Lung and Breast Cancer Prevention by an Integrated Intervention of Maternal Smoking Cessation and Breastfeeding
Phase: NA
Conditions: Smoking, Cigarette, Breastfeeding
Sponsor: Xiaozhong Wen

COVER PAGE 
 
Project title: 
Lung and breast cancer prevention by an integrated intervention of maternal smoking cessation and 
breastfeeding 
 
NCT number: STUDY00003067 
 
Date of the document: 04/01/2020  
 

PROJECT TITLE 
Lung and breast cancer prevention by an integrated intervention of maternal smoking cessation and 
breastfeeding 
 
INVESTIGATORS 
Name 
Title 
Institute 
Role 
Xiaozhong Wen, MD, PhD 
Associate Professor 
UB Dept. of Pediatrics 
PI 
Yukiko Washio, PhD 
Researcher 
RTI International 
Co-I 
Chi-Chen Hong, PhD 
Associate Professor 
Roswell Park Comprehensive 
Cancer Center 
Co-I 
Faye E. Justicia-Linde, MD 
Clinical Assistant Professor 
UB Dept. of OB-GYN 
Co-I 
Chang-Xing Ma, PhD 
Associate Professor 
UB Dept. of Biostatistics 
Co-I 
 
ABSTRACT (300 words maximum) 
The elevated risk of lung cancer due to cigarette or cigar smoking can be largely reversed by long-term 
smoking cessation. Pregnancy is a unique opportunity to quit smoking. However, most quitters return to 
smoking (“relapse”) after delivery. Sufficient breastfeeding protects against breast cancer. But smokers tend to 
not breastfeed. Our team has successfully developed two separate interventions for smoking cessation during 
pregnancy and breastfeeding maintenance, respectively. However, only 50% of quitters in our sample remain 
smoking abstinent at 6 months postpartum, and only 21% of quitters still breastfeed at 6 months postpartum. 
Observational research suggests smoking abstinence and breastfeeding reinforce each other. These 
reciprocal associations (a positive feedback loop) have not yet been leveraged in the design of more effective 
interventions.   
We are proposing the first randomized controlled trial to integrate maternal smoking cessation and 
breastfeeding interventions to enhance both cancer prevention behaviors. We will recruit 40 daily smoking 
women in their 1st or 2nd trimester of pregnancy (≤28 weeks) from local obstetric clinics, communities, and 
social media. They will be randomized into either the intervention (N=20) or control group (N=20). The two 
groups will complete the same number of sessions (6 during pregnancy and 3 postpartum), but focus on 
different topics. Specifically, the control group will receive instructions on general pregnancy and infant care. 
The intervention group will receive instructions on general pregnancy and infant care, plus an integrated 
multicomponent intervention that promotes both smoking cessation and breastfeeding (i.e., education and 
counseling, monitoring and feedback, and contingent financial incentives). Two female Certified Lactation 
Counselors (interventionists) will be trained to run study sessions during home visits. Interventionists will 
provide additional support via phone and text messaging until 6 months postpartum. Main outcomes include 
smoking abstinence and breastfeeding rates at 6 months postpartum within the duration of this award.  
 
Key words (5 max) 
Smoking cessation; Breastfeeding; Lung cancer; Breast cancer; Pregnancy 
 
Project description for general scientific audience 
We are proposing the first randomized controlled trial to integrate maternal smoking cessation and 
breastfeeding interventions to enhance both cancer prevention behaviors. We will recruit 40 daily smoking 
pregnant women, start integrated intervention during pregnancy and continue until 6 months postpartum.  
 
This study involves human subjects only.  
 
This study does not involve vertebrate animals.  
 
 
 

SPECIFIC AIMS 
Aim 1: to develop a protocol for training and mentoring Certified Lactation Counselors to implement an 
integrated intervention of maternal smoking cessation and breastfeeding. We hypothesize Certified Lactation 
Counselors can be trained to implement our intervention protocol with high fidelity.  
Aim 2: to examine the efficacy of an integrated intervention of maternal smoking cessation and 
breastfeeding on smoking abstinence rates. We hypothesize smoking abstinence rates at delivery and 6 
months postpartum will be higher in the intervention group than the control group. Among successful quitters 
during pregnancy in the intervention group, we expect smoking abstinence rate at 6 months postpartum will be 
higher than the rate that we previously observed when our smoking cessation intervention was delivered alone. 
Aim 3: to examine the efficacy of our integrated intervention on breastfeeding rates. We hypothesize 
breastfeeding rate at 6 months postpartum in the intervention group will be higher than the control group. We 
also expect breastfeeding rate at 6 months postpartum in the intervention group will be higher than the rate 
that we previously observed among smokers when our breastfeeding intervention was delivered alone. 
 
 
1. BACKGROUND AND SIGNIFICANCE  
1.1 Smoking cessation and lung cancer. Prevention of lung cancer is a top public health priority. 
Among U.S. women, lung cancer is the second most common cancer (102,625 new cases in 2014) and the 
leading cause of cancer death (70,667 deaths in 2014).1 Cigarette smoking is a well-established cause for lung 
cancer, causing 87% of lung cancer deaths in the U.S.2 Fortunately, the elevated risk of lung cancer due to 
smoking can be largely reversed by long-term smoking cessation.3-5 Pregnancy is a unique opportunity for 
women to quit smoking. About 23% of U.S. women smoke at conception and 54% of them report quitting 
smoking during pregnancy.6 But most women who quit smoking during pregnancy return to smoking (“relapse”) 
after delivery, e.g., 45% and 81% relapse by 6 and 12 months postpartum, respectively.7,8 Temporary smoking 
abstinence only during pregnancy may have limited benefits against lung cancer, as the risk of lung cancer 
seems to begin to decrease after 2 years of abstinence.3 However, there is little demonstrated success in 
preventing long-term postpartum smoking relapse using existing interventions.9  
1.2 Breastfeeding and breast cancer. Among U.S. women, breast cancer is the most common cancer 
(236,968 new cases in 2014) and the second most common cause of death from cancer (41,211 deaths in 
2014).1 Sufficient breastfeeding is a protective factor against breast cancer,10 besides its well-known nutritional 
and immunological benefits to the breastfed child.11 There is a dose-response inverse association between 
lifetime breastfeeding duration and risk of breast cancer: the longer breastfeeding lasts, the lower the risk of 
breast cancer.10,12 According to a large meta-analysis, the relative risk of breast cancer decreases by 4.3% for 
every 12 months of lifetime breastfeeding. Accordingly, National Cancer Institute (NCI) encourages women to 
breastfeed for 12 months or longer to reduce risk of breast cancer.13 The European Code against Cancer also 
recommends that, ‘‘Breastfeeding reduces the mother’s cancer risk. If you can, breastfeed your baby’’.14  
1.3 Rationale for an integrated intervention of maternal smoking cessation and breastfeeding. 
Interestingly, maternal smoking abstinence and breastfeeding can strongly reinforce each other, which has 
been demonstrated by two lines of research. First, smokers tend to not initiate breastfeeding or have shorter 
breastfeeding duration (e.g., a mean of 11 vs 28 weeks15) than non-smoking mothers,15-18 which can further 
increase their already elevated cancer risk due to smoking. Possible reasons include concerns of 
contaminated breast milk by smoking,19,20 smoking-related lactation inhibition,21-25 and the infant’s refusal of 
breast milk from smokers due to altered flavor26 and/or nutrient composition.22,27,28 In contrast, smoking 
cessation during pregnancy is associated with increased breastfeeding intention and practices.29-32 Secondly, 
successful breastfeeding is associated with 30-60% lower risk of postpartum smoking relapse,7,33,34 which may 
be attributed to breastfeeding-related emotional benefits. Breastfeeding mothers have lower perceived stress35-
37 and less negative affect (e.g., depression38-40 and anger38) than formula-feeding mothers. High levels of 
postpartum stress and negative affect are common triggers of postpartum smoking relapse. However, the 
reciprocal associations (a positive feedback loop) between maternal smoking abstinence and breastfeeding 
reported in previous observational studies have been not considered in existing interventions yet. An integrated 
intervention may achieve larger effects than traditional interventions that targeted each separately.  
1.4 Our supportive work. Our team has developed and tested an effective multicomponent smoking 
cessation intervention for pregnant smokers (PI, Wen).41 As high as 63% (19/30) of our participants quit 
smoking successfully during pregnancy,41 compared to 6% among pregnant smokers receiving usual care in a 
reference population.42 Participants’ intention of exclusively breastfeeding has been doubled by our smoking 
cessation intervention (39.1% at post-test vs 19.4% at pre-test).43 Quitters are 3.5 times (75% vs 20%) more 
likely to initiate breastfeeding than persistent smokers.44 But only a small proportion of our participants remain 

smoking abstinent (50%) or breastfeeding (21%) at 6 months postpartum, indicating the need of sustained 
postpartum support for relapse prevention and breastfeeding. In addition, we have developed an effective 
intervention to maintain breastfeeding among low-income mothers (PI, Washio): the breastfeeding rate at 6 
months postpartum was 72% in the intervention group, compared to 0% in the usual care group.45 
1.5 Clinical-translational relevance and impacts. This phase 2A clinical trial (proof-of-concept) will 
test the feasibility and preliminary impact of an integrated intervention of maternal smoking cessation and 
breastfeeding. It potentially advances this important field from the observational to intervention phase.  
 
2. APPROACH  
2.1 Study design. We are proposing the first randomized controlled trial to integrate maternal smoking 
cessation and breastfeeding interventions from pregnancy to 6 months postpartum (Table 1).  
Table 1. Study design (W-week, M-month) 
Recruitment 
Randomization 
Home-based, CLC-delivered intervention 
Outcomes 
1st & 2nd trimesters of 
pregnancy (≤28 w) 
After baseline 
assessment 
Pregnancy  
(6 weekly visits) 
Postpartum  
(3 bi-monthly visits) 
6 months postpartum 
40 daily pregnant 
smokers 
Intervention 
(N=20)  
Integrated smoking cessation & breastfeeding intervention* 
+ Instructions on general pregnancy and infant care 
1. Smoking abstinence 
2. Breastfeeding 
Control (N=20) 
Instructions on general pregnancy and infant care 
*Education and counseling, monitoring and feedback, and contingent financial incentives 
2.2 Recruitment and screening. We will recruit 40 daily smoking pregnant women from Erie County 
and Niagara County, NY (36,731 births in 2014-201646). Recruitment flyers will be distributed in local obstetric 
clinics, communities, and Facebook. Eligible participants must be at least 18 years old, at ≤28 weeks of 
gestation to ensure adequate time for interventions, and daily smoking cigarettes and/or cigars in the past 7 
days verified by urine cotinine testing. Exclusion criteria include being diagnosed with cancer, current heavy 
alcohol use, current use of marijuana and illegal drugs, uncontrolled mental disorders, with medical conditions 
contraindicating breastfeeding, and being strongly against breastfeeding. 
2.3 Randomization. After baseline assessments, the 40 eligible participants will be randomized into 
either the intervention (N=20) or control group (N=20). A sequence of random numbers in blocks of 2 will be 
used to ensure equal numbers of participants for each group over time. 
2.4 Intervention 2.4.1 Intervention group: integrated intervention of smoking cessation and 
breastfeeding. The intervention group will receive an integrated intervention of smoking cessation and 
breastfeeding: education and counseling, monitoring and feedback, and contingent financial incentives.41 
Intervention schedule. Participants need to complete 6 weekly prenatal visits and 3 bi-monthly 
postpartum visits (1, 3, 6 months) at their own home. Two female Certified Lactation Counselors (CLCs) will be 
trained as interventionist to run these home visits. Each home visit will last for about 60 minutes, which will be 
divided between smoking cessation intervention and breastfeeding promotion intervention. Interventionists will 
provide additional support via phone and text messaging until 6 months postpartum. 
Theories-based intervention. Our integrated intervention of smoking cessation and breastfeeding is 
guided by two theories: the Health Belief Model (HBM) 47,48 and Contingency Management (CM).49 According 
to the HBM, an individual behavior (e.g., smoking cessation) depends upon several factors: perceived 
susceptibility (e.g., smoking-related risk of low birth weight), perceived severity (e.g., cost and burden to raise a 
low-birth-weight infant), perceived benefits (e.g., saving money for baby items, removal of guilt of harming the 
baby), perceived barriers (e.g., daily stress and fear of nicotine withdrawal symptoms), self-efficacy (e.g., 
smoking craving management), and cues to action (e.g., fetal ultrasound scan).50 CM uses stimulus control 
and consequences to change behaviors. Positive behavior (e.g., smoking abstinence) is encouraged by 
providing reinforcing consequences (e.g., financial incentives), while the undesired behavior (e.g., continuous 
smoking or relapse) is discouraged by withholding reinforcing consequences or providing punitive measures.  
Intervention component #1: Education and counseling.  Our educational materials include readings and 
video-taped lectures that address several perceptions in the Health Belief Model through information on 
negative consequences of smoking and non-breastfeeding, benefits of quitting smoking and breastfeeding, 
barriers to quit smoking or breastfeed and related strategies. At each visit, participants will first take a quiz with 
10 multiple-choice questions on assigned educational materials, and receive a $5 reward for passing it (two 
attempts). Then, the interventionist will conduct behavioral counseling that focusing on self-efficacy 
enhancement through 1) planning for quitting smoking, progress review, feedback, craving analysis, and 
relapse prevention; and 2) making an individualized breastfeeding plan and addressing concerns including 
previous unsuccessful experience if applicable. After delivery, interventionists will help participants to initiate 
breastfeeding as soon as possible, and solve everyday problems during breastfeeding practices.  

 Intervention component #2: Monitoring and feedback. We will use the Internet and related technology 
(e-Health) to facilitate daily monitoring of smoking and breastfeeding behaviors. At the first prenatal 
intervention visit, participants will receive a free personal smartphone-based iCOTM Smokerlyzer breath carbon 
monoxide (CO) monitor (Bedfont Scientific Ltd, Kent, UK) and be instructed to test their CO level at home 
every day. This device has high validity.51 Breath CO is a sensitive biomarker reflecting recent smoking levels 
and provides timely feedback on smoking reduction or cessation. Maternal breath CO levels will also be 
converted into the fetal carboxyhaemoglobin (%COHb) OR “fetal blood CO”. A high fetal %COHb indicates 
fetal hypoxia (lack of oxygen), which can serve as a strong cue to action, i.e., smoking cessation. After 
delivery, participants will receive a free smartphone-based wireless baby weight scale (“Hatch Baby Grow”, 
Hatch Baby, Inc, Menlo Park, CA) to monitor their breastfeeding by weighing their baby before and after each 
breastfeeding, which can provide accurate information on how much breast milk that the baby consumes. The 
two smartphone Apps will automatically transmit results to interventionists who can remotely monitor each 
participant’s progress and provide timely feedback and assistance.  
 Intervention component #3: Contingent financial incentives. During pregnancy, if a participant reports 
smoking abstinence and all her daily breath CO levels since the last visit are within non-smoking range (≤4 
parts per million or ppm), she will receive a financial incentive that starts at $10 at the second prenatal 
intervention visit and escalates by $5/visit in next 4 weekly prenatal visits.41 After delivery, participants will 
receive incentives for breastfeeding if they are able to nurse or to provide breast milk by pumping in the 
presence of the interventionist. Contingent incentives will start at $20/visit at the 1-month postpartum visit and 
increase by $10/visit at the 3-month and 6-month postpartum visits.45  
2.4.2 Control group: instructions on general pregnancy and infant care. Participants in the control group 
will receive usual prenatal care from physicians, nurses, or social workers. They will receive best standard care 
on smoking cessation and breastfeeding, including referral to the New York State Smokers' Quitline52 and the 
Special Supplemental Nutrition Program for Women, Infants, and Children (WIC).53 Several efforts will be 
made to balance attention and compensation between two groups. First, participants in the control group will 
complete the same frequency and duration of visits as their counterparts in the intervention group. Instead of 
focusing on smoking cessation and breastfeeding, they will receive instructions on general pregnancy and 
infant care. Specifically, they will review educational materials with quizzes ($5 reward/quiz), and receive 
counseling guided by two authoritative books: “Your Pregnancy and Childbirth: Month to Month” published by 
the ACOG54 and “Caring for Your Baby and Young Child: Birth to Age 5” published by the AAP,55 respectively. 
These materials will be also given to the intervention group but without quizzes or counseling. Secondly, the 
control group will earn a total amount of financial compensation ($25/prenatal visit and $30/postpartum visit) 
that is similar to the intervention group, regardless of smoking status and feeding practice.  
2.4.3 Adherence and retention of participants. Adherence to intervention will be assessed by the 
number of completed visits, completed activities at each visit, passed quizzes, and self-monitoring of breath 
CO levels and infant feeding via smart-phone Apps.56 If we lose contact, we will reach out to the 3 contact 
people that participants indicated at enrollment.  
2.4.4 Training the interventionists. The interventionists need to complete 70-hour training (Table 2). In 
Step 1, they will study educational materials on smoking cessation and breastfeeding, the 5As model (ask, 
advise, assess, assist, arrange) for smoking cessation,57 behavioral change theories (HBM47,48 and CM49), and 
counseling skills. In Step 2, they need to complete ethical and compliance training (CITI) for being involved in 
human research. They will also learn to follow research protocols, use visit instructions/checklists, run breath 
CO and urine cotinine tests, use wireless devices and small-phone apps to monitor breath CO and infant 
feeding, and ensure safety during home visits. In Step 3, they will observe 5 smoking cessation and 
breastfeeding intervention visits in the PI’s clinic. In Step 4, they will run 5 clinic-based visits under supervision. 
In Step 5, they will practice 5 home visits along with the PI and Project Coordinator. Careful evaluation of 
interventionists’ readiness will be conducted via exams and trial runs.  
Table 2. Schedule for interventionist training 
Training content 
Trainer 
Location 
Time 
1. Knowledge, theories, and skills 
PI and Co-Is 
PI’s clinic and online 
40 hours 
2. Research ethics, tools, and safety 
PI’s research staff 
PI’s clinic and online 
10 hours 
3. Clinic visit observation (5 visits) 
PI’s research staff 
PI’s clinic 
5 hours 
4. Clinic visit practice (5 visits) 
PI’s research staff 
PI’s clinic 
5 hours 
5. Home visit practice (5 visits) 
PI and PI’s research staff 
Participants’ home 
10 hours 
2.4.5 Monitoring intervention (fidelity). Step-by-step instructions with a 10-item checklist will be used for 
each visit. The interventionists will take pictures of test sheets during home visits for later confirmation. Home 
visits will be audio-recorded for quality assurance and 20% will be randomly sampled for review. The 

interventionists and research staff will attend biweekly group meetings to review participants’ process and 
share work experiences. Fidelity of intervention delivery will be used for quality improvement.58 
2.5 Outcome measures. 2.5.1 Maternal smoking status. The interventionist will administer a timeline 
follow-back interview59 at enrollment to assess the participant’s use of cigarettes, cigars, vapor and electronic 
cigarettes since conception. Based on their recorded daily numbers of cigarettes and cigars smoked after 
enrollment, we will classify smoking abstinence status in the past 7 days (7-day point-prevalence).60,61 The self-
reported smoking abstinence will be biochemically confirmed by urine cotinine tests (<50 ng/mL62) using LC-
MS/MS assays (Kaleida Health Lab, Buffalo, NY) at the end of pregnancy and 6 months postpartum. 
Participants will be informed that use of nicotine replacement therapy (NRT, e.g., gums and patches), 
electronic cigarettes, or other nicotine-containing products will interfere with urine cotinine tests.  
2.5.2 Breastfeeding intention and practices.  During pregnancy, participants will report breastfeeding 
intention using questionnaires modified from the Infant Feeding Practices Study II.63 During postpartum, 
mothers will report feeding methods, frequency and duration of breastfeeding and/or formula use every month 
until 6 months postpartum. Breastfeeding status will be visually verified by a female researcher, looking for one 
of the following indicators of successful breastfeeding in the infant: audible swallowing, a regular 
suck/swallow/breath pattern, or visible milk in the infant’s mouth after they are not latched anymore.45  For 
mothers who pump milk, staff will observe pumping combined with the resulting milk being fed to the infant.  
2.6 Covariates. Covariates of interest include socio-demographics, health motivation,64 parity, 
pregnancy intention,65,66 gestational age at enrollment,67 baseline smoking frequency, intention to quit smoking, 
partner smoking, perceived stress,68 negative affect,69,70 breastfeeding intention, and breastfeeding experience. 
2.7 Statistical analysis. We will calculate the fidelity score for each intervention visit using a 10-item 
visit checklist. Trajectories of fidelity scores will be fitted with mixed models with interventionist, visit sequence 
number, and their interaction term (intervention*visit sequence number) being independent variable (Aim 1). 
Smoking abstinence (Aim 2) and breastfeeding (Aim 3) rates at 6 months postpartum will be analyzed by Chi-
squared tests and multivariable logistic regression models. Independent variables in the model will include 
group (intervention vs control), fidelity of intervention delivery, and unbalanced covariates at enrollment. The 
timing of termination of breastfeeding (weaning) will be analyzed with Cox regression. We will use Intent-to-
Treat analysis by including all women as assigned at randomization. Multiple imputation with 20 replicates will 
be used to impute missing data.71 
2.8 Sample size. Based on our smoking interventions29,41,60 and reported associations (~50% 
reduction) between breastfeeding and smoking relapse,7,33,34 we estimate smoking abstinence rate at 6 months 
postpartum to be 23.1% (=30% smoking cessation by the end of pregnancy x [100% - 23% postpartum relapse 
rate]) in the intervention group versus 5.5% (=10% x [100% - 45%]) in the control group. Accordingly, we need 
55 participants per group (110 in total) to detect difference in smoking abstinence with 80% power at a 
significance level of 0.05 (Aim 2). Based on our breastfeeding intervention45 and reported associations (~50% 
reduction) between smoking and breastfeeding,29-32,44 we estimate breastfeeding rate at 6 months postpartum 
to be 31% (=30% quitters x 80% breastfeeding rate + 70% persistent smokers x 10% breastfeeding rate) in the 
intervention group versus 17% (=10% x 80% + 90% x 10%) in the control group. Accordingly, we will need 126 
participants per group (252 in total) to detect difference in breastfeeding rate in a larger R01 (Aim 3). 
Therefore, in this pilot study, recruiting 20 participants per group (a total of 40) will be sufficient to test 
feasibility and preliminary impact of our integrated intervention. 
 
3. STUDY TIMELINE AND MILESTONES  
4. ROLE OF PILOT STUDY IN SECURING 
EXTRAMURAL FUNDING 
Preliminary data collected from this pilot study 
will be used to support re-submission of our 
NIH R01 grant application (1R01CA230255-01; 
NCI). Reviewers in the 1st submission rated our 
novel idea of integrating intervention positively 
with 2 of 3 reviewers giving a score of 1 for 
innovation criterion (see the attached Summary 
Statement). Primary concerns included the lack 
of piloting on efficacy of integrated intervention, unclear role of run-in period and feasibility of biological sample 
collection. These methodological concerns can be effectively addressed by this pilot study. 
 
TASKS 
Month 
1 2 3 4 5 6 7 8 9 10 11 12 
IRB approval (in advance) 
 
 
 
 
 
 
 
 
 
 
 
 
Materials and training staff 
X 
 
 
 
 
 
 
 
 
 
 
 
Recruitment 
X X X X X  
 
 
 
 
 
 
Prenatal intervention 
 
X X X X X X  
 
 
 
 
Postpartum intervention 
 
 
 
X X X X X X X X X 
Process & outcome evaluation 
 
X X X X X X X X X X X 
Data analysis 
 
 
 
 
 
 
 
 
 
 
X X 
Reports & manuscripts 
 
 
 
 
 
 
 
 
 
 
 
X