1 Epidemic Intelligence Service, Division of Applied Public Health Training, Epidemiology Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention Program Office, Centers for Disease Control and Prevention, Atlanta, GA.
2 Pregnancy and Infant Health Branch, Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA.
3 Statistics and Computer Resources Branch, Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA.
4 Program Services and Development Branch, Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA.
5 Childhood Vaccine Preventable Diseases Branch, Epidemiology and Surveillance Division, National Immunization Program, Centers for Disease Control and Prevention, Atlanta, GA.
6 Training, Development, and Management Activity, Division of Applied Public Health Training, Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta, GA.
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ABSTRACT |
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birth weight; cotinine; nicotine; pregnancy; smoking; tobacco
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INTRODUCTION |
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Information available to clinicians regarding smoking reduction in pregnancy is conflicting. Windsor et al. propose that reducing tobacco exposure by 50 percent or more during pregnancy has beneficial effects on birth weight and that biochemically validated reduction rates should be considered a "behavioral indicator of harm reduction" (10, p. 648) in studies of smoking during pregnancy. However, this conclusion is based on the results of a study that did not directly address a 50 percent reduction (5
). In contrast, the authors of several other papers have questioned the benefits of reduction in the absence of cessation (11
13
). Before clear guidelines can be developed regarding smoking reduction during pregnancy, additional studies are needed.
Birth weight is frequently selected as an outcome in studies of the effects of tobacco exposure on the fetus. Most existing studies are based on the assumption that the dose-response relation between tobacco exposure and infant birth weight is linear; that is, researchers have assumed that each incremental increase in exposure yields a commensurate decrease in birth weight. However, evidence from several studies suggests that the sharpest decline in birth weight occurs at low levels of tobacco exposure (11, 12
, 14
). If the relation between tobacco exposure and birth weight is nonlinear, the effects of reduction may not be equal among women with different levels of exposure. Thus far, to our knowledge, no studies of the effects of smoking reduction on infant birth weight have included consideration of this nonlinear relation between tobacco exposure and birth weight.
We used data from a large smoking-cessation intervention trial to determine whether a 50 percent or greater reduction in tobacco exposure during pregnancy has an effect on the birth weight of term infants. Because there is no accepted standard for measuring tobacco exposure (15), we conducted our analysis by using both self-reported cigarette use and a biomarker, urine cotinine concentration (cotinine is a primary metabolite of nicotine). We stratified our findings by level of exposure at the time of study enrollment to determine whether a reduction in tobacco exposure benefits infants of lighter smokers more than those of heavier smokers. To overcome the limitations inherent in categorical analyses, we then used regression smoothing techniques to obtain more detailed information about the functional relation between birth weight and tobacco exposure in early and late pregnancy.
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MATERIALS AND METHODS |
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All women who attended study clinics for their first prenatal visit were screened for eligibility. Those women who reported having smoked within 7 days before thinking they were pregnant or within 7 days before screening were considered smokers and were enrolled. Participants filled out questionnaires at enrollment (at the first or second prenatal visit, regardless of the gestational age), near the end of pregnancy (during the third trimester), and at the postpartum visit (around 612 weeks postpartum). On these questionnaires, women were asked how many cigarettes per day they had smoked in the previous 7 days. This number was their estimated daily cigarette use. Urine specimens were obtained for cotinine measurement within 2 days of the time when questionnaires were administered; for 97 percent of the patients, urine was collected on the same day that the questionnaire was filled out. The amount of time elapsed between the last cigarette smoked and the collection of urine was not elicited. Further details of the original study are presented elsewhere (16, 17
).
Subjects
For this analysis, we restricted the original study population to Black or White women who delivered singleton, term infants (37 or more completed weeks' gestation) with plausible birth weights (between the 0.5 and 99.5 percentiles for term infants, which is between 900 and 5,300 g). We included only women who delivered term infants in order to evaluate the effects of tobacco exposure on fetal growth independent of potential effects on preterm delivery. Subjects were required to have two sets of corresponding measures of tobacco exposure (self-reported cigarette use and urine cotinine concentration) separated by at least 8 weeks. We did this to exclude those women whose changes in tobacco exposure were of insufficient duration to affect birth weight. Ninety-seven percent of the study subjects were enrolled in the first or second trimester.
Birth weights were obtained from maternal interview at the postpartum visit when available. In Colorado and Missouri, data were merged with birth certificate records to obtain birth weights for infants of women lost to follow-up. In Maryland, data were merged with the state's Maternity Summary Form. For 86 percent of the subjects, infant birth weights were obtained from maternal interview, and the remaining 14 percent were obtained from vital records. For 83 percent of the subjects, birth weights were available from both sources. For 92 percent of these, birth weights were within 30 g of one another.
Data analysis
Effects of 50 percent reduction in exposure on birth weight. We first used enrollment and third-trimester reported cigarette use to assign subjects to one of four different categories based on their pattern of exposure: "quit after enrollment," "reduced," "increased," or "did not change," as defined in table 1. We then assigned the same study subjects to similarly defined categories on the basis of urine cotinine levels (also defined in table 1). Women who quit before enrollment were analyzed separately. We computed mean adjusted birth weights for infants of women in each of the four categories by using general linear models to adjust for potential confounding factors elicited at enrollment: maternal age; race; education; parity; prepregnancy body mass index; Women, Infants, and Children program enrollment; caffeine consumption; alcohol consumption; whether or not the woman had a husband or partner; the state in which the clinic was located; and clinic nested within intervention/control status. We also adjusted for hours of exposure to environmental tobacco smoke in the third trimester, infant sex, and gestational age at delivery. Potential confounders with p values of less than 0.20 were omitted from the final models. Women whose exposure did not change served as the reference group. Separate analyses were conducted using categories based on reported cigarette use and by urine cotinine concentration, respectively. Exposure to environmental tobacco smoke was not included in cotinine models because cotinine values reflect both active and passive exposure.
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In all analyses, we included terms for random effects to account for the clustering of the data by clinic. These effects were not significant and were omitted from final models.
Functional relation between tobacco exposure and birth weight. We used generalized additive models (18) to determine the contribution of enrollment and third-trimester tobacco exposure to birth weight for both reported cigarette use and urine cotinine concentration while controlling for maternal age, race, parity, prepregnancy body mass index, state of residence, and infant sex. Because in these models women were not categorized according to changes in exposure during pregnancy, women who quit before enrollment were not excluded from this analysis. The level of exposure at both points in pregnancy was included in each model to estimate the independent contributions of tobacco exposure early and late in pregnancy to infant birth weight. Likelihood ratio tests of models with and without the smoothed tobacco exposure variable (cigarettes per day or cotinine concentration) were performed to test for significance of the association between tobacco exposure and birth weight. Nonparametric smoothing techniques (locally weighted regression or LOESS) (19
) were used to examine the form of the relation between third-trimester tobacco exposure and birth weight. We visually inspected smoothed curves based on third-trimester exposure to identify the point at which the effects of tobacco on birth weight leveled off.
The study proposal, consent form, and questionnaires were reviewed and approved by the institutional review boards of the Centers for Disease Control and Prevention. Funding was supplied by the Centers for Disease Control and Prevention.
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RESULTS |
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Categories of tobacco exposure in these 1,583 women are summarized in table 1. A total of 224 women in the final study group reported at enrollment that they had quit smoking, 191 of whom reported at follow-up that they had not resumed smoking. An additional 1,359 women (86 percent) reported at enrollment that they were still actively smoking; these women reported smoking an average of 12.0 cigarettes per day. When we used a urine cotinine value of 85 ng/ml as the cutoff point for active smoking, 234 women had biochemical evidence that they were not actively smoking at enrollment, and 1,349 (85 percent) had evidence that they were actively smoking at enrollment. A total of 1,443 women had complete information available on all potential confounders and were included in the regression smoothing analysis.
Demographic characteristics varied among women with different exposure patterns. The mean ages of women who quit either before or after enrollment were lower than those of women who reduced, increased, or did not change their exposure. A greater percent of women who quit were nulliparous compared with women who reduced, increased, or did not change their exposure. Women who reduced their cigarette use smoked more cigarettes per day at the time of enrollment than did those whose exposure did not change (table 2). Similar findings were seen when urine cotinine concentration was used rather than reported cigarettes smoked per day (data not shown).
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Effects of reduction in exposure measured by cigarettes per day
Women who quit smoking before enrollment and those who quit after enrollment delivered infants with the highest adjusted mean birth weights (3,492 and 3,491 g, respectively). Overall, the mean adjusted infant birth weight for women who reduced their cigarette use was 32 g heavier compared with women whose cigarette use did not change; this difference was not significant (p = 0.33) (table 3). However, after stratification by level of cigarette use at enrollment, the mean adjusted infant birth weight for women with low exposure who reduced their cigarette use was 201 g heavier than that for light smokers whose cigarette use did not change (p = 0.03) (table 3). We found no significant interaction between the level of cigarette use at enrollment and the pattern of exposure during pregnancy (p = 0.2).
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Tobacco exposure and birth weight: regression smoothing techniques
As cigarette use at enrollment increased (adjusted for third-trimester cigarette use and other variables previously described), there was no coinciding change in infant birth weight (figure 1a). We found no significant association between the number of cigarettes smoked per day at enrollment and birth weight (p = 0.84) (figure 1a).
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DISCUSSION |
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Other studies
Previous studies of the effects of tobacco exposure reduction on birth weight have not been conclusive. Li et al. (5) compared mean birth weights of women who reduced their salivary cotinine concentration by 20 ng/ml (if baseline cotinine was <100 ng/ml) or 60 ng/ml (if baseline cotinine was >100 ng/ml) and found a 92-g increase in birth weight among infants of reducers that was not statistically significant. They also observed a 241-g improvement in infant birth weight among White reducers with baseline salivary cotinine levels of more than 100 ng/ml that was statistically significant. Secker-Walker et al. (13
) used regression equations to estimate the effects of a 50 percent reduction in self-reported cigarette use and urine cotinine concentration on birth weight and predicted improvements of 89 and 33 g, respectively . They concluded that women who continue to smoke throughout pregnancy are unlikely to see substantial improvements (>100 g) in infant birth weight unless they are able to reduce use by 10 cigarettes per day or more. They also noted that the "average infant birth weights were similar for women smoking between 6 and 20 cigarettes per day" (13
, p. 972). In an earlier study, Hebel et al. (12
) noted a nonlinear relation between tobacco exposure and infant birth weight in which the effects of increasing cigarette use leveled off at approximately five cigarettes per day. The authors concluded that among women who smoked at least 10 cigarettes per day, "only those who reduced their smoking to less than 5 cigarettes per day were able to modify their risk for low birth weight" (12
, p. 488). Our findings that most of the detrimental effects of tobacco on birth weight occur at less than eight cigarettes per day and that a 50 percent reduction in exposure appeared to benefit fetal growth only among women who reported low levels of exposure at enrollment (15 cigarettes/day) are consistent with studies conducted by Hebel et al. and by Secker-Walker et al. Our study extends these earlier works, however, by applying regression smoothing techniques to a large study population. In addition, using both self-reported cigarette use and urine cotinine concentration provides an opportunity to look for consistency of effects across different measures of tobacco exposure.
Methodological considerations
In this study, we observed substantial improvements in birth weight (>200 g) among infants of women who reported low cigarette use who then reduced exposure. However, we observed no improvement in birth weight among infants of women with low cotinine concentration who then reduced their tobacco exposure. One potential limitation of using cotinine as a measure of tobacco exposure is that the serum cotinine concentration of sporadic smokers (such as those who smoke on weekends only) may not be at a steady state. Hence, the urine cotinine concentrations used in our study may not have accurately reflected tobacco exposure, and this could have resulted in the exposure misclassification of some women. This type of misclassification could have diminished potential differences in infant birth weight between women who truly reduced their exposure and those who did not change.
In previous studies of the effects of smoking reduction on birth outcomes, researchers have relied on categorizing women according to changes in exposure (5, 13
). This approach was part of our analytic strategy as well; however, it is inherently limited. It diminishes power to detect exposure effects because information contained within categories of exposure is lost. To overcome this limitation, we also performed regression by using smoothing, which allowed us to characterize the functional relation between tobacco exposure and birth weight in detail. We found that third-trimester tobacco exposure is a more important determinant of birth weight than is early exposure. This is consistent with previous studies of smoking cessation in which women who quit smoking during pregnancy delivered infants who weighed as much as infants of never smokers (7
, 12
). Because we did find a significant association between urine cotinine concentration early in pregnancy and birth weight, we cannot rule out the possibility that early tobacco exposure has some minor effect on fetal growth. However, any effects of early exposure on birth weight are likely to be overshadowed by effects of third-trimester exposure. Finally, we found that most of the deleterious effects of tobacco on infant birth weight appear to occur at low levels of exposure (i.e., less than eight cigarettes per day or less than 700 ng/ml of urine cotinine). Hence, women with medium levels of exposure who reduced their cigarette use may not experience improvements in infant birth weight unless they achieve levels of less than eight cigarettes per day. In contrast, women who smoke fewer than eight cigarettes per day but who succeed in reducing exposure may see substantial improvements in birth weight, even if they are unable to quit. Our ability to interpret our findings at high levels of tobacco exposure is limited by the small number of heavy smokers in this study. It is possible that infants of women with high levels of exposure may benefit from reduction, as described by Li et al. (5
).
This study has a number of limitations. The study population consists of low-income women who used public clinics. There may be aspects of how women in this population smoke cigarettes and report their use that are unique to this group. As in many studies of this nature, data for many study subjects were incomplete, which may have led to bias. It is reassuring, however, that women from the larger study group who were excluded from this analysis did not differ greatly from those included in the analysis by self-reported cigarette use at enrollment or by infant birth weight. Finally, although we required 8 weeks between enrollment and third-trimester measurements, we do not know the exact time when reduction in exposure took place. Hence, meaningful changes in exposure may not have occurred in all women categorized as reducers.
The nature of the relation between tobacco exposure and other outcomes remains unclear. Therefore, we should not extrapolate from our findings about the effects of smoking reduction on infant birth weight to other outcomes. Smoking reduction may have other unmeasured fetal and maternal benefits.
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Conclusions |
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Future studies of the relation between smoking and fetal growth should incorporate the concept of a nonlinear relation between tobacco exposure and birth weight. It appears to be more appropriate to define reduction according the level of exposure achieved by the end of pregnancy, rather than as a percent change.
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ACKNOWLEDGMENTS |
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The authors acknowledge the important contributions of Dr. W. Harry Hannan at the National Center for Environmental Health, Centers for Disease Control and Prevention, and of the Smoking Cessation in Pregnancy project staff, especially the state coordinators, Nancy Miller (Missouri), Nancy Salas (Colorado), and Joan Stine (Maryland).
The study proposal, consent form, and questionnaires were reviewed and approved by the institutional review boards of the Centers for Disease Control and Prevention.
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NOTES |
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REFERENCES |
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