Financial Incentives for Smoking Cessation Among Disadvantaged Pregnant
Phase: NA
Conditions: Cigarette Smoking
Sponsor: University of Vermont

 
1
 
 
This document was prepared by the investigators to provide supplemental protocol and statistical 
methods details regarding the randomized clinical trial registered under ClinicalTrials.gov Identifier: 
NCT02210832. 
 
History of Modifications 
Modification on Oct 1, 2013: To assure that Best Practices were implemented, a decision was made to 
have study staff make initial and follow-up referrals of all trial participants in the Best Practices and 
Best Practices +Financial Incentives conditions to the Vermont Quitline rather than train referring 
physicians to make those referrals. 
 
Modification on August 15, 2019: In light of evolving guidance on the risk-benefits of breastfeeding 
among women continuing to smoke, we decided to expand our analyses of breastfeeding to also 
include the percent breastfeeding while sustaining smoking abstinence.   
 
Modification on January 23, 2020:  We replaced proposed low-birth weight as a birth outcome with 
small-for-gestational-age (<10th percentile) deliveries to reduce potential confounding with differences 
in gestational age based on information provided in the 2020 U.S. Department of Health and Human 
Services, Smoking Cessation: A Report of the Surgeon General. U.S. Department of Health and 
Human Services, Center for Disease Control and Prevention, National Center for Chronic Disease 
Prevention and Health Promotion, Office of Smoking and Health, 2020. 
 
Modification on September 1, 2021.  In completing the cost-effectiveness analyses we made updates to 
reflect guidelines and data sources published since our protocol was originally reviewed by funders 

 
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and local IRB in 2013.  Our final analyses follow recommendations published in 2016 from the Second 
U.S. Panel on Cost-Effectiveness in Health and Medicine (Neumann et al. Cost-effectiveness in Health 
and Medicine, 2nd edition. New York: Oxford University Press. 2017).  They state that cost-
effectiveness analyses should include a provider and/or public payer perspective to better inform 
producers and payers about the intervention’s costs of adoption.  In updating our data sources, we 
incorporated methods used in the only other cost-effectiveness analysis in the peer-reviewed literature 
on the use of abstinence-contingent financial incentives with pregnant women who smoke (Boyd et al. 
Are financial incentives cost-effective to support smoking cessation during pregnancy. Addiction. 
2016; 1111(2): 360-70).  More specifically, we adopted their method of translating smoking abstinence 
into QALY gains, which permits QALYs to be derived directly from data available in the trial based 
on “absolute difference percent” (ADP) (see Stapleton JA, West R. A direct method and ICER tables 
for the estimation of the cost-effectiveness of smoking cessation interventions in general populations: 
applications to a new cystine trial and other examples. Nicotine Tob Res. 2012. 14(4): 463-71).  
 
The protocol information provided below is what the local Institutional Review Board approved for 
this randomized clinical trial comparing Best Practices, Best Practices +Financial Incentives, and 
Never Smokers.   
 
 
 

 
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Table of Contents 
Content  
 
 
 
 
 
 
 
 
Page Number 
 
Project Summary:………………………………..………………………………………….……4 
Research Design and Methods:……………………………………………………………….......6 
Statistical Methods:………………………………………………………………………………13 
Protection of Human Subjects:…………………………………………………………………...19 
References:………………………………………………………………………………………..26 
 
 
 
 
 
 
 

 
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Project Summary 
Smoking during pregnancy is the leading preventable cause of poor pregnancy outcomes in the U.S. 
Most pregnant smokers continue smoking through pregnancy producing serious immediate and longer-
term adverse health consequences for the infant. Smoking during pregnancy is highly associated with 
economic disadvantage and a substantive contributor to health disparities. Efficacious interventions are 
available, but cessation rates are low (<15%) and improvements in birth outcomes often modest or 
absent. Current treatments usually entail relatively brief, low-cost interventions (e.g., pregnancy-
specific quitlines). There is broad consensus that more effective interventions are sorely needed. We 
have developed a novel behavioral economic intervention in which women earn financial incentives 
contingent on smoking abstinence. In a meta-analysis of treatments for smoking during pregnancy, 
effect sizes achieved with financial incentives were severalfold larger than those achieved with lower 
intensity approaches or medications. The intervention also appears to improve birth outcomes and 
increase breastfeeding duration. While highly promising, further research is needed in at least three 
areas. (1) The evidence on birth outcomes and breastfeeding is from studies that combined data across 
trials rather than a single prospective trial, (2) whether the intervention produces other postpartum 
improvements in health has not been investigated, and (3) the overall cost effectiveness of this 
approach has not been examined. To examine these unanswered questions, we are proposing a 
randomized, controlled clinical trial comparing the efficacy and cost effectiveness through one-year 
postpartum of current best practices for smoking cessation during pregnancy vs. best practices plus 
financial incentives among 230 pregnant, Medicaid recipients. We will also include a third condition of 
115 pregnant nonsmokers matched to the smokers on sociodemographic and health conditions to 
compare the extent to which the treatments reduce the burden of smoking and to estimate how much 
more might be accomplished by further improvements in this incentives intervention without 
exceeding cost effectiveness. We hypothesize that best practices plus financial incentives will be more 
effective than best practices alone, that the incentives intervention will be cost effective, and that while 

 
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adding the incentives reduces a greater proportion of the health and economic burden of smoking than 
best practices alone, more can be done while remaining cost effective. Overall, the proposed study has 
the potential to substantially advance knowledge on cost-effective smoking cessation for pregnant 
women. Importantly, because of the strong association between smoking during pregnancy and 
economic disadvantage, the proposed study also has the potential to contribute new knowledge 
relevant to reducing the serious challenges of health disparities. 
 
 

 
6
Research Design and Methods  
We proposed a parallel groups design involving three study conditions. Across two of the conditions 
we will employ a conventional randomized, controlled clinical trial research design comparing 
outcomes between two treatment approaches to smoking cessation during pregnancy. The third 
condition will represent a group of women who are biochemically-verified nonsmokers and matched to 
women in the smoking cessation conditions on characteristics that may influence health and health-
care-utilization outcomes. 
Participants 
Study participants will be 345 pregnant Medicaid recipients > 18 yrs of age who will be recruited from 
obstetric practices and the WIC office located in the greater Burlington, VT area using procedures 
developed in our prior trials (e.g., Heil et al., 2008; Higgins et al., 2004b). As noted above, 230 of 
these women will be smokers and 115 nonsmokers recruited from the same clinics. Pregnant women 
attending their first prenatal visit will be identified from the appointment schedules. The practices’ 
receptionists will request that women complete a brief self-administered smoking screening form 
containing a multiple-choice question on smoking status that has been validated to enhance accurate 
reporting (Mullen et al., 1991). Women who endorse smoking in the 7 days prior to screening will be 
invited for an intake assessment that will provide a more thorough determination of study eligibility. 
For inclusion in the cessation trial, women must report being smokers at the time that they learned of 
the current pregnancy, report smoking in the 7 days prior to the first prenatal care visit, be confirmed 
as a smoker by urine cotinine testing, be < 25 weeks pregnant, reside in the county in which the clinic 
is located, speak English, and plan on remaining in the geographical area through 12-months 
postpartum. Two hundred and thirty eligible smokers who agree to participate and provide written 
informed consent will be randomly assigned to one of the two treatment conditions described below. 
Women who endorse no smoking in the 7 days prior to screening will be similarly invited for the same 
detailed assessment and biochemical verification of smoking status. To be eligible they must report 

 
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being nonsmokers at the time they learned of the current pregnancy, report no smoking in the past 6 
month, and report smoking < 100 cigarettes in their lifetime, the conventional definition of a never 
smoker (Pomerleau et al., 2004). Recruiting never smokers will substantially reduce the likelihood of 
women in this condition converting to smoker status during the study. They must also meet other study 
inclusion criteria listed above and will be frequency matched to women in the two smoker conditions 
on the following characteristics that may influence outcomes: (1) maternal education (% < 12 years), 
(2) pre-pregnancy body mass index (% > 25, % > 30), (3) parity (% primigravida), (4) age (% < 20 
yrs), (5) comorbidities (% diabetic, % hypertensive), and (6) recreational use of cocaine/opioids in past 
12 months (% reporting yes). Initially, the distributions of these characteristics will be based on our 
previous trials but where necessary adjustments will be made as smokers are enrolled into the proposed 
trial. Because women will be recruited at the start of their prenatal care, we will not yet know infant 
sex and thus will not be able to balance across conditions on that characteristic. We anticipate 
comparable distribution of infant sex across study conditions, but will include it as a covariate in 
analyses of birth and infant health outcomes if it differs significantly across study conditions. 
Treatment Conditions 
Best Practices Alone. The 2008 Clinical Practice Guidelines for smoking cessation recommends that 
pregnant smokers should be provided with the 5As (Fiore et al., 2008). To ensure that referring 
obstetric practices in the proposed recruitment area are acquainted with the 5As, our staff will conduct 
office-based training sessions with all referring practices prior to the start of study recruitment and at 
least once annually throughout the course of the study using training procedures developed previously 
by our research team and utilized in our prior studies. Practitioners will be trained to implement the 
following steps: (1) Ask about smoking status starting at first prenatal care visit; (2) Advise those who 
endorse smoking about the potential harm of smoking to mother and fetus and recommend quitting; (3) 
Assess the willingness of smokers to make a quit attempt during pregnancy; (4) Assist those willing to 
make a quit attempt by helping to establish a quit plan, by referring them to the Vermont pregnancy-

 
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specific quit line described below and offering assistance with making the initial contact from the 
office, and by providing each woman with a copy of the pregnancy-tailored self-help guide “Need 
Help Putting Out That Cigarette?”, distributed by the American College of Obstetricians and 
Gynecologists; (5) Arrange for follow-up contacts on smoking at each subsequent prenatal care visit. 
They will refer women to the Vermont pregnancy-specific quitline, operated by Free & Clear, which 
provides eight proactive telephone counseling calls during the antepartum period, with one prior to a 
quit date, two within the first week of quitting, and the final antepartum call just before the woman’s 
delivery date. Two additional counseling calls are made during the postpartum period. Calls average 
about 10 min in length. The quitline makes five attempts to reach the woman within a 3-day period for 
each scheduled telephone counseling session. We will obtain permission from women to request from 
Free & Clear the number of telephone counseling sessions completed by each woman during the 
course of the study. 
Best Practices + Financial Incentives. Women assigned to this condition will receive the same 5As 
intervention from providers plus the incentives intervention described above that will be delivered by 
project staff. Briefly, women report to our smoking-cessation clinic or have a research assistant meet 
them at a location convenient for them according to a predetermined schedule. At these visits, the 
women can earn points recorded on vouchers contingent on biochemically-verified abstinence from 
recent smoking. Abstinence will be assessed for five consecutive days in week 1, decreasing to twice 
weekly in week 2 where it remains for the next 7 weeks, then decreasing to once weekly for 4 weeks, 
and then to every other week until delivery. During the postpartum period, abstinence monitoring will 
be weekly for 4 weeks and then every other week through 12 weeks postpartum at which point the 
voucher program will be discontinued. The monetary value of vouchers will be kept as they were in 
our prior trials for women who report smoking < 10 cigs/day at study intake assessment, with the 
initial negative test specimen worth 5 points at a value of $1.25 per point ($6.25). Each consecutive 
negative test specimen increments the number of points earned by 1 such that the 2nd consecutive 

 
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negative specimen is worth 6 points ($7.50), the 3rd negative specimen 7 points ($8.75), the 4th 
specimen 8 points ($10.00), etc. Voucher value continues to escalate upward based on consecutive 
negative test results until it plateaus at a maximal value of $45. A reset contingency is used wherein a 
positive test or failure to submit a specimen for a scheduled test resets the number of points earned 
back to the initial 5 points. This reset component of the schedule protects against relapse once an initial 
period of abstinence has been achieved (Roll & Higgins, 2000). Two consecutive negative tests 
following a reset returns the number of points earned back to the value that they were at prior to the 
positive test result. In the postpartum period, voucher value is set at a flat $45/negative test (36 points) 
independent of how much abstinence was achieved antepartum. A positive test result or failure to 
submit a scheduled specimen lowers the voucher value to 5 points ($6.25), but two consecutive 
negative tests returns voucher value back to $45 in the postpartum period. Total possible earnings for a 
woman who participated in the voucher program for 32 weeks antepartum (duration varies depending 
on where in the pregnancy a woman enters prenatal care) and 12-weeks postpartum and sustained 
abstinence throughout is $1,225 ($865 antepartum & $360 postpartum). For women who report 
smoking > 10 cigs/day at the study intake assessment the schedule described above will be identical 
except that voucher value will be increased 2-fold at each step such that maximal total earnings = 
$2,450 ($1,730 antepartum & $720 postpartum). Because vouchers are only paid out when women are 
abstinent, we project mean payouts of $613 and $1,226 across 9 months or approximately $2.27/day 
and $4.54 /day across the lower and higher voucher values. Women will not be informed of our criteria 
for determining who receives higher value incentives. We have conducted prior trials with differing 
voucher values among substance abusers without difficulty by explaining that interventions are 
individualized just as medications dosages often are (Higgins et al., 2007a). We anticipate being able 
to do so in the proposed study. Regarding use of pharmacotherapies, our practice is to explain to 
women the risks and benefits of using them but recommend against their use because they have not yet 
been shown to be effective among pregnant women and may interfere with the opportunity to earn 

 
10
vouchers through cross reactivity with urine cotinine testing. We will monitor use of all such products 
so that their use could be considered as a potential covariate in the data analysis. There has been 
minimal use in our prior trials (< 1%). 
Never-smokers condition. Women in this condition will be assessed at the study intake assessment, 
second prenatal care visit, at 28-weeks gestation, and then 2-, 4-, 8-, 12-, 24-, and 48-weeks 
postpartum using the battery outlined below. As described further below, they will also participate in 
the sonographic serial measures of fetal growth at 30 and 34 weeks and receive monthly postpartum 
calls from staff to monitor infant health and health care utilization. There will be no other contact with 
them. 
Assessments 
At the first prenatal visit all participants will complete an assessment addressing six areas: (1) 
Sociodemographics: age, yrs of education, race/ethnicity, marital status, and health insurance status. 
(2) Medical/pregnancy history: height/weight, self-reported pre-pregnancy weight, weeks pregnant, 
history of complications in prior pregnancies; unstable medical problems (e.g., preeclampsia) in 
current pregnancy; and use of medications, alcohol, and caffeine. (3) Smoking history: age started 
smoking, average number of cigarettes smoked per day now and immediately before this pregnancy, 
time to first cigarette in the morning, number of previous quit attempts, number of other smokers in the 
household, nicotine dependence/tolerance (Fagerstrom & Schneider, 1989), and nicotine withdrawal 
(Hughes & Hatsukami, 1986). Smoking Timeline Follow-back interviews will be conducted (Brown et 
al., 1998) to characterize daily smoking rates since learning of the current pregnancy. (4) Smoking 
attitudes: motivation to stop, confidence in ability to stop, intention to quit before the baby is born, 
intention to remain abstinent after the baby is born, and measures of perceived stress. (5) Biochemical 
verification of smoking status: breath CO and urine cotinine levels. (6) Mental health/executive 
function: lifetime history of depression, general psychiatric symptoms (Brief Symptom Inventory, 
Derogatis, 1993), current depressive symptoms (BDI, Beck & Beck, 1972), discounting of delayed 

 
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hypothetical monetary rewards (Johnson & Bickel, 2002). Appropriately modified versions of this 
battery will be completed again at the second prenatal care visit and 28-weeks gestation, and then 2-, 
4-, 8-, 12-, 24-, and 48-weeks postpartum. We will also assess breastfeeding, including initiation, 
duration, and different levels of breastfeeding (e.g., exclusive, predominate, any). All women will 
complete the Postpartum Bonding Questionnaire to examine associations between breastfeeding and 
maternal/infant bonding (Brockington et al., 2001). Breastfeeding is associated with significant 
improvements in a wide range of maternal and infant health outcomes, but there have been few 
opportunities to examine experimentally altered rates of breastfeeding due to the absence of ethical 
methods to manipulate them (Ip et al., 2007). The proposed study may provide an opportunity to do so 
by altering smoking status, which in turn impacts breastfeeding duration (Higgins et al., 2010b). These 
assessments will be conducted with all subjects independent of smoking status or treatment condition. 
Women will receive $50 per assessment independent of smoking status. We also plan to assess health 
outcomes and health care utilization for use in the cost-effectiveness analysis. Permission will be 
requested of all women to review maternal and infant health care records through one-year postpartum 
and to telephone mothers monthly during postpartum to review infant health and health care visits. 
Project staff will review records by obtaining faxed copies or visiting the offices of local 
providers/pharmacies at the time of each of the regularly scheduled assessments. We will track the 
incidence of smoking-related pregnancy complications, delivery complications, and maternal and 
infant health outcomes during the 1st year postpartum (all illnesses requiring a visit to a healthcare 
professional). Infant outcomes will include birth outcomes (mean birth weight, % low birth weight 
deliveries (< 2500 g), mean gestational length, % premature deliveries (< 37 weeks), incidence of 
NICU admissions and mean length of stay, and health outcomes through one year postpartum 
(respiratory distress syndrome, upper and lower respiratory infections, otitis media, sudden infant 
death syndrome, and other infant death). We will track all maternal prenatal and postpartum health care 
utilization including pharmacy use through one-year postpartum and infant utilization through one-

 
12
year postnatal. Greater than 99% of women in our trials deliver at our university teaching hospital and 
with maternal permission we will have access to all delivery and infant care records related to the 
delivery. Over the past 10 years 100% of women in our trials have provided permission to review 
maternal and infant medical records. We have used this system to obtain the birth outcomes data 
described above and will now extend that timeframe through the 1st year postpartum. We did not 
anticipate reviewing medical billings in our earlier studies and thus did not request permission. 
However, we anticipate no difficulty obtaining consent to review the cost data. Our staff has strong 
working relationships with local primary care clinicians, which will facilitate the logistics of our staff 
coordinating with them to review records. 
Biochemical Verification of Abstinence 
Breath and urine specimens will be collected at each clinic visit. Breath CO levels will be analyzed 
using a breath CO Monitor. Readings < 6 ppm will indicate abstinence during week 1. Beginning in 
week 2, abstinence will be verified using onsite urine cotinine (< 80 ng/ml) analyzed with an Enzyme 
Multiplied Immunoassay Test (EMIT). Smoking-status classifications based on EMIT urine-cotinine 
levels using a cutoff of < 80 ng/ml are in > 98% agreement with those made by gas chromatography 
mass spectroscopy using a cut-point of 12.5 or 25 ng/ml (Higgins et al., 2007b). Urine and breath 
specimens will be collected at each of the follow-up assessments and analyzed similarly. Specimens 
collected at the end-of-pregnancy, and 12 & 24-week postpartum assessments will be sent to an outside 
laboratory for confirmation testing. 
Monitoring Fetal/Infant Health 
Fetal Growth. We will compare the growth profiles for each of the fetal parameters measured across 
study conditions. This includes abdominal circumference, head circumference, femur length, estimated 
fetal weight and mid-thigh lean body and fat areas. We will also characterize birth weight between 
conditions employing birth weight percentiles (Bernstein et al., 1994; 1996; Fry, 2002). We have 
developed ultrasound techniques that are capable of distinguishing and quantifying specific fetal body 

 
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compartments with focus on the lean body and fat mass compartments (Bernstein et al., 1991; 1997; 
2000). We will use this ultrasound technology to examine participants at 30 and 34 weeks of 
pregnancy to estimate changes in overall fetal growth and body composition. We will estimate fetal 
weight according to the method of Hadlock et al (1985) employing head circumference, femur length 
and abdominal circumference. We will estimate fetal peripheral muscle and fat areas according to the 
methods we have developed (Bernstein et al., 1991; 1997; 2000) and are now used broadly (Galan, 
2001; Padoan, 2004; Larciprete et al., 2003). Infant Growth. Infant growth measures will also be 
obtained at 6 and 12 months. Weight will be obtained through the use of an electronic scale and length 
measurements will employ a measuring board that employs the tonic neck reflex for accurate 
assessment of infant length, thereby estimating ponderal index (Rohrer 1921, Walther & Ramaekers, 
1982). At 6 and 12 months we will also measure skinfold thickness at 5 sites (triceps, subscapular, 
flank, anterior thigh and abdominal wall) (Bernstein 1991, 1997) to estimate subcutaneous fat stores. 
At 12 months only we will conduct an assessment of infant body composition using whole body dual 
x-ray absorptiometry (DEXA). 
Statistical Methods 
Study conditions will be compared on baseline demographics and other characteristics using analysis 
of variance for continuous variables and chi-square tests for categorical variables. If a specific 
characteristic differs significantly across study conditions and is predictive of outcome, it will be 
considered as a potential covariate in subsequent analyses. Analyses of treatment effects on smoking 
status will be limited to smokers randomized to the two treatment conditions. We will adhere to an 
intent-to-treat approach (Armitage, 1983) wherein all women randomized to the study conditions will 
be included in the analyses independent of early dropout, noncompliance, etc., with the exception of 
excluding women for abortion/fetal demise as is convention in this research area. Cochran Mantel 
Haenszel tests (CMH) will be performed for comparisons of the two treatment conditions on point-
prevalence smoking abstinence at end-of-pregnancy and 6-months postpartum assessments with 

 
14
referring clinic as a stratification variable. The Breslow-Day Test will be used to examine the 
homogeneity of treatment effects across referring clinics. Comparisons of point-prevalence abstinence 
rates between treatment conditions across all assessments through one-year postpartum will be 
analyzed using mixed model repeated measures for categorical data based on generalized estimating 
equations (GEE) utilizing a logistic link function (SAS: PROC GENMOD, SAS Institute, Cary, NC). 
We will include women from the nonsmoker condition in analyses of fetal growth, birth outcomes, and 
breastfeeding and other postpartum outcomes. Comparisons of treatment conditions on dichotomous 
outcomes (e.g. % low birth weight, % preterm, % NICU admissions, % breastfeeding, % medical 
treatment in first year) will parallel categorical analyses for point prevalence abstinence using PROC 
GENMOD to adjust for strata (referring clinics) and potential covariate effects. Analysis of covariance 
will be used to compare study conditions on mean birth weight adjusting for variables known to predict 
birth weight (i.e., maternal prepregnancy BMI, parity, and sex), mean gestational age at delivery, and 
frequency measures of medical illnesses. Statistical analyses of fetal growth outcomes (i.e. estimated 
fetal weight, fetal lean area, fat area, femur length and head circumference) will be based on linear 
growth models with slope and intercept as random effects (SAS PROC MIXED). This methodology 
allows for the within-subjects ultrasound assessments not to be at identical timepoints across subjects. 
Study condition will be considered a fixed factor with fetus nested within study condition. Two-way 
analyses of covariance will also be used for analyzing effects of study condition and referring clinic on 
DEXA body composition measures at 12 months. Additional subject level covariates will include 
maternal pre-pregnancy body mass index, maternal age and fetal gender. Analyses of infant growth 
will parallel those used to examine fetal growth. Repeated measures analyses of variance will be used 
to test for differences between study conditions in skinfold thickness obtained during infant 1st year of 
life and continuous measures of medical illnesses. Significance will be based on alpha = .05 for all 
analyses. 
 

 
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Sample Size Justification 
Sample size was determined to have sufficient power to detect differences between study conditions 
corresponding to our primary hypotheses regarding point prevalence smoking abstinence at late 
pregnancy and 24weekpostpartum assessments, fetal growth, birth weight, and breastfeeding. 
Estimates of abstinence were based on our prior trials where 7-day point-prevalence abstinence in the 
incentives vs. control conditions were 34% vs. 7% at the late-pregnancy assessment and 14% vs. 1% at 
24weeks postpartum assessment, respectively (Higgins et al., 2010a). We estimated that the proposed 
increase in the value of the incentives used with heavier smokers will increase late-pregnancy 
abstinence rate to approximately 50% in the incentives condition while the best practices alone 
condition is estimated at <10%. Assuming a decline in abstinence of approximately 20% from late-
pregnancy to the 24-week postpartum assessment as we saw in our prior trials, we estimate abstinence 
rates of approximately 30% vs. < 5% at 24weeks postpartum in the best practices plus incentives vs. 
best practices alone conditions, respectively. The proposed sample size of 115 per study condition will 
result in greater than 90% power to detect a difference between the two treatment conditions in 
abstinence rates of 50% vs. 10% at late-pregnancy or 30% vs. 5% at 24weeks postpartum assessments 
using a chi-square test. The proposed sample size is also expected to be more than sufficient for 
examining differences between study conditions in fetal growth, birth weight, and breastfeeding 
outcomes. The proposed sample size after considering noncompliance in completing scheduled 
ultrasounds is estimated to have power of 80% for detecting a mean growth difference of 23 g/wk in 
estimated fetal weight between any two conditions based on our estimated pooled within group 
SD=49.7. This difference is slightly more than half the difference observed between the incentive and 
control condition in our 2008 study (Heil et al, 2008) and represents a conservative expected 
difference. With respect to mean birth weight, power is estimated to be 80% to detect a difference of 
approximately 200 g between any two study conditions assuming a pooled SD=550, which aligns well 
with treatment effects in our study combining results across prior trials (Higgins et al., 2010a) where 

 
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mean birth weights were 3295.6 + 588 g vs. 3093.6 + 603 g in the incentives and control conditions, 
respectively and with our estimate of a mean birth weight of 3595.6 + 404 g in the nonsmoker 
condition. For this estimate of the mean birth weight that might be expected in the nonsmoker 
condition, we examined birth weights in a sample (n = 88) of women followed in our clinic who were 
smokers at the time that they learned of the current pregnancy but quit prior to entering prenatal care 
(i.e., spontaneous quitters) and were continuously abstinent through the remainder of antepartum. We 
are estimating breastfeeding rates of 50% and 30% in the incentives condition and 17% and 13% in the 
best practices alone condition at 12 and 24 weeks postpartum, based on our prior study results (Higgins 
et al., 2010b) and our planned use of higher value vouchers with heavier smokers in the proposed 
study. Again using the same group of spontaneous quitters but restricting it to women who remained 
abstinent through 24-weeks postpartum (n=32), the estimated percent breastfeeding at 12- and 24-
weeks postpartum was 70% and 48%. Using chi-square tests, we will have over 80% power to detect 
differences in rates between any two of the three study conditions at the two assessments. Power 
calculations were done using a two-sided significance level of .05. 
Economic Evaluation 
Cost analysis. We will conduct an economic evaluation from the societal perspective including both 
cost-effectiveness and cost-benefit analyses (Drummond et al., 2005). The outcome measures in this 
trial were described above, with antepartum abstinence being primary and the related outcomes of 
longer-term abstinence, birth outcomes, and health and health care utilization in the 1st year 
postpartum important as well. Each of these outcomes can be viewed from the perspective of 
incremental cost effectiveness (e.g., the incremental cost to produce an additional abstinent mother at 
final antepartum assessment). We hypothesize that the best practices plus incentives intervention will 
be cost-effective (i.e., dominant) as compared to the best practices alone condition. To determine the 
cost of each intervention, we will employ the Brief Drug Abuse Treatment Cost Analysis Program 
(Brief DATCAP; French et al., 2004; French, 2010), which has been widely used in the area of 

 
17
substance abuse, including projects utilizing incentives (Knealing et al., 2008). The direct and indirect 
economic cost of treatment will be derived by allocating fixed costs based upon the proportion of time 
or space utilized by the programs (e.g., treatment facility costs), as well as costs that vary by patient 
engagement and smoking status (e.g., drug tests, quitline staff time, incentives). The total cost per 
treatment episode will be individual specific and will include the opportunity cost of the patient’s time 
while in treatment (Salomé et al., 2003; French 2005). The time period of the cost analysis will span 
from intake to discontinuation or completion of the program. However, since the duration of treatment 
will vary according to where in the pregnancy a woman enters the study, the economic cost per person 
per week will also be calculated. The cost of all research-specific resources consumed will be excluded 
from the evaluation. All costs and benefits will be expressed in a common dollar year without the need 
for discounting. Estimated treatment costs will be combined with the maternal and infant health 
outcomes outlined above to conduct the economic evaluation. Cost-effectiveness analysis (CEA). CEA 
will be conducted wherein the average (mean) difference in treatment costs across the two 
interventions will be divided by the average (mean) difference in each outcome to derive incremental 
cost-effectiveness ratios (ICERs). Statistical significance of these ICERs will be determined 
probabilistically by employing nonparametric bootstrapped standard errors (Drummond et al. 2005). 
Priority will be given to comparing ratios on key birth outcome measures and NICU admissions. 
Additionally, a special form of CEA, cost-utility analysis (CUA), will be performed. Based upon 
smoking status from the quit date through one year postpartum, the number of quality-adjusted life 
years (QALYs) gained by the mother—as measured by the proportion of time spent in ‘smoking’ 
and/or ‘nonsmoking’ status—will be derived using QALY weights recommended in the extant 
literature (e.g., Cromwell et al., 1997; Flack et al., 2007). Women still abstinent at 1year postpartum 
will be treated as long-term quitters. QALYs gained by the infant will be calculated using QALY 
weights recommended in the literature (Taylor et al., 2009). The incremental cost per QALY gained 

 
18
between the two modalities will be calculated and compared for mothers and infants separately and 
also summed across mother-infant dyads.  
Cost-benefit analysis (CBA). CBA can often be especially useful by allowing consideration of 
multiple, often very different, outcomes. CBA yields two specific evaluation metrics, which are both 
placed in monetary terms, the benefit-cost ratio and the net benefit, that can be compared across health 
programs and economic sectors. We will conduct a partial CBA from a societal perspective for the 
intake through 12month postpartum period. Total health care costs for the mother and infant will be 
measured using the ‘allowed’ amounts extracted from administrative insurance claims data collected 
from health care providers. Adding smoking cessation treatment costs to health care costs will yield the 
total economic cost of care for a mother/infant dyad for the specified time period. Given 
randomization, the mean difference across the treatment arms (the average net benefit) will be 
attributed to intervention effectiveness. Cost benefit ratios also will be calculated and compared across 
the two treatment conditions for statistically significant differences. Sensitivity analysis. A multiway 
sensitivity analysis will assess the levels to which our incremental cost effectiveness ratios (ICERs) are 
robust to changes in component assumptions and costs. For example, while a theoretical 100% quit 
rate may never reach the low cost of treating the group of nonsmokers in our third condition, we can 
explore the maximum threshold of incentive required to maximize health benefits with respect to their 
costs one year postpartum. More within a realistic target, a 50% quit rate, for example, may be cost 
effective under all exploratory ranges of incentive compensation. The sensitivity analysis will therefore 
explore changes to assumptions over a broad range. 
 
 

 
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PROTECTION OF HUMAN SUBJECTS 
 
1. RISKS TO THE SUBJECTS 
 
a. Human Subjects Involvement, Characteristics, and Design 
Participants will be 345 women seeking prenatal care at participating clinics who are insured by 
Medicaid. 230 women who endorse being smokers at the time that they learned of the current 
pregnancy will be informed that they might be eligible for a study on cigarette smoking cessation and 
birth outcomes while 115 women who endorse being nonsmokers will be informed that they might be 
eligible for a study on birth outcomes. Both will be offered the opportunity to participate in further 
screening to determine study eligibility. 
For inclusion in the smoking cessation component, women must report being smokers at the 
time that they learned of the current pregnancy, report smoking in the 7 days prior to the first prenatal 
care visit and have that confirmed by urine toxicology testing, be 18 years of age or older, be < 25 
weeks pregnant, reside in the county in which the clinic is located and immediately surrounding areas, 
speak English, plan on remaining in the geographical area through the pregnancy and 12-months 
postpartum, and provide written informed consent to participate. Failure to meet the aforementioned 
criteria, incarceration, untreated psychosis, current treatment with buprenorphine/methadone for opioid 
dependence, and refusal to participate will be reasons for exclusion. 
For inclusion in the nonsmoker component of the study, women must meet the same inclusion 
and exclusion criteria listed above with the exception of smoking status where they must report being 
nonsmokers at the time they learned of the current pregnancy, report no smoking in past 6 months, not 
even a puff, test negative in a urine-cotinine test for current smoking, and report smoking < 100 
cigarettes in their lifetime. Nonsmokers will also be matched to women in the smoker conditions on 
the following characteristics that may influence treatment outcome (educational attainment, 

 
20
prepregnancy BMI, parity, chronological age, comorbidities (i.e., diabetes, hypertension), and use of 
cocaine/opioids and thus could be excluded from study participation based on not aligning with our 
need to keep the conditions comparable on these characteristics. No participants will be excluded 
based on race or ethnicity. All study participants will complete informed consent. Smokers who 
consent to study participation will be randomly assigned to one of two treatment conditions: (1) Best 
practices for smoking cessation during pregnancy involving the 5 As and referral to 
pregnancy-specific telephone quitline counseling and self-help cessation materials or (2) Best practices 
for smoking cessation during pregnancy plus financial Incentives delivered contingent on smoking 
abstinence. Nonsmokers who consent to study participation will complete the same assessments as the 
smokers, but none of the smoking-cessation aspects of the study. 
b. Sources of Materials 
The research materials to be obtained include interviews, questionnaires, urine and breath 
specimens to verify smoking status, and medical records to assess birth and maternal and infant health 
outcomes through one-year postpartum. 
c. Potential Risks 
(a) A potential risk to all subjects in the proposed studies is that an unauthorized person would 
obtain access to the information contained in their study files. (b) There is the risk that some subjects 
may misuse vouchers or the money provided for completing the baseline and follow-up assessments. 
(c) Women in the financial-incentives condition could be enticed to use over the counter smoking 
cessation pharmacotherapies in order to obtain incentives, which have not been approved for use with 
pregnant women. 
2. ADEQUACY OF PROTECTION AGAINST RISKS 
a. Recruitment and Informed Consent 
All participants will provide written informed consent after having a face-to-face discussion of 
the research with PI, Co-I or research staff designated and trained to represent the PI/Co-I in this 

 
21
function. That discussion is conducted in a private setting and permits the prospective participants 
ample opportunity to raise questions and seek clarifications regarding the research. Later that day, the 
participant will take a consent form quiz to ensure she understands the critical elements of what she 
agreed to do (e.g. randomized to experimental or control condition, study is voluntary and can 
withdraw at any time). Incorrect answers will be carefully reviewed with the participant and the quiz 
will be readministered until all questions are answered correctly. 
We operate in full compliance with HIPAA regulations. All participants in the present study 
will receive a HIPAA authorization form upon entry into treatment and are fully informed regarding 
their rights with respect to the release of personal health information. We will comply with the new 
regulations for protection of pregnant women in research (effective December 13, 2001). Further, as 
mandated by NIH, all personnel funded by this project will complete the NIH required course on 
Human Subjects Research Training. 
b. Protection Against Risk 
We take the following actions to protect against the potential risks noted above: (a) All study 
files will be stored in locked filing cabinets. All study participants receive a participant identification 
code that is used in place of their name in all study data files. The key that connects participant names 
with identification codes is kept in a locked file and stored separately from the data files. (b) Study 
computers will be password protected and encrypted. (c) All voucher purchases must be approved in 
advance by project staff who retain veto power. If in the judgment of project staff there is a risk that 
the money obtained by completing the assessments might be misused, vouchers will be substituted for 
cash. Misuse of vouchers has not been a problem in our prior trials with this population. (d) Regarding 
pharmacotherapies, we inform women about the risks/benefits of over-the-counter pharmacotherapies, 
inform them that the use of nicotine replacement therapies will limit their ability to earn incentives, 
and make a recommendation that smoking cessation pharmacotherapies not be used. We have had no 
problems during the prior trials related to women using pharmacotherapies for smoking cessation. 

 
22
3. POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND 
OTHERS 
Among the smokers, we believe that the aforementioned risks are reasonable in relation to the 
anticipated benefits to the mother and fetus/neonate of treatment for smoking during pregnancy. There 
is a reasonable likelihood that women assigned to the Best Practices alone condition will not achieve 
outcomes as good as those assigned to the Best practices plus financial-Incentives condition. 
Nevertheless, all women will receive treatment that meets Best Practices as outlined in the 2008 
Clinical Practice Guidelines on Treating Tobacco (Fiore et al., 2008). To the extent that either 
intervention promotes smoking cessation, there is likely to be benefits to both mother and fetus/infant 
in terms of improved growth and birth outcomes. Any improvements in birth outcomes should also 
provide benefits to society in terms of lowered medical costs for infant care and improved child 
outcomes. 
Among the nonsmokers, we feel that the risks are justified by the potential to contribute new 
knowledge with the potential to enhance understanding of the adverse effects of smoking and provide 
insights into how much more might be invested into improving smoking-cessation interventions 
without exceeding cost-effectiveness. Although this study is considered high-risk by definition (i.e., 
pregnant population), the potential benefits are substantial in terms of our scientific understanding of 
the effectiveness of treating smoking cessation among pregnant smokers and for increasing knowledge 
regarding the impact of smoking cessation on birth outcomes and maternal and infant health outcomes. 
Overall, the risk/benefit ratio appears highly favorable. 
 
4. IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
Smoking during pregnancy is the leading preventable cause of poor pregnancy outcomes in the 
U.S. Despite 72 controlled trials involving more than 25,000 women, quit rates achieved with existing 
interventions are low (often < 15%). In addition, no intervention has reported significant main effects 

 
23
of treatment on birth outcomes for more than 25 years. The proposed study will continue research on 
the efficacy of a novel smoking-cessation intervention, voucher-based financial incentives, which has 
demonstrated promising effects on smoking abstinence rates and fetal/infant outcomes in at least four 
prior efficacy trials. The proposed trial will thoroughly contrast the effectiveness, especially the cost-
effectiveness, of adding financial incentives to current Best Practices compared to offering Best 
Practices alone in terms of increasing antepartum and postpartum smoking abstinence and improving 
birth outcomes, breastfeeding, and other maternal and infant health outcomes during the 1st year of 
life. The proposed study has the potential to be pivotal to the development, testing, and eventual 
dissemination of this incentives-based treatment approach and will contribute new and important 
scientific knowledge about how to effectively treat smoking during pregnancy and postpartum and the 
maternal, infant health, and economic benefits of doing so. 
5. DATA AND SAFETY MONITORING PLAN 
Our overall monitoring plan consists of ongoing, close monitoring of data and safety issues by 
the PI, Co-Investigators, and other project staff and prompt reporting of any adverse events (AEs) or 
serious adverse events (SAEs) to the institutional review board at the appropriate site and/or NIH, as 
suggested by Notice OD00038. We provide more detail below regarding particular areas recommended 
by Notice OD00038. 
Patient eligibility and status. All recruitment will be managed by trained research staff under 
the supervision of the PI using specialized forms and procedures. All information collected will be 
reviewed by the research staff, PI, or designated representatives, who will determine participant 
eligibility, contact them about scheduling and completing an intake assessment where appropriate. 
Eligible women will provide written informed consent. The status of all active participants will be 
reviewed weekly at staff meetings between the PI, Co-Investigators and trained support staff. Rigorous 
data management/quality assurance. Study data will come from participant screening and intake 

 
24
sessions, periodic assessments, urine and breath specimen collections, and medical and pharmacy 
records. 
Study data collection will be primarily with paper questionnaires that will be manually double-
entered into computers for analysis. Similar to prior and ongoing studies, we will create Excel 
databases for entry and coding of all data collected. All data will be independently coded by trained 
research staff. The two coded data sets at each site will be compared against each other for agreement 
and discrepancies will be resolved and corrected using source materials at each site. Once each month, 
current compared data sets will be delivered electronically to the University of Vermont 
Bioinformatics Facility where they will again be reviewed for accuracy. Any apparent errors will be 
resolved and corrected under supervision of the biostatistician and using source materials. The 
biostatistician and PI will discuss any problems at weekly data meetings. Auditing procedures. Review 
of any problems related to quality of data collection, transmission or analyses and of any AEs and 
SAEs that occurred during the past week will occur at weekly research staff meetings. Interim analyses 
of data will be conducted when half the subjects have been entered or at other times based on the 
discretion of the PI and biostatistician. 
Reporting mechanisms of AEs and SAEs to the UVM IRB and Funding Agency. In the 
proposed study, we will use the FDA's definition of AEs and SAEs. AEs and SAEs will be assessed at 
each subject visit by a trained staff member and copies of all reports noting AEs and SAEs will be kept 
in a central file as well as in the individual subject's chart. AEs will be discussed at the weekly research 
staff meetings. Any SAE will be brought to the attention of the PI or a Co-Investigator as soon as 
possible and not longer than 24 hours. Any AE or SAE that is both unexpected and related to study 
participation will be reported to the IRB within 7 days of the event. That IRB will make a 
determination as to whether additional reporting requirements are needed. IRB actions will be reported 
to the funding agency by the PI no less than annually and more frequently as recommended by the 
local IRB. Any SAEs will be summarized in the yearly Progress Reports to the funding agency, 

 
25
including a review of frequency and severity. All SAEs will be followed through ongoing consultation 
with the physician caring for the patient until they resolve, result in death, or stabilize and are not 
expected to improve. 
 
 
 

 
26
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