Hg and/
or systolic blood pressure 140 mm Hg,
because the number of preeclamptic
subjects remained the same (n 30). No
patients with only high systolic blood
pressure developed proteinuria in the
study cohort. The results for developing
gestational hypertension only changed
slightly but maintained the same pattern
(data not shown).
Similar results were observed if alternatively, plasma cotinine >4.85 ng/mL
was used as the cutoff to dene current
smokers (n 44), and 0.20-4.85 ng/mL
to dene previous and passive smokers
(n 45). For example, as compared to
nonsmokers, there remained a substantially increased risk of preeclampsia

www.AJOG.org

TABLE 1

Maternal characteristics by smoking status according to plasma

cotinine at 24-26 weeks gestation
Smoking status
(plasma cotinine)

Current
Previous or
Nonsmokers passive smokers smokers
(<0.20 ng/mL) (0.20-3.00 ng/mL) (>3.00 ng/mL) P valuea

516

42

47

Plasma cotinine, ng/mL

Median

0.00

0.71

63.4

Mean

0.00

0.90

64.8

0.67

52.7

SD
Minimal

0.00

0.22

3.3

Maximal

0.00

2.67

196.7

Age 35 y
Ethnicity, non-Caucasian

108 (20.9)

9 (21.4)

16 (34.0)

.12

57 (11.1)

2 (4.8)

7 (14.9)

.30

Nulliparous

426 (82.6)

34 (81.0)

34 (72.3)

.22

Education, less than

university

167 (32.4)

15 (35.7)

29 (61.7)

.0003

36 (7.0)

3 (7.1)

8 (17.0)

.04

85 (16.5)

6 (14.3)

7 (14.9)

.90

High-risk stratum

153 (29.7)

17 (40.5)

19 (40.4)

.13

Antioxidant treatment

245 (47.5)

20 (47.6)

23 (48.9)

.98

Unemployed
Obese

Data presented are n (%), unless otherwise specified.

a

P values in c2 tests for differences in proportions among 3 study groups; b All plasma cotinine values below limit of detection
(0.20 ng/mL) were set to 0 in calculating descriptive statistics; c Prepregnancy body mass index 30 kg/m2.

Luo. Plasma cotinine and preeclampsia. Am J Obstet Gynecol 2014.

among previous and passive smokers

(adjusted OR, 5.57; 95% CI, 2.16e14.36;
P < .001), while there was no signicant
risk change among current smokers
(adjusted OR, 1.09; 95% CI, 0.23e5.25;
P .91). Similar ndings were also
observed if plasma cotinine >14.0 ng/mL
was used as the cutoff to dene current
smokers (n 40), and 0.20-14.0 ng/mL
to dene previous and passive smokers
(n 49). As compared to nonsmokers,
there remained a substantially increased
risk of preeclampsia among previous
and passive smokers (adjusted OR, 5.05;
95% CI, 1.98e12.89; P < .001).
If plasma cotinine was treated as a
continuous variable, there were no signicant associations between increasing
plasma cotinine concentrations and the
risks of developing gestational hypertension, preeclampsia, or either condition (all P > .2).

232.e3 American Journal of Obstetrics & Gynecology MARCH 2014

C OMMENT
Main findings
To our knowledge, this is the rst report
on the risk of preeclampsia among previous and passive smokers based on a
biomarker indicator of tobacco exposure. A markedly increased risk of preeclampsia was observed among previous
and passive smokers according to plasma
cotinine at midgestation. This nding
remained valid irrespective of the plasma
cotinine cutoff used to dene smoking
status.
Data interpretation and comparisons
with previous studies
A recent systematic review identied only
one study on the risk of preeclampsia
in self-reported passive smokers19; the
study reported a nonsignicantly lower
risk of preeclampsia comparing passive

Obstetrics

www.AJOG.org

TABLE 2

Maternal smoking status according to plasma cotinine in association

with gestational hypertension and preeclampsia
Smoking exposure according to plasma cotinine

Variable

Nonsmokers
(<0.20 ng/mL)

Previous or
passive smokers
(0.20-3.00 ng/mL)

Current smokers
(>3.00 ng/mL)

n (605)

516

42

47

GH or preeclampsia
n (%)

79 (15.3)

Crude OR (95% CI)

a

Adjusted OR (95% CI)

1.0 (ref)
1.0 (ref)

13 (31.0)

5 (10.6)

2.48 (1.24e4.98)

0.66 (0.25e1.72)

2.63 (1.26e5.47)

0.64 (0.24e1.76)

Preeclampsia
n (%)

20 (3.9)

8 (19.1)

2 (4.3)
c

1.10 (0.25e4.87)

Crude OR (95% CI)

1.0 (ref)

5.84 (2.40e14.22)

Adjusted ORa (95% CI)

1.0 (ref)

6.06 (2.32e15.85)c

1.04 (0.22e4.95)

5 (11.9)

3 (6.4)

1.0 (ref)

1.28 (0.48e3.43)

0.53 (0.16e1.76)

1.0 (ref)

1.48 (0.54e4.07)

0.52 (0.15e1.81)

GH only
n (%)

59 (11.4)

Crude OR (95% CI)

a

Adjusted OR (95% CI)

CI, confidence interval; GH, gestational hypertension; OR, odds ratio; ref, reference.
a

ORs adjusted for maternal ethnicity (Caucasian, others), age (35 y, yes/no), parity (nulliparous, yes/no), education
(university, yes/no), unemployment (yes/no), obesity (body mass index 30 kg/m2, yes/no), and risk stratum (low risk, high
risk); b P < .01; c P < .001.

Luo. Plasma cotinine and preeclampsia. Am J Obstet Gynecol 2014.

smokers to nonsmokers.20 There have

been conicting ndings concerning the
risk of preeclampsia among self-reported
previous smokers.10-12 In contrast, our
biomarker-based exposure data suggest
an increased risk of preeclampsia among
previous and passive smokers, although
we could not distinguish between the
two.
Two previous studies based on a
biomarker smoking exposure conrmed
the protective effect of active smoking
against the development of preeclampsia:
Janakiraman et al14 observed a lower risk
using saliva cotinine to identify smokers
(130 smokers, 594 nonsmokers) but not
statistically signicantly so after adjusting
for other maternal risk factors, while Lain
et al15 observed a lower risk using urine
cotinine to identify smokers (50 preeclamptic cases, 50 controls). We did not
observe any signicant effect of smoking
on the risk of preeclampsia among current smokers, although there was a trend

of lower risk in developing either gestational hypertension or preeclampsia.

Caution is warranted in data interpretation since the power to detect a moderate
protective effect is relatively low in our
study cohort.
The mechanisms underlining the
increased risk of preeclampsia among
previous and passive smokers are unclear. We suspect that this could be
due to the adverse chronic effects of low
tobacco exposure in the absence of signicant exposure to certain transient
protective factors such as carbon monoxide in association with current smoking.8 It has been proposed that carbon
monoxide, a low moleculareweight
product of tobacco combustion, may be
the active agent in decreasing the risk of
preeclampsia.8 Indeed, a large Swedish
cohort study observed a lower risk
of preeclampsia among active tobacco
users but not smokeless nicotine snuff
users (absence of carbon monoxide)

Research

compared to nonnicotine users.4 Exposure to ambient carbon monoxide has

been associated with a reduced risk of
preeclampsia.21 Active smokers have
lower levels of plasma soluble fms-like
tyrosine kinase 1,22 an antiangiogenic
factor strongly predictive of the risk of
preeclampsia.23 Carbon monoxide has
been shown to down-regulate soluble
fms-like tyrosine kinase 1 release from
vascular cells in vitro studies.24 However, tobacco smoke contains numerous
chemicals, and certain tobacco combustion chemicals may exert a deleterious
effect. Smoking is associated with
increased risks of fetal growth restriction,
preterm birth, and placental abruptioneall may be partly related to impaired
placental implantation, a critical step in
the development of preeclampsia.25,26 It
can be speculated that certain tobacco
combustion chemicals may impair placental implantation, and consequently
confer an increased risk of preeclampsia.
However, this deleterious effect may be
offset or more than compensated by
certain protective tobacco combustion
molecules such as carbon monoxide
among active smokers, resulting in a
commonly observed reduced risk of
preeclampsia. In contrast, for previous
and passive smokers, the very small
protective effect of very low carbon
monoxide levels may be overwhelmed
by the deleterious effects of numerous
other hazardous tobacco chemicals.

Strengths and limitations

The main strength of the study is the
plasma cotinine providing an accurate
measure of current smoking exposure
in a prospective pregnancy cohort. The
study has limitations. First, the INTAPP
cohort was not originally designed to
examine the effects of smoking on the
risk of gestational hypertension and
preeclampsia. We are unable to distinguish between previous and passive
smokers according to plasma cotinine.
Our data should be interpreted according to the biomarker evidence on
maternal smoking status at 24-26 weeks
gestation only. The protective effect of
smoking against preeclampsia may be
absent for current smokers in the rst
half of pregnancy who quit in the second

MARCH 2014 American Journal of Obstetrics & Gynecology

232.e4

Research

Obstetrics

half of pregnancy.4 This may partly

explain the lack of a signicant effect
among current smokers in the study
cohort, although it is somewhat unlikely
that a woman would quit smoking if she
remained a smoker up to 6-7 months of
pregnancy. Patients were aware of blood
specimen collection in advance. However, it is somewhat unlikely that smokers
could have intentionally stopped smoking for a few days before the study visit to
lower plasma cotinine concentration
since they were unaware of the cotinine
measurement at the time of specimen
collection and were reconsented 2-3
years later. The plasma cotinine assay
technique used in the present study did
not allow for the detection of cotinine
<0.20 ng/mL, and thus could not capture
extremely low levels of exposure to
tobacco smoke. However, this limit of
detection appears to be sufcient for
identifying even light passive exposure
to tobacco smoke.18 Future studies may
use higher sensitivity cotinine assay
methods such as liquid chromatographymass spectrometry to capture very low
environmental tobacco exposure levels.

Conclusion
Previous and passive smoking may increase the risk of preeclampsia. Independent larger cohort studies with
carefully planned both questionnairebased and biomarker-based smoking
exposure measurements are required to
conrm this nding, and distinguish the
effects between previous and passive
smoking. Avoidance of exposure to
environmental tobacco smoke during
pregnancy may decrease the risk of
preeclampsia.
ACKNOWLEDGMENTS
We would like to thank the nursing and medical
staffs at all study participating hospitals.

REFERENCES
1. Higgins S. Smoking in pregnancy. Curr Opin
Obstet Gynecol 2002;14:145-51.

www.AJOG.org
2. Cnattingius S. The epidemiology of smoking
during pregnancy: smoking prevalence,
maternal characteristics, and pregnancy outcomes. Nicotine Tob Res 2004;6(Suppl):
S125-40.
3. Zhang J, Klebanoff MA, Levine RJ,
Puri M, Moyer P. The puzzling association
between smoking and hypertension during
pregnancy. Am J Obstet Gynecol 1999;181:
1407-13.
4. Wikstrom AK, Stephansson O, Cnattingius S.
Tobacco use during pregnancy and preeclampsia risk: effects of cigarette smoking and
snuff. Hypertension 2010;55:1254-9.
5. Cnattingius S, Mills JL, Yuen J, Eriksson O,
Salonen H. The paradoxical effect of smoking
in preeclamptic pregnancies: smoking reduces
the incidence but increases the rates of perinatal
mortality, abruptio placentae, and intrauterine
growth restriction. Am J Obstet Gynecol
1997;177:156-61.
6. Yang Q, Wen SW, Smith GN, et al. Maternal
cigarette smoking and the risk of pregnancyinduced hypertension and eclampsia. Int J Epidemiol 2006;35:288-93.
7. Magee LA, Helewa M, Moutquin JM,
von DP. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. J Obstet Gynaecol Can 2008;30(Suppl):
S1-48.
8. Bainbridge SA, Sidle EH, Smith GN. Direct
placental effects of cigarette smoke protect
women from pre-eclampsia: the specic roles
of carbon monoxide and antioxidant systems
in the placenta. Med Hypotheses 2005;64:
17-27.
9. Bainbridge SA, Belkacemi L, Dickinson M,
Graham CH, Smith GN. Carbon monoxide inhibits hypoxia/reoxygenation-induced apoptosis
and secondary necrosis in syncytiotrophoblast.
Am J Pathol 2006;169:774-83.
10. England L, Zhang J. Smoking and risk of
preeclampsia: a systematic review. Front Biosci
2007;12:2471-83.
11. England LJ, Levine RJ, Qian C, et al.
Smoking before pregnancy and risk of gestational hypertension and preeclampsia. Am J
Obstet Gynecol 2002;186:1035-40.
12. Xiong X, Zhang J, Fraser WD. Quitting
smoking during early versus late pregnancy:
the risk of preeclampsia and adverse birth
outcomes. J Obstet Gynaecol Can 2009;31:
702-7.
13. George L, Granath F, Johansson AL,
Cnattingius S. Self-reported nicotine exposure
and plasma levels of cotinine in early and
late pregnancy. Acta Obstet Gynecol Scand
2006;85:1331-7.
14. Janakiraman V, Gantz M, Maynard S,
El-Mohandes A. Association of cotinine levels

232.e5 American Journal of Obstetrics & Gynecology MARCH 2014

and preeclampsia among African-American

women. Nicotine Tob Res 2009;11:679-84.
15. Lain KY, Powers RW, Krohn MA,
Ness RB, Crombleholme WR, Roberts JM.
Urinary cotinine concentration conrms the
reduced risk of preeclampsia with tobacco
exposure. Am J Obstet Gynecol 1999;181:
1192-6.
16. Xu H, Perez-Cuevas R, Xiong X, et al. An
international trial of antioxidants in the prevention
of preeclampsia (INTAPP). Am J Obstet Gynecol
2010;202:239.e1-10.
17. Benowitz NL, Bernert JT, Caraballo RS,
Holiday DB, Wang J. Optimal serum cotinine
levels for distinguishing cigarette smokers
and nonsmokers within different racial/
ethnic groups in the United States between
1999 and 2004. Am J Epidemiol 2009;169:
236-48.
18. Sasaki S, Braimoh TS, Yila TA, Yoshioka E,
Kishi R. Self-reported tobacco smoke exposure and plasma cotinine levels during
pregnancyea validation study in Northern
Japan. Sci Total Environ 2011;412-413:
114-8.
19. Salmasi G, Grady R, Jones J,
McDonald SD. Environmental tobacco smoke
exposure and perinatal outcomes: a systematic
review and meta-analyses. Acta Obstet Gynecol
Scand 2010;89:423-41.
20. Kukla L, Hruba D, Tyrlik M. Smoking
and damages of reproduction: evidence of
ELSPAC. Cent Eur J Public Health 2001;9:
59-63.
21. Zhai D, Guo Y, Smith G, Krewski D,
Walker M, Wen SW. Maternal exposure to
moderate ambient carbon monoxide is associated with decreased risk of preeclampsia. Am J
Obstet Gynecol 2012;207:57-9.
22. Jeyabalan A, Powers RW, Durica AR,
Harger GF, Roberts JM, Ness RB. Cigarette
smoke exposure and angiogenic factors in
pregnancy and preeclampsia. Am J Hypertens
2008;21:943-7.
23. Levine RJ, Maynard SE, Qian C, et al.
Circulating angiogenic factors and the risk of
preeclampsia. N Engl J Med 2004;350:
672-83.
24. Cudmore M, Ahmad S, Al-Ani B, et al.
Negative regulation of soluble Flt-1 and soluble
endoglin release by heme oxygenase-1. Circulation 2007;115:1789-97.
25. Myatt L, Clifton RG, Roberts JM, et al.
The utility of uterine artery Doppler velocimetry in prediction of preeclampsia in a lowrisk population. Obstet Gynecol 2012;120:
815-22.
26. Redman CW, Sargent IL. Latest advances in
understanding preeclampsia. Science 2005;308:
1592-4.