Predictors of adverse events among pregnant smokers exposed in a nicotine replacement therapy trial

Article Outline

• Abstract
• Materials and Methods
• Results
• Comment
• Acknowledgments
• References
• Copyright

Objective

The purpose of this study was to determine the contribution of randomization to nicotine replacement therapy (NRT), sociodemographic and psychosocial factors, and pregnancy and medical history to serious perinatal adverse events among pregnant smokers.

Study Design

We performed a retrospective review of all medical records for participants in the Baby Steps Trial. Data that were abstracted from 157 records were combined with baseline characteristics for logistic regression modeling of serious adverse events and adjusted for covariates.

Results

Serious adverse events occurred in 17% (9/52 pregnancies) and 31% (33/105 pregnancies) of participants in the control and NRT arms, respectively. Black race, adverse pregnancy history, and use of analgesic medication during pregnancy were significant predictors (P = .02, .04, and .01, respectively). Remaining covariates, which included randomization to NRT, were not statistically significant.

Conclusion

Although race, poor pregnancy history, and use of analgesics were associated with serious adverse events, randomization to NRT during pregnancy was not a significant factor. Further research is needed to examine the safety of analgesic medications during pregnancy.

Key words: nicotine replacement therapy, pregnancy, preterm birth, smoking

Smoking during pregnancy, which is 1 of the most important modifiable causes of adverse pregnancy outcomes in the United States, has been associated with spontaneous abortion, fetal death, premature rupture of membranes, preterm birth, low birthweight, and perinatal death.¹, ², ³ It is estimated that the elimination of smoking during pregnancy would reduce infant mortality rates by 5%⁴ and singleton low birthweight rates by 10%.⁵ Despite awareness of the health consequences of smoking during pregnancy, at least one-half of women who smoke will continue to do so throughout pregnancy.⁶ Based on data from the general population, the most successful smoking cessation programs combine both behavioral and pharmacologic methods, and the addition of nicotine replacement therapy (NRT) nearly doubles long-term success rates.⁷ Given that 60% of women will attempt to quit smoking during their pregnancy, but that only one-quarter of these women will be successful,⁸ the use of NRT to assist pregnant women with smoking cessation is an attractive option. Although existing evidence suggests that NRT use during pregnancy is not more harmful to the fetus than smoking itself,⁹, ¹⁰, ¹¹, ¹² theoretic concerns are supported by animal models of nicotine's neurotoxicant effects.¹³ Further, although several smoking cessation studies have evaluated NRT use during pregnancy, the results have been affected by poor participant compliance with NRT and multimodal intervention strategies.¹⁴, ¹⁵, ¹⁶

We recently conducted a randomized, open label study (the Baby Steps trial) of cognitive behavioral therapy (CBT) alone vs CBT + NRT among pregnant smokers.¹⁷ The Baby Steps trial demonstrated that the addition of NRT to CBT increased the rate of smoking cessation during pregnancy nearly 3-fold, from 8-24%. However, recruitment was suspended early when an interim analysis found a higher rate of adverse perinatal outcomes in the NRT + CBT arm than in the CBT-only arm. Although the initial intent was to enroll 300 women in a 2:1 randomization scheme that would favor the intervention group, only 181 women were enrolled. There were differences in the baseline characteristics between the 2 arms that involved factors that could be related to adverse perinatal events. Final analysis showed no statistically significant difference in adverse events between the 2 arms after we controlled for previous preterm birth. Furthermore, women with an adverse event had a mean cotinine value of 189.3 vs 140.8 for those who did not have an adverse event (P = .85).

We propose that the increased incidence of adverse events in the NRT group was due to differences in predisposing baseline factors and not to the pharmacologic intervention. Cigarette smoking is often clustered with several social stressors and unhealthy behaviors that, in turn, are also associated with poor pregnancy outcomes. Women who smoke are more likely to be of lower socioeconomic status, have lower educational attainment, and experience low self-esteem.¹⁸ Data from the National Health Interview Survey indicate that cigarette smoking aggregates with alcohol use, marijuana use, and other illicit substance use.¹⁹ Furthermore, several studies have demonstrated a significant association between smoking and psychosocial distress (stress, depression, and anxiety) among women.²⁰, ²¹, ²² Given the well-known associations of smoking with adverse perinatal outcomes like preterm birth and low birthweight, we sought to determine the relative contribution of randomization to NRT, sociodemographic characteristics, health status and medication use, and psychosocial stressors to adverse perinatal events among pregnant smokers.

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Materials and Methods 

The Baby Steps trial, which was approved and monitored by the institutional review boards of all participating institutions, enrolled pregnant smokers who were between 13 and 25 weeks of gestation from 14 clinical sites in Durham, Raleigh, and Fayetteville, NC, from May 2003 through August 2005. One hundred eighty-one women were enrolled in the study; 59 women were in the CBT-only arm, and 122 women were in the NRT + CBT arm. Serious adverse events included preterm birth at <37 weeks of gestation, term low birthweight of <2500 g, preeclampsia, placental abruption, placental previa, neonatal intensive care unit admission, fetal death, and neonatal/infant death. Ten women in the CBT-only arm had at least 1 serious adverse event, compared with 34 women in the NRT + CBT arm.

We performed a retrospective review of all prenatal and hospital records for study participants. Data collected through medical record abstraction included insurance status, detailed obstetric and medical history, detailed antenatal history that included sexually transmitted infections, illicit substance use, medication use, and compliance with prenatal care. For those women who had had a previous pregnancy, poor pregnancy history was defined as at least 1 pregnancy that was affected by preterm birth, low birthweight or growth restriction, fetal death, preeclampsia, or placental abruption. Medication usage during pregnancy (prescription and over-the-counter drugs) included the following categories: antibiotics, anticoagulants, antihypertensive agents, respiratory agents, anticonvulsant medications, hyperglycemic agents, thyroid medications, gastrointestinal medications, psychiatric medications, and analgesia or pain management. Attendance to prenatal care was assessed by the Adequacy of Prenatal Care Utilization Index,²³ which is a 4-level Likert variable that considers both the timing of the initiation of prenatal care and the ratio of observed-to-expected number of prenatal visits with regards to gestational length.

Psychosocial stressors that included perceived stress and coping skills, self-esteem, and depression were measured at baseline entry into the Baby Steps trial. The Rhode Island Stress and Coping Inventory is a validated 10-item, 5-point Likert measure of perceived stress and coping items.²⁴ With a 7-point Likert scale to assess pregnancy-related self-esteem, participants were asked to rate the extent to which the pregnancy had made her feel (1) good about herself as a person and (2) bad about herself as a person. Depressive symptoms were measured by the Center for Epidemiologic Studies Depression Scale, which is a 10-item, 3-point Likert measure of frequency of depressive symptoms in the past week.²⁵

Our primary objective was to examine the randomization-arm effect on the incidence of adverse events and to control for a number of clinically meaningful baseline covariates. Because the total number of women with adverse events was small (42 women), it is only as a secondary objective that we describe the set of baseline covariates that were predictive of adverse event incidence. Nineteen candidate predictors were considered. Baseline sociodemographic characteristics included maternal age, race (African American/non–African American), education (less than high school/high school or greater), partner status (presence or absence of a romantic partner), and employment (any employment/no employment). Other baseline characteristics included average number of cigarettes smoked per day, psychosocial stress (continuous), coping skills (continuous), self-esteem (7-item Likert), and depression (continuous). Medical and psychosocial history included history of depression (yes/no), history of anxiety (yes/no), history of drug or alcohol use (yes/no), history of sexually transmitted infections (yes/no), and adverse obstetric history. Adverse obstetric history was analyzed as a 2 degrees of freedom categoric variable with the following 3 levels: no previous pregnancy, adverse history, no adverse history. Candidate predictors from the current pregnancy included study randomization arm, prenatal care adequacy (4-level Likert scale), use of analgesic medications during pregnancy (yes/no), and use of psychiatric medications (yes/no) during pregnancy.

The predictors of incidence of adverse events were analyzed both univariately and multivariately. Logistic regression modeling was used to calculate the probability value for the effect of each candidate predictor variable separately. Building on the model further, multivariate modeling was performed in a stepwise backwards elimination process. That is, all 19 candidate variables were included in the preliminary model, and stepwise backwards elimination was used to remove variables with probability values of > .50. The traditional removal from the model of all variables with probability values of > .05 “violates every principle of statistical estimation and hypothesis testing,” as described by renowned biostatistician Frank Harrell.²⁶

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Results 

Although 181 women were enrolled in the original study, birth outcome data were missing for 10 women because of participant withdrawal or loss to follow-up evaluation. Of the remaining 171 women, 157 women had complete records available for abstraction: 52 women in the CBT-only arm and 105 women in the NRT + CBT arm. Forty-two participants had at least 1 serious adverse perinatal event (9 women in the CBT-only arm and 33 women in the NRT + CBT arm). Preterm birth was the most common adverse event (32/42 participants) and was attributable to 13 of the 16 neonatal intensive care unit admissions. There were 5 cases of clinically diagnosed preeclampsia (2 cases in the CBT-only arm and 3 cases in the NRT + CBT arm) and 4 cases of term low birthweight (all in NRT + CBT arm). There were 4 cases of placental abnormalities in the NRT + CBT arm. There were 5 perinatal losses, which included 1 first-trimester miscarriage or embryonic death, 2 perinatal deaths because of extreme prematurity at 23 and 25 weeks of gestation, and 2 unexplained near-term perinatal deaths.

Table 1 describes the univariate effects of the 19 candidate predictors by incidence of adverse events, with dichotomization of continuous variables for purposes of presentation only. Serious adverse events occurred more frequently among African American women, compared with non–African American women (44% vs 21%; P = .004). Also, women with a history of poor pregnancy outcome were more likely to have an adverse event, compared with women without such a history or women for whom this was their first pregnancy (52% vs 20% vs 16%, respectively; P < .001). There were no differences in the remaining covariates.

TABLE 1. Probability of adverse events by candidate predictors among pregnant smokers

Characteristic	n	Adverse events, %	P valuea
Randomization
Cognitive-behavioral therapy	52	17	.06
Nicotine replacement therapy + cognitive-behavioral therapy	105	31
Age, y
≤25	78	23	.07
>25	79	30
Race
African American	38	44	.004
Non-African American	119	21
Education
<High school	45	22	.05
≥High school	112	37
Employment
Employed	74	25	.78
Unemployed	83	27
Partnered
No partner	50	30	.53
Partner	107	25
Obstetric history
First pregnancy	24	16
Healthy pregnancy history	99	20
Adverse pregnancy history	34	52	<.001
History of depression
Yes	43	30	.55
No	114	25
History of anxiety disorder
Yes	19	42	.11
No	138	24
History of drug or alcohol use
Yes	35	31	.48
No	122	25
History of sexually transmitted infection
Yes	38	25	.44
No	119	31
Adequate prenatal care index
1 or 2	38	18	.06
3 or 4	119	29
Baseline cigarettes/d, n
≤9	67	28	.82
>9	90	26
Baseline Center for Epidemiologic Studies Depression Scale/depression score (median)
≤13	75	27	.68
>13	82	27
Baseline self-esteem score
≤5	88	27	.58
>5	69	26
Baseline stress score
≤15	76	24	.42
>15	81	30
Baseline coping score
≤20	75	27	.83
>20	82	27
Analgesic medication use during pregnancy
Yes	38	36	.11
No	119	23
Psychiatric medication use during pregnancy
Yes	32	31	.52
No	125	25

Swamy. Predictors of adverse events for pregnant smokers in NRT trial. Am J Obstet Gynecol 2009.

Table 2 describes the results of the final logistic regression model with odds ratios and corresponding 95% confidence intervals (CIs) and probability values. A 2-sided α value of .05 was used to assess the covariate-adjusted arm effect; probability values for the other predictors are provided for completeness only and not for delineation of statistical significance. Using the backward stepwise regression approach for multivariate modeling as previously described, we eliminated 9 covariates from the final logistic regression analysis: baseline coping, psychiatric medication usage, baseline cigarettes usage, baseline self-esteem, employment status, partner status, history of sexually transmitted infections, history of illicit substance use, and history of anxiety. Study randomization arm (CBT alone vs CBT + NRT) was not a statistically significant risk factor for adverse perinatal events (odds ratio, 2.38; 95% CI, 0.91–6.25) and probability value of .08. The odds of an African American woman having an adverse event were 3.15 times higher (95% CI, 1.18–8.40; P = .02) than the odds for a non–African American woman. Use of analgesic or pain medications during pregnancy was also associated with adverse events (odds ratio, 2.63; 95% CI, 1.02–6.81; P = .04). Adverse pregnancy history was the strongest predictor of adverse events (P = .01); specifically, women with no history of adverse event and women for whom this was the first pregnancy both had a predicted incidence of adverse events of 17%; the women with a history of adverse event had a predicted incidence of 44%.

Table 2. Covariate-adjusted odds ratios for association of candidate predictors with the serious adverse events

CI, confidence interval.

Swamy. Predictors of adverse events for pregnant smokers in NRT trial. Am J Obstet Gynecol 2009.

In an attempt to determine whether concomitant smoking and NRT use contributed to adverse perinatal events, a subgroup analysis of participants in the CBT + NRT arm was performed. Adherence data, or the actual use of NRT, was available for 93 of the 105 participants in the CBT + NRT arm. Among the women who had a serious adverse event, 16 of 28 women (57.1%) reported using NRT and smoking for at least 1 day, compared with 31 of 65 women (47.7%) who did not have a serious adverse event.

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Comment 

Although there was an increased incidence of adverse perinatal events among women who were randomly assigned to the intervention arm than among those in the control arm, randomization to NRT for smoking cessation does not appear to be the attributable risk factor. In univariate and multivariate analysis, poor obstetric history and African American race were the strongest predictors of adverse perinatal events. Both traits are well-known risk factors for adverse pregnancy outcomes²⁷, ²⁸ and were more prevalent among participants in the intervention arm than in the control arm. The imbalance in baseline characteristics of our study population was possibly due to the 2:1 randomization scheme combined with early study closure. An unanticipated finding was the association between analgesic medications and adverse perinatal events. Although opioid narcotics are known to cause respiratory and neurologic depression in the fetus or neonate, such medications, when used appropriately during pregnancy, are not a recognized risk factor for adverse perinatal events such as preterm birth and low birthweight. Among the 38 women who used any analgesic medication during their pregnancy, 22 women used narcotics (such as acetaminophen + oxycodone, acetaminophen + hydrocodone, and acetaminophen + butalbital + caffeine), and 2 women were receiving chronic methadone maintenance therapy. The remaining 14 women used over-the-counter agents (such as nonsteroidal antiinflammatory drugs and acetaminophen) or prescribed agents (such as muscle relaxants). Although such agents do cross the placenta and could plausibly be contributors to adverse perinatal events, it is possible that the use of analgesic medications is a confounder or proxy for some other high-risk behavior that was not identified in this analysis.

A recent review article that focused more on the long-term developmental neurotoxicant effects of nicotine in animal studies staunchly opposes the use of NRT during pregnancy.¹³ The author claims that no studies have documented conclusively that NRT during pregnancy is successful for smoking cessation, has a better success rate than nonpharmacologic approaches, and is safe. Short-term data have shown that NRT use during pregnancy is no more harmful than nicotine from smoking.¹⁰, ¹² Although previous trials of NRT in pregnancy have not been powered for testing safety outcomes, no significant patterns or trends have raised concerns.¹⁶, ²⁹ The trials of Wisborg et al¹⁶ and Oncken et al²⁹ that investigated NRT vs placebo both demonstrated a statistically significant increase in mean birthweight among the women in the NRT arm relative to the placebo arm (186 g and 337 g, respectively); unfortunately, neither trial showed efficacy for smoking cessation. Alternatively, the Baby Steps trial, which combined NRT with behavioral therapy, clearly demonstrated the effectiveness of NRT for smoking cessation during pregnancy and showed that the addition of NRT was better than a nonpharmacologic approach alone for cessation.¹⁷ However, the Baby Steps trial did not show any improvement in birthweight and actually raised questions regarding the risk of adverse perinatal events that were associated with NRT, as previously described. Although all were randomized controlled trials, it is important to note the significant differences among the 3 studies that could impact the interpretation of the results. The study of Wisborg et al,¹⁶ which randomly assigned women to a nicotine or placebo patch, was conducted in Denmark where the population is quite homogeneous and the incidence of adverse perinatal events is much lower than in the United States. For example, the incidence of preterm birth in 2004 in Denmark was 6.3%, compared with 12.5% in the United States.³⁰, ³¹ Wisborg et al¹⁶ did not report their previous preterm birth rates; the study population of Oncken et al²⁹ had a previous preterm birth rate of 18%, compared with 26% in the Baby Steps trial. Furthermore, in the study of nicotine or placebo gum by Oncken et al,²⁹ >50% of study participants were Hispanic, and 7% of the participants were non-Hispanic black, compared with the Baby Steps trial in which 24% of participants were African American and <10% of the participants were Hispanic. Finally, the mean number of cigarettes that were smoked before pregnancy was 13 in the study by Wisborg et al,¹⁶ compared with 18 and 19 in the study by Oncken et al²⁹ and the Baby Steps trial, respectively. Given the well-documented racial disparity in adverse perinatal events with non-Hispanic black women who have higher rates of adverse outcomes compared with non-Hispanic white and Hispanic women, the potential differences in exposure from nicotine gum vs the patch and the differences in “nicotine addiction,” as measured by cigarettes smoked at baseline, comparisons of these trials on both efficacy and safety are challenging.

Our trial was not powered to study the safety of NRT during pregnancy; however, we were interested in examining whether inappropriate use of NRT (ie, concomitant smoking and NRT use) contributed to adverse perinatal events, because this is 1 hypothesized causal pathway.¹³ Although our limited subgroup analysis cannot be used to confirm or refute the concern for risk of adverse perinatal events that are associated with concomitant smoking and NRT use, it does support the importance of aggressive counseling on appropriate NRT use and possibly biologic measurement of nicotine levels in pregnant women who use NRT.

We performed a rigorous review of all available clinical documentation, which provided a comprehensive list of potential covariates for examination of the role of NRT in adverse perinatal outcomes. Previous similar studies have primarily described their adverse events in the context of a clinical trial but have not delved further into possible causal relationships. Retrospective chart review for data collection relies on the accuracy of documentation by physicians, nurses, and clerical staff and the truthfulness in disclosure by pregnant women. Although patient self-report is generally accurate for conditions such as diabetes mellitus or hypertension, there may be under reporting of conditions such as depression, substance use, and sexually transmitted infections that we included in this analysis. Finally, although our overall sample size was relatively small because of the lack of complete records or unavailability, our sample population represents an ethnically diverse group of women with varied education and income that allows for generalization to other diverse populations of pregnant smokers.

Although we were concerned by the interim analysis results that led the Data & Safety Monitoring Board to recommend suspension of participant recruitment, we were reassured by the combination of results from the final outcomes of the Baby Steps trial¹⁷ and this secondary analysis. Although randomization to the NRT-containing study arm was not a statistically significant contributor to adverse events, the odds ratio point estimate and wide confidence interval suggest a possible effect. Evaluation of the safety of NRT with regards to short-term perinatal outcomes and long-term neurotoxicant effects on human development requires a large sample population and measurement of cognitive functioning of children who are exposed to NRT in utero. Although reassuring, our results should serve as a guide to assist investigators who will design and implement additional studies to clarify further the potential risks and benefits of NRT use during pregnancy. The Smoking, Nicotine, and Pregnancy trial, which is a large-scale randomized trial of NRT during pregnancy that is being conducted in the United Kingdom, will provide useful insight into this potential safety concern because it will follow the offspring up to 2 years of age.³²

Women who smoke tobacco represent a high-risk population with significant socioeconomic, psychosocial, and environmental stressors and often have concomitant “unhealthy” lifestyles such as comorbid illnesses or illicit substance use. These same factors are known contributors to the multifactorial causes of adverse perinatal outcomes. Although it is unlikely that either smoking or NRT use alone functions as an isolated cause of adverse perinatal outcomes, further research is needed to determine the safety and benefit of NRT use during pregnancy.

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Acknowledgments 

We thank Pauline Lyna, MPH, and Rebecca J.N. Brouwer, MS, for their assistance with overall data collection and management for this study.

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