Published by Oxford University Press on behalf of the International Epidemiological Association The Author 2005; all rights reserved.

. Advance Access publication 22 November 2005

International Journal of Epidemiology 2006;35:288293 doi:10.1093/ije/dyi247

Maternal cigarette smoking and the risk of pregnancy-induced hypertension and eclampsia
Qiuying Yang,1,2,3* Shi Wu Wen,1,2,3,4 Graeme N Smith,5 Yue Chen,3,4 Daniel Krewski,3,4 Xi Kuan Chen1,2 and Mark C Walker1,2

Accepted

13 October 2005

Background Although previous studies have found that maternal smoking decreases the risk of pregnancy-induced hypertension (PIH), the difference of this effect between primiparous and multiparous women has not been well studied and the results of the exposureresponse relationships between maternal smoking and PIH are inconsistent. No previous study has specifically examined the relationship between maternal smoking and eclampsia. Methods We analysed data from a population-based retrospective cohort study of 3 153 944 singleton pregnancies in the US. The data were derived from the national linked birth/infant mortality database for 1998. Multiple logistic regressions were used to describe the relationship between cigarette smoking and PIH and eclampsia. The adjusted odds ratios (ORs) [95% confidence intervals (95% CIs)] for PIH were 0.80 (0.770.83) for primiparous women and 0.81 (0.780.83) for multiparous women among smokers compared with non-smokers. The corresponding adjusted ORs (95% CIs) for eclampsia were 0.74 (0.660.82) and 0.75 (0.680.83), respectively. For PIH, the adjusted OR (95% CI) for smokers vs non-smokers were 0.82 (0.790.86), 0.81 (0.780.83), 0.80 (0.770.83), and 0.88 (0.790.98), respectively, for 15, 610, 1120, and .20 cigarettes per day (test for trend: P 5 0.86). The corresponding figures for eclampsia were 0.85 (0.750.95), 0.74 (0.660.82), 0.68 (0.580.78), and 0.73 (0.491.04), respectively (test for trend: P 5 0.02). Maternal cigarette smoking decreases the risk of PIH and eclampsia, with a significant inverse exposureresponse relationship apparent for eclampsia. Smoking, pregnancy-induced hypertension, eclampsia, doseresponse, parity

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Results

Conclusion Keywords

Pregnancy-induced hypertension (PIH) is a major pregnancy complication, which may cause premature delivery, intrauterine growth restriction (IUGR), placental abruption, and fetal death, as well as maternal mortality and morbidity.1 The aetiology of PIH is largely unknown, although a number of risk factors have been identified.1,2 Maternal cigarette smoking is associated with
1 2 3 4 5

OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, Faculty of Medicine, Ontario, Canada. Ottawa Health Research Institute, Clinical Epidemiology Program, Ontario, Canada. McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, Ontario, Canada. Department of Epidemiology and Community Medicine, University of Ottawa, Ontario, Canada. Queens Perinatal Research Unit, Queens University, Ontario, Canada.

* Corresponding author. OMNI Research Group, Department of Obstetrics and Gynecology, The Ottawa Hospital, General Campus, 501 Smyth Road, Box 241, Ottawa, Ontario, Canada K1H 8L6. E-mail: qyang@ohri.ca

an increased risk of a number of adverse pregnancy outcomes, including placental abruption, placenta previa, premature rupture of the membranes, pre-term birth, IUGR, and perinatal death.36 Paradoxically, maternal smoking may decrease the risk of PIH and pre-eclampsia.511 Moreover, several researchers reported that women who quit smoking during early pregnancy also have a lower risk of hypertension in late gestation compared with non-smokers.8,12 However, a recent study found that cigarette smoking did not reduce the risk of developing pre-eclampsia.13 Primiparous and multiparous women may have different causes of PIH and pre-eclampsia.14 It is speculated that the effect of smoking may vary among them, which could be a reason for the inconsistent findings in previous investigations. Most previous studies combined primiparous and multiparous women, or focused only on primiparous women.6,8,12,15 Only two studies were based on analyses stratified by parity and the results were inconsistent.9,10 A large-scale study of the type

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conducted here is needed in order to evaluate results for primiparous and multiparous women separately with adequate statistical power. Consistent exposureresponse relationships between maternal smoking and PIH and pre-eclampsia are also lacking.6,8,12,1517 Other issues also need to be addressed. Most previous studies did not adjust for important confounding factors in the relationship between smoking and pre-eclampsia, such as socioeconomic status,18,19 and weight gain during pregnancy.19 No studies have specifically examined the relationship between maternal smoking and eclampsia, probably owing to the small number of cases available for analysis. The present analysis is based on data from a large populationbased study in the US. Our specific objective is to examine associations between maternal smoking and PIH and eclampsia in both primiparous and multiparous women and to determine whether smoking may affect PIH and eclampsia in a dose-dependent manner.

according to these characteristics. Crude and adjusted odds ratios (ORs) for maternal smoking associated with PIH and eclampsia were estimated using unconditional logistic regression. Potential confounding variables included in the regression models were maternal age, race, education, marital status, parity, alcohol drinking during pregnancy, adequacy of pre-natal care, weight gain during pregnancy, and gestational age. The modified Kessner index was applied to measure the adequacy of prenatal care which was pre-coded by the National Center for Health Statistics according to first trimester initiation of care and specified number of pre-natal care visits for the gestational age at delivery.22 The analysis was further stratified by parity. Exposureresponse relationships were assessed by testing for linear trend. All analyses were performed using SAS-PC statistical software version 8 (SAS Inc., NC).

Results
The data were derived from the national linked birth/infant mortality database for 1998. A total of 3 153 944 singleton pregnancies were included initially (except for California, Indiana, South Dakota, and New York State where information on maternal cigarette smoking was not available). We excluded women with cardiac disease (18 844 cases), diabetes (86 112 cases), chronic hypertension (20 796 cases), renal disease (8665 cases), gestational age ,20 weeks (6972 cases), and missing information on maternal smoking (185 867 cases) in states where data on tobacco use were recorded. We further excluded 279 175 women with missing covariates in multivariate analyses of PIH and 264 858 women in multivariate analyses of eclampsia. A total of 109 799 women with PIH were also excluded in the analysis of eclampsia. After these exclusions, 2 619 513 pregnancies were available for the analysis of PIH, along with 2 524 031 pregnancies for the analysis of eclampsia (some subjects had more than one exclusion condition). Maternal and fetal characteristics of the study subjects are shown in Table 1, along with the incidence of PIH and eclampsia (Table 1). About 12.7% of mothers smoked during pregnancy. The incidences of PIH and eclampsia were 3.7 and 0.3%, respectively. The incidence of both PIH and eclampsia was higher in non-smokers, teenage mothers, women >40 years of age, mothers whose gestational weight gain .45 pounds, and mothers who delivered their babies before 36 weeks. Multiparous women, mothers whose race was other than white and black, women whose weight gain was ,35 pounds, and those who delivered their babies .40 weeks were less likely to develop PIH and eclampsia. The risks of PIH and eclampsia in relation to maternal smoking are shown in Tables 2 and 3, respectively. The adjusted ORs [95% confidence intervals (95% CIs)] for PIH were 0.81 (0.790.83) for all women, 0.80 (0.770.83) for primiparous women, and 0.81 (0.780.83) for multiparous women among smokers compared with non-smokers. The corresponding adjusted ORs (95% CIs) for eclampsia were 0.75 (0.700.81), 0.74 (0.660.82), and 0.75 (0.680.83), respectively. Table 4 describes the exposureresponse relationships between maternal smoking and both PIH and eclampsia. Although a significant inverse exposureresponse relationship between maternal smoking and eclampsia was observed, the risk of PIH did not appear to depend strongly on the amount smoked.
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Methods
The data were derived from the 1998 US national linked birth/ infant mortality database provided by the National Center for Health Statistics, Centers for Disease Control and Prevention.20 Information on live births, fetal deaths, and infant deaths up to 1 year was recorded in the 50 states and the District of Columbia, pre-coded according to uniform specifications, and subjected to vigorous quality checks by the National Center for Health Statistics.21 Women with multiple births, gestational age ,20 weeks, cardiac disease, diabetes, chronic hypertension, renal disease, or no information on maternal smoking, were excluded from our analyses. This database included sociodemographic information on the parents, maternal lifestyle factors such as smoking and alcohol consumption during pregnancy, obstetric history, complications associated with pregnancy, maternal weight gain during pregnancy, type of delivery, birth weight, and gestational age at delivery. Subjects were classified into nonsmokers and smokers, with a smoker defined as a person who smoked at any time during pregnancy. The daily average smoking consumption was also recorded in one of four categories (15, 610, 1120, and .20 cigarettes per day). The sociodemographic information was collected from the mother or the medical records at the time of delivery when the birth certificate was completed. PIH and eclampsia were pre-coded in this database. PIH was referred to as an increase in blood pressure of at least 30 mm Hg systolic or 15 mm Hg diastolic on two measurements taken 6 h apart after the 20th week of gestation compared with previous assessment by professionals. Cases of chronic hypertension, defined as blood pressure persistently .140/90, diagnosed prior to onset of pregnancy or before the 20th week of gestation, were excluded from this diagnosis. Pre-eclampsia was defined as PIH with proteinuria of at least 11 or more on dipstick in two samples 6 h apart or .0.3 g in a 24 h urine collection. Eclampsia was referred to as the occurrence of convulsions and/or coma, unrelated to other conditions in women with signs and symptoms of pre-eclampsia. We tabulated the important characteristics of the study population and calculated the incidence of PIH and eclampsia

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Table 1 Maternal and fetal characteristics of pregnancies and the incidence of pregnancy-induced hypertension (PIH) and eclampsia in the US, 1998 Characteristic Maternal age (years) ,19 2024 2529 3034 3539 401 Race White Black Other Married Yes No Education (years) ,9 912 1315 161 Parity 0 1 21 Maternal smoking (cigarettes per day) Non-smoker 15 610 1120 211 Maternal drinking (drinks/week) Non-drinker 1 21 Weight gain during pregnancy (lbs) ,20 2135 3645 461 Pre-natal care Enough Medium Not enough Gestational age (weeks) 2031 3236 3740 411 Fetal sex Male Female 51.16 48.84 3.79 3.67 51.13 48.87 0.34 0.33 1.44 8.31 70.72 19.52 7.97 7.15 3.57 2.54 1.39 8.04 70.82 19.75 2.10 1.02 0.27 0.16 74.27 18.00 7.73 3.91 3.31 2.99 74.13 18.08 7.79 0.33 0.35 0.38 21.78 47.24 19.54 11.43 3.24 3.08 4.20 6.59 21.89 47.56 19.45 11.10 0.32 0.27 0.37 0.59 99.22 0.42 0.36 3.74 3.14 3.20 99.22 0.43 0.36 0.33 0.18 0.30 87.34 3.51 5.19 3.49 0.47 3.83 3.27 3.02 2.81 2.95 87.25 3.52 5.22 3.53 0.47 0.34 0.32 0.26 0.22 0.23 33.68 29.76 36.56 5.46 3.15 2.62 33.09 29.94 36.97 0.54 0.26 0.21 4.29 48.95 22.63 24.13 2.69 3.75 4.12 3.51 4.34 48.94 22.54 24.18 0.35 0.36 0.35 0.26 67.47 32.53 3.69 3.82 67.50 32.50 0.31 78.96 16.86 4.18 3.76 3.89 2.60 78.93 16.83 4.23 0.32 0.42 0.30 Percentage of subjects (n 5 2 619 513) 13.16 25.26 27.78 21.98 9.99 1.83 Percentage with PIH (n 5 97 778) 4.38 3.82 3.69 3.31 3.58 4.48 Percentage of subjects (n 5 2 524 031) 13.07 25.24 27.79 22.07 10.00 1.82 Percentage with eclampsia (n 5 8428) 0.51 0.36 0.30 0.26 0.29 0.40

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Table 2 Risk of PIH in pregnancies associated with maternal smoking by parity, US, 1998 Maternal smoking during pregnancy Non-smoker Smoker Incidence (%) 3.83 3.03 Age-adjusted odds ratios (95% CI) 1.00 (Reference) 0.76 (0.750.78) Adjusted odds ratios* (95% CI) 1.00 (Reference) 0.81 (0.790.83)

Table 4 Risk of PIH and eclampsia in singleton pregnancies associated with intensity of maternal smoking, US, 1998 Intensity of maternal smoking during pregnancy (cigarettes per day) PIH (n 5 2 619 513) Non-smoker 15 610 1.00 (Reference) 0.85 (0.820.88) 0.78 (0.760.81) 0.73 (0.700.75) 0.76 (0.690.85) 1.00 (Reference) 0.82 (0.790.86) 0.81 (0.780.83) 0.80 (0.770.83) 0.88 (0.790.98) Crude odds ratios (95% CI) Adjusted odds ratios (95% CI)

All women (n 5 2 619 513)

Primiparous women (n 5 882 197) Non-smoker Smoker 5.55 4.68 1.00 (Reference) 0.84 (0.820.87) 1.00 (Reference) 0.80 (0.770.83)

1120 211 Eclampsia (n 5 2 524 031)

Multiparous women (n 5 1 737 316) Non-smoker Smoker 2.92 2.43 1.00 (Reference) 0.84 (0.820.86) 1.00 (Reference) 0.81 (0.780.83)

Non-smoker 15 610 1120 211

1.00 (Reference) 0.94 (0.841.06) 0.75 (0.680.84) 0.63 (0.550.73) 0.66 (0.440.94)

1.00 (Reference) 0.85 (0.750.95) 0.74 (0.660.82) 0.68 (0.580.78) 0.73 (0.491.04)

OR and 95% CI with adjustment for maternal age, race, education, marital

status, maternal drinking, maternal weight gain during pregnancy, adequacy of pre-natal care, and gestational age.

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Table 3 Risk of eclampsia in pregnancies associated with maternal smoking by parity, US, 1998 Maternal smoking during pregnancy Non-smoker Smoker Incidence (%) 0.34 0.26 Age-adjusted odds ratios (95% CI) 1.00 (Reference) 0.72 (0.670.77) Adjusted odds ratios*

OR and 95% CI with adjustment for maternal age, race, education, marital status, parity, maternal drinking, maternal weight gain during pregnancy, adequacy of pre-natal care and gestational age. Trend test for PIH, P 5 0.8603; trend test for eclampsia, P 5 0.0197.

(95% CI)
1.00 (Reference) 0.75 (0.700.81)

All parous women (n 5 2 524 031)

Primiparous women (n 5 835 264) Non-smoker Smoker 0.55 0.45 1.00 (Reference) 0.77 (0.690.86) 1.00 (Reference) 0.74 (0.660.82)

Multiparous women (n 5 1 688 767) Non-smoker Smoker 0.24 0.20 1.00 (Reference) 0.83 (0.750.91) 1.00 (Reference) 0.75 (0.680.83)

OR and 95% CI with adjustment for maternal age, race, education, marital

status, maternal drinking, maternal weight gain during pregnancy, adequacy of pre-natal care, and gestational age.

Discussion
The present large-scale population-based study provides evidence that maternal cigarette smoking is associated with a decreased risk of developing PIH and eclampsia in both primiparous and multiparous women. There was a significant inverse exposureresponse relationship between maternal smoking and eclampsia. In a previous systematic review of available data from studies conducted in different countries, an odds ratio of 0.7 for PIH for current vs never smokers was reported,23 a value similar to the adjusted ORs of 0.80 for PIH and 0.75 for eclampsia in the present study. Our study, which involves a much larger sample size than previous studies by Marten et al.10 and Xiong et al.9 indicated that the effects of maternal smoking on PIH and eclampsia were similar in primiparous and multiparous women. Several papers have reported that maternal smoking may have relatively little impact on pre-eclampsia in multiparous women.1,9,24,25 However, the lack of an association in multiparous women may be due to inadequate sample size, since the incidence of preeclampsia is low in multiparous women.9 Our findings are consistent with those reported by Conde-Agudelo and Belizan26

in which the pattern of risk factors among primiparous and multiparous women were quite similar. In our study, eclampsia, but not PIH, demonstrated an inverse exposureresponse relationship. Ansari et al.27 also found that the association of eclampsia with tobacco smoking was inverse and dose related when they conducted a casecontrol study to examine the risk of eclampsia in relation to several maternal characteristics and exposure. Their results were very comparable with ours. Potential biological mechanisms underlying observed association between maternal smoking and PIH/pre-eclampsia/ eclampsia are not fully understood. Pre-eclampsia has been linked initially to the immune system.21 Women who smoke may have an underlying decreased immune response and, therefore, may be less likely to develop the exaggerated immune response seen in pre-eclampsia.28 Pre-eclampsia is a hypocalciuric state.29 Smoking, which alters parathyroid hormone levels30 and adrenal cortex steroid production,31,32 might contribute to an altered calcium metabolism. Zhang et al.8 speculated that smoking might induce some liver enzymes that could metabolize any endothelial toxins produced by the placenta because past smoking appeared to continue its protective effect during pregnancy. However, the incidence of phenobarbital (a well-known inductor of liver enzyme bioactivity) among women with hypertension was similar to that in the rest of the population. Since smokers are exposed to numerous chemicals present in cigarette smoke, it is important to determine the compound(s) that are involved in reducing the risk of developing PIH/pre-eclampsia/eclampsia. Thiocyamite may have a hypotensive effect.33 Nicotine may inhibit the production of thromboxane A2, a vascoconstrictor and a platelet aggregation stimulator.34 However, a recent study on the use of snuff (a non-combustible form of tobacco) in pregnancy demonstrated no effect on the incidence of pre-eclampsia, suggesting that the factors associated with a decreased incidence of pre-eclampsia in cigarette smokers may be combustible

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substances such as carbon monoxide.35,36 Cigarette smoking may also up-regulate antioxidant systems within the placenta,36 which is consistent with previous suggestions that placental oxidative stress may be involved in the aetiology of preeclampsia.2 The mechanism may be mediated by the effect of maternal smoking on endogenous oestrogen levels. Maternal smoking during pregnancy has been reported to lower oestrogen levels by 20%.37,38 Plasma oestrogen levels are lower in preeclamptic patients than in the normal pregnancies39,40 and using estradiol benzoate and progesterone for the treatment of severe pre-eclampsia has obtained good results.41 However, these studies were based on small number of patients and the possibility of type I error could not be excluded. Our study has several strengths in comparison with previous studies in this area. It is the largest population-based study conducted to date that allowed us insight into the relationship between maternal smoking and eclampsia. PIH and eclampsia were coded according to uniform specifications. The data contain detailed information on average daily cigarette consumption during pregnancy as well as maternal demographic and medical information. The limitations of using the birth certificate data must be acknowledged. As cigarette use during pregnancy was selfreported, underreporting is likely.42 In this case, the true magnitude of the effect of maternal smoking on PIH and eclampsia may have been underestimated. There was no information on paternal smoking or second-hand smoke, which might confound the relationship between maternal smoking and PIH, although Parazzini et al.11 did not find a relationship between paternal smoking and the risk of PIH. In addition, there was no information on pre-pregnancy smoking or smoking cessation during pregnancy. Occasional smokers were included in non-smokers in this database, which might attenuate our effect estimates. Another concern is related to possible misclassification of pregnancy outcomes. As eclampsia is a severe and acute disease, the misclassification of eclampsia might be very low. However, the incidence of PIH in the database appears to be lower than in previous studies.1 If the probabilities of misclassification of each variable are the same for each category of the other variable (non-differential misclassification) and if the errors for different variables are independent, the estimated effect is usually biased toward the null value.43 There is no reason to believe that the misclassification of PIH and eclampsia is related to (or dependent on) smoking status. Therefore, the effect of smoking would be stronger if there is no misclassification of PIH and eclampsia. Unfortunately, we could not examine the smoking effect on pre-eclampsia from PIH additionally because only PIH and eclampsia were coded in our database. Despite the apparent protective effect of smoking on the risk of PIH and eclampsia, smoking is associated with substantial increases in neonatal mortality and morbidity. Smokers with preeclampsia demonstrated very high risks of perinatal mortality, abrupto placentae, and small-for-age infants.6 Perinatal outcomes were significantly less favourable among pre-eclamptics who smoked.44 Consequently, pregnant women should be strongly encouraged to quit smoking. Nonetheless, a better understanding of the mechanisms by which smoking may affect the pathogenesis of hypertension during pregnancy may

provide clues to preventive and therapeutic measures that may be taken in the future.

Acknowledgements
The study was supported by a grant for the PE-NET from the Heart & Stroke Foundation of Canada (HSF, PG-03-0175-PENET) and the Canadian Institutes of Health Research (CIHR, FMI-63194). Q.Y. is a CIHR/STIRRHS fellow. S.W.W. and G.N.S. are recipients of New Investigators Award from CIHR. Y.C. is a recipient of the CIHR Investigator Award. D.K. is the NSERC/ SSHRC/McLaughlin Chair in Population Health Risk Assessment at the University of Ottawa. X.K.C. is an International Fellow of the University of Ottawa. M.C.W. is a Career Scientist of the Ontario Ministry of Health, Canada.

Author contributions
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Study concept and design: Q.Y., S.W.W. and M.C.W.; Analysis of the data: Q.Y. and X.K.C.; Interpretation of data: Q.Y., S.W.W., G.N.S., Y.C., D.K. and M.C.W.; Drafting of the manuscript: Q.Y.; Critical revision of the manuscript for intellectual content: S.W.W., G.N.S., Y.C., D.K. and M.C.W.; Statistical expertise: Q.Y. and S.W.W.; and Administrative, technical, and material support: M.C.W.

Financial disclosure
None of the authors share any financial conflict of interest.

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