Smoking cessation in Pregnancy

Stacey Rittmueller, DO, MPH Tacoma Family Medicine Rural / OB Fellow March 26, 2021

Objectives

Describe the epidemiology of smoking in pregnancy

Review evidence and recommendations for smoking cessation interventions in pregnancy

Describe the role of pharmacotherapy in smoking cessation

Discuss limitations of nicotine replacement therapy (NRT) evidence in pregnancy

Road Map

Background

❑ Why Cessation Matters

❑ Epidemiology

❑ Social Determinants

❑ Pharmacokinetics

• Nicotine Addiction

• Nicotine Metabolism

• Smoking in Pregnancy

Cessation Methods

❑ Behavioral Therapy

❑ Bupropion

❑ Varenicline

❑ NRT

❑ Metabolism nicotine and NRT in pregnancy

Results

❑ Cochrane: Claire 2020

❑ SNAP Trial, 2 year followup

❑ Adverse Events

❑ Limitations

Summary

❑ Conclusion

❑ Practice Guidelines

❑ Implications for Practice

❑ Resources

Smoking Cessation in Pregnancy

Why it matters

❑ 5-8% preterm deliveries

❑ 13-19% term infants with LBW

❑ 22-34% cases of SIDS

❑ $366 million

Annual total cost neonatal healthcare attributed to smoking (2002)

Scherman et al. 2018. Dietz et al., 2010 ; Anderson et al, 2019; Adams et al, 2002. ACOG 2020

Outcomes attributable to smoking in pregnancy

Why it matters

Scherman et al. 2018; Dietz et al. 2010; Adams et al, 2002.

https://www.cdc.gov/tobacco/basic_information/health_effects/pregnancy/

Reduces chance of pregnancy

MiscarriageEctopic Pregnancy

Increases complications

Premature Rupture of Membranes Placental Abruption

Placenta Previa

Neonatal harmsCleft lip and palate

Cardiac, limb and GI defects Decreased academic performance

Reactive airway disease Respiratory infections

Low birth weight HyperactivityShort statureOtitis media

Obesity SIDS

Epidemiology

Drake et al., 2016. NCHS Data Brief, no 305. Hyattsville, MD: National Center for Health Statistics. 2018. https://www.cdc.gov/nchs/products/databriefs/db305.htm

Scherman et al 2018.

Epidemiology: Age

Drake et al 2018. https://www.cdc.gov/nchs/products/databriefs/db305.htm

Epidemiology: Race/Ethnicity

Drake et al 2018. https://www.cdc.gov/nchs/products/databriefs/db305.htm

Epidemiology: Education

Drake et al 2018. https://www.cdc.gov/nchs/products/databriefs/db305.htm

CDC Tobacco Use Disparitieshttps://www.cdc.gov/tobacco/disparities/index.htm

Tobacco Use Disparities

https://www.cdc.gov/tobacco/disparities/african-americans/index.htm

Tobacco Use Disparities

Pharmacokinetics:Nicotine Addiction

Nicotine reaches the brain in <20s

Peak blood concentration in 5 min

(+) reinforcement: Binds nAChR→ dopamine and serotonin

Scherman et al. Smoking cessation in pregnancy: a continuing challenged in the United States. Ther Adv Drug Saf. 2018. 9(8):457-474

Pharmacokinetics:Nicotine Addiction

Nicotine reaches the brain in <20s

Peak blood concentration in 5 min

(+) reinforcement: Binds nAChR→ dopamine and serotonin

(-) reinforcement: continued smoking reduces withdrawal symptoms General discomfort, stress, agitation, depression

Scherman et al. Smoking cessation in pregnancy: a continuing challenged in the United States. Ther Adv Drug Saf. 2018. 9(8):457-474

Pharmacokinetics:Nicotine metabolism

Benowitz NL et al. Nicotine Chemistry, Metabolism, Kinetics and Biomarkers Handb Exp Pharmacol. 2009; (192): 29–60. doi: 10.1007/978-3-540-69248-5_2

Lower due to 1st

pass metabolismBioavailability Cigarette 80-90% NRT: 50-79%

Pharmacokinetics:Smoking in pregnancy

Scherman et al. Smoking cessation in pregnancy: a continuing challenged in the United States. Ther Adv Drug Saf. 2018. 9(8):457-474

Leung

❑ Nicotine and carbon monoxide (CO)

readily cross placenta

❑ Disrupts uterine artery blood flow and

fetal oxygenation

❑ Nicotine in amniotic fluid can exceed

maternal plasma levels by 88%

❑ Fetal serum nicotine can exceed

maternal circulating levels by >15%

Smoking Cessation Methods

BEHAVIORAL SUPPORT

❑ BRIEF INTERVENTION

PHARMACOTHERAPY

❑ WELLBUTRIN, VARENICLINE

❑ NRT

❑ BEHAVIORAL THERAPY✓

Behavioral interventions: General Population

Patnode et al. JAMA 2021 -- both are direct quotes

Quote 2 is from Hartmann-Boyce et al Cochrane 2019 *** ref 25 in Patnode

15 to 88% increased relative smoking cessation @ ≥6months ❑ in-person advice support from clinicians ❑ individual, group, telephone, and mobile phone support❑ interactive and tailored internet-based interventions ❑ use of incentives

Behavioral support + pharmacotherapy vs pharmacotherapy alone Increased rates of smoking cessation

RR 1.15 [95% CI 1.08 – 1.22]; k=65, n=23 331

Behavioral interventions: Pregnancy

Patnode et al 2021 (from Cochrane 2017)

2017 Cochrane ReviewSmoking cessation in late pregnancy

All Behavioral Interventions vs usual care35% increased rate of smoking cessation

Counseling vs usual care 44% increased rate of smoking cessation

Behavioral interventions: Pregnancy

Patnode 2021, data from Cochrane 2017

Behavioral interventions: Pregnancy

Cognitive behavioral therapy ❑ developing a sense of self-monitoring and control

❑ learning to manage cravings

❑ managing situations of stress and anxiety

❑ promoting self-efficacy

❑ goal setting and action planning

ACOG 2020

Behavioral interventions: Pregnancy

ACOG 2020

5 A’s of Tobacco and Nicotine Cessation:Ask

AdviseAssessAssist

Arrange

** Note this is different than Motivational Interviewing “Ask Tell Ask”

Smoking Cessation Methods

BEHAVIORAL SUPPORT

❑ BRIEF INTERVENTION

PHARMACOTHERAPY

❑ NRT

❑ BEHAVIORAL THERAPY

✓❑ BUPROPION, VARENICLINE

Bupropion: General Population

Howes S, et al. Cochrane 2020. *** need reference from Patnode 2021 (ref 15)

64% vs control (placebo or no drug) (k=46; n=17,866)

Cessation

Dopamine/Norepinephrine-Reuptake Inhibitor

150 mg daily x 3 days, then 150 mg BID for 7 to 12 weeks Quit attempt is generally initiated a week after starting

Bupropion: Pregnancy2 small RCTs (n=76)- No evidence that bupropion improved smoking cessation later in pregnancy - No evidence of bupropion’s impact on birth outcomes

Claire R et al, 2020 (Cochrane)

Bupropion: Pregnancy

Cochrane 2020

2018 systematic review (Turner et al)RCTs + cohort + case-control studies + case reports (k=18)Bupropion (k=14) and Varenicline (k=4) ❑ No evidence of increased congenital anomalies, LBW, or preterm birth❑ No strong evidence of safety

ACOG Limited data in pregnancy

No known risk of fetal anomalies or adverse pregnancy effects

Claire R et al, 2020 (Cochrane)

Varenicline: General Population

Cahill K, et al. Cochrane 2016 *** Reference obtained from 2021 patnode (ref 16)

124% (RR 2.24) vs control (placebo or no drug) (k=27; n=12625)

Cessation

Partial agonist for nAChR in the brain1 mg BID x 12 weeks, the first week titrated to reduce side effects

Quit date set for the 2nd week of use

Varenicline: Pregnancy

Cochrane 2020

Cochrane 2020No eligible RCTs of varenicline available for inclusion in the review

ACOG 2020 Several small studies that evaluated safety have not shown teratogenicity

Take away:Varenicline & Bupropion

ACOG❑ Counsel about risks of smoking + cessation benefits❑ Discuss resources for cessation, which may include varenicline & bupropion❑ Familiarity w/ risks, benefits, & updated FDA Drug Safety is prudent

ACOG 2020

No strong evidence

Smoking Cessation Methods

BEHAVIORAL SUPPORT

❑ BRIEF INTERVENTION

PHARMACOTHERAPY

❑ WELLBUTRIN, VARENICLINE

❑ NRT✓

❑ BEHAVIORAL THERAPY

NRT: General Population

Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T. Can nicotine replacement therapy (NRT) help people quit smoking? Cochrane Database of Systematic Reviews. 31 May 2018. https://doi.org/10.1002/14651858.CD000146.pub5Lindson N, Chepkin SC, Ye W, Fanshawe TR, Bullen C, Hartmann-Boyce J . Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation (Review). Cochrane Database of Systematic Reviews . 18 April 2019 https://doi.org/10.1002/14651858.CD013308

Increases rate of cessation 50-60% vs control (k=136; n=64,640)

Cessation

Combination NRT vs. single-form NRT

4 mg vs. 2 mg nicotine gum

NRT Safety in Pregnancy

Scherman et al. Smoking cessation in pregnancy: a continuing challenged in the United States. Ther Adv Drug Saf. 2018. 9(8):457-474

Metabolism of Nicotine and NRT in pregnancy

Diamanti et al., Smoking cessation in pregnancy: An update for maternity care practitioners. Tob Induc Dis. 2019;17:57. doi: 10.18332/tid/109906Lerman C et al., Serum nicotine and cotinine levels are lower (gum, nasal spray, patches) vs Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation. Clin Pharmacol Ther. 2006 Jun; 79(6):600

❑ Pregnancy, elevated estrogen CYP2A6 activity & nicotine metabolism

❑ Ad lib use of NRT = 1/3rd to 2/3rd lower serum [nicotine] vs smoking

❑ Nicotine delivered more slowly

❑ Avoids harmful substances, including CO and thousands of chemicals

The Upside to NRT and its increased metabolism:

Included studiesParticipants

(N)Cochrane Review,

Claire 2020

Placebo Controlled Trials

Berlin, 2014 402 X

Coleman, 2012 1050 X

Kapur, 2001 30 X

Oncken, 2008 194 X

Oncken, 2019 137 X

Wisborg, 2000 250 X

Non-Placebo Controlled Trials

El-Mohandes, 2013 52 X

Hotham, 2006 40 X

Pollak, 2007 181 X

Coleman T, Chamberlain C, Davey MA, Cooper SE, Leonardi-Bee J. Pharmacological interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev. 2015; (12): CD010078 (STEP 1)

Patnode CP, Henderson JT, Thompson JH, Senger CA, Fortmann SP, Whitlock EP. Behavioral Counseling and Pharmacotherapy Interventions for Tobacco Cessation in Adults, Including Pregnant Women: A Review of

Reviews for the U.S. Preventive Services Task Force. Evidence Synthesis No. 134. AHRQ Publication No. 14-05200-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015. (STEP 1)

Biochemical Validation

• Primary metabolite nicotine

• Accepted cut point ≤ 10ng/ml

• Included studies: < 9 - 26ng/ml

• Used in several studies as a safety check

Cotinine (ng/ml)

• Included studies: Exhaled CO ≤ 7 – 8ppm

• Shorter half-life

Carbon monoxide (CO; ppm)

• Included study: ≤1ug/ml

• Outlier in validation

• Affected by diet and pollution

Thiocyonate (ug/ml)

Claire et al, 2020

Pharmacological interventions for promoting smoking cessation during pregnancy Claire et al., 2020

PARTICIPANTS

INTERVENTION

COMPARITOR

OUTCOMES

Primary Outcome: Validated cessationClaire et al., 2020

Claire et al 2020

Statistical Heterogeneity

Rough guide for I

Claire et al 2020

Heterogeneity

Race/ethnicityAgeParityCig# per dayGestational AgeAdherence

CLINICAL METHODOLOGICAL

Dosing NRTNRT vehicleValidation methodBehavioral therapy style / durationTime of enrollmentDuration of follow up

Number of trials

Participants

(N)

Relative Risk (RR)

Effect Size [95% CI]

Miscarriage 5* 1916 1.60

[0.53 - 4.83]

Stillbirth 4* 1777 1.24

[0.54 - 2.84]

Low birth weight (<2500g) 7 2171 0.69

[0.439- 1.20]

Preterm birth (<37w) 7 2182 0.81

[0.59 - 1.11]

NICU admissions 4 1756 0.90

[0.64, 1.27[

Neonatal death 4* 1746 0.66

[0.17 - 2.62]

Congenital abnormalities 2 1401 0.73

[0.36 - 1.48]

Claire et al, 2020

*Non-placebo parallel-design RCT

Secondary Outcomes: Neonatal

Claire et al, 2020

Secondary Outcomes: Neonatal

SNAP long term followupCooper et al., 2014

Patnode CP, Henderson JT, Thompson JH, Senger CA, Fortmann SP, Whitlock EP. Behavioral Counseling and Pharmacotherapy Interventions for Tobacco Cessation in Adults, Including Pregnant Women: A Review of Reviews for the U.S. Preventive Services Task Force. Evidence Synthesis No. 134. AHRQ Publication No. 14-05200-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015. (STEP 1)Cooper et al. The SNAP trial: a randomized placebo-controlled trial of nicotine replacement therapy in pregnancy– clinical effectiveness and safety until 2 years after delivery, with economic evaluation. Health Technol Assess. 2014 Aug;18(54):1-128. doi: 10.3310/hta18540.

2 year followup from Coleman 2012; N=1050

❑ <1/3rd participants responded

❑ PCPs of nonrespondents also surveyed

❑ Both arms = 88% total response rate, with similar rates of nonresponse

At 2 years, children born to NRT-allocated mothers were

more likely to have unimpaired development

❑ 73% NRT vs 65% placebo OR 1.41 [95% CI, 1.05 to 1.87]

Adverse eventsNon-serious:General: Headache, nausea, fatigue, local site reaction, foul tasteInhaler: throat irritation, cough, and nausea

Perinatal harms and serious adverse events → underpowered for assessing rare harms with statistical confidence

Coleman et al, 2015 and Patnode et al, 2015

Adherence

Mean NRT use in one study:Patch: 3.3wGum: 8d Lozenge: 4dInhaler: 5w (but underdosed)

Completed Course NRT: 7 – 23%

(65%*)

Controls: 0 – 8% (88%*)

*outliers due to small sample size

<1-2 weeks: ~ 60%, by 3 weeks: 17%

DURATION TOO SHORT

❑ Interventions only a few weeks

❑ Low adherence

DOSE TOO LOW

❑ General population: higher doses NRT = greater use of NRT

→ Causally associated with successful cessation

❑ Pregnancy: Insufficient dose for accelerated nicotine metabolism

Hickson et al. Comparison of nicotine exposure during pregnancy when smoking and abstinent with NRT: systematic review and meta-analysis. Addiction. 2018;114. 406-424Hollands et al Adherence to and consumption of NRT and the relationship with abstinence within a smoking cessation trial in primary care.

Why does NRT appear less effective in pregnancy compared with the general population?

Faster metabolism → lower [nicotine] → Stronger withdrawal symptoms

→ perception NRT unhelpful → lower cessation rates

Conclusion for NRTEvidence with a high risk of bias suggests

that NRT combined with behavioral

support might help women to stop

smoking in later pregnancy.

When limited to only higher-quality,

placebo-controlled trials, the estimate of

the pooled effect increased, but was no

more effective than placebo

Practice Guidelines for NRT

https://www.rcog.org.uk/globalassets/documents/patients/patient-information-leaflets/pregnancy/pi-smoking-and-pregnancy-2.pdf

NRT delivers “clean forms of nicotine and are safe and effective aids for people who want to stop smoking”

Tobacco and Nicotine Cessation During Pregnancy. ACOG Committee Opinion: Number 807. May 2020. Vol 135 (5).

Should be considered only after detailed discussion:❑ known risks of continued smoking❑ the possible risks of NRT❑ need for close supervision

Used with the clear resolve to quit smoking

❑ Introduced as early as possible in pregnancy

❑ Use lowest dose that controls withdrawal symptoms and permits abstinence

❑ Short acting NRT to allow intermittent dosing is preferred with low levels of addiction and women who have quit smoking using the NRT patch for several weeks

❑ Remove NRT patch at night

❑ Combination of NRT patch and short acting NRT is recommended

Implications for Practice

Diamanti et al., Smoking cessation in pregnancy: An update for maternity care practitioners. Tob Induc Dis. 2019;17:57. doi: 10.18332/tid/109906

Disparities in Tobacco Use and Cessation

Apply standardized counseling and treatment to all pregnant women

Statewide and local comprehensive smoke-free laws

In 2020, the chair of the Tobacco Control Network and Tobacco & Vapor Product Prevention & Control Program Manager at the WSDOH

“implement policies that address the SDOH and disproportionate marketing practices that target low-income communities and those with behavioral health conditions”

Marketing mattersRestrict advertising, limit the number of retailers in neighborhoods, and prohibit price discounting can help reduce tobacco use and its negative health outcomes

https://www.cdc.gov/tobacco/disparities/index.htm

https://www.astho.org/StatePublicHealth/Beyond-Opioids-Tobacco-Other-Substance-Use-Among-Pregnant-Women/01-14-20/

Socio-economic determinants

https://www.cdc.gov/tobacco/disparities/index.htm

Resources

https://www.cdc.gov/tobacco/campaign/tips/groups/index.html

https://women.smokefree.gov/

https://www.doh.wa.gov/YouandYourFamily/Tobacco/HowtoQuit

Resources

https://www.astho.org/StatePublicHealth/Beyond-Opioids-Tobacco-Other-Substance-Use-Among-Pregnant-Women/01-14-20/

https://www.doh.wa.gov/YouandYourFamily/Tobacco/HowtoQuit/Selfhelpoptions

Text Message Program

Text START to 47848 Text DITCHVAPE to 88709

Text MOM to 222888

Free Smartphone Apps

https://smokefree.gov-tips/apps/

CHECK IT OUT!

Resources

1. https://www.acog.org/patient-resources/infographics/tobacco-and-pregnancy

2. QUIT FOR TWO: https://women.smokefree.gov/pregnancy-motherhood/quitting-while-pregnant/quit-for-two

3. Need Help Putting Out That Cigarette? Booklet https://www.acog.org/store/products/patient-education/booklet/need-help-putting-out-that-cigarette-booklet

AcknowledgmentsDrs Benko, Guirguis-Blake and all the faculty with MultiCare OBGynAssociates

Jean Basaraba

Susan Rowe, PharmD

References1. Coleman T, Chamberlain C, Davey MA, Cooper SE, Leonardi-Bee J. Pharmacological interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev. 2015; (12): CD010078 (STEP 1)2. Patnode CP, Henderson JT, Thompson JH, Senger CA, Fortmann SP, Whitlock EP. Behavioral Counseling and Pharmacotherapy Interventions for Tobacco Cessation in Adults, Including Pregnant Women: A Review of Reviews for the U.S. Preventive Services Task Force. Evidence Synthesis No. 134. AHRQ Publication No. 14-05200-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015. (STEP 1)3. Siu AL; US Preventive Services Task Force. Behavioral and Pharmacotherapy Interventions for Tobacco Smoking Cessation in Adults, Including Pregnant Women: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2015 Oct 20; 163(8):622-34. doi: 10.7326/M15-2023. Epub 2015 Sep 22. PMID: 26389730 (STEP 1)4. Scherman et al. Smoking cessation in pregnancy: a continuing challenged in the United States. Ther Adv Drug Saf. 2018. 9(8):457-474.5. Dietz et al. Infant morbidity and mortality attributable to prenatal smoking in the U.S. Am J Prev Med. 2010 Jul;39(1):45-52. doi: 10.1016/j.amepre.2010.03.009.6. Adams et al, Neonatal health care costs related to smoking during pregnancy. 18 March 2002. Health Economincs. Determinants of Health7. https://www.cdc.gov/tobacco/basic_information/health_effects/pregnancy/8. Drake P, Driscoll AK, Mathews TJ. Cigarette smoking during pregnancy: United States, 2016. NCHS Data Brief, no 305. Hyattsville, MD: National Center for Health Statistics. 2018. Benowitz, NL. Nicotine Addiction. N Engl J Med. 2010; 362:2295-2303. DOI: 10.1056/NEJMra08098909. Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T. Can nicotine replacement therapy (NRT) help people quit smoking? Cochrane Database of Systematic Reviews. 31 May 2018. https://doi.org/10.1002/14651858.CD000146.pub510. Lindson N, Chepkin SC, Ye W, Fanshawe TR, Bullen C, Hartmann-Boyce J . Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation (Review). Cochrane Database of Systematic Reviews . 18 April 2019 https://doi.org/10.1002/14651858.CD01330811. Diamanti et al., Smoking cessation in pregnancy: An update for maternity care practitioners. Tob Induc Dis. 2019;17:57. doi: 10.18332/tid/10990612. Lerman C et al., Serum nicotine and cotinine levels are lower (gum, nasal spray, patches) vs Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation. Clin Pharmacol Ther. 2006 Jun; 79(6):600-813. Cooper et al. The SNAP trial: a randomized placebo-controlled trial of nicotine replacement therapy in pregnancy– clinical effectiveness and safety until 2 years after delivery, with economic evaluation. Health Technol Assess. 2014 Aug;18(54):1-128. doi: 10.3310/hta18540.14. Hickson et al. Comparison of nicotine exposure during pregnancy when smoking and abstinent with NRT: systematic review and meta-analysis. Addiction. 2018;114. 406-42415. Zlowodzki M et al. How to interpret a meta-analysis and judge its value as a guide for clinical practice. Acta Orthopaedica, 2007;78(5):598-609, DOI: 10.1080/17453670710014284

16. https://handbook-5-1.cochrane.org/chapter_9/9_5_1_what_is_heterogeneity.htm17. https://search.creativecommons.org/photos/056a5a5d-009c-48c2-af87-858005663b3918. https://teens.drugabuse.gov/blog/post/pregnancy-and-drugs-update-part-1-smoking-and-vaping-0

19. https://www.cdc.gov/nchs/products/databriefs/db305.htm

References21. Anderson TM, Lavista Ferres JM, Ren SY, Moon RY, Goldstein RD, Ramirez JM, et al. Maternal smoking before and during pregnancy and the risk of

sudden unexpected infant death. Pediatrics 2019;143:e20183325.

22. Tran DT, Pree DB, Einarsdottier K, et al. Use of smoking cessation pharmacotherapies during pregnancy is not associated with increased risk of

adverse pregnancy outcomes: a population based cohort study. BMC Med 2020; 18: 15. OMID 32019533

23. Claire ***

24. Tobacco and Nicotine Cessation During Pregnancy. ACOG Committee Opinion: Number 807. May 2020. Vol 135 (5).25. https://www.astho.org/StatePublicHealth/Beyond-Opioids-Tobacco-Other-Substance-Use-Among-Pregnant-Women/01-14-2026. https://www.rcog.org.uk/globalassets/documents/patients/patient-information-leaflets/pregnancy/pi-smoking-and-pregnancy-2.pdf27. https://www.health.nsw.gov.au/tobacco/Factsheets/nrt-in-pregnancy.pdf

28. Turner E, Jones M, Vaz L, Coleman T. Systematic Review and Meta Anyalysis to Assess the Safety of Bupropion and Varenicline in Pregnancy.

Nicotine and Tobacco Research. Volume 21, Issue 8, August 2019, Pages 1001-1010.