Background
Smoking during pregnancy is a modifiable risk factor associated with adverse pregnancy outcomes. Smoking during pregnancy has been shown to increase the risk of spontaneous abortion, prematurity, low birthweight, congenital malformations, and sudden infant death syndrome. Despite the fact that it is well known that smoking can lead to adverse pregnancy outcomes, 13-25% of pregnant women overall continue to smoke during this critical period.
Objective
The objective of the study was to evaluate the effect of gestational use of bupropion and nicotine patch replacement therapy on the risk of the following: (1) smoking cessation, (2) prematurity, and (3) small for gestational age.
Study Design
Women included in the Quebec Pregnancy Cohort who filled the annual autoadministered questionnaire between Jan. 1, 1998, and June 30, 2009, were studied. Smokers before gestation with a pregnancy resulting in a live birth comprised the study population. Three mutually exclusive study groups were formed among those who smoked at the beginning of pregnancy: gestational users of nicotine patch replacement therapy, bupropion, and smokers who did not use nicotine patch replacement therapy or bupropion. Rate of smoking cessation during pregnancy as well as the risk of prematurity and small for gestational age were studied.
Results
Of the 1288 women who met inclusion criteria, 900 were smokers, 72 were bupropion users, and 316 were nicotine patch replacement therapy users. Bupropion and nicotine patch replacement therapy use during pregnancy were associated with higher rates of smoking cessation: 81% in the bupropion group; 79% for nicotine patch replacement therapy; and 0% in those not using buproprion or nicotine patch replacement therapy. After discontinuing smoking cessation medications, 60% of bupropion users and 68% of nicotine patch replacement therapy users did not smoke again during and after pregnancy. Adjusting for potential confounders, nicotine patch replacement therapy use was associated with a lower risk of prematurity (adjusted odds ratio, 0.21, 95% confidence interval, 0.13–0.34), and small-for-gestational-age (adjusted odds ratio, 0.61, 95% confidence interval, 0.41–0.90) compared to smoking. Bupropion was associated with a lower risk of prematurity only (adjusted odds ratio, 0.12, 95% confidence interval, 0.03–0.50).
Conclusion
Bupropion and nicotine patch replacement therapy have an impact on smoking cessation during and after pregnancy. Nicotine patch replacement therapy also decreased the risk of prematurity and small for gestational age.
Smoking during pregnancy has been shown to increase the risk of spontaneous abortion, prematurity, low birthweight, congenital malformations, and sudden infant death syndrome. Despite the fact that it is well known that smoking can lead to adverse pregnancy outcomes, 13-25% of pregnant women continue to smoke during this critical period.
At present, studies have shown that smoking during gestation may be one of the most important modifiable risk factors for pregnancy-related mortality and morbidity. Nevertheless, the majority of pregnant women who smoke prior to becoming pregnant continue smoking during gestation, and only up to 18% will discontinue with behavioral interventions.
Currently nicotine patch replacement therapy and bupropion are the 2 major pharmacological treatments used for smoking cessation in general and specifically during pregnancy. Nicotine patch replacement therapy has been studied in small populations of pregnant women and has shown very modest effects on rates of smoking cessation, partly explained by the high prevalence of nicotine patch replacement therapy discontinuation overall. Although bupropion has been shown to be effective as a smoking cessation treatment during pregnancy, its use has been limited because of controversial fetal safety data.
Although smoking cessation during pregnancy can also have a long-lasting impact after pregnancy for both the mother and her child, at present, no one has compared the rates of smoking cessation and pregnancy complications associated with the use of bupropion and nicotine patch replacement therapy during pregnancy. Therefore, the aim of this study was to quantify the effect of gestational use of bupropion and nicotine patch replacement therapy on the rate of smoking cessation during and after pregnancy as well as the risk of prematurity and small for gestational age.
Materials and Methods
Cohort
We conducted a population-based cohort study using data from the Quebec Pregnancy Cohort, built with the linkage of 4 databases in Quebec as well as a patient self-reported annual questionnaire. The Quebec Pregnancy Cohort is an ongoing population-based cohort with prospective data collection on all pregnancies that occurred between January 1998 and December 2009 in the province of Quebec. Data on the mothers and children after the end of pregnancy are also collected. Individual-level information is obtained from province-wide databases and linked using unique personal identifiers.
The Quebec Pregnancy Cohort was first constructed by identifying all pregnancies in the Régie de l’Assurance Maladie du Québec and the Quebec hospitalization archives (MedEcho) databases; subsequently, the first day of the last menstrual period (first day of gestation) was defined using data on gestational age, which were validated against patients’ charts. Prospective follow-up is available from 1 year before the first day of gestation, during pregnancy, and until December 2009.
The Quebec Pregnancy Cohort data sources for this study included the medical service database (Régie de l’Assurance Maladie du Québec: diagnoses, medical procedures, socioeconomic status of women, and prescribers), the Quebec Public Prescription Drug Insurance database (drug name, start date, dosage, duration), the hospitalization archive database (MedEcho: diagnoses and procedures), and the Quebec Statistics database (patient sociodemographic, birthweight). The Quebec Pregnancy Cohort is further described in Bérard and Sheehy.
To collect information on smoking status, maternal weight, height, and weight gain during pregnancy, and folic acid intake as well as information regarding nicotine patch replacement therapy purchased over the counter, a random sample of 8505 women taken within the Quebec Pregnancy Cohort were contacted annually and asked to fill a standardized questionnaire. To maximize the response rate, the questionnaires were sent twice and a toll-free telephone line was set up for women requiring further information. Questionnaire data were linked to the Quebec Pregnancy Cohort.
Study population
Within the Quebec Pregnancy Cohort, women meeting the following eligibility criteria were included in the present study be: (1) between 15 and 45 years of age on the first day of gestation; (2) continuously insured by the Régie de l’Assurance Maladie du Québec drug plan for at least 12 months before the first day of gestation and during pregnancy; (3) smokers before pregnancy; and (4) have a live birth.
We excluded the following: 1) women taking both bupropion and nicotine patch replacement therapy during pregnancy; 2) women diagnosed with depression during pregnancy; or 3) women exposed to known teratogens or fetotoxic drugs including antiepileptic drugs during pregnancy according to Chaabane and Berard, and Briggs et al. We excluded women with depression during pregnancy because bupropion is given for both smoking cessation and depression. By doing this, we restricted our study population to smokers at the beginning of pregnancy who used either bupropion or nicotine patch replacement therapy to stop smoking. Women with depression before pregnancy only were eligible.
Study design: longitudinal cohort study
Exposure groups
Three mutually exclusive exposure groups were considered and categorized at the beginning of pregnancy (among smokers before pregnancy who initiated bupropion or nicotine patch replacement therapy for the first time at the beginning of pregnancy): 1) pregnant women using bupropion alone with or without smoking; 2) pregnant women using nicotine patch replacement therapy alone with or without smoking; and 3) pregnant smokers without bupropion or nicotine patch replacement therapy exposures during pregnancy.
Bupropion exposure status including start and end date during gestation and dosage were obtained within the Régie de l’Assurance Maladie du Québec medication database; nicotine patch replacement therapy exposure data were obtained from the Régie de l’Assurance Maladie du Québec and from the mother from the autoadministered questionnaire.
Smoking status before and during pregnancy for all study subjects was self-reported by mothers in the autoadministered questionnaire; smoking status was dichotomized as smoking vs nonsmoking. Smoking status was asked retrospectively for each trimester of pregnancy and in the year after delivery.
In Quebec, the Régie de l’Assurance Maladie du Québec annually reimburses smokers with a prescription for nicotine patch replacement therapy (over the counter included) and bupropion; the Régie de l’Assurance Maladie du Québec covers 65–95% of the cost, depending on family income. Although nicotine patch replacement therapy can be obtained over the counter without a prescription and given that drug utilization is highly sensitive to out-of-pocket costs, we are confident that the Régie de l’Assurance Maladie du Québec can capture the majority of nicotine patch replacement therapy users in this study cohort. Nevertheless, maternal report of over-the-counter nicotine patch replacement therapy has also been obtained.
Women were considered exposed to bupropion or nicotine patch replacement therapy if they filled prescriptions for at least 1 of these drugs during pregnancy or if they filled prescriptions before the first day of gestation with duration overlapping the beginning of pregnancy; women were also considered exposed to nicotine patch replacement therapy when reporting over-the-counter nicotine patch replacement therapy use.
Data on prescription fillings have been validated and compared with maternal reports, which is more reliable than data on medication prescribing in medical charts; the positive predictive value of prescription drug data in the cohort was found to be at least 87% (95% confidence interval, 70–100%), and the negative predictive value was at least 92% (95% confidence interval, 86–98%). In addition, a copayment is required for all fillings, increasing the likelihood of medication intake.
Smoking cessation, prematurity, and small for gestational age
Smoking cessation during and in the year after pregnancy was self-reported by mothers in the 3 exposure categories.
Prematurity was defined as a birth before the 37th weeks of gestation. Small for gestational age was used as a combined measure of prematurity and low birthweight. Cases of small for gestational age, identified in the Quebec Pregnancy Cohort with the hospital archives database (gestational age) and the Quebec Statistics database (birthweight and sex), were defined as the lowest 10th percentile of the gestational age-specific birthweight in the cohort, according to the sex-specific, population-based Canadian references. Gestational age and birthweight have been validated against patients’ charts.
Covariates
Health care utilization variables such as hospitalisations and emergency department visits, medical visits, and number of prescribers were selected as markers of health status; these were measured in the 12 months before pregnancy.
We determined the presence of the following chronic comorbidities and the use of specific medications in the year before pregnancy: the diagnosis of chronic hypertension ( International Classification of Diseases , ninth revision, codes 401.0-405.9, 362.1, 416.0, 437.2, 796.2) or the use of antihypertensive drugs (American Hospital Formulary Service: 24:08); the diagnosis of diabetes ( International Classification of Diseases , ninth revision; 250.0-250.9, 271.4, 790.2) or the dispensing of oral hypoglycemic agents or insulin (American Hospital Formulary Service: 68:20.08, 68:20.20, 68:20.92); the diagnosis of asthma ( International Classification of Diseases , ninth revision, code 493) or the use of asthma medications (American Hospital Formulary Service: 48:00, 92:00); and the diagnosis of depression ( International Classification of Diseases , ninth revision, code 311) or the use of antidepressants (American Hospital Formulary Service: 28:16:04).
Pregnancy-related variables considered were the number of prenatal visits, visits to obstetricians, and dispensed comedications during gestation; another pregnancy in the year before as well as multiplicity was also considered. We also determined the following socioeconomic variables on first day of gestation: maternal age, region of residence (urban vs rural dwellers), maternal marital status (living alone vs cohabiting), and the Régie de l’Assurance Maladie du Québec insurance status (welfare beneficiary vs workers).
Finally, we also considered the following socioeconomic and pregnancy history covariates from the maternal self-administered questionnaire: education and family income level; maternal weight, height, and weight gain during pregnancy; folic acid intake; and parity. We further validated the absence of depression during pregnancy using the maternal self-report from the questionnaires.
Statistical analyses
We are presenting means and proportions for continuous and dichotomous variables, respectively. Univariate and multivariate unconditional logistic regression models were built to quantify the risk of smoking cessation during pregnancy as well as the risk of prematurity, and small for gestational age, separately, adjusting for potential confounders and socioeconomic variables.
Primary analyses considered smokers without bupropion or nicotine patch replacement therapy use as the reference category; secondary analyses compared the risk of smoking cessation, and adverse pregnancy outcomes between bupropion and nicotine patch replacement therapy users, adjusting for potential confounders including cigarette smoking during pregnancy.
Statistical analyses were done using SAS (SAS Institute Inc, version 9.2; Cary, NC). Differences were considered statistically significant when the 95% confidence intervals did not overlap 1.0 and when the value was P < .05 (2 tailed).
This study received ethics approval from the Research and Ethics Committee of Centre Hospitalier Universitaire Sainte-Justine, and data linkage was authorized by the Commission d’Accès à l’Information of Quebec.
Results
Of the 8505 women randomly sampled from the Quebec Pregnancy Cohort (1998–2009) for the annual autoadministered questionnaire, 6732 completed and returned their questionnaire (79%). Responders were similar to nonresponders regarding maternal age; region of residence; maternal marital status; and Régie de l’Assurance Maladie du Québec drug insurance status, gestational age, birthweight, and rate of major congenital malformations as well as health care use; presence of chronic comorbidities such as hypertension, diabetes, asthma, and depression; prevalence of multiplicity; newborn sex; and calendar year of delivery (data not shown); responders had delivered more recently than the nonresponders (data not shown).
Of the 6732 women who returned their questionnaire, 1288 pregnant women were smokers before pregnancy (19%) and therefore met inclusion criteria; 72 used bupropion (5.6%), 316 nicotine patch replacement therapy (24.5%), and 900 smoked during pregnancy but did not take bupropion or nicotine patch replacement therapy (69.9%) ( Table 1 ).
| Bupropion users with/without tobacco use (n = 72) | NRT users with/without tobacco use (n = 316) | Smokers without bupropion/NRT use (n = 900) | |
|---|---|---|---|
| Prematurity a | 2 (2.8) | 25 (7.9) | 240 (26.7) |
| Gestational age, wks, mean (SD) a | 39.1 (1.3) | 38.9 (1.9) | 37.5 (3.3) |
| Birthweight, g, mean (SD) a | 3315.9 (553.3) | 3257.9 (553.1) | 2943.5 (733.5) |
| SGA (<10th percentile), n, % b | 13 (18.1) | 44 (13.9) | 149 (16.6) |
| Duration of use, d, median [25th to 75th] | 87 [55–119] | 54 [36–72] | N/A |
| Maternal age, y, mean (SD) a | 28.6 (6.3) | 26.7 (5.7) | 27.2 (5.8) |
| Living alone c | 4 (19.1) | 11 (11.5) | 120 (14.7) |
| Working c | 7 (35.0) | 47 (51.7) | 399 (50.5) |
| Urban dwellers | 57 (79.2) | 237 (75.0) | 682 (75.8) |
| Welfare recipients | 26 (36.1) | 122 (38.6) | 335 (37.7) |
| Education level c | |||
| High school completed | 11 (52.4) | 61 (63.5) | 517 (61.9) |
| Postsecondary education | 10 (47.6) | 35 (36.5) | 318 (38.1) |
| Annual family income c | |||
| <30,000CAN$ | 15 (71.4) | 65 (67.7) | 586 (70.2) |
| 30,000–46,000CAN$ | 4 (19.1) | 18 (18.8) | 13 (13.5) |
| >46,000CAN$ | 2 (9.5) | 13 (13.5) | 103 (12.3) |
| Diabetes | 6 (8.3) | 28 (8.9) | 82 (9.1) |
| Hypertension | 6 (8.3) | 28 (8.9) | 73 (8.1) |
| Asthma | 23 (31.9) | 92 (29.1) | 279 (31.0) |
| Depression a | 34 (47.2) | 41 (13.0) | 194 (21.6) |
| Prenatal visits, mean (SD) | 9.0 (3.1) | 8.4 (3.6) | 8.8 (3.5) |
| Pregnancy care by an obstetrician (vs family physician) a | 57 (79.2) | 237 (75.0) | 757 (84.1) |
| Pregnancy in year before this pregnancy | 2 (9.5) | 12 (12.5) | 101 (12.1) |
| Newborn sex (male) | 37 (51.4) | 163 (51.6) | 490 (54.4) |
| Health services utilization in the year before pregnancy | |||
| Physician visits, mean (SD) a | 13.5 (12.4) | 8.5 (8.5) | 9.6 (9.3) |
| Emergency department visits or hospitalizations | 11 (15.3) | 57 (18.0) | 155 (17.2) |
| Number of different medications used, other than bupropion or NRT a | |||
| 0 | 0 (0.0) | 33 (10.4) | 113 (12.6) |
| 1–2 | 16 (22.2) | 97 (30.7) | 282 (31.3) |
| 3–5 | 27 (37.5) | 115 (36.4) | 299 (33.2) |
| ≥6 | 29 (40.3) | 71 (22.5) | 206 (22.9) |
| Number of different prescribers a | |||
| 0–2 | 27 (37.5) | 164 (51.9) | 513 (57.0) |
| ≥3 | 45 (62.5) | 152 (48.1) | 387 (43.0) |
| Health services utilization during pregnancy | |||
| Emergency department visits or hospitalizations a | 62 (86.1) | 267 (84.5) | 834 (92.7) |
| Number of different prescribers a | |||
| 0–2 | 33 (45.8) | 183 (57.9) | 652 (72.4) |
| ≥3 | 39 (54.2) | 133 (42.1) | 248 (27.6) |
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