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Smoking Cessation Medications and Pregnant Smokers

Smoking Cessation Medications and Pregnant Smokers. Cheryl Oncken, M.D., MPH University of Connecticut School of Medicine. Presentation prepared for UK Smoking Cessation Conference, June 28 th , 2013. Cheryl Oncken, MD, MPH Disclosures. Research/Grants

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Smoking Cessation Medications and Pregnant Smokers

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  1. Smoking Cessation Medications and Pregnant Smokers Cheryl Oncken, M.D., MPH University of Connecticut School of Medicine Presentation prepared for UK Smoking Cessation Conference, June 28th, 2013

  2. Cheryl Oncken, MD, MPH Disclosures • Research/Grants • National Institutes of Health (NICHD, NIDA) • Pharmaceutical: Nabi Biopharmaceuticals; Pfizer Inc.

  3. Risks of Smoking During Pregnancy(Surgeon General’s Report 2004) • Maternal smoking is responsible for a number of poor pregnancy outcomes • spontaneous abortion (RR=1.2-1.3 ) • preterm delivery (OR=1.3) • low birth weight (RR=1.5-2.5) • placenta previa (RR=1.3-4.4) • placental abruption (RR=1.4-2.4) • Perinatal mortality (RR=1.2-1.3) • SIDS (OR=1.4-3.0)

  4. Effect of Prenatal Tobacco Exposure on Children • Prenatal tobacco exposure • Attention deficit disorder (Romano et al., 2008) • Deficits in attention and auditory processing (Fried et al., 1997; Fried et al 2003) • Increased risk of becoming a smoker (Kendell et al., 1994; Buka et al., 2003) • Childhood obesity (Wideroe et. al., 2003)

  5. Benefits of Cessation • Early cessation is best: • Women quit smoking by 16 weeks gestation have normal birth weight infants (MaCarther et al, 1988) • Women who quit smoking by 30-36 weeks have near normal birth weight infants (Ahlsten et al., 1993) • Smoking Reduction may also be beneficial: • 50% reduction in cotinine has been shown to improve birth weight (Li et al., 1993)

  6. Objectives • Describe the natural history of smoking behavior during pregnancy • Review overall impact of behavioral interventions • Discuss smoking cessation research studies • Pharmacotherapy • Discuss areas of future research

  7. Natural History of Smoking During Pregnancy 25% spontaneously quit smoking after learning of pregnancy (Floyd et al., 1993; LeClere & Wilson, 1997; Severson et al., 1995) Another 12% quit later on; however, the majority of pregnant smokers cut down, but do not quit(Fingerhut et al., 1991) Of women who quit during pregnancy, about 70% relapse within 1 year following delivery(Fingerhut et al., 1991)

  8. Continued Smokers vs. Spontaneous Quitters (DiClemente et al., 2000; Phares TM et al., 2004) • Less educated, lower SES, white, unemployed women are less likely to quit • Heavier smokers are less likely to quit smoking • Partner smoking is an independent risk factor for continued smoking during pregnancy

  9. Behavioral Interventions • Two meta-analyses have shown that behavioral interventions have a consistent, although modest, impact on quit rates (Fiore, et al., 2008, Cochrane reviews 2009) • On average behavioral interventions increase quit rates by 6% compared to usual care (Fiore, et al., 2008, Cochrane reviews 2009)

  10. Considerations in the Use of Pharmacotherapy • Pregnancy quit rates in meta-analyses rarely exceed 18% • Pharmacotherapies double quit rates in non-pregnant smokers • However, the benefit/risk ratio is unknown among pregnant smokers

  11. Pharmacotherapies in Non-pregnant Smokers Fiore et al., 2008 (Table 6.26)

  12. Clinical Practice GuidelinesFiore et al. Clinical Practice Guidelines, 2008 “ Safety is not categorical… Although the use of NRT exposes pregnant women to nicotine, smoking exposes them to nicotine plus numerous other chemical that are injurious to the woman and the fetus. These concerns must be considered in the context of inconclusive evidence that cessation medications boost abstinence rates in pregnant smokers.”

  13. Expert opinions regarding pharmacotherapy • Intermittent vs. continuous NRT delivery system may deliver a lower total dose (Benowitz and Dempsey, 2004) • Nicotine metabolism is accelerated during pregnancy (Dempsey et al., 2002) • Pregnancy registries (prospective) would be useful to better determine the risk/benefit profile

  14. Pharmacotherapy in Practice • A survey of US obstetricians, showed that 30% of physicians prescribe pharmacotherapy (Oncken et al., 2003) • 30% of pregnant smokers discussed medication with their health care provider; 10% utilized either NRT or bupropion (Rigotti et al., 2008) • Older age, more education, living with a partner, having an ob who discussed medication, private insurance • English Stop Smoking Services, 15 % were not prescribed medication, 30% prescribed single form of NRT, 55% prescibed combination NRT (Brose et al., 2013)

  15. NRT Randomized-controlled trials • Three studies have examined the effectiveness of NRT for pregnant smokers (randomized, but not placebo-controlled) • Three studies have examined the efficacy of NRT for smoking cessation during pregnancy (randomized, placebo controlled)

  16. Effectiveness Studies

  17. Nicotine Replacement and Behavioral Therapy Randomized open-label two-arm design: 2:1 randomization with more in NRT group • Arm 1, Cognitive Behavioral Treatment • Arm 2, Cognitive Behavioral Treatment + NRT • Choice of patch, gum, or lozenge (72 patch, 32 gum, 12 chose the lozenge, 6 CBT) Pollak KI, Oncken CA, Lipkus et al., AJPM 2007;33:297-305

  18. Results: Cessation Rates Adjusted for number of completed counseling sessions * indicates p<.05 Pollak KI, Oncken CA, Lipkus et al., AJPM 2007;33:297-305

  19. Serious Adverse Events • 44/171 women had at least one SAE; 34/113 (30%) NRT vs. 10/58 (17%) CBT • RD=0.13, 95% CI: 0.00-0.26, p=0.07 • After controlling for hx preterm birth, adjusted SAE rate (27% NRT vs. 18% CBT) • RD=0.09, 95% CI: 0.05-0.21, p=0.26 • Data and Safety Monitoring Board suspended enrollment after interim AE report • Based on a priori stopping rule • Concluded AE’s likely not related to NRT use

  20. Efficacy Studies: Placebo-controlled

  21. Nicotine Gum for Pregnant Smokers: Randomized Placebo controlled Study • To evaluate the efficacy of 2 mg nicotine gum for smoking cessation during pregnancy • To evaluate the effects of nicotine versus placebo gum on smoking reduction and on birth outcomes • Trial was monitored by a DSMB, FDA and NIDA

  22. Methods • Recruitment of 268 pregnant smokers • Inclusion criteria • At least 16 years of age • English or Spanish • Intent to carry to term • Stable residence/phone • Daily smoker • 26 weeks gestation or less • Exclusion criteria • Current drug abuse or dependence • Twins or multiple gestation • Unstable psychiatric, medical, or pregnancy conditions

  23. Gum Instructions • Begin chewing gum on their quit date • Women who smoked at least 10 cigarettes/day • (instructed to chew 9-12 pieces of 2 mg gum/day) • Smokers < 10 cigarettes per day • (chew the same number of pieces as usually smoked) • Smokers who chose reduction (substitute one pieces of gum for one cigarette, with the goal of abstinence in 3 weeks)

  24. Study Flow

  25. DSMB recommendations • 157 subjects completed visit 4 (6 weeks) • Quit rates were • 7% and 14% in groups A and B at visit 4 • 14% and 16% in groups A and B at visit 5 • Recommended termination of the study given the very small chance of finding statistical significance in quit rates between groups

  26. Table 1-Demographics

  27. Table 1-Demographics

  28. Study Retention * Nicotine group had significantly higher retention, p<.05

  29. Gum Use • Days of use • Placebo (29.9 + 3.4 days) vs Nicotine Group (37.8 + 3.4 days) (p=NS) • Average gum use 3.22 + 2.3 pieces per day • In both groups: • 50% believed they were on nicotine gum • 25% believed they were on placebo • 20% didn’t know (χ²(2) = 3.71, p=.16)

  30. Efficacy Rates

  31. Mean (SD) Smoking Outcomes by Visit * P value using available data, P # value with substitution analyses

  32. Birth Outcomes* *Birth outcomes on live born infants † P value obtained from square root transformation due to skewness

  33. Conclusions • Treatment of pregnant smokers with nicotine gum for smoking cessation or reduction • Did not significantly improve quit rates • Associated with a modest decrease in tobacco exposure (cigs/day, cotinine concentrations, alkaloid concentrations) • Associated with improved infant outcomes (birth weight, gestational age)

  34. Nicotine Patch for Pregnant Smokers • 1050 pregnant smokers between 12 and 24 weeks gestation who smoked 10 cigarettes/day • Random assignment to 15 mg/ 16 hours or placebo patches for 4 weeks, followed by an additional 4 weeks contingent on cigarette abstinence • Prolonged abstinence was 9.4% in NRT and 7.6% in placebo groups • Low Compliance: 7.2% in NRT 2.8% in placebo group used greater than 4 weeks • No difference in birth outcomes between groups Tim Coleman, M.D., Sue Cooper, Ph.D., James G. Thornton, M.D., et al. A Randomized Trial of Nicotine-Replacement patches in Pregnancy. NEJM 2012 ;366:808-18.

  35. Quit Rates Tim Coleman, M.D., Sue Cooper, Ph.D., James G. Thornton, M.D., et al. A Randomized Trial of Nicotine-Replacement patches in Pregnancy. NEJM 2012 ;366:808-18. .

  36. Placebo-controlled NRT trials in pregnancy • All studies show low medication adherence, which could impact efficacy (Oncken et al., NEJM 2012) • Reasons for low adherence could include • Lack of efficacy • Increased withdrawal • Accelerated nicotine metabolism • Concern about medication use during pregnancy • Side effects • Other reasons

  37. NRT in Clinical Practice • 3880 pregnant smokers in one of 44 stop Smoking Services in England • Outcome was 4-week quit rates, verified by exhaled carbon monoxide (<10 ppm) • Combination NRT was associated with a higher quitting than no medication (OR=1.93, 95% CI 1.1-3.3, p <0.016); although single NRT showed no benefit (OR 1.1; 95% CI 0.6-1.86, p=0.84) Brose LS, McEwen A, West R. Association between NRT in pregnancy and smoking cessation. Drug and Alcohol Dependence, 2013.

  38. Bupropion SR

  39. Bupropion SR in pregnancy • Non-nicotine medication, Category C in pregnancy (US) • Teratogenicity: Two prospective studies of bupropion SR in the first trimester did not find an increase in congenital malformations (Chun-Fai-Cahn B et al., 2005; Cole et al., 2006) • Spontaneous Abortion: In a prospective observational study (N=136) women taking bupropion SR in the first trimester • The SA rate was higher in the bupropion vs. NTC group (14.7% vs. 4.5%; p=.009) • SA rate in bupropion SR group similar to an anti-depressant control group (14.7 vs. 12.3%;p=ns).

  40. Bupropion SR for Smoking Cessation during Pregnancy • Efficacy for smoking cessation • One pilot study does not support an effect of bupropion SR on cessation rates (Miller et al., 2003) • Effectiveness for smoking cessation • In a controlled observational study, of 10/22 (45%) pregnant smokers receiving bupropion quit smoking, as compared to 3/22 (14%) of controls (P = 0.047) (Chan et al., 2005)

  41. Varenicline • Category C in pregnancy • Not teratogenic in rats and rabbits at 50x human exposure • Theoretically, would not interact with alpha 7 nAchR, the receptor that controls apoptosis and developmental regulatory effects • Animal studies are needed to evaluate potential neurotoxicity

  42. Pharmacotherapy for Smoking Cessation During Pregnancy • Randomized placebo-controlled trials have not shown efficacy of NRT, but risk/benefit ratio seems favorable • Compliance has been poor either with dose (Oncken, et al., 2008) or duration of use (Wisborg et al. 2000, Coleman 2012) • Open-label, randomized trials have shown effectiveness for NRT • One trial raised questions regarding safety (Pollak et al., 2007) • Limited studies on buproprion SR • No studies on varenicline • More research is needed to better define the benefit/risk ratio

  43. Summary • Pregnant smokers should be treated with known effective interventions (Fiore et al., 2008) • Person-to-person psychosocial interventions that exceed minimal advice to quit • Treatment should be offered at each visit • Given the absence of definitive data on pharmacotherapy • individual decisions should be made between health care provider and pregnant smoker • More research is needed to inform clinical practice

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