Smoking Cessation Medications and Pregnant

Smokers

Cheryl Oncken, M.D., MPHUniversity of Connecticut School of Medicine

Presentation prepared for UK Smoking Cessation Conference, June 28th, 2013

Cheryl Oncken, MD, MPH Disclosures

• Research/Grants –National Institutes of Health

(NICHD, NIDA)–Pharmaceutical: Nabi

Biopharmaceuticals; Pfizer Inc.

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)

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)

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)

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

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)

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

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)

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

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)

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.”

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

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)

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)

Effectiveness StudiesNRT N Quit

RatesBirth 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.

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

Results: Cessation Rates

Time-point

CBT-only (n=59)

Unadj (Adj)

CBT+NRT (n=122)

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 p<.05

Pollak KI, Oncken CA, Lipkus et al., AJPM 2007;33:297-305

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

Efficacy Studies: Placebo-controlledNRT 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

• 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

Nicotine Gum for Pregnant Smokers: Randomized Placebo

controlled Study

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

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)

Study Flow

T a p e r 2 m g G um(W e e k s 7 -1 2)

2 m g N ic o tine(W e e k s 1 -6)

2 m g N ico tin e G um

T a p e r 2 m g P la c e bo(W e e k s 7 -1 2)

2 m g P la c e bo(W e e k s 1 -6)

P la ce bo

B a se lin e V is it-R an d o m iz a tion(-1 w e e k )

S c ree n ing

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 weeksgestation

Birth Outcomes

Visit 6 postpartum

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

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

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%)

0.870.57

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)

0.830.100.340.31

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%)

0.960.920.410.80

Study RetentionPlacebo 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, p<.05

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)

Efficacy Rates

0

2

4

6

8

10

12

14

16

18

Visit 4 (6 wks after QD)

Visit 5 (32-34 wks)

Postpartum

PlaceboNicotine

Mean (SD) Smoking Outcomes by Visit Placebo (n=94) Nicotine (n=100) 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

Birth Outcomes*

Placebo

n=84

Nicotine

n=94

P-Value*

Birth Weight (Grams) 2950 (653) 3287 (569) <0.001

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

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)

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.

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 (>24 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 ;366:808-18.

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

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.

Bupropion SR

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).

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)

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

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

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