Smoking Cessation Medications and Pregnant Smokers

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
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Cheryl Oncken, MD, MPH Disclosures

• Research/Grants
• National Institutes of Health (NICHD, NIDA)
• Pharmaceutical Nabi Biopharmaceuticals Pfizer
  Inc.

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Risks of Smoking During Pregnancy(Surgeon
Generals Report 2004)

• Maternal smoking is responsible for a number of
  poor pregnancy outcomes
• spontaneous abortion (RR1.2-1.3 )
• preterm delivery (OR1.3)
• low birth weight (RR1.5-2.5)
• placenta previa (RR1.3-4.4)
• placental abruption (RR1.4-2.4)
• Perinatal mortality (RR1.2-1.3)
• SIDS (OR1.4-3.0)

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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)

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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)

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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

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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)

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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

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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)

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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

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Pharmacotherapies in Non-pregnant Smokers
Type Number of Arms Estimated OR (95 CI) Estimated Abstinence Rate
Placebo 80 1.0 13.8
Nicotine gum 15 1.5 (1.2-1.7) 19.0 (16.5-21.9)
Nicotine inhaler 6 2.1 (1.5-2.9) 24.8 (19.1-31.6)
Nicotine nasal spray 4 2.3 (1.7-3.0) 26.7 (21.5-32.7)
Nicotine patch (6-14wks) 32 1.9 (1.7-2.2) 23.4 (21.3-25.8)
Buproprion SR 26 2.0 (1.8-2.2) 24.2 (22.2-26.4)
Varenicline (2mg/day) 5 3.1 (2.5-3.8) 33.2 (28.9-37.8)
Fiore et al., 2008 (Table 6.26)
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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.

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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

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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)

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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)

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Effectiveness Studies
NRT N Quit Rates Birth outcomes
Pollak et al., 2007 Gum, patch or lozenge 181 18 vs. 7 2x SAE rate in NRT group
Hotham et al., 2006 Patch 40 15 vs. 0 Not reported
Heggard et al., 2003 Gum, patch or both (heavier smokers only) 647 (75 received NRT) 7 vs. 2 BW similar in 2 groups.
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Nicotine Replacement and Behavioral Therapy

• Randomized open-label two-arm design
• 21 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
200733297-305
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Results Cessation Rates
Time-point CBT-only (n59) Unadj (Adj) CBTNRT (n122) Unadj (Adj)
7-weeks post-rand 3 (8) 18 (24)
38-weeks gestation 2 (7) 14 (18)
3-months postpartum 14 (14) 20 (17)
Adjusted for number of completed counseling
sessions indicates plt.05 Pollak KI, Oncken
CA, Lipkus et al., AJPM 200733297-305
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Serious Adverse Events

• 44/171 women had at least one SAE 34/113 (30)
  NRT vs. 10/58 (17) CBT
• RD0.13, 95 CI 0.00-0.26, p0.07
• After controlling for hx preterm birth, adjusted
  SAE rate (27 NRT vs. 18 CBT)
• RD0.09, 95 CI 0.05-0.21, p0.26
• Data and Safety Monitoring Board suspended
  enrollment after interim AE report
• Based on a priori stopping rule
• Concluded AEs likely not related to NRT use

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Efficacy Studies Placebo-controlled
NRT N Quit rates (Rx vs. control) Birth Outcomes
Wisborg et al., 2000 Patch (15 mg/16 hours) 250 28 vs. 25 NRT group 186 gm higher BW
Oncken et al., 2008 Gum (2 mg) 194 18 vs 15 ? BW and Gestational Age
Coleman et al., 2012 Patch (15 mg/16 hours) 1050 9.4 vs. 7.6 No difference in BW or gestational age
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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

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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

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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 lt 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)

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• Study Flow

Study Visits Relation to Quit Date
Screening
Baseline -1 week
Visit 1 3-7 days
Visit 2 2 weeks
Visit 3 3 weeks
Visit 4 6 weeks
Visit 5 32-34 weeks gestation
Birth Outcomes Birth Outcomes
Visit 6 postpartum
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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

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Table 1-Demographics
Age in Years Placebo (94) 24.7 (5.4) Nicotine (100) 25.5 (6.8) 0.31
Body Mass Index 26.6 (6.8) 26.6 (7.1) 0.99
Race/Ethnicity Hispanic Caucasian African-American Other 52 (55) 30 (32) 7 (7) 5 (5) 53 (53) 38 (38) 8 (8) 1 (1) 0.32
Education Less than high school High school More than high school 44 (47) 36 (39) 13 (14) 53 (53) 28 (28) 19 (19) 0.26
Marital Status Married/Live in partner 28 (30) 30 (30) 0.91
Insurance (Public) 80 (85) 81 (81) 0.45
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Table 1-Demographics
Methadone Maintenance 6 (7) 6 (6) 0.57
Antidepressant Use 8 (9) 6 (6) 0.51
Treatment History Mental health Substance use 38 (41) 19 (20) 42 (42) 17 (17) 0.87 0.57
Smoking Before pregnancy (cigs/day) cigs/day last 7 days Previous quit attempts Fagerstrom score 17.8 (9.3) 8.7 (5.7) 2.55 (5.66) 3.55 (1.95) 17.5 (9.6) 10.2 (6.6) 3.03 (5.69) 3.83 (1.91) 0.83 0.10 0.34 0.31
Smoke Menthol Cigarettes 75 (80) 81 (81) 0.83
Pregnancy Number of pregnancies Gestational entry (weeks) History preterm delivery First pregnancy 3.41 (2.56) 17.1 (5.5) 16 (17) 16 (17) 3.43 (2.11) 17.1 (5.6) 13 (13) 16 (16) 0.96 0.92 0.41 0.80
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Study Retention
Placebo Nicotine
Baseline 94 100
Visit 1 62 (66) 67 (67)
Visit 2 58 (62) 72 (72)
Visit 3 56 (60) 75 (75)
Visit 4 56 (60) 70 (70)
Visit 5 60 (64) 78 (78)
Postpartum 47 (50) 65 (65)
Nicotine group had significantly higher
retention, plt.05
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Gum Use

• Days of use
• Placebo (29.9 3.4 days) vs Nicotine Group
  (37.8 3.4 days) (pNS)
• 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 didnt know (?²(2) 3.71, p.16)

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Efficacy Rates
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Mean (SD) Smoking Outcomes by Visit
Placebo (n94) Nicotine (n100) P P
Cigs/ Day Screen/Baseline Visit 4 Visit 5 8.84 (5.7) 4.56 (5.4) 5.04 (6.1) 9.99 (6.1) 4.59 (4.7) 4.59 (4.9) 0.16 0.077 0.12 0.035
Cotinine Concentration Screen/Baseline Visit 4 Visit 5 633 (559) 577 (582) 512 (531) 672 (438) 542 (454) 492 (443) 0.10 0.17 0.047 0.043
Exhaled CO Screen/Baseline Visit 4 Visit 5 8.69 (10.1) 6.79 (10.4) 6.36 (8.8) 9.43 (6.3) 7.53 (6.0) 6.76 (6.2) 0.99 0.70 0.63 0.53
Anabasine Screen/Baseline Visit 4 Visit 5 4.73 (6.6) 4.94 (7.1) 4.17 (6.6) 4.74 (5.7) 4.18 (6.0) 3.23 (4.4) 0.30 0.31 0.086 0.61
P value using available data, P value with
substitution analyses
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Birth Outcomes
Placebo n84 Nicotine n94 P-Value
Birth Weight (Grams) 2950 (653) 3287 (569) lt0.001
Gestational Age (Wks) 38.0 (3.3) 38.9 (1.7) 0.014
Infant Length (Cms) 49.0 (4.4) 50.0 (2.7) 0.065
Head Circumference (Cms) 33.5 (2.0) 34.0 (1.7) 0.075
Apgar Score 1 Minute 5 Minutes 8 (8,9) 9 (9,9) 8 (8,9) 9 (9,9) 0.62 0.061
Length of Stay Baby Days 5.25 (11.4) 3.60 (5.6) 0.24
Birth outcomes on live born infants P value
obtained from square root transformation due to
skewness
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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)

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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 366808-18.

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Quit Rates
NRT Placebo Adjusted Odds Ratio (95 CI)
Prolonged Abstinence 9.4 7.6 1.27 (0.82-1.98)
1month after quit date 21.3 11.7 2.1 (1.49-2.97)
End of Pregnancy (gt24 hours) 12 10 1.24 (0.84-1.85)
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 366808-18.
.
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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

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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 (lt10 ppm)
• Combination NRT was associated with a higher
  quitting than no medication (OR1.93, 95 CI
  1.1-3.3, p lt0.016) although single NRT showed no
  benefit (OR 1.1 95 CI 0.6-1.86, p0.84)
• Brose LS, McEwen A, West R. Association between
  NRT in pregnancy and smoking cessation. Drug and
  Alcohol Dependence, 2013.

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Bupropion SR
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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 (N136) 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.
  12.3pns).

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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)

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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

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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

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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