The Stimulation To Induce Mothers (STIM) Study: A Parallel Group Randomized Controlled Trial
Phase: PHASE4
Conditions: Oxytocin, Labor Pain, Induction of Labor Affected Fetus / Newborn, Physiologic Effects of Drugs
Sponsor: Yale University

 
Study Title: The Stimulation To Induce Mothers (STIM) Study: A Parallel Group Randomized 
Controlled Trial 
NCT Number: NCT05079841  
Unique Protocol Id: 2000031338 
Date: 8/11/25 
 
 
Study Protocol 

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
CLINICAL STUDY PROTOCOL
The Stimulation Therapy to Induce 
Mothers (STIM) Study: A Multicenter 
Parallel Group Randomized Controlled 
Trial
Study Principal Investigator
Moeun Son
Yale University Principal Investigator
Molly McAdow
Northwestern University Principal Investigator
Lynn Yee
Weill Cornell Medicine Principal Investigator
Moeun Son
Protocol Version
28 July 2025
Version 14
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
2
Synopsis
Primary Objective
To determine whether intrapartum nipple stimulation therapy with or without synthetic 
oxytocin changes the likelihood of achieving a spontaneous vaginal delivery compared to 
receipt of synthetic oxytocin infusion without nipple stimulation to induce labor.
Secondary Objectives (if applicable)
The secondary objectives are as follows:
1. To determine if women who perform intrapartum nipple stimulation to induce labor have 
differences in other obstetric and maternal outcomes such as operative vaginal delivery, 
cesarean delivery, labor duration, postpartum hemorrhage, infection, and morbidities such 
as higher-order perineal lacerations, ICU admission, or death.
2. To determine if women who perform intrapartum nipple stimulation report differences in 
pain scores during labor, labor agentry and satisfaction scores, postpartum depression 
scores, and breastfeeding success compared to women who receive only intrapartum 
exogenous oxytocin infusion.
3. To determine if women who perform intrapartum nipple stimulation to induce labor have 
similar fetal and neonatal outcomes compared to women who receive only intrapartum 
exogenous oxytocin infusion.
4. At Yale, to measure circulating plasma and urine concentrations of proteins, microRNA, 
and small molecules using unbiased “omics” approaches, comparing patients undergoing 
induction of labor via intrapartum nipple stimulation versus continuous exogenous oxytocin 
infusion, un-ripened/unlabored control patients, and patients in spontaneous labor.
5.  To measure milk maturation biomarkers and milk composition, comparing patients 
undergoing induction of labor via intrapartum nipple stimulation versus continuous 
exogenous oxytocin infusion.
Study Design
This is a multi-site, pragmatic, open label parallel group randomized clinical trial of 
pregnant women at 36 weeks of gestation and greater to compare the effectiveness of 
inpatient nipple stimulation therapy with or without adjunctive synthetic oxytocin 
(intervention) versus immediate synthetic oxytocin infusion without nipple stimulation 
(comparator) during labor induction at Yale New Haven Hospital, Weill Cornell Medicine 
and Northwestern Memorial Hospital.
Study Population
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
3
Nulliparous women with live singleton gestations of 36 weeks and greater and are planned 
to receive synthetic oxytocin infusion for induction of labor. 
Number of Participants
A total of 988 participants will be enrolled across all study sites with roughly even 
distribution.
Number of Study Sites
The trial will be conducted at 3 sites: Yale New Haven Hospital (York Street Campus), 
Weill Cornell Medicine and Northwestern Memorial Hospital.
Primary Outcome Variables
The primary outcome is spontaneous vaginal delivery. 
Secondary and Exploratory Outcome Variables (if applicable)
The following secondary maternal outcome variables will be explored: operative vaginal 
delivery, cesarean delivery, time interval from randomization to delivery, postpartum 
hemorrhage, infection, 3rd or 4th degree perineal lacerations, maternal death, maternal 
intensive care unit admission.
The following secondary patient-centered outcome variables will be explored: labor pain, 
feelings of control during labor, satisfaction with the birthing process, ability to express 
and/or collect colostrum and/or breastmilk intrapartum, depression score, and 
breastfeeding success.
The following secondary perinatal outcome variables will be explored: perinatal death, 
Apgar score <3 at 5 minutes of life, umbilical artery acidemia, neonatal intensive care unit 
admission, and a composite neonatal severe morbidity measure. In addition, breastfeeding 
as the sole source of nutrition (BSSN) at the time of delivery hospitalization within the first 
72 hours and maximal percent newborn weight loss up to 14 days post-birth will be 
examined.
In the Yale biospecimen sub-cohort, we will measure circulating plasma concentrations of 
proteins and microRNA and urine metabolites of prostaglandins using unbiased “omics” 
approaches, comparing patients undergoing induction of labor via intrapartum nipple 
stimulation versus continuous exogenous oxytocin infusion. The change in these labor 
biomarkers will also be evaluated in a cohort of patients presenting in early spontaneous 
labor who will be evaluated as a control.
In the milk biospecimen sub-cohort, we will measure milk conductivity and sodium levels to 
estimate milk maturation (MM) before and after birth. When milk volume allows, we will 
also measure milk composition (macronutrients) and will use an unbiased approach to 
study mammary gland function using milk RNA sequencing. We will compare patients 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
4
undergoing induction of labor via intrapartum nipple stimulation versus continuous 
exogenous oxytocin infusion. 
Visit Schedule Table (Optional)
Study Flow Chart (optional)
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
5
Table of Contents
Synopsis
2
Primary Objective.................................................................................................................2
Secondary Objectives (if applicable)....................................................................................2
Study Duration......................................................................................................................2
Study Design........................................................................................................................2
Study Population ..................................................................................................................3
Number of Participants.........................................................................................................3
Number of Study Sites .........................................................................................................3
Primary Outcome Variables .................................................................................................3
Secondary and Exploratory Outcome Variables (if applicable)............................................3
Visit Schedule Table (Optional)............................................................................................4
Study Flow Chart (optional)..................................................................................................4
1 – Introduction
8
1.1 Introductory Statement...................................................................................................8
2 – Background
9
2.1 Background/prevalence of research topic......................................................................9
3 – Rationale/Significance
12
3.1 Problem Statement.......................................................................................................12
3.2 Purpose of Study/Potential Impact...............................................................................12
3.3.1 Potential Risks.......................................................................................................13
3.3.2 Potential Benefits...................................................................................................14
4 - Study Objectives
15
4.1 Hypothesis....................................................................................................................15
4.2 Primary Objective.........................................................................................................15
4.3 Secondary Objectives (if applicable)............................................................................15
5 - Study Design
16
5.1 General Design Description .........................................................................................16
5.1.1 Study Date Range and Duration............................................................................17
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
6
The study is expected to start in October 2021 at Yale, July 2023 at Northwestern and 
Spring 2024 at Weill Cornell Medicine and will be conducted over 7 years, with the final 
participant expected to be enrolled in June 2026. Final data collection and analysis is 
expected to be completed by June 2028........................................................................17
5.1.2 Number of Study Sites...........................................................................................17
5.2 Outcome Variables.......................................................................................................17
5.2.1 Primary Outcome Variables...................................................................................17
5.2.2 Secondary and Exploratory Outcome Variables (if applicable) .............................17
5.3 Study Population ..........................................................................................................21
5.3.1 Number of Participants ..........................................................................................21
6 - Methods
23
6.1 Treatment.....................................................................................................................23
6.1.1 Intervention administration and schedule ..............................................................23
6.1.2 Method of Assignment/Randomization..................................................................24
6.1.3 Concomitant therapy..............................................................................................24
6.2 Assessments................................................................................................................24
6.2.1 Efficacy......................................................................................................................26
6.2.2 Safety/Pregnancy-related policy............................................................................26
6.2.2.1 Adverse Events Definition and Reporting...........................................................26
6.2.3 Pharmacokinetics (if applicable)............................................................................27
6.2.4 Biomarkers (if applicable) ......................................................................................27
6.3
 Study Procedures..............................................................................................................28
6.3.1 Study Schedule......................................................................................................32
6.3.2 Informed Consent ..................................................................................................33
6.3.3 Screening...............................................................................................................34
6.3.4 Recruitment and Enrollment Procedures...............................................................34
6.3.5 On Study Visits ......................................................................................................34
6.3.6 End of Study and Follow-up...................................................................................35
6.3.7 Removal of subjects ..............................................................................................35
6.4 Statistical Method.........................................................................................................36
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
7
6.4.1 Statistical Design ...................................................................................................36
6.4.2 Sample Size Considerations..................................................................................36
6.4.3 Planned Analyses......................................................................................................39
6.4.3.1 Primary Analyses................................................................................................39
6.4.3.2 Secondary Objectives Analyses .........................................................................40
6.4.3.3 Safety/Pregnancy-related policy.........................................................................41
6.4.3.4 Analysis of Subject Characteristics.....................................................................42
6.4.3.5 Interim Analysis (if applicable)............................................................................42
Not applicable.................................................................................................................42
6.4.3.6 Health economic evaluation................................................................................42
6.4.3.7 Other...................................................................................................................42
6.4.4 Subsets and Covariates.........................................................................................43
6.4.5 Handling of Missing Data.......................................................................................43
7 - Trial Administration
44
7.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization ..............44
7.2 Institutional Review Board (IRB) Review......................................................................44
7.3 Subject Confidentiality..................................................................................................44
7.4 Deviations/Unanticipated Problems .............................................................................45
7.5 Data Collection.............................................................................................................45
7.6 Data Quality Assurance................................................................................................45
7.7 Study Records..............................................................................................................46
7.8 Access to Source .........................................................................................................46
7.9 Data or Specimen Storage/Security.............................................................................46
7.10 Retention of Records..................................................................................................46
7.11 Study Monitoring ........................................................................................................46
7.12 Data Safety Monitoring Plan.......................................................................................47
7.13 Study Modification......................................................................................................49
7.14 Study Discontinuation.................................................................................................49
7.15 Study Completion.......................................................................................................49
7.16 Conflict of Interest Policy............................................................................................49
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
8
7.17 Funding Source..........................................................................................................50
7.18 Publication Plan..........................................................................................................50
References
51
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
9
1 – Introduction
1.1 Introductory Statement
This protocol describes the background, design and organization of the trial. It will be 
reviewed and approved by the Data Safety and Monitoring Board and the Institutional 
Review Board (IRB) prior to trial initiation. Any changes to the protocol during the study will 
require approval by the IRB.
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
10
2 – Background
2.1 Background/prevalence of research topic
More than one-quarter of the almost four million U.S. women who give birth annually 
undergo labor induction (1). Generally, labor induction is indicated when the benefits of 
expeditious delivery outweigh the risks of continuing pregnancy. Additionally, labor induction 
is increasingly seen as a potentially therapeutic intervention even in the absence of any 
pregnancy complications for nulliparous women after 39 weeks of gestation (2) (3). 
However, compared to physiologic labor, induction is often associated with a longer latent 
phase which can have untoward consequences, including the need for cesarean delivery 
when an induction attempt fails. (4)  Further, it has been shown that women who are induced 
are less likely to be satisfied with their birth experience compared to those with physiologic 
labor. (5)  Women are increasingly interested in a less medicalized birth experience and 
desire more control during labor. (6)  It has also been suggested that women who are 
induced or receive exogenous oxytocin may have less optimal breastfeeding outcomes. (7)  
Nipple stimulation therapy has been purported as a natural and inexpensive non-medical 
method for inducing labor. Nipple stimulation was historically used for medically inducing 
contractions for the purpose of contraction stress testing (CST) (8) (9) (10). But, it is also a 
biologically plausible method of labor induction that may be more physiologic and allow labor 
induction to be more efficient and have other benefits. These may include effects related to 
improved uterine contractility (e.g., decreased postpartum hemorrhage risk), improved 
patient satisfaction, and stimulation of endogenous oxytocin which may improve 
breastfeeding and positive emotional responses.
Most prior studies have tested nipple stimulation as a tool to induce physiologic labor at 
home or did not have an appropriate comparison group. (11) (12)  Data on nipple stimulation 
versus exogenous synthetic oxytocin infusion (the appropriate clinical alternative) are much 
more limited, but promising. In the two studies (13)  (14)  analyzed together in a Cochrane 
review (11) , there was a nonsignificant trend towards reduction in cesarean delivery with 
nipple stimulation (n=99, RR 0.60, 95% CI 0.31-1.18), no cases of hyperstimulation, and no 
significant difference in the number of women with an unfavorable or unchanged cervix. 
Chayen et al. (13) detected a significantly shorter time to onset of contractions and 
achievement of 200 Montevideo units without differences in rates of failed induction, tetanic 
contractions, or fetal bradycardia. Unfortunately, interpretation of the existing data is critically 
limited by small sample sizes.
Oxytocin is a nine amino acid neuropeptide primarily made in the hypothalamus, and to a 
lesser extent by other tissues including the endometrium, decidua, amnion, and placenta 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
11
(17). Within the nervous system, oxytocin signaling interacts with other neurotransmitter 
pathways including serotonin and endogenous opioids; surges in oxytocin during parturition 
have been associated with aspects of maternal adaptation including stress reactivity, mood, 
and lactation (18). Whether exogenous oxytocin, which theoretically does not cross the 
blood-brain barrier, interacts with these pathways while stimulating uterine contractions is 
unknown. Given these unknowns and their potential long-term effects on both maternal and 
fetal wellbeing, some have argued that exogenous oxytocin use should be used judiciously 
until more research can be performed on the long-term outcomes associated with 
exogenous oxytocin (18). These questions suggest that stimulation of endogenous oxytocin 
may be preferable for some women if it is also effective for labor induction and vaginal birth.
Although oxytocin is one of the most used medications in obstetrics, the kinetics of oxytocin 
during spontaneous labor and the dosages used for labor induction are based on a few 
small older trials, and still poorly understood. In an early series evaluating oxytocin signaling 
during spontaneous labor, among laboring women, plasma oxytocin concentrations were 
27.6 pg/mL prior to labor and rose to 45.2 pg/mL in “advanced labor” (19). Among women in 
spontaneous labor, oxytocin concentration demonstrated minimal change over the course of 
labor from a mean of 47.2 pg/mL in early labor (less than 4cm dilated) to 45.8 pg/mL when 
the woman was found to be 10 cm dilation.(20) In contrast, oxytocin concentrations seem to 
rise in a dose-dependent manner in women being induced with exogenous oxytocin, with a 
mean plasma concentrations of 110 pg/mL in those receiving infusion at a rate of 10-16 
mU/min. (20) (21) (22) It has been shown that over the course of labor, there is decreased 
responsiveness to oxytocin infusion which may be due to down-regulation of oxytocin 
receptors 17-20. This phenomenon may contribute to the longer labor durations and labor 
dystocia patterns seen in induced labor when compared to physiologic labor. Interestingly, in 
women undergoing breast stimulation for CST, oxytocin concentration initially doubled from 
baseline after initiation of breast stimulation but then rapidly plateaued 21.  This study was 
limited in that it only evaluated oxytocin concentration over 40 minutes and labor was not 
reported. However, it is plausible that the kinetics of oxytocin concentrations among women 
who undergo nipple stimulation may be more similar to those experiencing physiologic labor 
rather than those who are induced with exogenous oxytocin. Lastly, physiologic stimuli, such 
as parturition or suckling, result in pulsatile release of oxytocin hormone into the peripheral 
circulation. On the other hand, exogenous synthetic oxytocin is usually administered as a 
continuous infusion. Previous trials have compared pulsatile versus continuous 
administration of exogenous oxytocin, and found that less total exogenous oxytocin was 
required with pulsatile administration, which suggests that it may have behaved as if it was 
more physiologic.(23) (24) (25) However, pulsatile administration of exogenous oxytocin did 
not improve clinical outcomes compared to continuous infusion, and it is plausible that even 
pulsatile administration is not enough to adequately emulate endogenous oxytocin. 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
12
In conclusion, despite excellent theoretical acceptance of nipple stimulation for labor 
induction from patients and providers (26), we lack robust data demonstrating its efficacy 
and safety. A well-designed randomized clinical trial is needed, particularly in comparison to 
the standardly accepted clinical alternative (exogenous oxytocin). Further, more data related 
to oxytocin concentrations and dose response are needed to inform our understanding of the 
biology of oxytocin during labor induction, especially when comparing exogenous oxytocin 
versus stimulation of endogenous oxytocin.
It is thought that breast stimulation induces uterine contractility by increasing the level of 
endogenous oxytocin hormone (15) (16). However, the exact mechanism remains unclear.
To our knowledge, only one previous published randomized clinical trial tested breast 
stimulation by electric breast pump (Medela, Inc) (13) which showed that the time to reach 
the active phase of labor was significantly reduced among women who underwent nipple 
stimulation compared to those who received oxytocin in the hospital setting. There was no 
difference in the length of labor between groups once women were in the active phase of 
labor or mode of delivery, but the trial included just 62 women. Reassuringly, only one of the 
30 women assigned to breast stimulation requested discontinuation due to nipple soreness 
after 5.5 hours of intermittent stimulation. There were no serious maternal or perinatal 
adverse events reported in the trial.
At Yale, our research team recently completed our external pilot feasibility and acceptability 
randomized clinical trial (Yale IRB #2000029909, Clinicaltrials.gov NCT04756089). In this 
pilot trial, 24 women were randomized in a 3:1 ratio to nipple stimulation with a breast pump 
or exogenous oxytocin infusion. Of the 18 women randomized to breast pump stimulation, 
one woman withdrew due to delay of clinical care and received oxytocin (cross-over rate of 
1/24 (4.2%)). Of the 6 women randomized to exogenous oxytocin infusion, one woman did 
not receive it due to spontaneous labor progress. All other participants followed their 
assigned intervention (22/24, 92%). The 17 women who performed breast pump stimulation 
stimulated for a median duration of 198 (IQR 125-291) minutes. There were no serious 
adverse events for either the mothers or their fetuses/infants.
As part of the pilot feasibility study, our team measured oxytocin in patients performing 
nipple stimulation and receiving IV oxytocin. We found that patients receiving nipple 
stimulation achieved regular contractions despite a smaller change in plasma oxytocin 
compared to patients receiving IV oxytocin to achieve the same contraction pattern. This 
suggests that nipple stimulation may be activating additional pathways in addition release of 
endogenous oxytocin. 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
13
3 – Rationale/Significance
3.1 Problem Statement
Over 1 million women have their labor induced in the United States each year, and synthetic 
oxytocin infusion is the most common method used. However, compared to spontaneous 
labor, medical induction is resource-intensive, has increased obstetric risks, and is 
associated with less successful breastfeeding. In contrast to endogenous oxytocin hormone 
which is released in a pulsatile fashion in the brain, synthetic oxytocin is continuously 
infused intravenously, resulting in important limitations related to efficacy, safety, and cost.
3.2 Purpose of Study/Potential Impact
It has been purported that nipple stimulation may help induce labor and has been 
successfully utilized for inducing contractions for the purposes of contraction stress testing. It 
may be an attractive option for induction of labor for both de-medicalization of birth, patient 
satisfaction, cost reduction, and other clinical benefits. The purpose of this clinical trial is to 
determine whether nipple stimulation can increase the likelihood of a spontaneous vaginal 
delivery, and therefore decrease the likelihood of an operative vaginal or cesarean delivery. 
We also seek to examine whether intrapartum nipple stimulation can decrease labor duration 
and improve other patient-centered outcomes such as patient pain score, patient agentry, 
patient satisfaction, depression scores, and breastfeeding success. Further, we aim to 
examine whether breast stimulation is associated with any significant differences in fetal or 
neonatal outcomes. 
We propose a multicenter randomized trial at Yale, Weill Cornell Medicine and Northwestern 
Universities to compare inpatient nipple stimulation therapy via electric breast pump versus 
immediate synthetic oxytocin infusion without nipple stimulation for nulliparous women 
undergoing labor induction. This trial of 988 nulliparous women will provide adequate 
statistical significance to detect clinically meaningful differences in delivery mode and 
breastmilk as the sole source of nutrition for newborns. Successful completion of this 
proposal will provide rigorous data to help us show how this novel and potentially cost-
effective method can radically change the way we induce labor and positively impact 
breastfeeding success and early infant nutrition through lactation.
At Yale, we will additionally measure oxytocin concentration among those who are being 
induced with nipple stimulation versus exogenous oxytocin, which has not been measured or 
reported by our groups to our knowledge. In our preliminary findings in 20 patients (n=10 per 
arm), we found no significant rise in oxytocin among patients who performed nipple 
stimulation therapy despite achieving adequate contractions, suggesting that other pathways 
are activated to promote contractions in these patients. Importantly, the biological 
measurements taken in this study will be correlated with clinical outcomes, which will further 
inform our understanding of the biology of oxytocin during induction of labor. If regular 
contractions are achieved with nipple stimulation, comparison between oxytocin levels in the 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
14
two groups will help us to understand whether absolute oxytocin concentration is predictive 
of ultimate mode of delivery. For example, if in more patients, consistent with preliminary 
findings, breast stimulation is found to result in equal rates of vaginal birth but lower 
concentration of oxytocin, this would provide evidence that endogenous oxytocin signaling 
acts through other methods such as affecting oxytocin receptor availability or interaction with 
other hormones. On the other hand, if oxytocin concentrations are similar or greater in 
women undergoing breast stimulation, it would suggest that oxytocin concentration is the 
main driver in successful versus unsuccessful inductions of labor. Similarly, if breast 
stimulation is found to result in lower oxytocin concentrations and not to be as effective as 
exogenous oxytocin, this would provide evidence that concentrations do need to reach some 
critical threshold to effect myometrial contractility. 
Because, in our preliminary studies, we have found less rise in maternal oxytocin among 
patients undergoing nipple stimulation, it is possible that other pathways are being activated 
in these patients. We intend to explore those other pathways using “omics” approaches to 
look at plasma proteins and microRNAs and urine prostaglandin metabolites. These studies 
have the potential to identify the mechanism(s) by which nipple stimulation induces labor, 
may point to differences with IV oxytocin that lead to the increased morbidities associated 
with prolonged and failed induction of labor, and may elucidate novel pathways involved in 
the stimulation of labor, which would contribute to our understanding of induction of labor. In 
order to understand the mechanisms by which nipple stimulation therapy induces labor, we 
will also compare the measurements of these biological variables in subjects prior to 
induction of labor and in control patients in early spontaneous labor.
Lastly, lactation is activated and triggered when a very tightly regulated cascade of events 
occurs at the end of the pregnancy and during labor, but may be negatively impacted by 
obstetric interventions.  Secretory activation of the mammary gland initiates mature milk 
production in epithelial cells (usually occur 48-72h postpartum) and then milk ejection is 
triggered by oxytocin hormone and nipple stimulation (e.g., infant suckling or breast pump). 
Factors such as nulliparity, labor induction, and cesarean delivery have been shown to 
increase the risk of early lactation difficulties. Delayed secretory activation is a key predictor 
of suboptimal breastfeeding outcomes. It is biologically plausible that with IV oxytocin the 
normal secretory activation process for lactation is altered. Using milk biomarkers, we will 
examine the effect of nipple stimulation induced labor on lactation initiation in the first 48-72 
hours after birth. 
3.3.1 Potential Risks
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
15
Risk related to study interventions
To promote additional safety related to study interventions, both study intervention arms 
(immediate intrapartum nipple stimulation therapy via electric breast pump versus immediate 
synthetic oxytocin infusion without nipple stimulation) will require continuous fetal 
cardiotocography during intervention use to monitor fetal heart rate patterns and contraction 
frequency. There will be clear recommendations in the study protocol for titration of both 
interventions to ensure that the frequency of contractions is within the recommended goal 
range. Therefore, no serious or life-threatening adverse events directly related to the study 
intervention are expected. To prevent the risk of nipple soreness or pain related to the 
incorrect use of an electric breast pump, each subject assigned to the study intervention will 
undergo a tutorial prior to the initiation of an electric breast pump to review correct breast 
pump flange fit and placement. Lanolin ointment will also be provided to subjects. The 
device manual or Instructions of Use will be provided to each subject to be the primary 
source of information of risks of the device provided by the study, should they choose to use 
it. The subject will also have the option to use their own home electric breast pump if they 
desire.
Risks related to biospecimen collection
There is a small risk associated with biospecimen collection. The risks include discomfort 
from the needle stick and/or IV catheter for venous blood draw, the possibility of pain or 
bruising at the site of the blood draw, the possibility of feeling lightheaded, and the rare risk 
of infection at the site of blood draw. There are no significant risks to providing mid-stream 
urine collection or collecting urine from an indwelling foley catheter. If the patient is having 
intermittent bladder catheterization, additional catheterization events will not be performed 
purely for study purposes. 
There is minimal risk in milk collection including temporary discomfort in the breast/nipple for 
a short time after pumping. We anticipate that the small volume of milk (0.5ml up to twice a 
day) collected for the study will not affect infant growth or interfere with the nutritional needs 
of full-term infants.   
Risk related to study interactions and subject confidentiality
There will be multiple procedures in place to minimize the risk of subject confidentiality, and 
will be outlined in the study protocol. Subject confidentiality will be held in strict trust by all 
members of the research teams. Subject medical record review will be limited to just the 
elements needed to complete the study. Only authorized HIPAA and GCP trained study 
team members will be allowed to extract research data from medical records and enter it into 
the REDCap database. 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
16
At each study site, subject records are maintained in the Epic System® EMR and all 
research data will be collected in and maintained in REDCap, an established, secure, web-
based capture and management tool developed at Vanderbilt University). Any paper records 
(e.g. signed consent forms) will be kept in a locked cabinet within a locked office that is 
secured always and located on the main campus within the departmental research 
administrative office space at each study site to ensure confidentiality of subject data.
Data use agreements will be obtained and approved across all three institutions: Weill 
Cornell as the primary grant institution where the PD resides, Yale University (grant sub-
award institution), and Northwestern University (grant sub-award institution).
The IRB may inspect study records at any given time. In addition, all scientific publications 
will refer to the subjects by study identifiers only. At no time will any of the subjects in the 
study be identified. Identifiable study information will be maintained for up to ten years after 
the research is complete. After that time, it will be destroyed or de-identified. The principal 
investigator will keep a link that identifies subjects to coded information, but this link will be 
kept secure and available only to the PIs or selected members of the research team.
All samples collected at WCM will be de-identified. A secure, access-restricted linkage key 
connecting study IDs to patient identifiers will be maintained solely by the local research 
teams. Dr. Golan’s lab will only receive de-identified samples and coded data labeled with 
the study ID, and will have no access to patient identifiers. Results generated by Dr. Golan’s 
lab will be uploaded to the WCM REDCap database using the matched study IDs provided 
with the samples, ensuring all data remain de-identified and participant confidentiality is 
maintained throughout the study.
3.3.2 Potential Benefits
There are potential direct medical benefits to individuals participating in the study if 
intrapartum nipple stimulation therapy via electric breast pump does shorten the duration of 
labor induction, reduce the risk for operative delivery and other obstetric complications, and 
improves lactation outcomes. Further, there are potential direct medical benefits to the 
newborns of individuals participating in the study if intrapartum nipple stimulation therapy via 
electric breast pump does improve lactation and infant feeding. Some of these outcomes, if 
beneficial, may also have indirect benefits on medical costs. Further, aside from potential 
direct medical benefits to the subjects, the subjects will know that they are contributing to the 
better understanding of labor induction and lactation and potentially improving to the 
methods used through this proposal. 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
17
4 - Study Objectives
4.1 Hypothesis
Our central hypothesis is that nipple stimulation with an electronic breast pump to induce 
labor increases spontaneous vaginal delivery, shortens duration of labor induction, improves 
patient-reported pain scores during labor, improves patient satisfaction and sense of self 
agentry with the birthing process, and improve scores on the postpartum depression scale. 
We also hypothesize that participants assigned to nipple stimulation therapy during labor will 
be more likely to use breastfeeding as the sole source of nutrition at hospital discharge, 
which will be associated with improved maternal perception of milk supply, less severe 
newborn weight loss, and sustained breastfeeding for the recommended 6 months. 
Secondarily, we hypothesize that intrapartum nipple stimulation will not increase fetal or 
neonatal morbidity outcomes. Last, by examining cost of care and health-related quality of 
life, we hypothesize that performing nipple stimulation therapy during labor will be more cost-
effective than the comparator after considering their overall impact on labor and delivery, 
breastfeeding, and early infant nutrition and care in the first 6 months.
We also hypothesize that nipple stimulation therapy invokes the wide cascade of events that 
promote labor to a greater extent than IV oxytocin alone. We hypothesize that oxytocin in the 
plasma of patients performing nipple stimulation will rise less than among subjects receiving 
IV oxytocin at the time when the subject is first contracting regularly. We hypothesize that 
other proteins associated with labor (including but not limited to IL6, IL1beta, plasminogen 
activator inhibitor 1, C reactive protein, ICOS ligand, and ERP29 will rise more in the 
circulation of subjects receiving nipple stimulation therapy compared with IV oxytocin. We 
hypothesize that urinary metabolites of prostaglandin E2 and F2alpha will be higher in 
subjects receiving nipple stimulation therapy. We hypothesize that, on a systematic level, 
plasma changes among subjects partaking in nipple stimulation will differ from subjects 
receiving IV oxytocin. We hypothesize that nipple stimulation therapy will have earlier 
secretory activation as measured by milk sodium and conductivity) in the early days 
postpartum, compared to individuals receiving IV oxytocin alone.  
4.2 Primary Objective
To determine whether intrapartum nipple stimulation changes the likelihood of achieving a 
spontaneous vaginal delivery compared to receipt of exogenous oxytocin infusion to induce 
labor.
4.3 Secondary Objectives (if applicable)
The secondary objectives are as follows:
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
18
1. To determine if women who perform intrapartum nipple stimulation to induce labor have 
differences in other obstetric and maternal outcomes such as operative vaginal delivery, 
cesarean delivery, labor duration, postpartum hemorrhage, infection, and morbidities such 
as higher-order perineal lacerations, ICU admission, or death.
2. To determine if women who perform intrapartum nipple stimulation report differences in 
pain scores during labor, labor agentry and satisfaction scores, postpartum depression 
scores, and breastfeeding success scores compared to women who receive only intrapartum 
exogenous oxytocin infusion.
3. To determine if women who perform intrapartum nipple stimulation report differences in 
their intention to breastfeed postpartum and their breastfeeding success scores, as well as 
continuation of breastfeeding for 6 months postpartum. In addition, to determine if neonates 
of women who perform intrapartum nipple stimulation have differences in breastfeeding as 
the sole source of nutrition (BSSN) at the time of their birth hospitalization discharge within 
the first 72 hours and their maximal percent weight loss up to 14 days post-birth compared to 
neonates of women who receive only intrapartum exogenous oxytocin infusion.
3. To determine if women who perform intrapartum nipple stimulation therapy to induce labor 
have similar fetal and neonatal outcomes compared to women who receive only intrapartum 
synthetic oxytocin infusion without nipple stimulation (comparator).
4. To examine the cost-effectiveness of inpatient nipple stimulation therapy via electric 
breast pump, in comparison to synthetic oxytocin infusion without nipple stimulation 
(comparator).
5. In a sub-cohort of women who are enrolled in the trial at Yale, to measure circulating 
plasma concentrations of proteins and microRNA and urinary prostaglandin metabolites 
using unbiased “omics” approaches, comparing patients undergoing induction of labor via 
intrapartum nipple stimulation versus continuous exogenous oxytocin infusion.
6. To compare the molecular changes observed with nipple stimulation therapy oor 
continuous exogenous oxytocin infusion with changes seen in early spontaneous labor. 
7. In a sub-cohort of women who provide milk samples, we will compare milk composition 
before and after delivery for the nipple stimulation therapy group to see how the milk is 
changing and we will compare milk biomarkers after birth between patients undergoing 
induction of labor via intrapartum nipple stimulation versus continuous exogenous oxytocin 
infusion.
5 - Study Design
5.1 General Design Description
The proposed study is a multicenter, pragmatic, open label, parallel group randomized trial 
of nulliparas to compare the effectiveness of intrapartum nipple stimulation therapy with or 
without adjunctive synthetic oxytocin (intervention) versus immediate synthetic oxytocin 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
19
infusion without nipple stimulation (comparator) during labor induction. Potential subjects will 
be recruited from the Labor & Birth units at three study sites: Yale New Haven Hospital in 
New Haven, Connecticut, Weill Cornell Medicine in New York, New York and Northwestern 
Memorial Hospital in Chicago, Illinois. We aim to test the central hypothesis that intrapartum 
nipple stimulation increases spontaneous vaginal delivery, shortens labor duration, improves 
other patient-centered outcomes, improves breastfeeding success, and does not increase 
adverse neonatal and maternal outcomes. We chose a randomized controlled trial, the 'gold 
standard' of clinical research design, with the goal of obtaining the highest quality evidence 
to inform clinical practice. Randomly allocating subjects to different interventions minimizes 
selection bias and results in groups that are comparable with regards to important 
confounding variables, both measured and unmeasured. Blinding of subjects, maternity care 
providers, and investigators is not feasible given the intervention being studied (nipple 
stimulation). With the limitations of the existing data, we estimated our sample size and plan 
our data analysis based on two-tailed tests. This will ensure that we identify the optimal 
management strategy for labor induction that increases spontaneous vaginal delivery, 
irrespective of the direction of our findings. 
We will follow the Consolidated Standards of Reporting Trials (CONSORT) guidelines 
wherever appropriate in the conduct and reporting of this trial. (27)   We will use computer-
generated random sequences to assign participants to the two interventions with 
stratification by study site and membrane status (intact versus ruptured). Labor management 
will be similar in the two groups except for use of nipple stimulation (intervention group) 
versus immediate synthetic oxytocin infusion without nipple stimulation (control). Analysis 
will follow the intention-to-treat principle.
5.1.1 Study Date Range and Duration
The study is expected to start in October 2021 at Yale, July 2023 at Northwestern and 
Spring 2024 at Weill Cornell Medicine and will be conducted over 7 years, with the final 
participant expected to be enrolled in June 2026. Final data collection and analysis is 
expected to be completed by June 2028.
5.1.2 Number of Study Sites
The trial will be conducted at three sites: Yale New Haven Hospital (York Street Campus), 
Weill Cornell Medicine and Northwestern Memorial Hospital.
5.2 Outcome Variables
5.2.1 Primary Outcome Variables
For the main trial, the primary outcome is spontaneous vaginal delivery, defined as a 
delivery that occurs without the use of forceps, vacuum, or cesarean. This is because 
spontaneous vaginal delivery is the most desirable outcome for laboring women
5.2.2 Secondary and Exploratory Outcome Variables (if applicable)
The following secondary maternal outcomes will be explored:
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
20
●
Operative vaginal delivery (defined as delivery with the assistance of forceps or 
vacuum) and indication
●
Cesarean delivery and indication
●
Interval from randomization to delivery
●
Postpartum hemorrhage (defined as a cumulative blood loss of ≥1,000 mL within 24 
hours after the birth process)
●
Severe postpartum hemorrhage (defined as any of the following: transfusion; non-
elective hysterectomy; use of ≥2 uterotonic medications other than oxytocin; other 
interventions such as uterine compression sutures, uterine artery ligation or 
embolization, hypogastric artery ligation, balloon tamponade)
●
Suspected intraamniotic infection, intrapartum chorioamnionitis, or postpartum 
endometritis (defined as maternal fever ≥38° Fahrenheit with planned or initiated 
administration of therapeutic antibiotics) after randomization and prior to delivery 
hospitalization discharge
●
Third- or fourth- degree perineal lacerations 
●
Lactational mastitis (assessed up to 12 weeks postpartum from breastfeeding survey 
performed at 4-12 weeks postpartum and medical records)
●
Maternal death (assessed until delivery hospitalization discharge)
●
Admission to Intensive Care Unit (assessed until delivery hospitalization discharge)
●
Subject-reported pain experienced during childbirth using the visual analog scale (28) 
, measured at 2 hours after start of intervention
●
Subject-reported feelings of control during labor using the Labor Agentry Scale (29) , 
assessed during the hospital postpartum stay
●
Subject-reported satisfaction with the birthing experience using the validated Birth 
Satisfaction Scale-Revised (BSS-R) (30) (31), assessed during the hospital 
postpartum stay
●
Subject-reported ability to express and/or collect colostrum and/or breastmilk 
intrapartum
●
Subject-reported perception of milk supply using the validated Perception of 
Insufficient Milk Supply (PIMS) (40), 2 weeks postpartum 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
21
●
Subject-reported depression score using the validated Edinburgh Postnatal 
Depression Scale, assessed (32), 4-12 weeks postpartum
●
Subject-reported breastfeeding success using the validated Maternal Breastfeeding 
Evaluation Scale (MBES) (33), assessed 4-12 weeks postpartum
●
Subject-reported breastfeeding success by assessing infant feeding method 
(breastmilk, formula, or combination) via questionnaire, assessed 6 months 
postpartum
Among the women enrolled in the translational sub-study at Yale, the following secondary 
outcomes will be explored:
●
Plasma proteomic profiles (measured by mass spectrometry) after 2 hours of 
treatment comparing patients receiving IV oxytocin and nipple stimulation. Plasma 
samples from patients who have not undergone cervical ripening will be collected as 
additional control to account for differences achieved from cervical ripening alone. 
Plasma samples from patients in early spontaneous labor will be obtained to 
compare how closely nipple stimulation therapy and IV oxytocin approximate the 
molecular phenotype of spontaneous labor.
●
Changes in plasma proteomic profiles from baseline (prior to treatment), 2 hours, and 
the time of adequate contractions in each treatment group 
●
Plasma micro-RNA profiles (measured by bulk RNA sequencing) after 2 hours of 
treatment among patients receiving IV oxytocin, nipple stimulation, and patients in 
early spontaneous labor.  
●
Changes in plasma micro-RNA profiles from baseline (prior to treatment), 2 hours, 
and the time of adequate contractions in each treatment group
●
Urine prostaglandin profiles (measured by mass spectrometry) at 2 hours comparing 
patients receiving IV oxytocin, nipple stimulation, nipple stimulation who cross-over to 
IV oxytocin, un-ripened control patients, and patients in spontaneous labor. 
●
Changes in urine prostaglandin profiles from baseline (prior to treatment), 2 hours, 
and the time of adequate contractions in each treatment group
Among the women enrolled in the translational sub-study for milk collection, the following 
secondary outcomes will be explored:
●
Changes in milk sodium and conductivity levels from before delivery (in the nipple 
stimulation therapy group only), and 12, 24, 48 hours after delivery. For mothers 
hospitalized for a longer period, additional samples at 72 hours will be collected or 
later up to twice a day.
●
Milk macronutrient composition at 48 hours after delivery in each treatment group.
●
Milk RNA profile at 48 hours after delivery in each treatment group.     
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
22
The following secondary neonatal outcomes will be explored:
●
Intrapartum fetal death or neonatal death (assessed until birth hospitalization 
discharge or death)
●
Neonatal Apgar score ≤3 at 5 minutes of life 
●
Umbilical cord arterial pH <7.0 or base excess >12 mmol/L; or umbilical cord venous 
pH <7.0 or base excess >12 mmol/L if arterial blood sample not available
●
Any admission to Neonatal Intensive Care Unit (assessed until birth hospitalization 
discharge or death)
●
Admission to the Neonatal Intensive Care Unit >24 hours (assessed until birth 
hospitalization discharge or death)
●
Composite neonatal severe morbidity measure including any of the following: 
Intrapartum fetal death or neonatal death; intubation, continuous positive airway 
pressure (CPAP) or high-flow nasal cannula (HFNC) for ventilation or 
cardiorespiratory support within first 72 hours of life; neonatal encephalopathy as 
defined by Shankaran et al (34) ; seizures; need for hypothermic treatment (cooling); 
sepsis (defined as presence of a critically ill infant in whom systemic infection is 
suspected with a positive blood, cerebrospinal fluid, or catheterized/suprapubic urine 
culture, or in the absence of positive culture(s), clinical evidence of cardiovascular 
collapse or an unequivocal X-ray confirming infection); pneumonia confirmed by X-
ray or positive blood culture; major birth injury (brachial plexus injury, bone fractures, 
other neurologic injury, retinal hemorrhage, facial nerve injury); meconium aspiration 
syndrome; intracranial hemorrhage or subgaleal hemorrhage; and hypotension 
requiring pressor support
●
Breastfeeding as the sole source of nutrition (BSSN) at the time of birth 
hospitalization postpartum discharge within the first 72 hours. This timepoint is 
chosen because it is the most likely to be causally linked to the study intervention, 
avoids the risk of attrition bias, and predicts the likelihood of sustained breastfeeding 
for the recommended 6 months postpartum. BSSN is defined as the infant receiving 
breastmilk without any supplementary formula or water within the first 72 hours of life. 
infant feeding method (breastmilk only, mixed feeding which includes both breastmilk 
and infant formula, or infant formula only) is standardly documented in the EMR at 
least daily until day of birth hospitalization discharge. 
●
Maximal percent newborn weight loss up to 14 days post-birth. Maximal percent 
newborn weight loss is defined as the difference between birth weight and the lowest 
weight recorded subsequently up to 14 days post-birth, calculated as a percentage of 
the birth weight, as is typically done daily in clinical practice. Participants will sign a 
medical release form allowing the study team to obtain/access newborn data in this 
timeframe, not only from the site’s electronic medical record but also from outside 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
23
practices/institutions. For the assessment of maximal newborn weight loss, it is 
standard hospital practice at study sites to regularly weigh each newborn during their 
birth hospitalization. Infants are weighed naked using a digital scale, and the weight 
is expressed in kilograms. At the study site, newborns are weighed at birth and then 
at least daily until day of discharge. The first weight measured after birth is usually 
performed after at least 6 hours post-birth. Weighing is typically discontinued if the 
newborn regains his or her birth weight prior to discharge. Infant birth weights are 
recorded in a standardized fashion in specific EMR flowsheets at study sites. The 
date and time of each weight are recorded which allows calculation of precise age. 
●
The following cost outcomes will be assessed: 1) cost of relevant care, and 2) health-
related quality of life. Both outcomes will be measured for the mother-infant pair.
o
Cost of care will include direct medical cost, direct non-medical care, and 
indirect cost. Direct medical cost will encompass hospital facility costs and 
provider professional fees associated with relevant care (maternal labor and 
delivery hospitalization, newborn’s initial birth hospitalization, and infant’s 
postnatal pediatric visits). Direct non-medical cost will account for breast 
pump use at home, infant formula use, and transportation to relevant care. 
Indirect cost (i.e., maternal productivity loss) will measure participants’ work 
loss in the postpartum period. As the project will span multiple years, we will 
use consumer price index to inflation adjust all cost estimates to a constant 
year U.S. dollars
o
Health-related quality of life for participants will be measured by the 
EuroQol five dimensions (EQ-5D) instrument (41). EQ-5D is a validated 
instrument for measuring and valuing health. Participants’ response to the five 
dimensions of the EQ-5D descriptive system will be converted to a utility 
score using a validated U.S. population-based algorithm. Utility score takes 
values ranging from 0 to 1, with 0 referring to a health state equivalent to 
death and 1 equivalent to perfect health. EQ-5D is a recommended and 
widely used instrument for measuring utility score in clinical trials and in 
maternal health research. For infants, the South Africa EQ-TIPS™ Paper 
Proxy 1 questionnaire (previously known as Toddler and Infant (TANDI) 
Health Related Quality of Life instrument) (42) will be completed by 
participants (as proxy reporters for their infants). This questionnaire has been 
shown to be valid and reliable for use in very young children (42). It contains a 
six-dimension descriptive system (movement, play, pain, social interaction, 
communication, and eating) with three severity levels (no, some, or a lot of 
problems), along with a visual analogue scale (VAS) assessing an infant’s 
overall health. As utility score based on the EQ-TIPS™ descriptive system 
has not been developed yet, we will linearly transform the VAS score to a 
utility score on a 0 to 1 scale.   
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
24
 
5.3 Study Population
Pregnant women who are nulliparas with live gestations of 36 weeks and greater who are 
planned to receive (but have not yet received) exogenous oxytocin infusion for induction of 
labor. While pregnant women represent a vulnerable population, they represent the study 
population of interest.
5.3.1 Number of Participants
The sample size for the trial is based on the primary outcome of spontaneous vaginal 
delivery. Therefore, the sample size of n=988 (shared between Yale, Weill Cornell Medicine 
and Northwestern) is selected for this proposed study to detect a 10% absolute increase 
while accounting for an expected 5% attrition rate. We then estimate, on the basis of the 
sample size for the primary outcome, the power we will have to detect clinically significant 
differences in the secondary outcomes.
For the translational sub-study at Yale, we will seek consent to obtain plasma and urine from 
patients enrolled in the main study (n=192). In addition, plasma will be obtained from 48 
patients in spontaneous labor. 
For the milk collection sub-study at Yale and Weill Cornell Medicine, to detect a 10 mM 
difference in sodium concentration between the intrapartum nipple stimulation therapy group 
and the immediate synthetic oxytocin infusion group at 48 hours postpartum, with a standard 
deviation of 20 mM, 80% power, and a significance level of 0.05, a sample size of 32 
participants per group is required. Accounting for an expected 30% dropout rate, we plan to 
recruit 46 participants per group. 
5.3.2 Eligibility Criteria/Vulnerable Populations
We will use broad inclusion criteria to ensure generalizability of our results.
Inclusion criteria
●
Age 18 years and older
●
Nulliparous women (a prior pregnancy that ended at <20 0/7 weeks of gestation is 
acceptable)
●
Gestational age 36 0/7 weeks and greater at enrollment
●
Singleton gestation (a multiple gestation reduced to a singleton, either spontaneously 
or therapeutically, before 14 0/7 weeks of gestation is acceptable)
●
Planned to undergo initiation of exogenous oxytocin infusion by their maternity care 
provider
●
Cervix dilated <6 cm within one hour of enrollment (if membranes intact) OR ruptured 
membranes with less than 3 contractions in a 10-minute window averaged over 30 
minutes prior to enrollment (regardless of cervical exam)
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
25
●
Ability to give informed consent
Exclusion criteria
●
Unable to understand English or Spanish 
●
Presence of tachysystole (defined as more than 5 contractions in 10 minutes 
averaged over 30 minutes), recurrent variable or late fetal decelerations, and 
bradycardia in the prior 30 minutes before enrollment
●
Non-vertex presenting fetus at time of enrollment
●
Planned for cesarean delivery or contraindication to labor by institutional policy 
(e.g., placenta previa, vasa previa, active genital herpes infection, previous 
transmural myomectomy)
●
Multi-fetal gestation (e.g., twins, triplets, and higher-order multiples)
●
Intrauterine fetal death
●
Major fetal anomaly suspected prenatally (defined as a fetal anomaly with 
anticipated neonatal intensive care unit admission)
●
Suspected alloimmunization (given the increased likelihood for anticipated 
neonatal intensive care unit admission)
●
Known severe fetal growth restriction (estimated fetal weight <3rd percentile) or 
abnormal umbilical artery Doppler studies (given the increased likelihood for 
anticipated neonatal intensive care unit admission)
●
HIV infection (nipple stimulation is not encouraged given the recommendation for 
these mothers not to breastfeed)
●
Participation in another interventional study that influences management of labor 
and delivery or perinatal morbidity or mortality
●
History of mastectomy or other contraindication to manual nipple stimulation or 
use of electronic breast pump
●
Known allergic reactions to components of the electronic breast pump or to 
synthetic oxytocin intravenous solution
●
Significantly impaired consciousness or executive function (e.g., intubated or 
sedated)
For collection of plasma and urine from patient participants in early spontaneous labor 
(defined as <6 cm dilated with intact membranes), inclusion criteria will be:
●
Age 18 years and older 
●
Nulliparous 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
26
●
Gestational age 36 0/7 and greater
●
Singleton gestation 
●
Ability to give informed consent 
●
Presenting in early spontaneous labor defined as <6cm dilated with intact 
membranes. 
●
Patient and primary obstetric provider intend for patient to continue spontaneous 
labor
For collection of plasma and urine from patient participants in early spontaneous labor 
(defined as <6 cm dilated with intact membranes), exclusion criteria will be:
●
Patient has performed nipple stimulation in the preceding 24 hours, received 
outpatient prostaglandin therapy, or had “membrane stripping” in the preceding 
24 hours
●
Patient is expected to have labor complications preventing continued 
spontaneous labor, such as arrest of dilation or fetal intolerance of labor
6 - Methods
6.1 Treatment 
6.1.1 Intervention administration and schedule
Subjects will be encouraged to perform nipple stimulation with the aid of an electronic breast 
pump to promote standardization of the stimulation. The subject will be provided with a 
hospital-grade breast pump. The subject may choose to use their own personal non-hospital 
breast pump instead. Subjects can also alternatively choose to perform nipple stimulation by 
hand if they desire. Subjects will receive a 5-10 minute tutorial on either method by their 
labor nurse and supported by their labor nurse with the additional assistance of hospital 
lactation consultants if needed during their stimulation process. All labor nurses and hospital 
lactation consultations are educated on proper breast pump use.
6.1.2 Method of Assignment/Randomization
Enrolled subjects will be randomly assigned in a 1:1 ratio to both study groups. A web-based 
randomization sequence will be prepared using blocks of variable sizes, stratified by study 
site and amniotic membrane status (intact versus ruptured), and maintained centrally by the 
study statistician. The advantage of this method is that it provides a good probability of 
balance, and future assignments are unpredictable. A subject’s group assignment will be 
obtained only after the subject is confirmed to continue to meet inclusion criteria, and a study 
number is entered and locked in using REDCap (Research Electronic Data Capture), an 
established, secure, web-based capture and management tool developed at Vanderbilt 
University. Although blinding of both subjects and their obstetrical clinicians would be ideal, 
blinding is clearly not possible in this trial. We will minimize systematic bias by applying the 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
27
same standard procedures for other labor and management strategies between groups at 
each study site. Further, the group assignment of subject will not be taken into account by 
trained study staff collecting maternal and neonatal outcomes. Importantly, the main study 
outcomes of spontaneous vaginal delivery and breastfeeding as the sole source of infant 
nutrition at hospital discharge are objective measures.
6.1.3 Concomitant therapy
There are no restrictions on use of concomitant medications. However, for those who are 
randomized to nipple stimulation, the use of exogenous oxytocin intravenous solution will not 
be permitted until at least two hours of nipple stimulation alone has been attempted, unless 
this is decided by the treating obstetric provider. Stimulation may be discontinued at any time 
that the treating obstetric provider decides. If there are any signs of fetal heart rate 
abnormalities on the cardiotocography, the obstetric provider should provide usual care 
measures such as discontinuation of stimulation, lateral positioning, intravenous hydration, 
etc. Initiation of exogenous oxytocin intravenous solution prior to two hours of nipple 
stimulation alone will be considered a cross-over. 
6.2 Assessments
Obstetric and perinatal clinical outcomes will be assessed and abstracted through chart 
review of the electronic medical record of both subjects and their infants by certified trained 
research members according to the outcome definitions listed in the protocol. Postpartum 
assessments will be conducted at 2 weeks postpartum and 4-12 weeks postpartum. While 
the ideal time period is 6-8 weeks postpartum, such a short time-window for follow-up may 
result in less-than-ideal protocol adherence, and 12 weeks is still within the typically 
described postpartum period (the “4th trimester”). In addition, economic costs and infant 
feeding method will be assessed at 6 months postpartum.
To assess patient-centered outcomes, several study questionnaires will be conducted:
1. To assess subject-reported pain experienced during childbirth, the visual analog pain 
scale (28) will be administered at three different timepoints: (1) prior to initiating study 
intervention (to obtain baseline); (2) two hours after initiating study intervention; and (3) 
during postpartum stay prior to delivery hospitalization discharge.
2. To assess subject-reported satisfaction with the childbirth process, the Birth Satisfaction 
Scale-Revised (BSS-R) (30) (31) will be administered during postpartum stay prior to 
delivery hospitalization discharge.
3. To assess subject-reported feelings of control during childbirth, the Labor Agentry 
questionnaire (29) will be administered during postpartum stay prior to delivery 
hospitalization discharge.
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
28
4. To assess subject-reported feelings of depression after childbirth, the Edinburgh Postnatal 
Depression Scale (EPDS) (32) will be administered at two different timepoints: (1) prior to 
initiating study intervention (to obtain baseline) and (2) at 4-12 weeks postpartum (ideally 6-8 
weeks postpartum). The baseline EPDS will be reviewed, and the total score will be 
tabulated in real-time. The EPDS at 4-12 weeks postpartum will be completed by the subject 
online or with a certified study team member via telephone. A certified study team member 
will check daily (Monday-Friday) to review any completed online surveys and tabulate scores 
during these daily (Monday-Friday) reviews. If the EPDS at 4-12 weeks postpartum is 
completed with the subject via telephone, the total score will be tabulated at the conclusion 
of the telephone encounter. Any score ≥10 on either the baseline or 4-12 weeks postpartum 
EPDS will be reported to the subject’s primary obstetric provider team as this is the threshold 
that suggests increased risk of depressive illness.
5. Prior to delivery hospitalization discharge, subjects will be asked if they had any 
intrapartum expression of colostrum or breast milk, the quantity (mL or ounces) expressed if 
known, whether they collected and stored it for their infant, and whether they fed it to their 
infant.
6. After delivery hospitalization discharge 2 weeks postpartum, all subjects will be 
administered the Perception of Inadequate Milk Supply (PIMS) (40) survey to assess their 
perception of their milk supply. In addition, the EQ-5D™ and EQ-TIPS™ surveys will be 
administered.
7. After delivery hospitalization discharge, between 4 to 12 weeks postpartum (ideally 6 to 8 
weeks postpartum), all subjects will be contacted by text message, telephone, or by email 
(based on subject preference) to evaluate if they experienced any unanticipated outpatient 
or inpatient visits for them or their infants since delivery hospitalization discharge. Subjects 
will also be asked if they ever attempted to breastfeed postnatally.
8. Among subjects who state they attempted to breastfeed at least once postnatally; these 
subjects will be administered the Maternal Breastfeeding Evaluation Scale (MBES) (33) 
between 4 to 12 weeks postpartum (ideally 6 to 8 weeks postpartum) to assess their 
breastfeeding success. In addition, the EQ-5D™ and EQ-TIPS™ surveys will be 
administered. 
9. After delivery hospitalization discharge, at 6 months postpartum, all subjects will be sent 
an electronic survey to assess infant feeding method. In addition, the EQ-5D™ and EQ-
TIPS™ surveys will be administered. Subjects may be contacted by telephone or by email 
(based on subject preference) to follow-up any incomplete surveys.
10. For spontaneous labor control patients, time/duration since contractions began, receipt 
of outpatient prostaglandins such as misoprostol, outpatient nipple stimulation, and time of 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
29
last membrane stripping will be collected by a combination of patient recall and medical 
record review. 
11. Oxytocin concentration will be measured by mass spectrometry. Cytokines will be 
determined by enzyme-linked immunosorbent assay. 
12.  Plasma samples will be analyzed for proteomic profile by the Keck MS & Proteomic 
Resource and for microRNAs by the Yale Center for Genome Analysis. De-identified urine 
samples will be sent to an external core facility with expertise in prostaglandin measurement 
(Vanderbilt Eicosanoid Laboratory).
13. Milk samples will be analyzed at the Golan Lab (Cornell University, Ithaca). Sodium 
concentration and conductivity in milk will be measured using the LAQUATwin electrodes 
(Horiba, TX, USA). Milk lactose, fat and total protein will be measured in samples where a 
larger milk volume (>1ml) is available using the SpectraStar™ XT-R - High-Performance 
Extended Range NIR Analyzer (KPM, Analytics, MA, USA).
6.2.1 Efficacy
6.2.2 Safety/Pregnancy-related policy
The study protocol has been designed to minimize risks to subjects and their neonates 
including the requirement for continuous fetal monitoring during receipt of either study 
intervention, as well as detailed steps outlined to ensure the desired contraction frequency 
pattern to minimize risk of abnormal fetal heart rate patterns. All subjects who are 
undergoing continuous fetal monitoring are observed by labor nurses, and fetal monitoring is 
continuously reviewed and recorded.
6.2.2.1 Adverse Events Definition and Reporting
Adverse study events are expected to be rare. However, Reportable Events (which are 
events that are serious or life-threatening and unanticipated (or anticipated but occurring 
with a greater frequency than expected) and possibly, probably, or definitely related to study 
procedures or Unanticipated Problems Involving Risks to Subjects or Others (UPIRSO) that 
may require a temporary or permanent interruption of study activities, as determined by the 
Principal Investigator or sub-site PI(s) will be reported to the Yale IRB. Events that may 
require a temporary or permanent interruption of study activities by the Principal Investigator 
to avoid potential harm to subjects will be reported to the IRB immediately (if possible), 
followed by a written report to the IRB using the UPIRSO Reporting Form (710 FR 4) no 
more than 5 calendar days after the Yale Principal Investigator (M.S.) becomes aware of 
the event.
Detailed information concerning adverse events will be collected and evaluated throughout 
the conduct of the protocol. Any adverse events deemed serious unexpected and definitely, 
possibly or probably related, will be immediately (within twenty-four hours of notification) 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
30
forwarded by the Yale Principal Investigator (M.S.) to the DSMC Chair and any other DSMC 
member who requests notification. If a death is reported, a copy of the patient's medical 
record will be made.
 Adverse events which do not qualify under the below definition will be collected and sent to 
the Chair, and any other requesting DSMC member on a monthly basis. The Chair decides 
whether the adverse event reports should be disseminated to the rest of the committee, and 
whether a follow-up call or meeting is required.  All adverse events will be considered along 
with other interim safety data in the DSMC deliberations.
The following events may represent UPIRSOs that should be promptly reported:
●
Adverse device effects that are unanticipated
●
Adverse events or injuries that are serious, unexpected, and related
●
Breaches of confidentiality involving risks
●
Revisions to safety information, such as Investigational New Drug (IND) Safety 
Reports and MedWatch Reports, that meet the definition of a UPIRSO
●
New information indicating an unexpected increase in risks or decrease in potential 
benefits (e.g., literature/scientific reports or other published findings)
●
Protocol deviations, violations, or other accidental or unintentional changes to the 
protocol or procedures involving risks or with the potential to recur
●
Unapproved changes made to the research to eliminate an apparent immediate 
hazard to a subject
●
Other problem or finding (e.g., loss of study data or forms) that an investigator or 
research staff member believes could influence the safe conduct of the research
6.2.3 Pharmacokinetics (if applicable)
Oxytocin concentration will be measured by enzyme-linked immunosorbent assay (ELISA) 
using a commercially available kit using internal standards and controls to assess intra-
assay and inter-assay coefficients of variance. All samples will be run in duplicate.  The 
primary outcome is the difference (delta) in oxytocin concentration between baseline and 
when the patient first achieves adequate contraction pattern in patients undergoing nipple 
stimulation compared to patients receiving exogenous oxytocin. 
6.2.4 Biomarkers (if applicable)
Unbiased screening approaches will be applied to plasma samples from patients in the two 
arms of the study. Protein profiling will be performed by the Keck MS & Proteomics 
Resources. microRNA screen will be conducted at the Yale Center for Genome Analysis. 
Prostaglandin measurements will be conducted by an external core facility with expertise in 
prostaglandin measurement (Vanderbilt Eicosanoid Laboratory). Proteomic, small molecule 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
31
(prostaglandin), or microRNA changes may be identified that represent novel biomarkers for 
labor. 
Milk RNA extraction of de-identifiable milk samples will be performed at the Golan Lab at 
Cornell University. RNA sequence will be performed at the Genomic Core at Cornell 
University or sent to NovoGene for sequencing. Data analysis will be performed at the Golan 
Lab. 
 
6.3 Study Procedures
Main Trial Study Procedures:
1. Recruitment
●
A letter will be sent to all practicing obstetricians and midwives at each site to provide 
information about this study and to ask them if their patients may be approached for 
potential recruitment once they are admitted for labor induction.
●
Trial information will be available on clinicaltrials.gov.
●
All nulliparous women with singleton gestations at or greater than 36 weeks of 
gestation undergoing labor induction or augmentation are potentially eligible for 
screening. 
●
The research team at Yale may also utilize the Joint Data Analytics Team (JDAT) in 
two ways:
o
1. Direct-to-patient recruitment method. This is a behind-the-scenes electronic 
medical record search run by JDAT for the Yale New Haven Health System 
(YNHHS), based on study-specific inclusion/exclusion criteria. This search will 
not identify potential participants to the researchers. Once JDAT identifies 
eligible patients, these potential participants will be sent a message via 
MyChart providing information about the research study and information on 
how to contact study personnel if they are interested in participating. Potential 
subjects who do not use MyChart may receive a paper mailing with the same 
information.
o
2. We will request a report of patients who are potentially eligible and their 
treating obstetrician or midwife from JDAT through the Induction of Labor 
scheduling tool. We will request permission from the OB doctor/midwife to 
contact their patient directly to inform them of this research study. Given the 
number of potentially eligible patients and the time-sensitive nature of 
recruitment (must occur after induction is planned and before actual induction, 
which could be less than 1 and up to 7 days), it is not feasible to ask the 
treating provider to contact the patients first, and this would also place a 
significant burden on the treating provider. A member of the research team 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
32
will send the following message to the patient through MyChart or call the 
patient if MyChart is not available:
▪
Dear [Patient Name], 
My name is [Name] and I am a [insert job title] at Yale University and 
part of the research team for the STIM Study. I spoke with your 
doctor/midwife, and we believe you may be eligible to participate in 
this free and confidential research study investigating two different 
methods of labor induction. One method involves nipple stimulation 
using a breast pump and the other uses intravenous oxytocin infusion 
according to standard of care and hospital protocol. If you enroll, you 
will also be asked to complete brief surveys at 5 different times. You 
will be compensated [$X] each time you do a survey, for a total of 
[$X]. If you're interested in learning more, please reply to this 
message or call [insert phone]. We will also be available to answer 
any questions while you are at Labor & Birth at Yale New Haven 
Hospital. If you choose not to participate, you will continue with your 
usual care from your doctor/midwife. Thank you for your time.
Sincerely,
[Name]
●
Inclusion/exclusion criteria will be reviewed with the patient's chart and/or discussion 
with the patient’s responsible physician or midwife prior to approaching the patient to 
ensure that she meets eligibility criteria.
●
If a patient appears to meet criteria for the trial, she will be told about the study and 
asked for written informed consent to participate in the trial. Consent will be obtained 
from a trained research team member. 
2. Baseline Procedures
In addition to information collected for eligibility, the following information will be obtained at 
randomization from a subject interview followed by a review of her chart:
●
Indication for labor induction
●
Demographic information
●
Medical history
●
Obstetrical history including outcome(s) of any prior pregnancies (e.g., ectopic 
pregnancy, spontaneous or elective abortion prior to 20 weeks of gestation)
●
Social history 
●
Current pregnancy complications (e.g., hypertensive disorders of pregnancy, 
gestational diabetes, etc.)
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
33
●
Estimated fetal weight based on ultrasound (if within 2 weeks of randomization) or 
Leopold maneuvers
●
Group B Streptococcus carrier status
3. Study Interventions
Women randomized to nipple stimulation will undergo the following procedures (intervention 
arm):
●
Nipple stimulation will be done in the hospital after subjects receive proper training, 
and under the direction of the study and nursing teams.
●
Subjects will be encouraged to stimulate with the aid of an electric breast pump, but 
they will also have the option to perform nipple stimulation by hand if desired.
●
Subjects will undergo a 5-minute tutorial on the use of the electronic breast pump 
and hand stimulation technique by the labor nurse or certified research staff. 
Information handouts will be given to the subject.
Women randomized to exogenous oxytocin infusion (control arm) will undergo the following 
procedures as current standard of care:
●
Continuous fetal monitoring will be maintained as per hospital protocol.
●
Oxytocin will be administered using only premixed oxytocin intravenous solutions 
prepared by the pharmacy as per current standard of care.
●
Oxytocin will be initiated via infusion smart pump at a starting rate of 2 mU/min.
●
Dosage may be increased every 15 minutes for 2-hours, then every 30 minutes 
thereafter.
●
Rate changes for oxytocin administration are based on the assessment of all three of 
the following: fetal status, contraction status, and maternal coping 
●
Decreases of the infusion rate by 1 mU/min require reassessment after 15 minutes.
●
Oxytocin maximum dosage should not exceed 20 mU/min per institutional policy.
●
The oxytocin will be stopped, and the provider will be notified for the following 
reasons:
●
If oxytocin has been discontinued, it may be restarted after a minimum of 15 minutes
o
If oxytocin had been discontinued for <40 minutes and the fetal heart rate 
tracing is reassuring and uterine activity has returned to normal, oxytocin may 
be restarted at no more than one half of the rate that resulted in the non-
reassuring FHR and/or uterine tachysystole and then increased by 1 or 2 
mU/min per original provider order
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
34
o
If oxytocin had been discontinued for >=40 minutes and the fetal heart rate 
tracing is reassuring and uterine activity has returned to normal, oxytocin may 
be restarted at 1 or 2 mU/min and increased by 1 or 2 mU/min per original 
provider order.
●
The oxytocin line will be disconnected from the main IV line if it has been determined 
that a cesarean section will be performed.
4. Other Interventions
The use of amniotomy (if the subject has intact membranes) and other labor procedures will 
be at the discretion of each subject's responsible maternity care provider (pragmatic study) 
and considered standard of care. If standard of care is altered based on clinical decision 
making by the subject’s responsible treating physician or midwife, the subject will still remain 
in the study as long as the subject does not withdraw her consent to continue in the study.
5. Subject Management and Follow-Up
All subjects will be monitored for progression of labor and their fetus' response to labor by 
their responsible treating obstetrician or midwife. Each subject will undergo individualized 
assessment by their treating obstetrician or midwife, and the clinical decision will be made by 
the treating obstetrician or midwife if or when subjects in the nipple stimulation arm will be 
switched to the standard of care with exogenous oxytocin administration. There can be no 
absolute cut-offs for time or contraction responses since standard of care dictates 
individualized assessments for labor progression and fetal response; each birth experience 
is unique. Subjects in both arms of the trial should be allowed adequate time to labor before 
considering the induction "failed" and proceeding to cesarean section. An induction will be 
considered "failed" after at least 24 hours of exogenous oxytocin administration has failed to 
generate regular (e.g., every 3 minutes) contractions and cervical change, as is considered 
standard of care (36).  Additionally, exogenous oxytocin generally should be administered for 
at least 12 hours after membrane rupture before considering the induction to have failed as 
is considered standard of care. (37).  The time devoted to cervical ripening and/or nipple 
stimulation will not be included when calculating the length of induction for diagnosing failed 
induction.
It is expected that the fetal heart rate and uterine activity will be monitored continuously 
during labor and that subjects will stay in the hospital until delivery once the induction is 
started as is considered standard of care. Aside from the interventions described above, 
labor and delivery management decisions will be left to the discretion of the subject's 
responsible maternity care provider as is considered standard of care.
Subjects will be administered study questionnaires at multiple timepoints, as outlined below. 
Questionnaires will be administered using the REDCap Survey tool, and electronic QR 
codes will be provided to the subjects via email or text message (whichever the subject 
prefers). Paper versions will also be available if requested.
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
35
After randomization, subjects will be asked to complete four questionnaires to establish 
baseline: the visual analog pain scale (28), the Edinburgh Postnatal Depression Scale 
(EPDS) (32), the Infant Feeding Intention Scale (IFI) (39), and the EQ-5D survey (41).  Two 
hours after initiation of study intervention, subjects will again be asked to complete the visual 
analog pain scale (28) to assess their pain after intervention start.
During their hospital postpartum stay prior to discharge, subjects will be asked to complete 
three questionnaires: the visual analog pain scale (28) to rate their pain experienced during 
childbirth; the Labour Agentry scale (29) to assess their feelings of control during childbirth; 
and the Birth Satisfaction Scale-Revised (BSS-R) (30) (31) to rate their satisfaction with the 
childbirth process. They will also be asked about whether they plan to attempt to breastfeed 
their infant. They will also be asked if they had any intrapartum expression of colostrum or 
breast milk, the quantity (mL or ounces) expressed if known, whether they collected and 
stored it for their baby, and whether they fed it to their baby.
After hospital discharge (preferably two weeks postpartum, but up to three weeks 
postpartum will be acceptable), all subjects, regardless of study group, will be asked to 
complete one questionnaire: the Perception of Milk Supply (40). The unique QR code or link 
to this electronic survey will be emailed or texted to the subject based on their preference. 
Follow-up phone call will be made if needed.
After hospital discharge (preferably six to eight weeks postpartum, but anytime within the 
window of four to twelve weeks postpartum will be acceptable), all subjects, regardless of 
study group, will be contacted to ask about any unanticipated outpatient or inpatient visits for 
them or their infants since discharge. Subjects will also be asked to complete two 
questionnaires: the Maternal Breastfeeding Evaluation Scale (33) and the EPDS (32).
After hospital discharge (6 months postpartum), all subjects will be asked to complete one 
questionnaire to assess infant feeding method.
Biospecimen Procedures:
Specimen collection will be conducted as described in the previously published methodology 
(38). 
For patients in non-spontaneous labor, blood and urine will be collected at 1) prior to cervical 
ripening, 2) after cervical ripening, and 3) after 2 hours of treatment (IV oxytocin or nipple 
stimulation). This is a maximum of 3 blood samples per subject. For control patients in 
spontaneous labor, a blood and urine specimen will be obtained at enrollment. Blood may be 
drawn in several ways depending on what is clinically appropriate: (1) venipuncture; (2) IV 
catheter placed as part of standard of care (SOC); and/or (3) IV catheter placed for research 
purposes. The research IV may be placed in addition to the SOC IV and may be used 
instead of research venipuncture. That is, research venipuncture and research IV will not 
both occur at the same time (only one or the other).
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
36
Urine samples (amount variable by patient) will be collected mid-stream in a sterile screw-
top container 1) prior to cervical ripening, 2) after cervical ripening, and 3) after 2 hours of 
treatment (IV oxytocin or nipple stimulation). If a patient has an indwelling foley catheter, 
urine from the tubing will be collected at the time of adequate contractions. If a patient is 
being intermittently catheterized for urine, a urine sample will be collected as able, but the 
patient will not undergo additional bladder catheterization for the purpose of this study. 
Blood and urine samples may not be collected at one or more of the specified time points 
due to logistical issues (eg. patient enrolled after cervical ripening, labor floor acuity prevents 
nurse from drawing blood, patient delivers before time point, etc.) and/or clinical care taking 
precedence. 
Proteomic profiling will be conducted by mass spectrometry at the Keck MS & Proteomics 
Resource. Prostaglandin measurements will be performed by an external core facility with 
expertise in prostaglandin mass spectrometry methods (Vanderbilt Eicosanoid Facility). 
microRNA profiling will be conducted via bulk RNA sequencing by the Yale Center for 
Genome Analysis/Keck Core.  
Milk samples will be collected up to twice a day. Antepartum milk samples (10 drops to 
up to ½ teaspoon) will be collected from individuals in the nipple stimulation group during the 
intrapartum phase. Samples will be collected every 12 hours until labor. Volume will be 
determined by the mothers based on the amount of milk produced and how much they want 
to use to feed the infant postpartum. 
Postpartum milk samples will be collected from IV oxytocin and nipple stimulation treatments 
participants at approximately 12, 24, and 48 hours postpartum. At 12, 24 and 72 hours 6-10 
drops of milk (or more if participant allows) will be collected to a sterile tube using a pump or 
manually expressed from the breast. At ~48 hours postpartum, we will aim to collect 0.5-
2.5ml of milk to perform all the sodium and milk conductivity assays mentioned below. If 
mothers are still hospitalized at 72 hours, additional samples will be collected every 12 hours 
up to twice per day (6-10 drops). 
0.5ml of milk is needed for analysis of Sodium and milk conductivity, 0.5ml of milk for RNA 
analysis and 1ml of milk for macronutrients analysis. 
Biological samples will be collected and stored at Yale and Weill Cornell Medicine (WCM) 
under secure, temperature-controlled conditions before shipment to Dr. Golan’s lab in Ithaca. 
At collection time, all samples will be de-identified and labeled with unique study ID numbers 
and time since delivery, which contain no personally identifiable information. Yale and WCM 
sites will use REDCap to code and manage the associated clinical data and sample 
collection records. A secure, access-restricted linkage key connecting study IDs to patient 
identifiers will be maintained solely by the local research teams. Dr. Golan’s lab will only 
receive de-identified samples and coded data labeled with the study ID, and will have no 
access to patient identifiers. Results generated by Dr. Golan’s lab will be uploaded to the 
WCM REDCap database using the matched study IDs provided with the samples, ensuring 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
37
all data remain de-identified and participant confidentiality is maintained throughout the 
study.
6.3.1 Study Schedule
There will be five expected study visits or encounters:
Study 
Encounter 
#1
●
Screening and consent 
●
Enrollment and randomization
●
Assess subject's baseline pain level using 
visual analog scale 
●
Administer Edinburgh Postnatal Depression 
Scale to establish baseline
●
Administer Infant Feeding Intention Survey to 
establish baseline
●
Administer EQ-5D questionnaire to establish 
baseline
●
Initiation of assigned intervention
●
Assess subject's pain level two hours after 
intervention start using visual analog scale
●
Plasma and urine samples will be collected at 
Yale site
●
Milk samples will be collected
During hospitalization 
for induction of labor
Study 
Encounter 
#2
●
Assess subject's pain experienced during 
childbirth with visual analog scale
●
Administer Labour Agentry questionnaire
●
Administer Birth Satisfaction Scale-Revised 
questionnaire
●
Administer EQ-5D™ questionnaire
●
Administer EQ-TIPS™ questionnaire
●
Milk samples will be collected up to twice a day 
(if applicable) postpartum
During hospital 
postpartum stay prior 
to discharge
Study 
Encounter 
#3
●
Administer PIMS questionnaire
●
Administer EQ-5D™ questionnaire
●
Administer EQ-TIPS™ questionnaire
Contacted by email or 
text message 2 weeks 
postpartum
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
38
Study 
Encounter 
#4
●
Administer Maternal Breastfeeding 
Evaluation Scale (MBES) questionnaire to 
all subjects who report at least one attempt 
at breastfeeding during the postpartum 
period. 
●
Administer Edinburgh Postnatal Depression 
Scale questionnaire
●
Administer EQ-5D™ questionnaire
●
Administer EQ-TIPS™ questionnaire
Contacted by email or 
text message 4-12 
weeks postpartum
Study 
Encounter 
#5
●
Administer short questionnaire to assess infant 
feeding method
●
Administer EQ-5D™ questionnaire
●
Administer EQ-TIPS™ questionnaire
Contacted by email or 
text message 6 
months postpartum
6.3.2 Informed Consent
Informed consent will be obtained by trained study personnel who are qualified to obtain 
informed consent. Informed consent will be obtained in a private room, free of distraction, on 
the Labor and Birth Units at study sites. A full explanation of study procedures will be 
provided to the subject and all subjects will be given the opportunity to ask questions. All 
questions will be answered to the best of the ability of study personnel, and if queries are 
made that cannot be addressed at that time, the site investigators will be asked to respond. 
The subject will be notified of the IRB contact should she have any questions. The subject’s 
level of comprehension will be assessed by study personnel, and if not sufficient to assure 
that consent is truly informed, additional information will be provided. Patients will be 
informed that study participation is voluntary to minimize undue influence or coercion and 
they will be offered sufficient time to review the study prior to obtaining their informed 
consent. Women will be given ample time to review the consent, ask questions, and discuss 
with their partners (if applicable) before deciding to enroll in the study. Women ages 18+ will 
be enrolled, so parental permission is not required. Women will only be included if they are 
English or Spanish speaking. We do have study consent personnel who are fluent in 
Spanish. If there is no available research member who is fluent in Spanish, we will use a 
hospital phone interpreter to review the consent form and study information with the patient. 
If another person is with the woman during this process, she will be asked if she would like 
to discuss the study on her own or together with the accompanying person or people. 
Informed consent will be documented with the subject’s signature and date. Subjects will be 
provided with a copy of the informed consent form. The form will be placed in the subject’s 
coded chart, which will be maintained in a location separate from any clinical care 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
39
documents and will be coded with an alphanumeric code. This code will be the subject’s 
unique identifier that will carry through the entire study. 
6.3.3 Screening
All patients who are scheduled for an induction of labor or are admitted to the hospital's labor 
and birth unit to undergo induction of labor will be screened for study eligibility by a trained 
member of the investigative team.  With the assent of their primary obstetric physician or 
midwife, patients meeting eligibility criteria will be approached for potential recruitment, The 
study will be explained in detail and all questions will be answered prior to signing written 
informed consent to participate in the study. Screening will occur before planned exogenous 
oxytocin intravenous infusion has been initiated.
6.3.4 Recruitment and Enrollment Procedures
A certified member of the investigative team will review the list of patients admitted to the 
labor and delivery unit for labor induction and assess their eligibility using the inclusion and 
exclusion criteria. A partial waiver of consent will be obtained to allow review of their medical 
chart to ensure their eligibility prior to approaching patients. A certified member of the team 
will enroll a consented subject into the study. The subject will be randomized to a study arm 
with RedCap database, and the assigned intervention will be initiated. All study data will be 
entered into the RedCap database.
6.3.5 On Study Visits
Study 
Encounter 
#1
●
Screening and consent
●
Enrollment and randomization
●
Assess subject's baseline pain level 
using visual analog scale
●
Administer Edinburgh Postnatal 
Depression Scale to establish 
baseline
●
Administer IFI Survey to establish 
baseline
●
Administer EQ-5D questionnaire to 
establish baseline
●
Initiation of assigned intervention
●
Assess subject's pain level two 
hours after intervention start using 
visual analog scale
●
Milk samples will be collected
During 
hospitalization for 
induction of labor
40 
minutes
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
40
Study 
Encounter 
#2
●
Assess subject's pain experienced 
during childbirth with visual analog 
scale
●
Administer Labour Agentry 
questionnaire
●
Administer Birth Satisfaction Scale-
Revised questionnaire 
●
Administer EQ-5D™ questionnaire
●
Administer EQ-TIPS™ questionnaire
●
Milk samples will be collected up to 
twice a day (if applicable) postpartum
During hospital 
postpartum stay 
prior to discharge
40 
minutes
Study 
Encounter 
#3
●
Administer PIMS questionnaire
●
Administer EQ-5D™ questionnaire
●
Administer EQ-TIPS™ questionnaire
Contacted by email 
or text message 2 
weeks postpartum
15 
minutes
Study 
Encounter 
#4
●
Administer Maternal Breastfeeding 
Evaluation Scale (MBES) questionnaire 
to all subjects who report at least one 
attempt at breastfeeding during the 
postpartum period
●
Administer Edinburgh Postnatal 
Depression Scale questionnaire 
●
Administer EQ-5D™ questionnaire
●
Administer EQ-TIPS™ questionnaire
Contacted by email 
or text message 4-
12 weeks 
postpartum
30 
minutes
Study 
Encounter 
#5
●
Administer short questionnaire to 
assess infant feeding method
●
Administer EQ-5D™  questionnaire
●
Administer EQ-TIPS™ questionnaire
Contacted by email 
or text message 6 
months postpartum
10 
minutes
6.3.6 End of Study and Follow-up
The study will be concluded when the planned sample size of women has been enrolled, 
randomized, have delivered, and the last subject to deliver is past the 6-month postpartum 
timepoint, and all planned data have been collected.
If a subject withdraws from the interventional portion of the study but agrees to continued 
follow-up of associated clinical outcome information (as described in the original informed 
consent form), these data will be collected from the medical record. If a subject withdraws 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
41
from the interventional portion of the study and does not consent to continued follow-up of 
associated clinical outcome information, we will not access for purposes related to the study, 
the subject's medical record or other confidential records requiring the subject's consent.
6.3.7 Removal of subjects
Subjects will be informed that they may withdraw from the study at any time for any reason, 
without prejudice to their medical care. The investigators also have the right to withdraw 
subjects from the study for the following reasons: non-adherence to the protocol 
requirements (both in the intrapartum nipple stimulation and exogenous oxytocin infusion 
arms) by the subject or the subject's primary maternity care provider, or the subject no 
longer meets the protocol eligibility criteria. If a subject withdraws from the study, the primary 
reason for a subject's withdrawal will be recorded in the data collection.  Subject who 
withdraw or are withdrawn from the study will not be replaced.  If immediate deviation from 
the protocol is required to eliminate an immediate hazard(s) to subjects, the investigators will 
contact the IRB, if circumstances permit, to discuss the planned course of action. Any 
departures from the protocol must be fully documented.  Unplanned protocol deviations will 
be reported to the IRB per institutional requirements.  If the opinion of the study Principal 
Investigator (M.S.) is that there is sufficient reasonable cause for premature study 
termination, written notification documenting the reason(s) for study termination will be 
provided to the IRB. If a subject withdraws from the study, the data collected on the subject 
to the point of withdrawal will remain part of the study database and will not be removed. 
Removal of already collected data would undermine the scientific, and therefore the ethical, 
integrity of the research.  Incomplete data could potentially put enrolled study subjects and 
future study subjects at unreasonable risk as a result of inaccurate data/conclusions.
If a spontaneous labor control patient develops labor complications including prolonged or 
arrested labor requiring IV oxytocin or cesarean delivery, vaginal bleeding, or fetal heart rate 
decelerations requiring resuscitative efforts by the primary obstetric provider, biospecimens 
will not be collected at the time of entering active labor. The initial sample will still be used 
and medical records will still be reviewed unless the patient opts to withdraw from 
participation. 
If a subject randomized to nipple stimulation withdraws from her intervention, her maternity 
care provider will be informed so the subject can be transitioned to routine obstetric care 
(e.g. initiation of exogenous oxytocin infusion).
If a subject withdraws, biological specimens that have not yet been analyzed will be 
destroyed and not analyzed further. 
6.4 Statistical Method
6.4.1 Statistical Design
Data analyses will adhere closely to the CONSORT guidelines. (27) Analyses will follow the 
intention-to-treat principle in which subjects will be analyzed in the group to which they were 
randomized, regardless of whether or not they received the assigned intervention.
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
42
6.4.2 Sample Size Considerations
1) Total sample size for the trial: The sample size for the trial is based on the primary 
outcome of spontaneous vaginal delivery. Therefore, the sample size of n=988 is selected 
for this proposed study to detect a 10% absolute increase while accounting for an expected 
5% attrition rate. We then estimate, on the basis of the sample size for the primary outcome, 
the power we will have to detect clinically significant differences in the secondary outcomes.
Sample size estimation for primary outcome:
Detectable absolute 
difference
Anticipated with nipple 
stimulation therapy
Total Sample size Across 2 
Study Groups for 90% 
power
15%
79%
426
14%
78%
492
13%
77%
574
12%
76%
676
11%
75%
812
10%
74%
988
9%
73%
1,222
All sample size and power estimates are based on two-tailed tests. This is important 
because we will be powered to detect both increases and decreases in outcomes with 
intrapartum nipple stimulation therapy (intervention) versus immediate synthetic oxytocin 
infusion without nipple stimulation (comparator). The expected rate of spontaneous vaginal 
delivery in the setting of immediate synthetic oxytocin infusion without nipple stimulation 
used for the sample size estimation is based on averaged institutional data from the study 
sites. We estimate that a total of 988 (494 nipple stimulation therapy and 494 immediate 
synthetic oxytocin infusion without nipple stimulation) will be sufficient to detect a 10% 
absolute difference (estimated 74% versus 64%) in spontaneous vaginal delivery with 90% 
power (alpha of 0.05).
Justification: At first glance, the anticipated 10% or greater absolute increase in the 
spontaneous vaginal delivery rate in our proposed trial appears modest. On the contrary, 
because the potential public health impact is large, this effect size is significant. It is 
estimated that 40% of the one million women who undergo inpatient labor induction each 
year in the U.S. are nulliparas. Therefore, a 10% increase in spontaneous vaginal delivery 
translates to 40,000 more spontaneous vaginal deliveries and 40,000 fewer operative 
deliveries each year. Avoiding 40,000 operative deliveries each year will have substantial 
impact on overall morbidity and healthcare resource utilization in the U.S. and beyond. 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
43
2) The sample size of 988 for the primary outcome will be sufficient to detect a 9.4% or 
10.8% absolute difference in breastfeeding as the sole source of nutrition (BSSN) at the time 
of delivery hospitalization postpartum discharge with 80% power and 90% power, 
respectively (two-sided test, alpha=0.05). This represents the difference between an 
expected BSSN rate of 47% in the setting of synthetic oxytocin infusion without nipple 
stimulation (average rate at the study sites based on institutional data) and 56.4% (with 80% 
power) or 57.8% (with 90% power) with nipple stimulation therapy.
3) Assuming a 15% attrition rate at 2 weeks postpartum (the time frame for our primary cost-
effectiveness analysis in Aim 3), the sample size of 988 will have 90% power for detecting a 
standardized effect size of 0.22 for the between-group difference in cost and difference in 
quality adjusted life years (QALY) (two-sided test, alpha=0.05). This is considered a small 
effect size based on conventional criteria, hence if we observe an even larger effect size, we 
should be sufficiently powered.
The sample size for this biospecimen trial is based on the primary comparison, specifically the 
difference in primary biomarkers from baseline to after 2 hours of treatment between patients 
performing nipple stimulation therapy and those receiving IV oxytocin. Sample size 
calculations are based on differences between non-laboring and laboring patients from prior 
reports (Table). Sample size was determined to achieve 80% power to detect a difference with 
a two-tailed alpha level of 0.05. The final sample size of 48 per exposure group is based on 
the largest sample size required (IL1beta). Therefore, there is more than adequate power for 
the remainder of the biomarkers of interest. 
To detect a 10 mM difference in sodium concentration between the intrapartum nipple 
stimulation therapy group and the immediate synthetic oxytocin infusion group at 48 hours 
postpartum, with a standard deviation of 20 mM, 80% power, and a significance level of 0.05, 
a sample size of 32 participants per group is required. Accounting for an expected 30% 
dropout rate, we plan to recruit 46 participants per group. 
To preserve the overall 5% false positive error rate, we first defined primary, secondary, and 
exploratory hypotheses with respect to the comparison groups. Second, we defined our 
hypotheses with respect to the each biomarker of interest (Table) as either disjunctive, 
conjunctive or individual.64 When hypotheses are disjunctive, a rejection of one of them would 
yield a rejection of the overarching (joint) null hypothesis, which requires an adjustment of the 
alpha level for multiplicity of tests. Conceptually, since hypotheses are divided into primary, 
secondary, and exploratory, and individual biomarker targets identified, we created individual 
overarching null hypotheses where alpha-level adjustments are not required. Additionally, if 
we set them as conjunctive hypotheses where all the individual null hypotheses must be 
rejected to reject the overarching (joint) null hypothesis, the alpha level adjustment would also 
not be needed.  
Sample Size Estimation for Biospecimen Sub-Study:
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
44
Biomarker
Reported 
Group 
Difference
Standard 
deviation
Sample size 
(per group) a
Estimated 
Effect Size b
Detectable 
Difference 
for n=48 c
Primary: Oxytocin
24.25%d
40.8
45
528 pg/mL
23.6%
Cytokines
Primary: IL1b
1.56 pg/mL
2.19
48
1.56 pg/mL
1.56 pg/mL
IL6
3.34 pg/mL
2.69
23
2.5 pg/mL
1.77 pg/mL
Acute phase reactants
Primary: PAI-1
2.27 e
2.655
23
23.2 ng/mL
1.76 e
Plasminogen
1.32 e
1.32
16
-3.5 mg/L
1.17 e
C reactive protein
1.91 e
1.19
21
-2.3 mg/L
1.11 e
Immune mediator
Primary: ICOS Ligand
3.07 e
2.73
13
n/a
1.79 e
SFTPD
3.76 e
3.39
14
n/a
2.02 e
Metabolic
Primary: Apolipoprotein A4
-0.79 e
1.19
9
n/a
-1.11 e
IGFBP1
-0.57 e
1.97
23
n/a
-1.48 e
Apolipoprotein E
-27.5 mg/L
23
16
-27.5 mg/L
-13.3 mg/L
Apoptosis
ERP29
1.54 e
1.51
15
n/a
1.27 e
Prostaglandins
PGE2
10ng/mL
4.2
3
10ng/mL
2.4 ng/mL
PGF2a
3.7 ng/mL
1
8
3.7ng/mL
0.58 ng/mL
a Sample size (per group) that would provide 80% power to detect the reported group difference with the 
reported standard deviation using two-tailed tests. 
b For percent change in oxytocin, effect size was estimated based on average values in two treatment 
groups at the time of adequate contractions in our preliminary data. For MS data, effect size was 
estimated based on group differences expressed in log scale ratios converted to typical laboratory units. 
n/a indicates concentration in maternal circulation is unknown for estimation. Effect size refers to effect 
size if the study was only powered for that biomarker. 
c Detectable difference is calculated as what difference we anticipate being able to identify given the final 
sample size of 48. For MS counts,
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
45
d Based on our preliminary data
e MS counts 
6.4.3 Planned Analyses
6.4.3.1 Primary Analyses
1) Overview: Data analyses will adhere closely to the CONSORT guidelines. Analyses will 
follow the intention-to-treat principle in which subjects will be analyzed in the group to which 
they were randomized, regardless of whether or not they received the assigned intervention.
2) Primary Analyses: 
Descriptive statistics will characterize the group of individuals recruited and investigate 
comparability of the two study groups at baseline. Formal statistical testing will be limited to 
select baseline characteristics considered to be prognostic factors for the primary outcome 
including hospital admission body mass index (BMI), primary indication for labor induction, 
Bishop score at randomization, and birth weight. Categorical variables will be compared 
between trial groups by using the Chi-squared or Fisher’s exact tests as appropriate, and 
continuous variables will be compared using Student’s t-test or Wilcoxon Rank Sum Test, as 
appropriate. Distributions of continuous variables will be assessed by visual inspection of 
histograms. 
The primary outcome (spontaneous vaginal delivery) and other categorical secondary 
outcomes will be compared between trial groups using Chi-square or Fisher's exact tests as 
appropriate. The estimates of the relative risk and 95% confidence intervals (95% CI) 
associated with the primary and secondary outcomes will be calculated using Agresti and 
Coull method. The time to event regression analyses for labor length (regardless of delivery 
mode) and labor length censored for cesarean will be evaluated by Kaplan-Meier estimates 
and plots, and tested with the log-rank test, whereas Cox proportional hazards analysis will 
be used in adjusted analyses accounting for Bishop scores at study entry (proportionality 
assumption will be checked graphically with ln(-lnSurvival) plots), and results summarized 
using hazard ratios (HR) and 95% CI). A sensitivity analysis will be performed using the 
induction method that the patient actually received (per-protocol analysis) to determine 
whether crossovers influenced the results. The distribution of maximal percent newborn 
weight loss is not expected to follow a normal distribution in the population, so we plan to use 
Wilcoxon Rank Sum Tests to compare the distribution of the maximal percent weight loss 
between treatment groups, and summarize the results as medians (25th and 75th percentiles) 
and bootstrapped 95% CIs. Similarly, the distributions of the PIMS survey scores and MBFES 
survey scores are not expected to follow normal distributions in the population, so we will use 
Wilcoxon Rank Sum Tests to compare the distribution of the MBFES scores between 
treatment groups and summarize the results using the group medians (25th and 75th 
percentiles) and bootstrapped 95% CIs. 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
46
6.4.3.2 Secondary Objectives Analyses
Adjusted Analyses and Planned Subgroup Analyses
We will perform other analyses as needed aimed at obtaining adjusted assessments of 
treatment effectiveness, adjusting for baseline patient characteristics (covariates). The 
objectives of these analyses are to estimate the influence of covariates on the outcome and 
to use covariates to improve the estimated difference between treatment groups. The 
Poisson regression model (link=log) with robust standard errors stratified by study site will be 
used to identify and estimate the effect of multiple prognostic factors on the probability of 
spontaneous vaginal delivery and other categorical outcomes, with results summarized as 
adjusted risk ratios. For continuous secondary outcomes such as maximal newborn weight 
loss and PIMS and MBFES survey scores, quantile regression, e.g., modeling 50th 
percentile, will be considered to adjust for prognostic factors. Interaction tests will be used to 
determine whether the effectiveness of nipple stimulation therapy significantly differs across 
these subgroups. These analyses will be considered exploratory in nature and will not be 
viewed as providing confirmatory tests of hypotheses.
The following pre-specified subgroup analyses will be conducted:
1.
Study site
2.
Amniotic membrane status (intact versus ruptured) at enrollment
3.
Presence versus absence of maternal diabetes (inclusive of pre-gestational and 
gestational diabetes)
4.
Insurance type (commercial versus public insurance)
5.
Maternal race (Black versus White versus Other)
6.
Obesity (obese versus non-obese)
In separate models, each of these sub-group variables will be included as an additional 
covariate in the models for outcomes of interest, plus their interaction with treatment 
variable; followed by stratified analyses (by each of the above variables) of the effect of 
treatment on each outcome of interest.
Data Analysis Plan for the Biospecimen Sub-Study:
The primary comparison for Aim 1 is the difference in biomarker concentration or MS counts 
from baseline to 2 hours of treatment between patients performing nipple stimulation therapy 
and those receiving IV oxytocin. Secondary comparisons evaluate the change with labor 
induction versus spontaneous labor. This unadjusted between-group comparison of the within-
group change will be based on a Student’s t-test, with a supportive analysis using Analysis of 
Covariance (ANCOVA) where the baseline biomarker level will be a covariate in a mean 
response profile model (MRP), which allows for different variances and covariances across 
time. The primary exposure variable will be treatment group with either compound symmetry 
(CS) covariance or heterogenous compound symmetry covariance (HCS) to account for the 
within-patient correlation in biomarker values across the time points of data collection; and the 
choice between the two covariance matrices will be made using a likelihood ratio test (LRT) 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
47
as these are nested models. Results will be summarized as estimated means of fold change 
at adequate contractions for each group and the between-group mean differences, with 
surrounding 95% Confidence Intervals. By specifying the model as an MRP, we can also 
conduct any comparisons of means (within/between groups across time), by using linear 
contrasts and the multivariate Wald Test. In the adjusted analyses, we will include in the MRP 
as covariates the between-group differences identified in the between-group comparisons. In 
a sensitivity analysis, since we will know the timing of each measurement relative to the 
initiation of treatment, we will use the actual time (compare linear, polynomial or spline effect 
of time) instead of the categorical time point in a linear mixed effects model (LME) with a 
random intercept for each woman and a possible random slope for each woman (also tested 
using an LRT). All biomarkers listed in the Table will be analyzed in the same manner, as all 
will be treated as continuous variables. For the exploratory hypothesis using the time to active 
labor, we will use a joint modeling approach: time to active labor modeled jointly with the mean 
trajectory of change over time in biomarker values; this model will allow us to estimate the 
between-group differences in the time to active labor, as it is also influenced by the biomarker 
values within each group.
Data Analysis Plan for the Milk Biospecimen Sub-Study:
The primary comparison will be looking at milk composition before and after birth for 
participants in the nipple stimulation group. We will  use Student’s t-test to compare the paired 
milk samples from the same individuals. 
Secondary comparison will be looking into milk composition between patients performing 
nipple stimulation therapy and those receiving IV oxytocin versus spontaneous labor at 12, 
24, 48 and 72 hours postpartum. We will account for multiple measurements for each 
participant (if multiple samples will be collected) and those will be used for a mixed effect 
model. Structural equation model will be used for modeling the effect of additional variables 
(delivery mode, intentions to breastfeed, feeding frequency, maternal intention to feed etc.) on 
milk biomarkers and breastfeeding outcomes.  
6.4.3.3 Safety/Pregnancy-related policy
The study PD/PI (M.S.) will be informed of and review any potential Adverse Events. The 
DSMB will review all Adverse Event Reports and other interim safety data and will provide a 
report to the local IRB in compliance with local standards. If a participant develops a serious 
adverse event, the safety of continuing the intervention will be ascertained by the 
participant's obstetric care provider in collaboration with the site PI.
Maternal and perinatal morbidity outcomes are pre-specified secondary outcomes and will 
be statistically compared between intervention groups to assess for any signal of safety 
concerns. 
6.4.3.4 Analysis of Subject Characteristics
Descriptive statistics including frequencies, percentages, means (+/- standard deviations) 
and medians (interquartile ranges) will be obtained. Baseline univariate and bivariate 
analyses will be performed using Fisher's exact tests and Chi-squared tests for categorical 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
48
variables and Student t-tests and Mann-Whitney U tests as appropriate based on the 
normality of the data.
6.4.3.5 Interim Analysis (if applicable)
Not applicable
6.4.3.6 Health economic evaluation
To estimate difference in cost and difference in quality adjusted life years (QALY) between 
the intervention and comparator groups, we will use a generalized linear model (GLM) with 
log link and gamma distribution for cost (given skewness in cost data) and identity link and 
normal distribution for QALY. Explanatory variable will be an indicator for intervention (vs. 
comparator) group. All analyses will follow the intention to treat principle. As randomization 
will be stratified by study site and amniotic membrane status, we will test if they are 
associated with cost or QALY and decide whether to include them as covariates in analysis. 
Cost-effectiveness will be evaluated by calculating the incremental cost effectiveness ratio 
(ICER), defined as ΔC/ΔE where ΔC denotes the estimated difference in cost between the 
intervention and comparator groups and ΔE reflects the estimated difference in QALY 
between the two groups. ICER informs the additional cost associated with the intervention 
for each additional QALY gained. We will use non-parametric bootstrap resampling to 
estimate 95% CI of ICER and produce a cost-effectiveness plane and cost-effectiveness 
acceptability curve. In special situations where the intervention leads to significantly lower 
cost and higher QALY, the intervention is considered the dominant strategy. In situations 
where there is no significant difference in QALY between the two groups, a comparison of 
cost will inform the cost-effectiveness of the intervention; and vice versa. Our primary cost-
effectiveness analysis will examine costs and health effects up to 2 weeks postpartum. We 
will also conduct two secondary analyses by: 1) extending the time period to 6 months 
postpartum, and 2) calculating QALY using participants’ EuroQol five dimensions (EQ-5D) 
visual analogue scale (VAS) rating as a utility score (with linear transformation to a 0 to 1 
scale). 
6.4.3.7 Other
None
6.4.4 Subsets and Covariates
Adjusted Analyses and Planned Subgroup Analyses
We will perform other analyses as needed aimed at obtaining adjusted assessments of 
treatment effectiveness, adjusting for baseline patient characteristics (covariates). The 
objectives of these analyses are to estimate the influence of covariates on the outcome and 
to use covariates to improve the estimated difference between treatment groups. The 
Poisson regression model (link=log) with robust standard errors stratified by study site will be 
used to identify and estimate the effect of multiple prognostic factors on the probability of 
spontaneous vaginal delivery and other categorical outcomes, with results summarized as 
adjusted risk ratios. For continuous secondary outcomes such as maximal newborn weight 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
49
loss and PIMS and MBFES survey scores, quantile regression, e.g., modeling 50th 
percentile, will be considered to adjust for prognostic factors. Interaction tests will be used to 
determine whether the effectiveness of nipple stimulation therapy significantly differs across 
these subgroups. These analyses will be considered exploratory in nature and will not be 
viewed as providing confirmatory tests of hypotheses.
The following pre-specified subgroup analyses will be conducted:
1.
Study site
2.
Amniotic membrane status (intact versus ruptured) at enrollment
3.
Presence versus absence of maternal diabetes (inclusive of pre-gestational and 
gestational diabetes)
4.
Insurance type (commercial versus public insurance)
5.
Maternal race (Black versus White versus Other)
6.
Obesity (obese versus non-obese)
6.4.5 Handling of Missing Data
Data quality reports will be generated monthly and include volume of missing data, edits, 
time to edit resolution and number of overdue forms. Remedial measures, including re- 
abstraction of data and retraining of staff, will be used as needed to minimize missing data. 
At the time of statistical analysis, if there is significant missing data, multiple imputation 
methods will be employed as necessary.
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
50
7 - Trial Administration
7.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization
Women will be assumed to have capacity to provide informed consent for research unless 
there is indication to the contrary. These indications include known cognitive impairment, 
altered mental status, difficulties in communication observed during research staff 
interaction, psychotic symptoms, bizarre behavior. Women with these indications will not be 
included in the research study. If any of these symptoms or behaviors are new, their medical 
provider will be informed immediately for further assessment.
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki.
7.2 Institutional Review Board (IRB) Review
The protocol will be submitted to the IRB for review and approval. Approval of the protocol 
must be obtained before initiating any research activity. Any change to the protocol or study 
team will require an approved IRB amendment before implementation.  The IRB will 
determine whether informed consent and HIPAA authorization are required. 
The IRB will conduct continuing review at intervals appropriate to the degree of risk, but not 
less than once per year.
A study closure report will be submitted to the IRB after all research activities have been 
completed.   
Other study events (e.g., data breaches, protocol deviations) will be submitted per Yale's 
IRB's policies.
7.3 Subject Confidentiality
There will be multiple procedures in place to minimize the risk of subject confidentiality and 
will be outlined in the study protocol. Subject confidentiality will be held in strict trust by all 
members of the research teams. Subject medical record review will be limited to just the 
elements needed to complete the study. Only authorized HIPAA and GCP trained study 
team members will be allowed to extract research data from medical records and enter it into 
the REDCap database. 
At each study site, subject records are maintained in the Epic System® EMR and all 
research data will be collected in and maintained in REDCap, an established, secure, web-
based capture and management tool developed at Vanderbilt University. Any paper records 
(e.g. signed consent forms) will be kept in a locked cabinet within a locked office that is 
secured always and located on the main campus within the departmental research 
administrative office space at each study site to ensure confidentiality of subject data.
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
51
The IRB may inspect study records at any given time. In addition, all scientific publications 
will refer to the subjects by study identifiers only. At no time will any of the subjects in the 
study be identified. Identifiable study information will be maintained for up to ten years after 
the research is complete. After that time, it will be destroyed or de-identified. The principal 
investigator will keep a link that identifies subjects to coded information, but this link will be 
kept secure and available only to the PIs or selected members of the research team.
This study will comply with the National Institutes of Health (NIH) Data Sharing Policy. Data 
obtained from biospecimens will be sent to an NIH-supported Scientific Data Repository.  All 
samples and related data will be coded and de-identified, and the NIH will not identify or 
make any attempt to identify information as coming from a specific participant. NIH will share 
the collected information with researchers who submit applications to NIH to do research 
with information from the NIH-supported Scientific Data Repository. Special data sharing 
committees within the NIH will review those applications and decide whether or not to share 
the information with the researcher.  
7.4 Deviations/Unanticipated Problems
If the study team becomes aware of an anticipated problem (e.g., data breach, protocol 
deviation), the event will be reported to the IRB office within five (5) working days of 
becoming aware of the incident/issue via a Reportable New Information (RNI) mechanism in 
IRES IRB.
7.5 Data Collection
Inclusion criteria and randomization data will be entered in real time, screening information 
entered weekly, data extraction every other week, and chart completion monthly.
The medical record of each subject's hospital stay will be reviewed and used to collect data. 
The Data Collection Form (Appendix) will be configured into the REDCap (Research 
Electronic Data Capture) database and will be utilized by the study investigators to extract 
and enter data from each subject's medical record. All study questionnaires will be 
completed by subjects using REDCap survey tools and data will be stored and analyzed 
using this tool. As stewards of the research data, the Study Principal Investigator and site 
PI’s will be responsible and accountable for research data as it is collected, processed, 
stored, analyzed, and reported.  Every effort will be made to maintain high quality data that 
will remain protected and kept strictly confidential in accordance with local, state, and federal 
law; as such, institutional resources REDCap will be used for data entry and monitoring. 
Once all data collection forms and medical charts have been reviewed, all identifiers will be 
removed, and subject data will be stored and archived in a de-identified manner.  The 
identifiable data will be permanently discarded by permanently deleting the password 
protected encrypted database with subject identifiers at the earliest opportunity.
7.6 Data Quality Assurance
The data form will be configured into the REDCap (Research Electronic Data Capture) 
database and utilized by the study investigators to extract data from each subject's medical 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
52
record. All subjects will complete study questionnaires using the Yale Qualtrics Survey tool, 
and data will be stored and analyzed using this tool. Every effort will be made to maintain 
high quality data that will remain protected and kept strictly confidential in accordance with 
local, state, and federal law; as such, institutional resources REDCap and Qualtrics will be 
used for data entry and monitoring.
7.7 Study Records
The study protocol, consent forms, subject medical records, and surveys will all be 
considered study records.
7.8 Access to Source
The source documents will include the consent forms, subject medical records, and 
completed surveys. Only certified members of the investigative team will have access to 
these documents. All data will be entered into the REDCap database, and de-identified at 
the earliest opportunity to do so.
7.9 Data or Specimen Storage/Security
Every effort will be made to maintain high quality data that will remain protected and kept 
strictly confidential in accordance with local, state, and federal law; as such, institutional 
resources REDCap (Research Electronic Data Capture) will be used for data entry and 
monitoring. This database is on a server on a secure, encrypted hospital-issued computer. 
Once all data collection forms and medical charts have been reviewed, all identifiers will be 
removed, and subject data will be stored and archived in a de-identified manner with the use 
of unique study identification numbers.  The identifiable data will be permanently discarded 
by permanently deleting the password protected encrypted database with subject identifiers 
at the earliest opportunity. The paper records (e.g., signed written informed consent forms) 
will be stored in a locked cabinet in the Principal Investigator (M.S.)'s private academic office 
that is locked and only accessible by key and university badge access. 
Data use agreements will be obtained and approved across all three institutions: Weill 
Cornell as the primary grant institution where the PD resides, Yale University (grant sub-
award institution), and Northwestern University (grant sub-award institution).
7.10 Retention of Records
The study records will be retained for a minimum of seven (7) years after the conclusion of 
the study investigation. If permission is needed to move or destroy the records, the Principal 
Investigator (M.S.) will be contacted.
7.11 Study Monitoring
Plan for Monitoring trial performance to ensure protocol adherence and data fidelity
The Data Management Team will create electronic data capture forms. Conference calls will 
be held at least monthly with all site investigators as well as a separate call monthly for study 
coordinators, or more frequently as needed. Data will be available in REDCap regarding 
recruitment, retention and protocol adherence by site with specific details regarding 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
53
subgroups deemed clinically important such as race/ethnicity, body mass index, and 
maternal age. This will be reviewed on a monthly basis by the Principal Investigator and sub-
site PI(s), to ensure that appropriate milestones are met. REDCap® is the secure web 
platform for building and managing online databases and surveys that will be employed at 
study sites. The software allows for data quality checks, secure file storage and sharing, 
custom reporting, and data-based triggers and alerts. In addition to the above-mentioned 
mechanisms in place to ensure fidelity and data integrity, all research staff will be trained in 
good clinical practice and will follow GCP regulations and guidelines. The PD/PI and site PI’s 
will meet on a monthly basis, or more frequently as needed, with their respective site-specific 
staff to discuss recruitment, enrolled participants, regulatory updates, safety issues, data 
entry and any other pertinent topics. Detailed meeting minutes will be kept, ensuring proper 
documentation of such oversight. Any adverse event, near miss or protocol deviation will be 
reported to the site PIs as soon as it is discovered, and the site PIs will then take the 
appropriate actions discussed above. These items will be discussed collectively during bi-
monthly conference calls, with the exception of protocol deviations, adverse events and any 
other issues that would require immediate reporting.
7.12 Data Safety Monitoring Plan
The interventions compared in this trial are exogenous oxytocin infusion (current standard of 
care) and nipple stimulation with an electric breast pump or manual stimulation. Both 
interventions require continuous fetal heart rate and contraction frequency monitoring, with 
clear recommendations for titration of both interventions to ensure frequency of contractions 
within the recommended goal range. Therefore, no serious or life-threatening adverse 
events are expected. However, the risks associated with the current study are deemed 
greater than minimal for the following reasons:
1.
We do not view the risks associated with nipple stimulation as minimal risks since the 
data surrounding its use remain limited. 
2.
However, given the limited reassuring data and our experience with breast pump 
stimulation from our pilot study (IRB# 2000029909, Clinicaltrials.gov NCT04756089) 
and the fact that exogenous oxytocin use is current standard of care and widely used 
in obstetric practice, we do not view the proposed study as high risk.
Although we have assessed the proposed study as one of greater than minimal risk, the 
potential exists for anticipated and/or unanticipated adverse events, serious or otherwise, to 
occur since it is not possible to predict with certainty the absolute risk in any given individual 
or in advance of first-hand experience with the proposed study methods. Therefore, we 
provide a plan for monitoring the data and safety of the proposed study as follows:
The data safety monitoring plan is as follows:
1. Personnel responsible for the safety review and its frequency:
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
54
The principal investigator will be responsible for monitoring the data, assuring protocol 
compliance, and conducting safety reviews at the study completion of each subject. During 
the review process, the principal investigator (monitor) will evaluate whether the study 
should continue unchanged, require modification/amendment, or close to enrollment. Either 
the principal investigator or the IRB have the authority to stop or suspend the study or 
require modifications.
2. Independent Data and Safety Monitoring Board (DSMB): 
We will establish an independent study-specific Data Safety and Monitoring Board (DSMB) 
to oversee the trial. Members of the DSMB will be at least four physicians who represent the 
appropriate expertise (perinatology, epidemiology, biostatistics, neonatology, and clinical 
trials) and will provide appropriate oversight to assure that the trial accrues at a sufficient 
rate, and that the safety and privacy of all study participants is assured. Members will not be 
involved in any aspect of the trial operation. The DSMB will meet regularly (at least quarterly) 
to review study progress and to monitor adverse events. The DSMB will be briefed before 
each meeting regarding study progress (recruitments and drop-outs), and study outcomes. 
The DSMB will issue a written report to the investigators after each meeting outlining any 
study problems or needed actions
3. Adverse event reporting: Detailed information concerning adverse events will be 
collected and evaluated throughout the conduct of the protocol (Appendix). The PI and 
DSMB will determine whether the adverse event meets the criteria for a Serious Adverse 
Event (SAE).  If a participant develops a serious adverse event, the safety of continuing the 
intervention will be ascertained by the subject's obstetric care provider in collaboration with 
the PI. The Principal Investigator will conduct a review of all adverse events upon completion 
of every study subject. The DSMB will review all Adverse Event Reports and other interim 
safety data and will provide a report to the local IRB in compliance with local standards. The 
PI and the DSMB will evaluate the frequency and severity of the adverse events and 
determine if modifications to the protocol or consent form are required.
4. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to 
the study procedures/design by the Principal Investigator and the DSMB according to the 
following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s).
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s).
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s).
d.) Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s).
e.) Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s).
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
55
5. Plan for reporting UPIRSOs (including Adverse Events) to the IRB
The principal investigator will report the following types of events to the IRB:
Any incident, experience or outcome that meets ALL 3 of the following criteria:
1.
Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the 
research procedures described in the protocol-related documents, such as the IRB-
approved protocol and informed consent document and (b) the characteristics of the 
subject population being studied; AND
2.
Is related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); AND
3.
Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, legal, or social harm) than was 
previously known or recognized.
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical or 
non-medical in nature, and include — but are not limited to — serious, unexpected, and 
related adverse events and unanticipated adverse device effects.  Please note that adverse 
events are reportable to the IRB as UPIRSOs only if they meet all 3 criteria listed above.
These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using 
the appropriate forms found on the website. All related events involving risk but not meeting 
the prompt reporting requirements described in IRB Policy 710 should be reported to the IRB 
in summary form at the time of continuing review. If appropriate, such summary may be a 
simple brief statement that events have occurred at the expected frequency and level of 
severity as previously documented.  In lieu of a summary of external events, a current DSMB 
report can be submitted for research studies that are subject to oversight by a DSMB (or 
other monitoring entity that is monitoring the study on behalf of an industry sponsor).
7.13 Study Modification
All modifications to the study will be submitted through IRES IRB. The research will continue 
to be conducted without inclusion of the modification(s) until IRB approval is received, except 
where necessary to eliminate apparent immediate hazards to human subjects.
7.14 Study Discontinuation
Reportable Events (which are events that are serious or life-threatening and unanticipated 
(or anticipated but occurring with a greater frequency than expected) and possibly, probably, 
or definitely related to study procedures or Unanticipated Problems Involving Risks to 
Subjects or Others (UPIRSO) that may require a temporary or permanent interruption of 
study activities. Such events will be reported to the IRB to determine whether the study 
needs to be discontinued based upon review. 
7.15 Study Completion
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
56
The study is expected to complete within 7 years of initiation. The IRB will be notified when 
the study is completed.
7.16 Conflict of Interest Policy
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the trial. The study leadership in conjunction with the appropriate conflict of interest review 
committee has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest.
All investigators will follow the applicable conflict of interest policies.
7.17 Funding Source
This trial is funded in part by the Albert McKern Scholar Award and the National Institutes of 
Health. The materials for biospecimen collection and analysis are funded by a Trainee Grant 
from the Perinatal Research Consortium. The funders of the study will have no role in the 
design and conduct of the study; collection, management, analysis, and interpretation of the 
data; preparation, review, or approval of the manuscript; or decision to submit the 
manuscript for publication.
7.18 Publication Plan
Every attempt will be made to publish the results of this trial after they are completed, all 
data are collected and analyzed. The Principal Investigator (M.S) will hold primary 
responsibility for publishing the study results. The funders of the study will have no role in 
the decision to submit the manuscript for publication.
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
57
References
1. Martin, J. A. Hamilton, B. E. Osterman, M. J. K. Driscoll, A. K.. Natl Vital Stat Rep Births: 
Final Data for 2018. 2019; 13:1-47. 
2. Grobman, W. A. Rice, M. M. Reddy, U. M. Tita, A. T. N. Silver, R. M. Mallett, G. Hill, K. 
Thom, E. A. El-Sayed, Y. Y. Perez-Delboy, A. Rouse, D. J. Saade, G. R. Boggess, K. A. 
Chauhan, S. P. Iams, J. D. Chien, E. K. Casey, B. M. Gibbs, R. S. Srinivas, S. K. Swamy, G. 
K. Simhan, H. N. Macones, G. A. Eunice Kennedy Shriver National Institute of Child, Health 
Human Development Maternal-Fetal Medicine Units, Network. N Engl J Med Labor Induction 
versus Expectant Management in Low-Risk Nulliparous Women. 2018; 6:513-523. doi: 
10.1056/NEJMoa1800566. 
3. Ghartey, J. Macones, G. A.. Am J Obstet Gynecol 39-Week nulliparous inductions are not 
elective. 2020; 6:519-520. doi: 10.1016/j.ajog.2020.01.055. 
4. Obstetrics, Acog Committee on Practice Bulletins --. Obstet Gynecol ACOG Practice 
Bulletin No. 107: Induction of labor. 2009; 2 Pt 1:386-97. doi: 
10.1097/AOG.0b013e3181b48ef5. 
5. Shetty, A. Burt, R. Rice, P. Templeton, A.. Eur J Obstet Gynecol Reprod Biol Women's 
perceptions, expectations and satisfaction with induced labour--a questionnaire-based study. 
2005; 1:56-61. doi: 10.1016/j.ejogrb.2005.03.004. 
6. Downe, S. Finlayson, K. Oladapo, O. T. Bonet, M. Gulmezoglu, A. M.. PLoS One What 
matters to women during childbirth: A systematic qualitative review. 2018; 4:e0194906. doi: 
10.1371/journal.pone.0194906. 
7. Erickson, E. N. Emeis, C. L.. J Midwifery Womens Health Breastfeeding Outcomes After 
Oxytocin Use During Childbirth: An Integrative Review. 2017; 4:397-417. doi: 
10.1111/jmwh.12601. 
8. Chayen, B. Scott, E. Cheng, C. C. Perera, C. Schiffer, M. A.. Acta Obstet Gynecol Scand 
Contraction stress test by breast stimulation as part of antepartum monitoring. 1985; 1:3-6. 
doi: 10.3109/00016348509154678. 
9. Copel, J. A. Otis, C. S. Stewart, E. Rosetti, C. Weiner, S.. J Reprod Med Contraction 
stress testing with nipple stimulation. 1985; 6:465-71. 
10. Rosenzweig, B. A. Levy, J. S. Schipiour, P. Blumenthal, P. D.. J Reprod Med 
Comparison of the nipple stimulation and exogenous oxytocin contraction stress tests. A 
randomized, prospective study. 1989; 12:950-4. 
11. Kavanagh, J. Kelly, A. J. Thomas, J.. Cochrane Database Syst Rev Breast stimulation 
for cervical ripening and induction of labour. 2005; 3:CD003392. doi: 
10.1002/14651858.CD003392.pub2. 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
58
12. Singh, N. Tripathi, R. Mala, Y. M. Yedla, N.. Biomed Res Int Breast stimulation in low-risk 
primigravidas at term: does it aid in spontaneous onset of labour and vaginal delivery? A 
pilot study. 2014; 695037. doi: 10.1155/2014/695037. 
13. Chayen, B. Tejani, N. Verma, U.. J Reprod Med Induction of labor with an electric breast 
pump. 1986; 2:116-8. 
14. Damania, K. K. Natu, U. Mhatre, P. N. Mataliya, M. Mehta, A. C. Daftary, S. N.. J 
Postgrad Med Evaluation of two methods employed for cervical ripening. 1992; 2:58-9. 
15. Takahata, K. Horiuchi, S. Tadokoro, Y. Shuo, T. Sawano, E. Shinohara, K.. PLoS One 
Effects of breast stimulation for spontaneous onset of labor on salivary oxytocin levels in 
low-risk pregnant women: A feasibility study. 2018; 2:e0192757. doi: 
10.1371/journal.pone.0192757. 
16. Takahata, K. Horiuchi, S. Tadokoro, Y. Sawano, E. Shinohara, K.. BMC Pregnancy 
Childbirth Oxytocin levels in low-risk primiparas following breast stimulation for spontaneous 
onset of labor: a quasi-experimental study. 2019; 1:351. doi: 10.1186/s12884-019-2504-3. 
17. Arrowsmith, S. Wray, S.. J Neuroendocrinol Oxytocin: its mechanism of action and 
receptor signalling in the myometrium. 2014; 6:356-69. doi: 10.1111/jne.12154. 
18. Bell, A. F. Erickson, E. N. Carter, C. S.. J Midwifery Womens Health Beyond labor: the 
role of natural and synthetic oxytocin in the transition to motherhood. 2014; 1:35-42: quiz 
108. doi: 10.1111/jmwh.12101. 
19. Fuchs, A. R. Fuchs, F. Husslein, P. Soloff, M. S. Fernstrom, M. J.. Science Oxytocin 
receptors and human parturition: a dual role for oxytocin in the initiation of labor. 1982; 
4538:1396-8. doi: 10.1126/science.6278592. 
20. Fuchs, A. R. Goeschen, K. Husslein, P. Rasmussen, A. B. Fuchs, F.. Am J Obstet 
Gynecol Oxytocin and initiation of human parturition. III. Plasma concentrations of oxytocin 
and 13,14-dihydro-15-keto-prostaglandin F2 alpha in spontaneous and oxytocin-induced 
labor at term. 1983; 5:497-502. 
21. Perry, R. L. Satin, A. J. Barth, W. H. Valtier, S. Cody, J. T. Hankins, G. D.. Am J Obstet 
Gynecol The pharmacokinetics of oxytocin as they apply to labor induction. 1996; 5:1590-3. 
doi: 10.1016/s0002-9378(96)70611-7. 
22. Seitchik, J. Amico, J. Robinson, A. G. Castillo, M.. Am J Obstet Gynecol Oxytocin 
augmentation of dysfunctional labor. IV. Oxytocin pharmacokinetics. 1984; 3:225-8. doi: 
10.1016/s0002-9378(84)90355-7. 
23. Cummiskey, K. C. Dawood, M. Y.. Am J Obstet Gynecol Induction of labor with pulsatile 
oxytocin. 1990; 6 Pt 1:1868-74. doi: 10.1016/0002-9378(90)90766-z. 
24. Randolph, G. W. Fuchs, A. R.. Am J Perinatol Pulsatile administration enhances the 
effect and reduces the dose of oxytocin required for induction of labor. 1989; 2:159-66. doi: 
10.1055/s-2007-999568. 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
59
25. Tribe, R. M. Crawshaw, S. E. Seed, P. Shennan, A. H. Baker, P. N.. Am J Obstet 
Gynecol Pulsatile versus continuous administration of oxytocin for induction and 
augmentation of labor: two randomized controlled trials. 2012; 3:230 e1-8. doi: 
10.1016/j.ajog.2011.11.001. 
26. Curtis, P. Resnick, J. C. Evens, S. Thompson, C. J.. Birth A comparison of breast 
stimulation and intravenous oxytocin for the augmentation of labor. 1999; 2:115-22. doi: 
10.1046/j.1523-536x.1999.00115.x. 
27. Schulz, K. F. Altman, D. G. Moher, D. Group, Consort. Trials CONSORT 2010 
Statement: updated guidelines for reporting parallel group randomised trials. 2010; 32. doi: 
10.1186/1745-6215-11-32. 
28. Ludington, E. Dexter, F.. Anesth Analg Statistical analysis of total labor pain using the 
visual analog scale and application to studies of analgesic effectiveness during childbirth. 
1998; 3:723-7. doi: 10.1097/00000539-199809000-00045. 
29. Hodnett, E. D. Simmons-Tropea, D. A.. Res Nurs Health The Labour Agentry Scale: 
psychometric properties of an instrument measuring control during childbirth. 1987; 5:301-
10. doi: 10.1002/nur.4770100503. 
30. Hollins Martin, C. J. Martin, C. R.. Midwifery Development and psychometric properties 
of the Birth Satisfaction Scale-Revised (BSS-R). 2014; 6:610-9. doi: 
10.1016/j.midw.2013.10.006. 
31. Martin, C. R. Hollins Martin, C. J. Burduli, E. Barbosa-Leiker, C. Donovan-Batson, C. 
Fleming, S. E.. Women Birth Measurement and structural invariance of the US version of the 
Birth Satisfaction Scale-Revised (BSS-R) in a large sample. 2017; 4:e172-e178. doi: 
10.1016/j.wombi.2016.11.006. 
32. Cox, J. L. Holden, J. M. Sagovsky, R.. Br J Psychiatry Detection of postnatal depression. 
Development of the 10-item Edinburgh Postnatal Depression Scale. 1987; 782-6. doi: 
10.1192/bjp.150.6.782. 
33. Riordan, J. M. Woodley, G. Heaton, K.. J Hum Lact Testing validity and reliability of an 
instrument which measures maternal evaluation of breastfeeding. 1994; 4:231-5. doi: 
10.1177/089033449401000416. 
34. Shankaran, S. Laptook, A. R. Ehrenkranz, R. A. Tyson, J. E. McDonald, S. A. Donovan, 
E. F. Fanaroff, A. A. Poole, W. K. Wright, L. L. Higgins, R. D. Finer, N. N. Carlo, W. A. 
Duara, S. Oh, W. Cotten, C. M. Stevenson, D. K. Stoll, B. J. Lemons, J. A. Guillet, R. Jobe, 
A. H. National Institute of Child, Health Human Development Neonatal Research, Network. 
N Engl J Med Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. 
2005; 15:1574-84. doi: 10.1056/NEJMcps050929. 
35. Bishop, E. H.. Obstet Gynecol Pelvic Scoring for Elective Induction. 1964; 266-8. 
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
60
36. Spong, C. Y. Berghella, V. Wenstrom, K. D. Mercer, B. M. Saade, G. R.. Obstet Gynecol 
Preventing the first cesarean delivery: summary of a joint Eunice Kennedy Shriver National 
Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, and 
American College of Obstetricians and Gynecologists Workshop. 2012; 5:1181-93. doi: 
http://10.1097/AOG.0b013e3182704880 10.1097/aog.0b013e3182704880. 
37. American College of, Obstetricians Gynecologists Society for Maternal-Fetal, Medicine 
Caughey, A. B. Cahill, A. G. Guise, J. M. Rouse, D. J.. Am J Obstet Gynecol Safe prevention 
of the primary cesarean delivery. 2014; 3:179-93. doi: 10.1016/j.ajog.2014.01.026. 
38. Grewen, K. M. Davenport, R. E. Light, K. C.. Psychophysiology An investigation of 
plasma and salivary oxytocin responses in breast- and formula-feeding mothers of infants. 
2010; 4:625-32. doi: 10.1111/j.1469-8986.2009.00968.x. 
39. Nommsen-Rivers LA, Dewey KG. Development and validation of the infant feeding 
intentions scale. Matern Child Health J 2009;13:334-42.
40. Kent JC, Ashton E, Hardwick CM, Rea A, Murray K, Geddes DT. Causes of perception 
of insufficient milk supply in Western Australian mothers. Matern Child Nutr 2021;17:e13080. 
41. EQ-5D-5L User Guide: Basic information on how to use the EQ-5D-5L instrument. 
EuroQol Research Foundation. (Accessed May 18, 2022, at https://euroqol.org/wp 
content/uploads/2021/01/EQ-5D-5LUserguide-08-0421.pdf )
42. Verstraete J, Ramma L, Jelsma J. Validity and reliability testing of the Toddler and Infant 
(TANDI). Health Related Quality of Life instrument for very young children. J Patient Rep 
Outcomes 2020;4:94.
43. Hebisch G, Neumaier-Wagner PM, Huch R, von Mandach U. Maternal serum interleukin-
1 beta, -6 and -8 levels and potential determinants in pregnancy and peripartum. J Perinat 
Med. 2004;32(6):475-80. doi: 10.1515/JPM.2004.131. PubMed PMID: 15576267.
44. Wood EM, Hornaday KK, Slater DM. Prostaglandins in biofluids in pregnancy and labour: 
A systematic review. PLoS One. 2021;16(11):e0260115. Epub 20211118. doi: 
10.1371/journal.pone.0260115. PubMed PMID: 34793529; PMCID: PMC8601582.
45. Christensson K, Nilsson BA, Stock S, Matthiesen AS, Uvnas-Moberg K. Effect of nipple 
stimulation on uterine activity and on plasma levels of oxytocin in full term, healthy, pregnant 
women. Acta obstetricia et gynecologica Scandinavica. 1989;68(3):205-10. doi: 
10.3109/00016348909020990. PubMed PMID: 2618602.
46. Hatjis CG, Morris M, Rose JC, Kofinas AD, Penry M, Swain M. Oxytocin, vasopressin, 
and prolactin responses associated with nipple stimulation. South Med J. 1989;82(2):193-6. 
doi: 10.1097/00007611-198902000-00012. PubMed PMID: 2916146. 
47. Bhatti G, Romero R, Gomez-Lopez N, Chaiworapongsa T, Than NG, Theis KR, Galaz J, 
Gotsch F, Pique-Regi R, Berry SM, Kavdia M, Tarca AL. The amniotic fluid proteome 
changes with term labor and informs biomarker discovery in maternal plasma. Sci Rep. 
2023;13(1):3136. Epub 20230223. doi: 10.1038/s41598-023-28157-3. PubMed PMID: 
36823217; PMCID: PMC9950459.
48. Satoh K, Yasumizu T, Fukuoka H, Kinoshita K, Kaneko Y, Tsuchiya M, Sakamoto S. 
Prostaglandin F2 alpha metabolite levels in plasma, amniotic fluid, and urine during 
pregnancy and labor. American journal of obstetrics and gynecology. 1979;133(8):886-90. 
doi: 10.1016/0002-9378(79)90306-5. PubMed PMID: 434032.
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025

APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025
IRB #2000031338
6 May 2025 - version 14 
61
49. Phillips RJ, Heesom, K.J., Trinder, J., Bernal, A.L. Human maternal plasma proteomic 
changes with parturition. EuPA Open Proteomics. 2014;5:10-20.
50. Yuan W, Heesom K, Phillips R, Chen L, Trinder J, Lopez Bernal A. Low abundance 
plasma proteins in labour. Reproduction. 2012;144(4):505-18. Epub 20120802. doi: 
10.1530/REP-12-0114. PubMed PMID: 22859520.
51. Volpato LK, Nadkarni S, Horevicz VV, Donatello N, Cremona Parma GO, Martins DF, 
Piovezan AP. Contribution of plasma, placental, inflammatory and pro-resolving mediators in 
labor induction. Placenta. 2022;122:9-17. Epub 20220331. doi: 
10.1016/j.placenta.2022.03.014. PubMed PMID: 35390665.
APPROVED BY THE YALE UNIVERSITY IRB 8/11/2025