Smoking, nicotine and pregnancy 2 (SNAP2) trial: protocol for a randomised controlled trial of an intervention to improve adherence to nicotine replacement therapy during pregnancy

Miranda M Clark; Sue Cooper; Felix Naughton; Michael Ussher; Joanne Emery; Lisa McDaid; Ross Thomson; Lucy Phillips; Linda Bauld; Paul Aveyard; David Torgerson; Ivan Berlin; Sarah Lewis; Steve Parrott; Catherine Hewitt; Charlie Welch; Gill Parkinson; Anne Dickinson; Stephen Sutton; James Brimicombe; Katharine Bowker; Andrew McEwen; Kavita Vedhara; Tim Coleman

doi:10.1136/bmjopen-2024-087175

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Smoking, nicotine and pregnancy 2 (SNAP2) trial: protocol for a randomised controlled trial of an intervention to improve adherence to nicotine replacement therapy during pregnancy

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SNAP2 trial is ethical
Tim Coleman
Published on: 5 July 2024
SNAP2 “Baby, Me & NRT” Ignores Nicotine Risks
John R. Polito
Published on: 12 June 2024

Published on: 5 July 2024
SNAP2 trial is ethical
- Tim Coleman, Professor in Primary Care / Chief Investigator for SNAP2 Trial Centre for Academic Primary Care, University of Nottingham
We share Polito’s concerns about harms from smoking in pregnancy; by finding effective ways to help pregnant women become smokefree, our work seeks to help eliminate these. We take our responsibilities to study participants very seriously. SNAP2 was approved by an independent research ethics committee which assessed all patient-facing materials, including the participant information sheet. After approval, any modifications to these documents require further approvals.

Giving nicotine to pregnant animals is widely accepted to be harmful for animal offspring.(1) It is logical to suspect similar effects in humans, and so, studies investigating nicotine use by pregnant women who do not smoke, would very likely be judged unethical. Consequently, the only robust information on how nicotine affects human pregnancies is from comparisons, within pregnant women who smoke, of those who do and do not use NRT (i.e. nicotine) for quitting. Systematic reviews of such studies indicate that NRT (nicotine) helps pregnant women stop smoking without having adverse effects on birth outcomes.(2, 3) Although there is currently insufficient research evidence to be completely sure, the most likely impact is that NRT (nicotine) used in pregnancy for quitting improves birth outcomes relative to continued smoking.(3) NRT has marketing autorisation for use in pregnancy in several European countries (e.g. in France, since 1997), many of which use sophisticated pharmacovigilance sy...
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We share Polito’s concerns about harms from smoking in pregnancy; by finding effective ways to help pregnant women become smokefree, our work seeks to help eliminate these. We take our responsibilities to study participants very seriously. SNAP2 was approved by an independent research ethics committee which assessed all patient-facing materials, including the participant information sheet. After approval, any modifications to these documents require further approvals.

Giving nicotine to pregnant animals is widely accepted to be harmful for animal offspring.(1) It is logical to suspect similar effects in humans, and so, studies investigating nicotine use by pregnant women who do not smoke, would very likely be judged unethical. Consequently, the only robust information on how nicotine affects human pregnancies is from comparisons, within pregnant women who smoke, of those who do and do not use NRT (i.e. nicotine) for quitting. Systematic reviews of such studies indicate that NRT (nicotine) helps pregnant women stop smoking without having adverse effects on birth outcomes.(2, 3) Although there is currently insufficient research evidence to be completely sure, the most likely impact is that NRT (nicotine) used in pregnancy for quitting improves birth outcomes relative to continued smoking.(3) NRT has marketing autorisation for use in pregnancy in several European countries (e.g. in France, since 1997), many of which use sophisticated pharmacovigilance systems to monitor for potential harms. To date, none of these systems has detect any signal indicating that NRT might be harmful in pregnancy.

The SNAP2 RCT tests the effectiveness of the ‘Baby, Me & NRT’ (BMN) smoking cessation intervention, one component of which is the offer of a NRT patch, plus short acting NRT used on demand (‘dual NRT’).(4) Before SNAP2 started, during BMN’s development, we carefully assessed impacts of offering dual NRT on women’s exposures to carbon monoxide (CO, a proxy for tobacco smoke exposure) and cotinine (a proxy for nicotine).(5) We found that, in women offered BMN, compared to when they smoked, cotinine concentrations were no different [mean difference = −32.31 ng/ml, 95% confidence interval (CI) = −68.11 to 3.5 ng/ml], but women had lower exhaled CO concentrations, reflecting this lighter smoking (ratio of geometric means = 0.30 p.p.m., 95% CI = 0.17–0.52 p.p.m.; P < 0.001) and reported smoking fewer daily cigarettes [mean difference = −7 cigarettes, 95% CI = −8.35 to −5.42 cigarettes, P < 0.001]. (5) Despite being urged to set a date after which they should abstain from smoking, many women smoked after their quit dates, sometimes on days when they also used NRT. Within this group, we found a strong, inverse relationship between nicotine dose from NRT, and daily cigarettes smoked; women smoked less as they used more NRT.(6) Taken together, these findings provide no evidence that BMN may cause harm; they suggest that, even in women who do not manage to fully stop smoking, the principal effect of BMN is to reduce women’s exposure to the toxic products of combustion transmitted in tobacco smoke.

We employ a cautious, evidence-based and ethical methods for developing and testing new stop smoking interventions for pregnant women. The SNAP2 trial has recruited over 600 women; it is not an exception to this approach, and it is entirely rational for the study to be completed.

NB: All SNAP2 protocol authors have approved this letter which has been submitted on behalf of the full team; see SNAP2 protocol paper for SNAP2 team membership.

REFERENCES
1. Phillips L, Thomson R, Coleman-Haynes T, Cooper S, Naughton F, McDaid L, et al. Developing a taxonomy to describe offspring outcomes in studies involving pregnant mammals' exposure to non-tobacco nicotine: A systematic scoping review. PLoS One. 2023;18(2):e0280805.
2. Claire R, Chamberlain C, Davey MA, Cooper SE, Berlin I, Leonardi‐Bee J, et al. Pharmacological interventions for promoting smoking cessation during pregnancy. Cochrane Database of Systematic Reviews. 2020(3).
3. Taylor L, Coleman T, Coleman-Haynes T, Campbell K, Cooper S, A. D. Systematic review of observational studies to compare the safety of nicotine replacement therapy (NRT) use and smoking in pregnancy. PROSPERO 2018 CRD42018085834 Available from
https://wwwcrdyorkacuk/prospero/display_recordphp?RecordID=85834 [Internet]. 2017.
4. McDaid L, Emery J, Thomson R, Coleman T, Cooper S, Dickinson A, et al. Development of "Baby, Me, & NRT": A Behavioral Intervention to Improve the Effectiveness of Nicotine Replacement Therapy in Pregnancy. Nicotine Tob Res. 2023;25(11):1770-80.
5. Slaich B, Claire R, Emery J, Lewis S, Cooper S, Thomson R, et al. Comparison of saliva cotinine and exhaled carbon monoxide concentrations when smoking and after being offered dual nicotine replacement therapy in pregnancy. Addiction. 2022;117(3):751-9.
6. Orton S, Szatkowski L, Naughton F, Coleman T, team NR. The Relationship Between Reported Daily Nicotine Dose from NRT and Daily Cigarette Consumption in Pregnant Women Who Smoke in an Observational Cohort Study. Nicotine Tob Res. 2024;26(2):212-9.
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Conflict of Interest:
None declared.
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Published on: 12 June 2024
SNAP2 “Baby, Me & NRT” Ignores Nicotine Risks
- John R. Polito, Nicotine Cessation Educator WhyQuit
Clark and colleagues’ SNAP2 clinical trial is recruiting 1,320 pregnant UK smokers to the largest and possibly most aggressive pregnancy nicotine replacement therapy (NRT) cessation program to date. Noting accelerated nicotine metabolism during pregnancy, they contend that it’s “very likely that for NRT to work in pregnancy, higher nicotine doses and dosing consistency are needed than are currently used.” Recommending dual use of a nicotine patch plus either a nicotine inhaler, spray, or lozenges, they anticipate a 36-week pregnancy smoking cessation rate of 16% in the “Baby, Me & NRT” (BMN) intervention arm. As for safety, the authors state, “[W]e do not anticipate any harm being caused, and there is no adverse event monitoring.”[1]

Stated “Objective 1” of the “Baby, Me & NRT” behavioral program is to “strongly encourage high-dose, combination NRT use.” Objective 3 is to create the perception that NRT is “safe to use in pregnancy.”[2] Clark and colleagues SNAP2 Data Supplement 2 is a “Participant Information Sheet.” The sheet does not mention any known fetal nicotine risk. Instead, it states, “We do not foresee there being any risks from taking part in this study.” Data Supplement 3 is a “Consent Form.” The form does not mention any risk.[1]

Noting the gravity of potential smoking-induced fetal harms, Clark and colleagues assert that since 2000 “there has been expert consensus for using NRT to stop smoking in pregnancy.” But a simple “fetal + n...
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Clark and colleagues’ SNAP2 clinical trial is recruiting 1,320 pregnant UK smokers to the largest and possibly most aggressive pregnancy nicotine replacement therapy (NRT) cessation program to date. Noting accelerated nicotine metabolism during pregnancy, they contend that it’s “very likely that for NRT to work in pregnancy, higher nicotine doses and dosing consistency are needed than are currently used.” Recommending dual use of a nicotine patch plus either a nicotine inhaler, spray, or lozenges, they anticipate a 36-week pregnancy smoking cessation rate of 16% in the “Baby, Me & NRT” (BMN) intervention arm. As for safety, the authors state, “[W]e do not anticipate any harm being caused, and there is no adverse event monitoring.”[1]

Stated “Objective 1” of the “Baby, Me & NRT” behavioral program is to “strongly encourage high-dose, combination NRT use.” Objective 3 is to create the perception that NRT is “safe to use in pregnancy.”[2] Clark and colleagues SNAP2 Data Supplement 2 is a “Participant Information Sheet.” The sheet does not mention any known fetal nicotine risk. Instead, it states, “We do not foresee there being any risks from taking part in this study.” Data Supplement 3 is a “Consent Form.” The form does not mention any risk.[1]

Noting the gravity of potential smoking-induced fetal harms, Clark and colleagues assert that since 2000 “there has been expert consensus for using NRT to stop smoking in pregnancy.” But a simple “fetal + nicotine” PubMed search returns a plethora of experts raising serious fetal nicotine harm concerns, some questioning the 2005 proposed UK pregnancy NRT policy change allowing NRT use until birth.[4]
Significant fetal nicotine concerns raised include alterations in brain structure and function,[5] possible brain stem damage,[6] sudden infant death syndrome,[7] ADHD,[8] impaired fetal lung development,[9] cardiovascular dysfunction,[10] kidney injury,[11], offspring impaired fertility, type 2 diabetes, obesity and hypertension,[12] perturbation of male spermatogenesis,[13] and fetal-originated metabolic diseases in adulthood.[14]

Prenatal nicotine alters the trajectory of normal brain development via premature stimulation of nicotinic acetylcholine receptors (nAChRs).[15] Should nicotine-induced damage occur, by what age will it become apparent, by 2 to 3 years of age, or while learning to read and write, or when trying to muster the concentration necessary to conduct simple math calculations? Will the type or degree of harm correspond to when during pregnancy nicotine was used, the type or number of delivery devices used, or the daily amount of nicotine administered? How will we know without nicotine-free controls and long-term postpartum study follow-up?

Although research is lacking, I hypnotize that the vast majority of pregnant UK women who fully and permanently arrest their dependence upon nicotine do so via abrupt nicotine cessation (cold turkey), with or without accompanying support, counseling, or other self-help resources. Women quitting cold turkey are unlikely to join NRT quitting studies. So, what is cold turkey’s 36-week success rate and how does it compare to the 16% rate that BMN is expected to generate?

Lacking answers to such fundamental pregnancy quitting method productivity, effectiveness, and method enhancement questions, what basis exists for declaring any non-evaluated method inferior or a less than 20% BMN rate significant? Does BMN alter the fact that 44%-90% of women who quit smoking resume smoking by 1 year postpartum?[16] Without postpartum follow-up, how will we know?

Generating a risk ratio of 14.42 (1.77-117.25) among 505,584 women who smoked before pregnancy, while a fear that smoking will harm her unborn baby is by far the greatest smoking cessation predictor,[17] it’s a double-edged sword as to both pregnancy cessation failure and postpartum relapse. As a 25-year nicotine cessation educator, to my mind, the most fundamental pregnancy cessation factor is aiding mothers-to-be in shifting their core cessation motivation from fear and dread about fetal harm to getting excited about permanently arresting their chemical dependence and enjoying the full glory of nicotine-free motherhood.[18] Quitting for others, including the unborn, roots the attempt in self-deprivation and sacrifice. In that they can only remain afraid for so long before either growing numb to it or having their core motivation evaporate upon giving birth, it’s a recipe for relapse.

Will her baby ever know its mother’s natural scent, or instead bond to the thousands of chemicals that smoke deposits on her hair, skin, clothing, and kisses? First and foremost, she needs to see recovery as her long overdue and loving gift to herself, with her baby inheriting freedom’s fruits. We need to help her appreciate that the up to 3 days needed to move beyond peak withdrawal is good and wonderful, as what better evidence could there be of healing than feeling it?

In closing, this “Baby, Me & NRT” study was written as if there is little or no risk of fetal harm after intentionally encouraging the simultaneous use of more than one method of nicotine delivery. Respectfully, scores of studies suggest otherwise. I submit that a fair reading of this study’s format, together with recent nicotine fetal harm research, and the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects, raises multiple concerns regarding ethical compliance.[19]

References:

1. Clark MM, Cooper S, Naughton F, et al. Smoking, nicotine and pregnancy 2 (SNAP2) trial: protocol for a randomised controlled trial of an intervention to improve adherence to nicotine replacement therapy during pregnancy. BMJ Open. 2024 May 28;14(5):e087175. doi: 10.1136/bmjopen-2024-087175. PMID: 38806422; PMCID: PMC11138292.
2. McDaid L, Emery J, Thomson R, et al. Development of "Baby, Me, & NRT": A Behavioral Intervention to Improve the Effectiveness of Nicotine Replacement Therapy in Pregnancy. Nicotine Tob Res. 2023 Sep 4;25(11):1770-1780. doi: 10.1093/ntr/ntad102. PMID: 37349134; PMCID: PMC10475605.
3. McGrath-Morrow SA, Gorzkowski J, Groner JA, et al. The Effects of Nicotine on Development. Pediatrics. 2020 Mar;145(3):e20191346. doi: 10.1542/peds.2019-1346. Epub 2020 Feb 11. PMID: 32047098; PMCID: PMC7049940.
4. Ginzel KH, Maritz GS, Marks DF, et al. Critical review: nicotine for the fetus, the infant and the adolescent? J Health Psychol. 2007 Mar;12(2):215-24. doi: 10.1177/1359105307074240. PMID: 17284486.
5. Kohlmeier KA. Nicotine during pregnancy: changes induced in neurotransmission, which could heighten proclivity to addict and induce maladaptive control of attention. J Dev Orig Health Dis. 2015 Jun;6(3):169-81. doi: 10.1017/S2040174414000531. Epub 2014 Nov 11. PMID: 25385318.
6. Polli FS, Kohlmeier KA. Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence. World J Psychiatry. 2022 Feb 19;12(2):212-235. doi: 10.5498/wjp.v12.i2.212. PMID: 35317337; PMCID: PMC8900586.
7. Beltrán-Castillo S, Bravo K, Eugenín J. Impact of Prenatal Nicotine Exposure on Placental Function and Respiratory Neural Network Development. Adv Exp Med Biol. 2023;1428:233-244. doi: 10.1007/978-3-031-32554-0_10. Erratum in: Adv Exp Med Biol. 2023;1428:C1. PMID: 37466776.
8. Xavier J, Singh S, Kumari P, Ravichandiran V. Neurological repercussions of neonatal nicotine exposure: A review. Int J Dev Neurosci. 2022 Feb;82(1):3-18. doi: 10.1002/jdn.10163. Epub 2021 Dec 30. PMID: 34913189.
9. Bednarczuk N, Williams EE, Dassios T, Greenough A. Nicotine replacement therapy and e-cigarettes in pregnancy and infant respiratory outcomes. Early Hum Dev. 2022 Jan;164:105509. doi: 10.1016/j.earlhumdev.2021.105509. Epub 2021 Nov 20. PMID: 34823165.
10. Nordenstam F. Prenatal nicotine exposure was associated with long-term impact on the cardiovascular system and regulation-Review. Acta Paediatr. 2021 Sep;110(9):2536-2544. doi: 10.1111/apa.15914. Epub 2021 May 25. PMID: 33982809.
11. Popham K, Kandasamy Y. The impact of smoking and nicotine exposure during pregnancy on fetal nephrogenesis: a systematic review. J Dev Orig Health Dis. 2023 Oct;14(5):559-569. doi: 10.1017/S2040174423000302. Epub 2023 Nov 16. PMID: 37969035.
12. Bruin JE, Gerstein HC, Holloway AC. Long-term consequences of fetal and neonatal nicotine exposure: a critical review. Toxicol Sci. 2010 Aug;116(2):364-74. doi: 10.1093/toxsci/kfq103. Epub 2010 Apr 2. PMID: 20363831; PMCID: PMC2905398.
13. Dali O, Muriel-Muriel JA, Vargas-Baco A, et al. Prenatal nicotine exposure leads to epigenetic alterations in peripheral nervous system signaling genes in the testis of the rat. Epigenetics Chromatin. 2024 May 7;17(1):14. doi: 10.1186/s13072-024-00539-5. PMID: 38715099; PMCID: PMC11075221.
14. He B, Zhang Q, Guo Y, et al. Prenatal smoke (Nicotine) exposure and offspring's metabolic disease susceptibility in adulthood. Food Chem Toxicol. 2022 Oct;168:113384. doi: 10.1016/j.fct.2022.113384. Epub 2022 Aug 27. PMID: 36041661.
15. Slotkin TA. If nicotine is a developmental neurotoxicant in animal studies, dare we recommend nicotine replacement therapy in pregnant women and adolescents? Neurotoxicol Teratol. 2008 Jan-Feb;30(1):1-19. doi: 10.1016/j.ntt.2007.09.002. PMID: 18380035.
16. De Genna NM, Qu Y, Cheng Y, Emery Tavernier RL, Kolko Conlon RP, Levine MD. Trajectories of Return to Cigarette Smoking Up to 1 Year Postpartum Among People Who Quit Smoking During Pregnancy. Nicotine Tob Res. 2023 Apr 6;25(5):875-881. doi: 10.1093/ntr/ntac263. PMID: 36402742; PMCID: PMC10077935.
17. Riaz M, Lewis S, Naughton F, Ussher M. Predictors of smoking cessation during pregnancy: a systematic review and meta-analysis. Addiction. 2018 Apr;113(4):610-622. doi: 10.1111/add.14135. Epub 2018 Jan 30. PMID: 29235189.
18. Polito JR. 100 reasons to get excited about quitting smoking. WhyQuit: https://whyquit.com/pr/012717.html Accessed June 5, 2024.
19. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191-4. doi: 10.1001/jama.2013.281053. PMID: 24141714.
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Conflict of Interest:
John R. Polito is the 1999 founder of WhyQuit, an abrupt nicotine
14 cessation website, and author of two cold turkey quitting books.
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