INTER-PREGNANCY CHANGE IN SMOKING STATUS AND HYPERTENSIVE
DISORDERS OF PREGNANCY IN WA STATE 2003-2012
Sylvia Badon and Jennifer Carroll Preceptor: Amanda Phipps
Abstract Objective: To compare the risk of hypertensive disorders of pregnancy in women according to changes in smoking patterns across their first and second singleton pregnancies.
Methods: In this population-based cohort study, we used maternally linked longitudinal birth certificate data selected from the first two singleton births for women who delivered at least two full-term births in Washington state from 2003-2012 (N=25,773). We calculated Mantel- Haenszel relative risk estimates for gestational hypertensive disorders according to maternal smoking behavior, comparing all mothers who smoked during both pregnancies (N=5,476), only the first (N=3,563), or only the second pregnancy (N=3,312) to a random sample of women who did not smoke during either pregnancy (N=13,422). Women who did not smoke were frequency matched on year of first birth to mothers who smoked during either pregnancy. Analyses were adjusted for category of pre-pregnancy BMI. Additional analyses assessed the relative risk of hypertensive disorders according to the quantity of cigarettes smoked during the first trimester of the second pregnancy.
Results: Mothers who smoked during both pregnancies were less likely to experience gestational hypertensive disorders during their second pregnancy than mothers who never smoked (RR= 0.77, 95% CI: 0.65-0.92). No association was observed for mothers who smoked during their first pregnancy only (RR = 1.04, 95% CI: 0.86-1.25) or for those who smoked in their second pregnancy only (RR = 0.91, 95% CI: 0.74-1.11). Compared to never smokers, mothers who reported smoking between half a pack and a full pack per day during the first trimester of the second pregnancy (N=1,084) were less likely to be diagnosed with gestational hypertensive disorders (RR = 0.64, 95% CI: 0.43-0.94), whereas those who smoked more than a pack per day (N=423) were at slightly increased risk (RR = 1.40, 95% CI: 0.92-2.11); no association was observed for those who smoked less than half a pack per day during the first trimester (RR = 0.96, 95% CI: 0.74-1.24).
Conclusion: A significant protective association with gestational hypertensive disorders was seen in women who smoked during both pregnancies. The risk of gestational hypertensive disorders also appeared to vary considerably according to quantity of tobacco consumed, with a significantly reduced risk among smokers who consumed between half of a pack and a full pack of cigarettes per day during their first trimester, but an increased risk among those who smoked more than one pack per day during this time. Further study is needed to verify these relationships. These findings may have implications for clinicians who counsel or provide care for women who choose to smoke tobacco products during pregnancy.
2 Introduction
Hypertensive disorders of pregnancy include gestational hypertension (sustained high blood pressure with onset after the 20 th week of pregnancy in women with no history of hypertension and no evidence of proteinuria), preeclampsia (de novo hypertension and proteinuria with onset after the 20 th week of pregnancy), and eclampsia (the presence of seizures that cannot be attributed to other causes in women with preeclampsia) (1). In the United States, gestational hypertension affects 27 per 1,000 deliveries and preeclampsia affects 21 per 1,000 deliveries; incident rates for both of these conditions have been on the rise in recent years (2). Preeclampsia is associated with risk of a number of adverse outcomes including preterm birth, restriction of fetal growth, and perinatal mortality (35).
Although maternal smoking during pregnancy is associated with numerous adverse outcomes, including behavioral and cognitive disorders, mood disorders, the restriction of fetal growth, and low birth weight (6,7), an inverse relationship has been observed between maternal smoking and preeclampsia (812). To date, several large cohort studies investigating the relationship between maternal smoking and preeclampsia risk have been conducted (69,11,13). These studies have confirmed that maternal smoking is inversely associated with the condition, but have not addressed how the risk of such hypertensive disorders is affected by the level of maternal smoking or changes in those smoking habits during or between pregnancies. The objective of this project was to compare the risk of hypertensive disorders of pregnancy in women with two pregnancies according to changes in smoking patterns across those two pregnancies.
3 Methods
We conducted a population-based cohort study using maternally linked longitudinal birth certificate data selected from the first two singleton births for women in Washington State from 2003-2012. Data was collected via the Washington State birth certificate form during hospitalization for labor. All women who reported smoking during at least one of their first two pregnancies were included, as was a random sample of women who did not smoke during either pregnancy. Women who did not smoke during either pregnancy were frequency matched on year of first birth to women who smoked during either pregnancy. Women for whom information about hypertensive disorders during pregnancy was not available were excluded (N=199). Thus, we included 5,476 women who smoked during both pregnancies (yes-yes), 3,312 women who did not smoke during their first pregnancy but did smoke during their second pregnancy (no-yes), 3,563 women who smoked during their first pregnancy but did not smoke during their second pregnancy (yes-no), and 13,422 women who did not smoke during either pregnancy (no-no). The association of inter-pregnancy changes in smoking status with risk of hypertensive disorders in pregnancy was evaluated using Mantel-Haenszel adjusted relative risk estimates and their 95% confidence intervals. Associations were evaluated separately for each exposure group, relative to women who did not smoke in either pregnancy, controlling for race, inter-pregnancy period, and pre-pregnancy BMI. Potential confounders were identified from the scientific literature and were examined for an association with the exposure (smoking category) and outcome (hypertensive disorder in second pregnancy). Potential confounders considered included preeclampsia in first pregnancy (yes/no), inter-pregnancy interval (0-1, 2, 3, 4, 5 years), change in paternity between first and second pregnancy (yes/no), and the following characteristics in second pregnancy: pre- 4 pregnancy body mass index (BMI) (<18.5, 18.5-24.9, 25.0-29.9, 30 kg/m 2 ), maternal age (<20, 20-29, 30-34, 35 years), race (white, black, Asian, Hispanic, other), education (less than high school, high school diploma, more than high school), chronic hypertension (yes/no), and pre- existing or gestational diabetes (yes/no for each). Through this method, mothers race, pre- pregnancy BMI, and inter-pregnancy interval were found to be associated with smoking category (exposure) and hypertensive disorder in second pregnancy (outcome) in our data set. These variables were evaluated for confounding in our analysis by comparing unadjusted and Mantel- Haenszel adjusted relative risk estimates. A change in relative risk of greater than 10% after adjustment was considered evidence of confounding. To test for a dose-response relationship between smoking and hypertensive disorders in pregnancy, women who only smoked during their second pregnancy were categorized into three exposure groups based on reported number of cigarettes smoked in the first trimester of their second pregnancy: those who smoked less than 10 cigarettes per day (less than half a pack), those who smoked 10-20 cigarettes per day (between half-pack and a full pack), and those who smoked more than 20 cigarettes per day (more than a full pack). Relative risk estimates for hypertensive disorders in pregnancy were determined for each of these first trimester smoking categories, using mothers who never smoked as the reference category, controlling for race, inter-pregnancy period, and pre-pregnancy BMI. All analyses were conducted in Stata 13.0 (College Station, TX). Institutional review board approval was obtained from the University of Washington. Results
Mothers who smoked in either pregnancy tended to be younger and were more likely to be white and have achieved lower education levels than mothers who did not smoke during their 5 first two pregnancies (Table 1). Mothers who never smoked were much less likely to be obese, though history of diabetes and chronic hypertension was similar across smoking categories. Fewer non-smoking mothers had demonstrably different paternity in their first and second pregnancies than mothers with any history of smoking, although a significant proportion of birth records did not have adequate information to assess changes in paternity across pregnancies. In the relationship of inter-pregnancy changes in smoking status and risk of hypertensive disorders in pregnancy, pre-pregnancy BMI was identified as a confounder. Adjustment for pre- pregnancy BMI (Table 2) showed a relative risk of 0.77 (95% CI: 0.65-0.92) among mothers who smoked during both pregnancies, 0.91 (95% CI: 0.74-1.11) for mothers who began smoking after their first pregnancy, and 1.04 (95% CI: 0.86-1.25) among mothers who smoked during their first pregnancy but quit before their second. In the relationship between the quantity of tobacco consumption during the first trimester and risk of hypertensive disorders in pregnancy, pre-pregnancy BMI was again found to impact the observed association (Table 3). The pre-pregnancy BMI-adjusted analysis showed a relative risk (compared to women who did not smoke in either pregnancy) of 0.96 (95% CI: 0.74-1.24) among women who smoked less than half a pack per day during the first trimester of their second pregnancy, 0.64 (95% CI: 0.43-0.94) among women who smoked between half a pack and a full pack per day during their first trimester, and 1.40 (95% CI: 0.92-2.11) among women who smoked more than a pack per day. Discussion This study assessed the relationship between changes in maternal smoking behaviors and risk of hypertensive disorders of pregnancy. Our results show that mothers who smoked during both pregnancies were 23% less likely to experience gestational hypertensive disorders during 6 their second pregnancy than mothers who never smoked. No association between hypertensive disorders and smoking behaviors was observed for mothers who smoked during their first pregnancy only or for those who smoked in their second pregnancy only. This suggests that cessation of smoking between pregnancies may normalize the risk of mothers with a history of smoking to a level comparable to that of mothers who never smoked. To date, large cohort studies investigating the relationship between maternal smoking and risk of pre-eclampsia have been conducted in Germany (6,9), Sweden (4,5), Canada (12), and the US (7,8,11,13), including two studies conducted in Washington State. One such study conducted using data from the Swedish birth register, including all singleton births in Sweden between 1996 and 2006, compared the affect of changes in smoking habits across two pregnancies on the risk of pre-eclampsia. Consistent with the present study, this prior study found a significantly lower risk of pre-eclampsia among women who smoked during both pregnancies, relative to never smokers (OR =0.54, 95% CI: 0.47, 0.63); however, contrary to the findings of the present analysis, this prior study also noted significantly lower risk among those who smoked only during their second pregnancy or only during their first pregnancy (OR=0.76, 95% CI: 0.58, 0.99, and OR=0.81, 95% CI: 0.70, 0.84, respectively) (5). Of the two prior studies conducted in Washington state, one, which used birth data between 2003 and 2008, found an inverse association between smoking and pre-eclampsia (8). A second study, using birth data from 1987- 2007, found that both smoking and multiparity were inversely associated with pre-eclampsia (13). Both of these studies confirmed earlier findings that maternal smoking is inversely associated with risk of hypertensive disorders of pregnancy; however, unlike the present study, these prior studies did not address how the level of maternal smoking or changes in those smoking habits during or between pregnancies may affect that risk. 7 The present study also assessed the presence of a dose-response relationship between the quantity of tobacco smoked and the risk of hypertensive disorders of pregnancy. Compared to mothers who never smoked, mothers who reported smoking between half a pack and a full pack per day during the first trimester of the second pregnancy were 36% less likely to be diagnosed with gestational hypertensive disorders, however, there is evidence that those who smoked more than a pack per day were more at risk. No association was observed for those who smoked less than half a pack per day during the first trimester, suggesting that smoking intensity is an important consideration in evaluating associations with pregnancy outcomes and complications. This identification of a dose-response relationship between the quantity of tobacco smoked during the first trimester of the second pregnancy and the risk of hypertensive disorder also confirms previous findings. An observational study conducted in Ontario, Canada compared incidence of pre-eclampsia according to levels of exposure to carbon monoxide (CO), which is found in cigarettes smoke. Subjects were divided into four quartiles according to their level of CO exposure, and the rates of pre-eclampsia in those quartiles were 2.32%, 1.97%, 1.59% and 1.26% respectively, showing an inverse relationship between CO exposure and the risk of pre- eclampsia (3). A different study looking at pre-eclampsia risk in the same Swedish birth register described above found that women classified as light smokers had an OR of 0.66 (95% CI: 0.61, 0.71) compared to non-tobacco users, whereas heavy smokers had an OR of 0.51 (95% CI: 0.44, 0.58); this study also suggested that smoking habits in later pregnancy were more strongly inversely associated with pre-eclampsia than smoking before or early in the pregnancy (4). The finding that women who smoked more than a pack of cigarettes per day during the first trimester of their second pregnancy may be at increased risk for hypertensive disorders of pregnancy is particularly noteworthy, as it contradicts the straightforward dose-response 8 relationship between the quantity of tobacco smoked and the decrease in risk for hypertensive disorders. The basis for this observed pattern, however, remains unclear. The biological mechanisms that link maternal smoking to decreased risk for hypertensive disorders of pregnancy are not well understood. Earlier research has suggested that cigarette smoke may reduce the risk of pre-eclampsia by affecting placental adrenomedullin expression (14) or angiogenesis-related gene expression (15). It has also been suggested that nicotine consumption may affect vascular development in the placenta by suppressing interleukin-6 production from vascular endothelial cells (16). Though these studies offer fruitful directions for future research, the full mechanism of the interaction between smoking behavior and preeclampsia risk remains to be fully understood. Hypothesized biological mechanisms are, however, unlikely to explain the observed pattern of dose-response. That is, it is unlikely that a secondary biological mechanism, such as exposure to a toxin in cigarette smoke, would suddenly take effect at higher levels of cigarette consumption and overpower the observed protective effect against hypertensive disorders. A more likely explanation for observed patterns is residual confounding among heavy smokers. Smoking during pregnancy is known to be associated with lower self-esteem (17), high levels of stress and anxiety (18,19), and emotional difficulties and life trauma (20,21). Smoking is often used as a coping mechanism for managing these and other stressors (17). There is also evidence that these risks and stressors are elevated among disadvantaged women, such as those with lower SES (19), racial minorities (20,22), and those experiencing partner violence (21). Given these known relationships between smoking during pregnancy and other social and environmental risk factors, the results of this study suggest that women who smoke more than a pack of cigarettes per day may be at heightened risk for adverse outcomes for reasons beyond 9 their smoking behaviors. Thus, further research into the unique behavioral and environmental risk factors faced by pregnant women who are heavy smokers in Washington state and elsewhere is merited and necessary. This study had several limitations that should be considered when interpreting these results. First, smoking was measured by self-report on the birth certificate, which is a method vulnerable to both recall bias and response bias. Second, we were only able to assess the smoking habits of mothers at two points in time: their first and their second pregnancy. Smoking behaviors before and between pregnancies is unknown and could not be taken into account. Third, our outcome of interest, hypertensive disorders of pregnancy, is heterogeneous. Hypertensive disorders include several distinct diagnoses, including gestational hypertension, pre-eclampsia, and eclampsia. Between 2003 and 2012, the Washington State birth certificate form did not ask clinicians to record the incidence of these specific diagnoses, only the presence or absence of any hypertensive disorder of pregnancy. We were unable, therefore, to investigate differences in the risks of and mechanisms behind each specific hypertensive condition. We were only able to assess relationships between smoking and hypertensive disorders in general. In this large, population-based sample of births in WA from 2003-2012, we observed a significant association between smoking during first and second pregnancy and decreased risk of hypertensive disorders of pregnancy. Among mothers who smoked between a half and a full pack a day during the first trimester of their second pregnancy only, a significantly reduced risk of hypertensive disorders of pregnancy was observed. Further study is needed to verify these relationships. These findings do not impact the recommendation to quit smoking during pregnancy, as smoking is associated with increased risk of serious, adverse pregnancy outcomes. However, these results may help to elucidate the etiology of hypertensive disorders and may 10 have implications for clinicians who counsel or provide care for women who choose to smoke tobacco products during pregnancy.
11 Table 1. Maternal and obstetric characteristics among women giving birth to their 1st and 2nd child in Washington State according to changes in smoking behaviors, 2003-2012
Smoker in both pregnancies (N=5,476) Quit smoking after 1st pregnancy (N=3,563) Started smoking after 1st pregnancy (N=3,312) Non-smoker in both pregnancies (N=13,422)
N % N % N % N % Socio-demographic characteristics reported at 2 nd birth Age (years)
Less than high school 2,249 41.1 1,037 29.1 1,251 37.8 1,761 13.1 High school diploma 2,074 37.9 1,359 38.1 1,210 36.5 2,576 19.2 More than high school 1,106 20.2 1,141 32.0 827 25.0 8,950 66.7 Missing 47 0.9 26 0.7 24 0.7 35 0.3 Medical history reported at 2 nd birth BMI (kg/m 2 ) prior to 2nd pregnancy
Pre-existing type I or type II 42 0.8 17 0.5 16 0.5 92 0.7 Gestational diabetes 271 5.0 173 4.9 126 3.8 698 5.2 Missing 0 0 0 0 0 0 0 0 Obstetric history Inter-pregnancy interval (years)
12 0-1 1,063 19.4 596 16.7 508 15.3 1,852 13.8 2 1,683 30.7 1,062 29.8 865 26.1 5,192 38.7 3 1,200 21.9 777 21.8 797 24.1 3,532 26.3 4 685 12.5 509 14.3 452 13.7 1,561 11.6 5 845 15.4 619 17.4 690 20.8 1,285 9.6 Missing 0 0 0 0 0 0 0 0 Differing paternity * 1,430 33.1 812 27.3 980 37.9 1,050 8.3 Missing 1,158 21.1 591 16.6 726 21.9 801 6.0 History of hypertensive disorder in 1st pregnancy 362 6.7 302 8.6 234 7.1 1,017 7.7 Missing 65 1.2 46 1.3 30 0.9 214 1.6 * Paternity was considered different if fathers reported state or country of birth was not the same in both pregnancies or if the difference in paternal age at 1 st and 2 nd birth was not within the inter-pregnancy interval 1 year
13
Table 2. Association of change in smoking behavior and hypertensive disorders of pregnancy among women giving birth to their 1st and 2nd child in Washington State, 2003-2012
Smoker in both pregnancies (N=5,444) Quit smoking after 1st pregnancy (N=3,540) Started smoking after 1st pregnancy (N=3,297) Non-smoker in both pregnancies (N=13,300)
RR 95% CI RR 95% CI RR 95% CI RR 95% CI Unadjusted 0.88 0.74, 1.04 1.16 0.97, 1.38 1.00 0.82, 1.22 1.00 - Adjusted* for pre-pregnancy BMI 0.77 0.65, 0.92 1.04 0.86, 1.25 0.91 0.74, 1.11 1.00 - Among women with no missing data for pre-pregnancy BMI. *Mantel-Haenszel adjustment Bold indicates p<0.05
Table 3. Association of 1 st trimester smoking intensity and hypertensive disorders in 2 nd pregnancy among women who did not smoke in their 1 st pregnancy in Washington State, 2003-2012
Less than half a pack/day (N=1,792) Half a pack to less than a pack/day (N=1,083) One pack/day or more (N=419) Non-smoker in both pregnancies (N=13,300)
RR 95% CI RR 95% CI RR 95% CI RR 95% CI Unadjusted 1.03 0.80, 1.33 0.71 0.49, 1.04 1.58 1.06, 2.36 1.00 - Adjusted* for pre-pregnancy BMI 0.96 0.74, 1.24 0.64 0.43, 0.94 1.40 0.92, 2.11 1.00 - Among women with no missing data for first trimester smoking in second pregnancy and pre-pregnancy BMI. *Mantel-Haenszel adjustment Bold indicates p<0.05
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