Promoting Stretching Exercise to Reduce Cardiovascular Health Risk in Late Pregnant Women With Obesity
Phase: NA
Conditions: Pregnancy Related, Cardiovascular Risk Factor, Obesity
Sponsor: University of North Carolina, Chapel Hill

PROTOCOL  
 
 
 
 
 
 
 
Complete Title: Promoting stretch exercise to reduce cardiovascular health risk in late pregnant women with 
obesity  
Short Title: Prenatal Heart Smart 
Sponsor: National Institute of Nursing Research (NINR) 
Protocol Date: 10/23/2025 
NCT04291560 
 
 
 
 
 
 
 
 
Study Principal Investigator: SeonAe Yeo  
Email: syeo@email.unc.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................................................................................... 3 
PROTOCOL SYNOPSIS .......................................................................................................................................................................................... 4 
BACKGROUND AND RATIONALE ......................................................................................................................................................................... 6 
1 
STUDY OBJECTIVES ............................................................................................................................................................................ 8 
2 
INVESTIGATIONAL PLAN ................................................................................................................................................................... 8 
3 
STUDY PROCEDURES ......................................................................................................................................................................... 9 
4 
STUDY EVALUATIONS AND MEASUREMENTS .................................................................................................................................. 9 
5               STATISTICAL CONSIDERATIONS ...................................................................................................................................................... 11 
6 
STUDY INTERVENTION (DEVICE, DRUG, OR OTHER INTERVENTION) ................................................ ERROR! BOOKMARK NOT DEFINED. 
7               STUDY INTERVENTION ADMINISTRATION (IF APPLICABLE) ........................................................................................................... 13 
8           SAFETY MANAGEMENT ................................................................................................................................................................... 13 
9           DATA COLLECTION AND MANAGEMENT ........................................................................................................................................ 13 
10           RECRUITMENT STRATEGY ................................................................................................................................................................ 14 
11           CONSENT PROCESS .......................................................................................................................................................................... 15 
12           PLANS FOR PUBLICATION ................................................................................................................................................................ 15 
13           REFERENCES ..................................................................................................................................................................................... 15 
APPENDIX .............................................................................................................. ERROR! BOOKMARK NOT DEFINED. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Abbreviations and Definitions of Terms 
 
 
 
 
Abbreviation 
Definition 
cf-PWV 
Carotid femoral pulse wave velocity 
eUC 
Enhanced Usual Care 
GW 
Gestation week  
HF 
High frequency 
HRV 
Heart rate variability 
LF 
Low frequency 
PA 
Physical activity 
RPE 
Rate of perceived exertion 
SE 
Stretch exercise 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
  
Study Title 
Promoting stretch exercise to reduce cardiovascular health risk in late pregnant 
women with obesity 
Funder 
National Institute of Nursing Research (NINR) 
Clinical Phase 
Phase 2 
Study Rationale 
This project is important because stretching exercise (SE) may promote health and 
prevent complications of pregnancy when most pregnant women become 
sedentary. Stretching exercise may be practical for obese pregnant women, many 
of whom happen to be minority and underserved. Stretching exercise is known to 
have high acceptance, better adherence, no known untoward side effects, and 
promising preliminary evidence of effectiveness. 
Study Objective(s) 
Primary  
• 
To evaluate change in blood pressure, sympatho-vagal balance, and 
arterial stiffness from baseline to 32 and 37 weeks’ gestation. 
Secondary 
• 
To evaluate 6 maternal outcomes (pre-eclampsia/gestational hypertension, 
gestational diabetes, preterm delivery, elective or emergency caesarean 
section) and 4 fetal/neonatal outcomes (intrauterine death, small for 
gestational age, large for gestational age, admission to NICU). 
Test Article(s) 
(If Applicable) 
Stretching Exercise. The exercise regimen consists of sequential static stretching 
of large skeletal muscle groups for 20 seconds, 3 times per muscle group for a 
total of 30 minutes. 
Study Design 
 
In this 2-arm randomized control trial, we will determine if a stretch exercise (SE) 
is superior to a control condition of enhanced usual care (eUC) which includes 
moderate/vigorous activity, specifically walking, for 30 minutes 5 days/week as 
recommended by the American College of Obstetricians and Gynecologists. Both 
the treatment and control arms will receive a supportive behavioral intervention to 
facilitate adherence. Primary outcomes are BP, sympatho-vagal balance, and 
arterial stiffness assessed at baseline (27 weeks' gestation), then at 5 and 10 weeks 
later, and at 32 and 37 weeks' gestation. We will compare SE to eUC (n = 306; 
153 per arm) and examine selected cardiovascular functions by which SE may be 
effective. 
Subject Population 
key criteria for Inclusion and 
Exclusion: 
Inclusion Criteria 
1. Pregnant at less than 24 weeks gestation 
2. Singleton pregnancy 
3. BMI ≥ 30 kg/m^2 at their first prenatal care visit 
4. English or Spanish speaking 
Exclusion Criteria 
1. Women who expect or are scheduled to deliver prior to 37 weeks 
gestation 
2. Women who expect to move from the area during their participation in 
the study 
3. Women who are unable to exercise for 30 or more minutes 3 times per 
week 
Number Of Subjects  
 
Enrollment goal is 352 pregnant women  

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Study Duration 
• 
Each subject’s participation will last 10 weeks (27-37 weeks gestation) 
• 
The entire study is expected to last five years 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
(1) Screening: screening for eligibility and obtaining consent will be conducted 
at UNC- Women’s Health clinics 
(2)  Intervention: the study intervention includes a prescribed exercise regimen 
for 10 weeks. Treatment condition: Supportive intervention + stretching 
exercise (SE). Usual Care (UC) condition: UC is enhanced by supportive 
intervention + walking exercise (WE). 
(3) Follow up: none 
Efficacy Evaluations 
Primary evaluation measurements that will be used to assess the efficacy of the 
intervention are change in blood pressure, sympatho-vagal balance, and arterial 
stiffness from baseline to 32 and 37 weeks’ gestation. 
Safety Evaluations 
Exercise prescribed in the study will be approved by subject’s obstetrical care 
providers. The care providers will fill out the screening form for physical 
activities that pregnant women can engage. 
Statistical And Analytic Plan 
Statistical analyses will be conducted using SAS, and all hypothesis tests will use 
a two-sided alpha of 0.05. Missing visits and measures of physical activity or 
physiology will not be imputed, but missing items on psychosocial measures may 
be imputed according to the scoring rules for the particular measure. We expect 
that, compared to eUC, participants in the SE group will have lower blood 
pressure (systolic and diastolic), sympatho-vagal balance (HF), and arterial 
stiffness (cf-PWV). We will fit a linear mixed-effects model to each of these 
outcomes at 32 and 37 gw. We will control for the 27 gw value of the outcome 
and covariates though to be related to the outcomes (anxiety, age, race/ethnicity, 
BMI and smoking) and any other covariates that are found to differ between the 
SE and eUC groups. 
 
DATA AND SAFETY MONITORING 
PLAN 
The PI and the Study Statistician (Dr. Crandell) will oversee and train the project 
coordinator to establish a system to ensure the verification of source data 
compliance. The source data will include original records necessary for the 
reconstruction and evaluation of the clinical trial. It will be clear who documented 
the data, documentation will be readable, signature identifiable, contemporaneous, 
original, copy accurate and consistent, long-lasting and durable, available and 
accessible, complete, credible, and corroborated. All data will be first checked by 
two separate Research Assistants (RAs) at different times. REDCap will be used 
as our Research Electronic Data Capture System.  
 
The safety of participants in this study will be ensured through a local and 
impartial Data Safety and Monitoring Committee (DSMC). DSMC will consist of 
3 voting faculty members. Study progress and safety will be reviewed monthly 
(and more frequently if needed). Progress reports, including participant 
recruitment, retention/attrition, and AEs will be provided to Dr. Schwartz 
(DSMC) every six months. An annual report will be compiled and will include a 
list and summary of AEs and SAEs.  
 
 
 
 
 
 
 

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1. BACKGROUND AND RATIONALE 
 
 
1.1 
Introduction 
More than 50% of pregnant women in the U.S. are obese, increasing their risk for serious complications 
including preeclampsia, gestational hypertension, and giving birth to preterm and/or low birth weight 
infants 1-4. Physical activity (PA) is recommended to manage obesity; PA of moderate or vigorous 
intensity for at least 150 minutes each week greatly improves health in all stages of life 5. Although 
being sedentary can lead to excess risk for maternal and child mortality and morbidity 6, most pregnant 
women reduce their PA and only 8% meet the recommendations in the 3rd trimester 7. Behavioral 
approaches to increase moderate and vigorous PA in women late in pregnancy have been tested with 
limited success 8. More recently, researchers have shown interest in light intensity physical activity that 
may improve adherence,9 lower blood pressure (BP)10 and improve sympatho-vagal balance.11 In our 
randomized controlled trial with sedentary overweight/obese pregnant women with preeclampsia in a 
previous pregnancy,10 we found that compared to walking (a moderate PA), to which pregnant women 
adhered poorly, 10 or more weeks of stretching exercise (a light PA) reduced the incidence of 
preeclampsia - a significant risk factor for cardiovascular disease - by lowering BP and enhancing 
antioxidant up-regulation and production. From our pilot study of healthy pregnant women, of which 
84% were overweight/obese, (Preliminary Study 3), we reported promising results of the short-term 
effects of stretching exercise on sympatho-vagal balance (measured by heart rate variability), and 
established the protocol for arterial stiffness, a long-term effect measure. We are now positioned to test 
if this effect can be extended to broader populations of pregnant women. Thus, we propose to test the 
effects of a novel stretching exercise (SE) intervention on cardiovascular health in obese pregnant 
women in the 3rd trimester. Because women often do not adhere to PA recommendations in late 
pregnancy, we include evidence-based 
behavioral strategies to enhance adherence. 
 
We define a session of SE as 30 minutes of sequential static stretching of large skeletal muscle groups 
for 20 seconds, 3 times per muscle group. In our preliminary studies with small samples, we linked SE 
to improvements in BP and oxidative stress markers,10,12,13 findings that are highly consistent with a 
protective effect against preeclampsia. Both systolic and diastolic BPs were 4 mmHg lower in the 
stretching than the walking condition. Moreover, two antioxidants biomarkers (superoxide dismutase 
and transferrin) were significantly higher in the stretching than walking condition.13 Although little is 
known about cardiovascular effects of stretching exercise, these findings were unexpected yet consistent 
across our preliminary studies. If they persist, SE would be an effective, accessible, cost-efficient way 
for obese pregnant women to promote their health and reduce risk of cardiovascular complications of 
pregnancy. The study of SE interventions is therefore justified, and is especially important because 
studies of moderate/vigorous PA interventions for women in late pregnancy have yielded poor results, 
possibly due to low adherence, which we will address. In this 2-arm RCT we will determine if SE is 
superior to a control condition of enhanced usual care (eUC) which includes moderate/vigorous activity, 
specifically walking, for 30 minutes 5 days/week; both treatment and control arms will receive 
supportive behavioral intervention to facilitate adherence. Primary outcomes are BP, sympatho-vagal 
balance, and arterial stiffness. We will compare SE to eUC (n = 200; 100 per arm) and examine selected 
cardiovascular functions by which stretching may be effective. 
 
The Aims are: 
Aim 1 (primary outcomes): To test the efficacy of SE intervention on improving cardiovascular health 
compared to eUC with respect to selected indicators of cardiovascular function (blood pressure, 
sympatho-vagal balance and arterial stiffness), controlling for anxiety, age, race/ethnicity, BMI, and 

Page 7 of 18 
 
smoking. Hypothesis 1: SE will result in lower BP, reduced sympatho-vagal balance, and lower arterial 
stiffness compared to eUC. 
 
Aim 2 (secondary outcomes): To test the efficacy of the SE intervention on maternal, fetal, and neonatal 
composite outcomes compared to eUC. We will use a composite pregnancy outcome that includes 
preeclampsia, pregnancy induced hypertension, gestational diabetes, preterm delivery, elective and 
emergency cesarean section, intrauterine death, small or large for gestational age, and admission to 
NICU.14 Hypotheses 2: SE will result lower composite score compared to eUC. 
 
Aim 3: To explore adherence and overall physical activity in this group of obese pregnant women: 3a. 
Compare the two groups with respect to adherence to the recommended exercise and examine the 
relationships between adherence and the primary and secondary outcomes; 3b. Examine the overall level 
of physical activity in the two arms as measured by accelerometer, and make adjustments to the analyses 
in Aims 1 and 2 accordingly.  Participants will be recruited from UNC- Women’s Health clinics. 
 
1.2 
Name and Description of Investigational Product or Intervention  
 
Stretching Exercise. The exercise regimen consists of sequential static stretching of large skeletal 
muscle groups for 20 seconds, 3 times per muscle group for a total of 30 minutes. A demonstration 
video, based on one that we developed for preliminary studies,15 will have an introduction covering safe 
exercise environment and a posture of the stretches. The sequence of movements shows how to stretch 
the major muscle groups, namely the lower extremities (quadriceps, hamstring, adductor, and 
gastrocnemius muscles), upper extremities (pectoralis major and minor, triceps, latissimus dorsi), and 
neck and trunk (flexion, extension, and rotation) through their full range of motion.15,16 
 
1.3 
Non-Clinical and Clinical Study Findings 
We propose to investigate whether and how a stretching exercise intervention improves cardiovascular 
function in obese pregnant women. Although we tested small samples, our preliminary data suggest that 
stretching modifies mechanisms leading to preeclampsia in a high-risk group of pregnant women, i.e., 
women with a history of preeclampsia.10,13,17 Scholars agree that preeclampsia is a cardiovascular 
condition that increases risk for cardiovascular illness in later life.18-23 Obese pregnant women, a 
population of public health concern, also are at risk for cardiovascular illness.24-26 This suggests that a 
stretching intervention may reduce risk of cardiovascular illness in pregnant women of obesity.27 
Generally, pathophysiology of cardiovascular conditions are explained using frameworks of 
oxidative stress, systemic inflammation, and enhanced sympathetic activity.28Given that stretching 
exercise enhanced antioxidants better than walking exercise in our prior study,10,13,17 we will test a new 
mechanism, sympatho-vagal balance, a theory of which we developed using existing literature29,30 and 
our own preliminary data (published31,32 and unpublished Study 3). We also will evaluate arterial 
stiffness, a demonstrated measure of overall cardiovascular health.15, 33-42 Thus, we posit that a stretching 
intervention will improve cardiovascular function in obese pregnant women, which in turn will result in 
fewer pregnancy complications. This study addresses weaknesses in prior research. We have an 
available sample adequate to assure robust power, have explicated a promising physiological framework 
to explore underlying mechanisms, and have included a rigorous plan to facilitate adherence. This study 
will advance knowledge about mechanisms for stretching and wellness promotion in obese pregnant 
women. Shifting the focus from a narrow, very high-risk population of women with a history of 
preeclampsia to another group at significant risk for cardiovascular illness serves a larger population and 
changes the focus from illness to wellness. The potential impact is even broader, as a stretching 
intervention may help reduce cardiovascular risk in other populations who are unable to adhere to 
recommendations for moderate to vigorous exercise. 
 

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1.4 
Relevant Literature and Data 
Pregnancy Physical Activity Questionnaire (PPAQ): Participants will be asked to fill out the PPAQ  
It has been validated against ActiGraph43(the intraclass correlation coefficients for reproducibility were 
0.78 for total activity, 0.82 for moderate activity, and 0.81 for vigorous activity) and has been used for 
diverse pregnant populations.44-47 This questionnaire assesses duration (time spent), frequency, and 
intensity of daily PA during the previous 4 weeks. The PPAQ has 33 items about activities of daily 
living in 6 domains: household, caring, sedentary non-occupational, occupational, sports/exercise, and 
transportation. It estimates daily energy expenditure related to physical activity. Anxiety will be 
measured because it may affect HRV48, adherence to exercise, and overall daily physical activity.49 The 
State-Trait Anxiety Inventory (STAI) includes self-report scales measuring state and trait anxiety (STAI 
not included due to copyright restrictions). The state anxiety scale includes statements about the 
intensity of feeling at a particular moment, while the trait anxiety scale includes statements about the 
frequency of feelings. The total score for each ranges from 20 to 80, with higher scores indicating more 
anxiety. The STAI is reliable and valid and has been used with pregnant women.50,51 Cronbach’s alphas 
are > 0.92 for both state and trait anxiety. 
 
2. STUDY OBJECTIVES 
 
2.1  
Primary Objective 
The primary purpose of this study is to test the efficacy SE intervention on improving cardiovascular 
health compared to eUC with respect to selected indicators of cardiovascular function (blood pressure, 
sympatho-vagal balance and arterial stiffness), controlling for anxiety, age, race/ethnicity, BMI, and 
smoking. 
 
2.2       Secondary Objective 
The secondary purpose of this study is to test the efficacy of the SE intervention on maternal, fetal, and 
neonatal composite outcomes compared to eUC. We will use a composite pregnancy outcome that 
includes preeclampsia, pregnancy induced hypertension, gestational diabetes, preterm delivery, elective 
and emergency cesarean section, intrauterine death, small or large for gestational age, and admission to 
NICU.14 
 
3. INVESTIGATIONAL PLAN (brief overview) 
 
3.1       Study Design 
We propose a two-arm RCT with n=153 per group. The treatment group receives a supportive 
intervention to promote stretching exercise (SE), with a target of 30 minutes per day, 5 days per week. 
The control group is an enhanced usual care (eUC) group receiving the same type of supportive 
intervention to promote adherence to the standard recommendation from the American College of 
Obstetricians and Gynecologists (ACOG) of moderate/vigorous physical activity (walking) at 30 
minutes per day, 5 days per week. 
 
We will use a parallel group design, comparing effects of eUC to stretching on blood pressure, 
autonomic nervous system activity, arterial stiffness, and pregnancy complications. Participants in both 
conditions receive an identical behavioral intervention to facilitate adherence; at baseline, participants 
and interventionists make a behavior plan to adhere to the exercise; participants report their adherence 
weekly to an intervention facilitator and, in return, receive brief counseling via phone call. 
 
The supportive intervention consists of behavior change strategies for adhering to individual-based 
home exercise. SE consists of sequential static stretching of a 20 seconds each for 3 repetitions per 

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muscle group of large skeletal muscle groups. Walking consists of a moderate intensity walking; we will 
instruct participants about their target heart rate and the Rating of Perceived Exertion (RPE), which will 
be prescribed based on individual fitness. Participants will keep an exercise log and wear a heart rate 
monitor (Polar H10) when performing their assigned exercise. To monitor their overall physical 
activities, all participants will wear ActiGraph for 7 days at 3 time points: baseline (27 weeks’ 
gestation), 32 and 37 weeks’ gestation. 
 
a. Allocation to Treatment Groups and Blinding (if applicable) 
 
After baseline data collection, we will randomly assign participants to intervention or control groups 
using a 1:1 ratio with a block size 5-10, which will be randomly sequenced. The statistician will 
generate the allocation sequence before the study starts, using a computerized randomization program 
for pre-sequence generation and allocation concealment. The coordinator will reveal group assignment 
to participants sequentially. Participants are not blinded to arm assignment, but will be blind to the study 
hypotheses. Group assignments will not be included on data in the computer systems until final analysis. 
 
b. Study Duration, Enrollment and Number of Subjects 
This is a five-year study with expected enrollment of 352 pregnant women. 
 
c. Study Population 
Inclusion Criteria: 1) Pregnant at less than 24 weeks gestation; 2) Singleton pregnancy; 3) BMI ≥ 30 
kg/m^2 at their first prenatal care visit; 4) English or Spanish speaking 
Exclusion Criteria: 1) Women who expect or are scheduled to deliver prior to 37 weeks gestation; 2) 
Women who expect to move from the area during their participation in the study; 3) Women who are 
unable to exercise for 30 or more minutes 3 times per week. 
 
4. STUDY PROCEDURES  
a. Baseline Visit procedures- Find biobehavioral lab (BBL) procedures at end of document. 
b. Intervention/Treatment procedures – Find intervention procedures at end of document. 
c. Follow- up procedures (by visits) – Find biobehavioral lab procedure at end of document. 
 
5. STUDY EVALUATIONS AND MEASUREMENTS (how measurements will be made)   
Self-report physical activity, anxiety, BP, sympatho-vagal balance, arterial stiffness, weight, and daily 
physical activity will be assessed at 3 time points (27 gestational weeks [gw], 32 gw, and 37 gw). 
Pregnancy and birth outcomes will be extracted after the birth. Exercise adherence (HRM and diary for 
SE; HRM, RPE and diary for WE) will be recorded weekly. 
 
Self-Report Measures 
 
Demographic (age, race/ethnicity, occupation, marital status, and education), health (pregnancy history, 
medical history, medication, family medical history), and lifestyle (smoking) information will be 
collected during the run-in. 
 
Pregnancy Physical Activity Questionnaire (PPAQ): Participants will be asked to fill out the PPAQ It  
has been validated against ActiGraph43(the intraclass correlation coefficients for reproducibility were 
0.78 for total activity, 0.82 for moderate activity, and 0.81 for vigorous activity) and has been used for 
diverse pregnant populations.44-47 This questionnaire assesses duration (time spent), frequency, and 
intensity of daily PA during the previous 4 weeks. The PPAQ has 33 items about activities of daily 

Page 10 of 18 
 
living in 6 domains: household, caring, sedentary non-occupational, occupational, sports/exercise, and 
transportation. It estimates daily energy expenditure related to physical activity. 
 
Anxiety will be measured because it may affect HRV 48, adherence to exercise, and overall daily 
physical activity.49The State-Trait Anxiety Inventory (STAI) includes self-report scales measuring state 
and trait anxiety (STAI not included due to copyright restrictions). The state anxiety scale includes 
statements about the intensity of feeling at a particular moment, while the trait anxiety scale includes 
statements about the frequency of feelings. The total score for each ranges from 20 to 80, with higher 
scores indicating more anxiety. The STAI is reliable and valid and has been used with pregnant 
women.50,51 Cronbach’s alphas are > 0.92 for both state and trait anxiety.52,53 
 
Medical Record Extraction 
A trained research team member blinded to intervention assignment will extract medical records for 
outcomes, including preeclampsia, eclampsia, gestational hypertension, gestational diabetes, elective or 
emergency caesarean section, small for gestational age, large for gestational age, intrauterine growth 
restriction, and preterm birth. 
 
Monitoring Daily Physical Activity 
Physical activity will be measured using ActiGraph GT3 accelerometers worn at the right side of the 
waist during waking hours for 7 consecutive days at 3 time points. Accelerometry data are the gold 
standard for measurement of overall activity when worn for a minimum of 3 days and for at least 10 
hours a day.54,55 Accelerometry can be used to categorize movement as sedentary (<100 counts per 
minute), light (100–1,951 counts per minute), and moderate to vigorous (1,952 counts per minute).56 We 
will report minutes per day and percent of total wear time in sedentary, light, and moderate/vigorous 
physical activity. We will follow the methods reported by our consultant Evenson and colleague.57 
 
Physiological Measures Taken in Laboratory 
Physiological measures will be assessed at all three timepoints. Participants will be asked to avoid 
caffeine, food, and vigorous exercise for two hours before testing. If participants do not comply, the 
assessment will be rescheduled. After arrival, participants will change into a hospital gown without 
removing undergarments and be given the opportunity to void. Height and weight will be measured and 
recorded, and participants will be asked to rest quietly without a pillow, in a slightly tilted supine 
position to avoid orthostatic hypotension due to the growing uterus. To achieve correct positioning, a 
rolled towel or small cushion will be placed under the left hip.58 While the participant is resting, 
electrodes will be affixed to the chest for lead II configuration for heart rate variability (HRV). Proximal 
and distal measurement for pulse wave verbosity (PWV) will be taken following an established protocol. 
Blood pressure will be taken. Participants will quietly rest with normal breathing for 10 minutes while 
cf-PWV and HRV procedures are being prepared and completed. 
 
Blood pressure (BP) and resting heart rate (HR). Brachial BP will be measured by a DINAMAP 
monitor. Because incorrect cuff size causes error in BP measurement,59 the mid-section circumference 
of the dominant upper arm will be measured to select the proper-sized cuff. BP and HR will be 
measured twice in the dominant arm with a 2-minute rest between measurements; then the two measures 
will be averaged.60 
 
Sympatho-vagal balance: Parasympathetic (PNS) activity will be assessed by measuring high 
frequency (HF) of HRV. HRV is a non-invasive measure of the variation in beat-to-beat intervals to 
assess the sympatho-vagal balance at the sinoatrial node of the heart. The standard measures of HRV 
include time domain methods and frequency domain methods. More knowledge exists on physiological 
interpretation of the frequency domain methods (than time domain methods) and short-term HRV 

Page 11 of 18 
 
measure (than long-term HRV measure). For the frequency domain methods of HRV, the oscillations of 
the heart rate signal are decomposed at different frequencies (the low frequency band [LF], the high 
frequency band [HF])62 HF of HRV is a well-known marker of PSNS tone.63 In investigating short-term 
HRV, two 5-minute recording segments (a total of 10 minutes) are preferred.62 Since respiration 
influences HRV, subjects will be asked to breathe at their normal rate (14-16 per minute). While 
electrocardiography (ECG) wave form are being recorded, respiration frequency will also be recorded 
by the respiration transducer and BioNex data acquisition system.61ECG recordings that are free of body 
movements and ectopic beats will be divided into 5-min segment(s). Using the Mindware HRV 
software,61RR-intervals (RRI) will be generated, and respiration rate and frequency will also be 
determined with data where respiration frequency is within the respiration sinus arrhythmia (RSA) band 
(0.15-0.4hz). HF power in absolute and normalized units will be calculated and averaged. 
Electrocardiogram (ECG) data for HF will be obtained over a 10-minute period. Subjects will be 
instructed to rest quietly, keeping as still as possible with normal breathing. After 10 minutes, data 
acquisition will be terminated, and the reports of HF will be generated. 
 
Arterial stiffness will be measured by carotid femoral pulse wave velocity (cf-PWV) using the 
SphygmoCor system (AtCor Medical, Itasca, IL). cf-PWV is considered the "gold-standard" 
measurement of arterial stiffness. Each carotid and femoral waveform will be acquired by applying a 
pressure sensitive transducer (tonometer) on the carotid and femoral sites. The transit time of the pulse 
from the left ventricle to the carotid artery (t1) and the transit time of the pulse from the left ventricle to 
the femoral artery (t2) will be calculated by the system software on the basis of the ECG, using the foot-
to-foot method. The straight distance from the suprasternal notch to the carotid artery site (d_carotid) 
and the distance from the suprasternal notch to the femoral artery site (d_femoral) will be measured 
using a pelvimeter, which allows measuring a distance without interference of the bulging abdominal 
surface due to pregnancy. cf-PWV is the difference in the distances from suprasternal notch to two 
arterial sites divided by the mean time difference. 64,65 Pulse Wave Velocity (cf-PWV) will be measured 
by applying a tonometer to the carotid and femoral pulses, and will be visually displayed. The tonometer 
may need to be angled slightly, optimizing wave forms until uniform and free of artifact. Once five 
consecutive and uniform waves are displayed, data will be captured. Pressure waves of insufficient 
quality will automatically be rejected by the SphygmoCor device and will generate an error message. 
 
STATISTICAL CONSIDERATIONS 
 
a. Primary Endpoint 
Statistical analyses will be conducted using SAS, and all hypothesis tests will use a two-sided alpha of 
0.05. Missing visits and measures of physical activity or physiology will not be imputed, but missing 
items on psychosocial measures may be imputed according to the scoring rules for the particular 
measure. Aim 1(primary outcomes): We expect that, compared to eUC, participants in the SE group will 
have lower blood pressure (systolic and diastolic), sympatho-vagal balance (HF), and arterial stiffness 
(cf-PWV). We will fit a linear mixed-effects model to each of these outcomes at 32 and 37 gw. We will 
control for the 27 gw value of the outcome and covariates though to be related to the outcomes (anxiety, 
age, race/ethnicity. BMI and smoking) and any other covariates that are found to differ between the SE 
and eUC groups. 
 
b. Secondary Endpoint 
Aim 2 (secondary outcomes): The use of pre-specified composite outcomes is common in clinical trials 
studies of pregnancy outcomes 66,67 and has been recommended in the evaluation of lifestyle 
interventions in pregnancy.14 The composite outcome is dichotomization of several negative outcomes- 
“yes” if one or more outcomes was experienced, and “no” otherwise. In addition to serving as general 
measures of pregnancy wellness, composite outcomes overcome the large sample sizes needed to 
identify intervention effects on rare events. We propose maternal and fetal/neonatal composite outcomes 

Page 12 of 18 
 
based on Yeo et al.’s work.14 We will fit a logistic regression model predicting each composite outcome 
from intervention assignment, controlling for covariates (anxiety, age, race/ethnicity. BMI and smoking) 
and any other covariates that are found to differ between the SE and control group. We will repeat this 
model for each individual component of the composite outcomes, though power is low to detect a 
difference for outcomes with low prevalence. 
 
Aim 3: a. Using a t-test, we will compare overall adherence (percent of recommended sessions and 
percent of recommended time) in the SE and eUC arms. Within each arm, we will look at the association 
between adherence to the intervention and the primary and secondary outcomes using correlation 
coefficients and t-tests. Additionally, we will add interactions between adherence and exercise type to 
the models for Aims 2 and 3 to explore adherence as a potential effect modifier of the relationship 
between exercise type and outcome. This model will be exploratory (i.e. looking for trends), as we are 
only powered to detect very large effect modification. b. Using a t-test, we will compare overall physical 
activity as measured by the accelerometer (percent time spent in light and moderate/vigorous physical 
activity) in the SE and eUC arms. We will use correlations and t-tests to examine the relationships 
between physical activity and the outcomes. If there is evidence of associations (i.e., potential 
confounding), we will re-fit the models for Aims 2 and 3 using physical activity level as a covariate. 
 
c. Sample Size and Power 
Power calculations for the continuous dependent variables in Aim 1were performed with POWERLIB20 
SAS/IML modules that incorporate methods for hypothesis tests in repeated measures linear 
models.68 Diastolic blood pressure was measured at clinic visits 32 and 37/38 weeks in our stretching vs. 
walking pilot study (N=61 at 32 weeks, 57 at 37/38 weeks), and effect sizes (Cohen’s d) were 0.34 at 32 
weeks and 0.33 at 37/38 weeks. These effects correspond to ~3 mmHg. Though the pilot did not 
measure sympatho-vagal balance or arterial stiffness, the effect on resting heart rate was similar (d=.37). 
Assuming a within-participant correlation of 0.37 (also from the pilot study), our sample size of 153 per 
group (after dropout) yields 80% power for d=0.35 or higher, which is similar to what was seen in the 
pilot study. The components of the composite outcomes in Aim 2 have the following estimated 
prevalence rates in our population: Maternal- pre-eclampsia/gestational hypertension, 10% 69,70, 
gestational diabetes 5% 71, preterm delivery 7%72, elective or emergency c-section, 25%; fetal/neonatal- 
intrauterine death, 1%73; large for gestational age, 9%74; small for gestational age, 11%74; and NICU 
admission, 8%75. We conservatively estimate the overall prevalence of the composite outcome in the 
eUC group to be 25% for the maternal outcome and 15% for the fetal/neonatal outcome. With N=306 
(153 per group), we have at least 80% power to detect a difference in the eUC group vs. SE group of 
25% vs. 13% for the maternal outcome and 15% vs. 6% for the fetal/neonatal outcome. The detectable 
difference is smaller than the reduction in preeclampsia rates seen in preliminary study 1. Power is low 
to detect differences in individual components of the composite outcomes, but we will examine these for 
the purposes of understanding which changed outcomes are driving changes in the composite outcome. 
The analysis in Aim 3 consists of t-tests and correlations in the entire sample (N=306) and within each 
arm (N=153). With an alpha level of 0.05, we have 80% power to detect d=0.32 and a correlation of 
0.16 in the entire sample; and d=0.46 and a correlation of 0.22 in a single arm. These are adequate for 
the exploration of the association of adherence and overall physical activity with treatment arm and 
primary/secondary outcomes. 
 
d. Interim Analysis 
The project coordinator will generate semi-annual interim analysis reports on data obtained during the 
lab visits, weekly phone calls, and medical record for birth outcomes to understand issues related to the 
measurements, adherence, usability, and fidelity of this project protocols. We will evaluate the screening 
and enrollment procedures, barriers to participation and retention, acceptability, technology problems 
encountered if any, and user feedback from the participants and providers. This information gained from 

Page 13 of 18 
 
this structured process will be used to both guide the refinement of the current protocol. Stopping rules 
with regard to benefit--The rate of preeclampsia and other birth outcomes. Stopping rules are planned 
when the effect of stretching exercise is statistically undeniable. Stopping rules with regard to statistical 
power and adverse events--The DSMC will review subject accrual and adverse events for compelling 
evidence of futility or harm and will address these using appropriate measures. 
 
6        STUDY INTERVENTION ADMINISTRATION (IF APPLICABLE)  
After baseline data collection, we will randomly assign participants to intervention or control groups 
using a 1:1 ratio with a block size 5-10, which will be randomly sequenced. The statistician (JC) will 
generate the allocation sequence before the study starts, using a computerized randomization program 
for pre-sequence generation and allocation concealment. The coordinator will reveal group assignment 
to participants sequentially. Participants are not blinded to arm assignment, but will be blind to the study 
hypotheses. Dr. Caughey, who will be unaware of participants’ group assignment, will assess 
cardiovascular function. Group assignments will not be included on data in the computer systems until 
final analysis. 
 
7. 
  SAFETY MANAGEMENT  
The PI will responsible for ensuring that all AE and SAEs are reported to the NIH/NINR and UNC-  
CH’s IRB in compliance with their requirements. Any AE will be reported by the PI or PC to the 
Adverse Event Monitoring Committee within one week. An incident report will be created and sent by 
electronic email by the PI or PC to Drs. Thorp, Wilbur, Mottola, Caughey, Logan, Hinderliter, Evenson, 
Crandell (Study Statistician), and Blumenthal. The PI will follow-up with the participant and will prepare 
a report. The AEs will be reviewed every six months and a report prepared for the Human Participants 
Committee and Dr. Yoon at NIH/NINR. Process notes will be kept concerning any decisions. 
 
The safety of participants in this study will be ensured through a local and impartial Data Safety and 
Monitoring Committee (DSMC). DSMC will consist of 3 voting faculty members: Dr. Andrea K. Knittel, 
MD, PhD is a board-certified Obstetrician and Gynecologist, and Assistant Professor at UNC-CH School 
of Medicine, Department of General Onstetrics. She received her medical scientist training program for 
MD/PhD at the Department of Health Behavior and Health Education at the University of Michigan 
Medical School and School of Public Health. Dr. Todd Schwartz, PhD is a Biostatistician Research 
Associate Professor at the UNC-CH School of Nursing and Gillings School of Global Public Health. He 
is a Methodology Core Co-Director and Principal Investigator at National Institute of Arthritis, 
Musculoskeletal and Skin Diseases’ Multidisciplinary Clinical Research Center in the Thurston Arthritis 
Research Center. He will assume the Chair of DSMC. Dr. Carmen Samuel-Hodge is Research Assistant 
Professor of Public Health and the Center for Health Promotion and Disease Prevention. She served a 
role of reviewer for UNC-CH IRB from 2007 till 2017. All three members are not associated with this 
research project and thus works independently of the PI. They are not any key personnel involved in this 
project. They are qualified to review the participant safety data generated by this study because of their 
expertise in human research. 
 
8.  
DATA COLLECTION AND MANAGEMENT  
The team of investigators will convene monthly meetings to review the activities of the study including 
management, personnel, recruitment, performance, and any emerging problems. All data from 
participants screened for the study will be entered into the REDCap electronic study database. 
Designated research staff will collect, gather, and enter required data (written informed consent, Health 
Insurance Portability and Accountability Act (HIPAA) authorization, medical history and 
demographics) onto study data forms. Screened patients who do not meet study eligibility will have 
specific screening data entered into the study database. The collected data will be helpful in examining 

Page 14 of 18 
 
the patient population and feasibility of enrollment criteria and will include gender, age, race and reason 
for exclusion. All dates will be shifted and other Personal Health Information (PHI) will be removed 
from the study database upon study completion. All data obtained from this study will be used for 
research purposes only and will comply with Federal HIPAA regulations. 
 
All proposed study specific case report forms (source documents) for data collection will be designed by 
the PI and PM in concert with the Study Statistician and transferred by the PC into electronic Case 
Report Forms (eCRFs) for use in the study’s REDCap database. These study specific eCRFs source 
documents (study logs for correspondence, contacts, compensation and other forms such as pre-
eligibility screens) will be coded by the participant’s unique study identification number for all data 
collected including study instruments will be maintained in the participant research record that will be 
made accessible to study monitors. Completed instruments that require a signature on a paper CRF will 
be scanned and uploaded into the study database as well as maintained on file in accordance with UNC-
CH policies and applicable Federal Regulations for the Conduct of Human Participant Research. 
 
The PI and the Study Statistician (Dr. Crandell) will oversee and train the project coordinator to 
establish a system to ensure the verification of source data compliance. The source data will include 
original records necessary for the reconstruction and evaluation of the clinical trial. It will be clear who 
documented the data, documentation will be readable, signature identifiable, contemporaneous, original, 
copy accurate and consistent, long-lasting and durable, available and accessible, complete, credible, and 
corroborated. All data will be first checked by two separate Research Assistants (RAs) at different times. 
REDCap will be used as our Research Electronic Data Capture System.  
 
The safety of participants in this study will be ensured through a local and impartial Data Safety and 
Monitoring Committee (DSMC). DSMC will consist of 3 voting faculty members. Study progress and 
safety will be reviewed monthly (and more frequently if needed). Progress reports, including participant 
recruitment, retention/attrition, and AEs will be provided to Dr. Schwartz (DSMC) every six months. An 
annual report will be compiled and will include a list and summary of AEs and SAEs. 
 
 
9.        RECRUITMENT STRATEGY 
 
We have planned and will implement this study with the support of four UNC entities: the University of 
North Carolina at Chapel Hill (UNC) Women’s Health Clinics, UNC research participant recruitment 
list, UNC School of Nursing Biobehavioral Lab (BBL), and UNC Communication for Health 
Applications & Interventions (CHAI CORE). Participants will be: 1) Identified at the UNC-Women’s 
Health Clinics or by the recruitment media (CHAI CORE) and UNC Campus-wide email system; and 2) 
Measured for physiological data at the BBL. 
 
The UNC-Women’s Health clinics provide prenatal care each year to ~3,000 adult pregnant women 
through 8 sites in Orange, Durham, Wake, and Alamance counties and their vicinities. Of these, 56% 
(1,700 women) are overweight/obese. 103We thus estimate ~600 eligible potential participants (see 
Enrollment criteria below). From previous experience, we predict 40% enrollment, for availability of 
240 per year. Our enrollment goal is 352 (allowing for 15% attrition), therefore we require 60 enrolled 
participants in year 1, 90 in each of years 2 - 4, and 22 in year 5. To ensure timely recruitment, we will 
supplement clinic recruitment by contacting the university-controlled research study participant 
recruitment list, which is an effective way to reach out to the demographically diverse campus 
community. 103Because women who can communicate in English or Spanish will be recruited, we 
anticipate lower than the population percentage among small groups who speak a language other than 

Page 15 of 18 
 
English or Spanish. Using and monitoring multiple recruitment processes, we will ensure that diversity 
is maintained to reflect the region’s population of pregnant women. 
 
 
 
10. 
CONSENT PROCESS  
 
At clinics, trained RNs will approach eligible patients to provide fliers about the study and assess 
patients’ interest, willingness of the study candidates and obtain informed consent after providing 
detailed study information. RNs will talk to eligible patients in a private area such as an exam room or a 
consultation room. Candidates will be contacted in the candidate preferred way. Before screening 
questions, the candidate will be guided to find a private area. Eligible candidates will have sufficient and 
multiple times for consenting. When eligible candidates are interested but are not in a position to 
consent, the project manager will email consent form to the patient and schedule a telephone consent 
conference with a research nurses or research assistants in order to screen the candidates and obtain 
informed consent after providing detailed study information. 
 
11.      PLANS FOR PUBLICATION 
We will prepare and submit a presentation and manuscript focused on the design and protocol of the 
study. Graduate students will be encouraged to conduct secondary data analysis on the data for their 
dissertations and theses. We will deposit our de-identified data into the Biomedical Research Informatics 
Computing System at the National Institute of Nursing Research. 
 
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