Progestin-Only Pill Use and Breastfeeding Study
Phase: PHASE4
Conditions: Contraception, Breastfeeding
Sponsor: University of California, San Diego

 
 
 
 
 
 
 
 
Postpartum Progestin-Only Pill Use and Breastfeeding Study 
Protocol Number: 803604 
National Clinical Trial (ClinicalTrials.gov) Identifier Number: NCT04965116  
Principal Investigator: Dr. Sarah Averbach, MD, MAS 
Funded by: Society of Family Planning 
Version: 10.01.2021 
 

Postpartum Progestin-Only Pill and Breastfeeding Study 
 
Protocol 803604 
 
 
1 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title:  
Postpartum progestin-only pill use and breastfeeding study 
 
Study Description: 
This study will assess the impact of early initiation (less than one week 
postpartum) and delayed initiation (4 weeks postpartum) of two types of 
progestin-only contraceptive pills on maternal, breastmilk, and infant 
outcomes. This is a placebo-controlled randomized controlled trial 
enrolling dyads of mothers and their newborn babies. We will explore if 
the type and timing of initiation of pills is acceptable to the user with 
minimal side effects, impacts the supply or composition of breastmilk, 
and/or affects infant growth. 
 
 
Aims: 
Specific Aim: To determine whether the type of progestin used 
(drospirenone in drospirenone-containing progestin-only pills (d-POPs) vs. 
norethindrone in norethindrone-containing progestin-only pills (n-POPs)) 
or the timing of progestin initiation (early vs. delayed) affects: 
 
Aim 1a Maternal: the duration of exclusive breastfeeding continuation or 
the rates and types of breastfeeding supplementation over 8 weeks 
postpartum. 
Aim 1b Maternal: the proportion of mothers using progestin-only pills at 8 
weeks postpartum.  
Aim 2 Milk: the composition of breastmilk (fat, protein, carbohydrates) at 
4 weeks postpartum.  
Aim 3 Infant: infant growth (weight, length, and head circumference) from 
birth to 4 weeks. 
  
Study Population: 
Postpartum women who delivered an infant within the previous 7 days 
 
 
Description of Sites 
Enrolling Participants: 
University of California, San Diego (UCSD)  
  
Study Duration: 
1 year 
 
Participant Duration: 
8 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Postpartum Progestin-Only Pill and Breastfeeding Study 
 
Protocol 803604 
 
 
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INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Drospirenone-containing progestin-only pills (d-POPs) may be an acceptable alternative to 
Norethindrone-containing progestin-only pills (n-POPs) in the postpartum period when initiated either a 
week or month after delivery with fewer side effects and no impact on breastfeeding, breastmilk, and 
infant outcomes. Providing women with more options of safe, effective postpartum (PP) contraception 
has the potential to reduce unintended pregnancy and short inter-pregnancy intervals, thereby 
decreasing maternal and infant morbidity and mortality.  
 
2.2 
BACKGROUND  
 
Use of postpartum (PP) contraception can help women achieve their reproductive goals and prevent 
short inter-pregnancy intervals (IPIs). Short IPIs (<18 months between birth and subsequent pregnancy) 
are associated with an increased risk of maternal and infant morbidity and mortality including preterm 
birth. One-third of pregnancies in the United States occur after short IPIs; and approximately 70% of 
pregnancies in the first year after delivery are unintended. Women who receive contraception after 
delivery are significantly less likely to have an unintended pregnancy and short IPI. 
Contraception is typically initiated around 6 weeks after delivery; however, the timing is based on 
historical precedent, not evidence. By 6 weeks PP, more than half of women have resumed intercourse. 
The CDC provides guidance that it is difficult to be “reasonably certain that woman is not pregnant” 
beyond 4 weeks PP unless she meets the very stringent criteria for lactational amenorrhea (LAM) which 
includes exclusive breastfeeding and no interval of greater than 4-6 hours between feeds. Delaying 
access to PP contraception beyond 4 weeks may increase the risk of undesired pregnancy and short IPIs.  
 
Breastfeeding has many important health benefits for both mothers and infants, as well as economic 
and environmental benefits for families and communities. The American Academy of Pediatrics 
recommends exclusive breastfeeding for the first 6 months of life. Many women want to understand the 
effects, if any, of contraceptives on breastfeeding outcomes. Among 1,308 pregnant and PP women, 
79% reported that safety during breastfeeding was an “extremely important” consideration when 
choosing contraception. 
 
The natural PP decline in serum progesterone triggers lactogenesis; therefore, there is theoretical 
concern that use of progestin-containing contraceptives within the first weeks after delivery could 
inhibit initiation of breastfeeding or impact establishment of supply or composition of breastmilk. In 
addition, since progestins have been detected in breastmilk, there is concern about the effect of 
progestin exposure on early infant growth and development. Most existing studies on PP use of 
progestins initiated within days of delivery are small and of poor to fair quality, but the available data 
suggest that there is no effect on onset of lactogenesis, quantity or composition of breastmilk, 
breastfeeding rates, or infant growth. However, the Centers for Disease Control and Prevention (CDC) 
Medical Eligibility Criteria (MEC) for contraceptive use cites a paucity of high-quality data for ongoing 
concerns about the potential effect of progestins on breastfeeding and infant growth and their decision 
to categorize progestins use in the early PP period as Category 2 (advantages generally outweigh 
theoretical or proven risks) instead of Category 1 (no restriction). Whether progestin use affects 

Postpartum Progestin-Only Pill and Breastfeeding Study 
 
Protocol 803604 
 
 
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breastfeeding performance or infant health was identified as a priority research gap by the CDC. High-
quality data on the potential effects of the timing of progestin initiation on breastfeeding are urgently 
needed to inform national and international guidelines on contraceptive use during breastfeeding. 
A new progestin-only pill containing drospirenone has benefits compared to traditional norethindrone 
progestin-only pills, including less reliance on a narrow window of time for pill intake to maintain 
efficacy, but data on use of this type of progestin in breastfeeding are lacking. Because estrogen-
containing contraceptives are contraindicated for a minimum of 21 days PP due to the risk of 
thromboembolism, and have been associated with decreased breastmilk supply, progestin-only 
contraception, including progestin-only pills (POPs) are commonly used for contraception among 
breastfeeding women regardless of time since birth. Approximately 16-20% of PP women who intend to 
breastfeed choose POPs for contraception following delivery in the U.S, approximately 500,000 women 
per year. 
Until recently, POPs containing 0.35 mg daily of the oral progestin Norethindrone (n-POPs) have been 
the only available POP (Table 1). Norethindrone is a variant of progestin derived from testosterone. N-
POPs do not consistently inhibit ovulation; the contraceptive mechanism of action is primarily through 
progestin effects on the cervical mucous and endometrium. They require daily use with a narrow 
window of time for intake to maintain efficacy and are associated with unpredictable vaginal bleeding 
patterns and acne. Fewer than half of women who intend to use n-POPs PP use the method at 3 
months. Women who choose n-POPs for PP contraception are significantly more likely to have a short 
IPI compared to women choosing all other reversible methods. 
Drospirenone is a novel progestin derived from spironolactone (Table 1). POPs containing 4 mg of oral 
drospirenone (d-POPs) became available for use in the U.S. in 2019. D-POPs consistently suppress 
ovulation and allow for a wider missed-pill window and cyclic use with hormone-free days which offer 
the potential to improve ease of use and to decrease irregular bleeding. Unlike norethindrone, 
drospirenone has anti-androgenic properties and should not exacerbate acne and may improve it. The 
efficacy of d-POPs among non-breastfeeding women is similar to combined estrogen-progestin pills. 
However, little is known about the effect of d-POPs on breastfeeding performance or PP contraceptive 
use, efficacy, or side effects among PP women. 
 
Table 1: Progestin types available as progestin-only pills for contraception in the United States 
 
D-POPs are promoted for use while breastfeeding despite a lack of data on the effect of d-POPs on 
breastfeeding or infant outcomes. The package insert states, “no effects on breastfed infants are 
Progestin 
Progestin 
Classification 
Available 
in U.S.  
Hormone-free 
days, 28-day 
cycle 
Androgen effect 
Metabolized 
into Ethinyl 
Estradiol 
Norethindrone 
19-nor 
testosterone, 
Estrane 
1970 
None  
Medium-high 
Small amount 
Drospirenone 
Spironolactone 
2019 
4 
Antiandrogenic 
None 

Postpartum Progestin-Only Pill and Breastfeeding Study 
 
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anticipated”  but the only data presented to support the safety of d-POPs among breastfeeding women 
is an average drospirenone concentration in breastmilk over a 24-hour period of 5.6 ng/mL. Only 11 
breastfeeding women were included in the published study on d-POP efficacy in the U.S.  The single 
other published study evaluating d-POPs and breastfeeding outcomes was conducted among only 12 
women and showed that 18.13% of plasma drospirenone was found in breastmilk.  High quality data are 
required to inform CDC guidelines on use of differing progestin types during breastfeeding. 
Most previous studies have failed to show a negative effect of progestins on breastfeeding or infant 
growth. However, most existing studies are small, are of poor to fair quality, do not include assessments 
of d-POPs users and do not use validated outcome measures. Furthermore, most studies evaluating the 
effect of POPs on breastfeeding have initiated the method at 6 weeks PP or later. The single study 
specifically evaluating the effect of early initiation of POPs was not randomized and compared all 
progestin users (including pills, injectables, and implants) to non-hormonal contraception users. That 
study did not show a deleterious effect of progestins on breastfeeding, but it was limited by lack of a 
comparison group allowing for assessment of differences in outcomes by progestin type or by timing of 
progestin initiation. Other randomized studies comparing the effect of early versus delayed initiation of 
progestins have evaluated different delivery systems such as intrauterine devices (IUDs) and implants. 
There are no studies comparing breastfeeding outcomes among d-POP and n-POP users. Most studies 
have examined the effect of progestins on maternal, milk, or infant outcomes in isolation and have 
failed to evaluate the effect of progestin exposure during breastfeeding on the mother-milk-infant triad. 
An adequately powered, high-quality, randomized controlled trial (RCT) using validated measures of 
maternal, infant and milk outcomes and including d-POP users is needed to minimize the effects of bias 
and confounding and overcome the weaknesses in the rigor of the prior research. Our goal with this 
pilot study is to inform a future large-scale randomized controlled trial. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
1. There are potential risks of loss of confidentiality.  
2. There is risk of stress, emotional distress, inconvenience, and possible loss of privacy associated 
with participating in a research study. 
3. These are known risks of POPs, however they are routinely prescribed for women, both post-
partum and otherwise.  
2.3.2 KNOWN POTENTIAL BENEFITS  
Patients may not experience a direct benefit from participation in this study. However, we hope that this 
study will help us determine if POPs can be provided during the early postpartum period with minimal 
impact on breastfeeding, infant growth and high patient satisfaction rates. There may be a benefit to 
women in the early initiation POP group to avoid unplanned early repeat pregnancies. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The potential benefit of early postpartum POP use outweighs the potential risks of changes to 
breastmilk, breastfeeding or infant growth changes.  
 
 
3 
OBJECTIVES AND ENDPOINTS 

Postpartum Progestin-Only Pill and Breastfeeding Study 
 
Protocol 803604 
 
 
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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
Aim   
Variable  
Description 
Source  
Maternal Outcomes  
1a 
Breastfeeding 
Exclusive breastfeeding: own mother’s milk via breast or 
bottle.  
Predominant breastfeeding: greater than 75% of the infant’s 
diet is their own mother’s milk; the remainder of the diet is 
formula, donated milk, or other supplemental foods 
Mixed Breastfeeding: 25-75% or more of the infant’s diet is 
their own mother’s milk 
Predominantly supplementing: <25% diet is breastmilk 
No breastfeeding: infant is not consuming own mother’s milk 
End of weeks 2-8 
1a 
Supplementation 
type 
Donated breastmilk, formula, other milks (cow, plant-based, 
nut), juice, water, cereal, other foods  
End of weeks 2-8  
1b 
Progestin-only 
pill use  
Any use, timing of initiation of POP use (assigned), type of POP 
(assigned), number of missed pills  
End of weeks 2-8. 
1b. 
Contraception 
use 
Sterilization (male and female), intrauterine devices, 
subdermal implants, oral contraceptives (combined), condoms 
(male and female), injectables, emergency contraceptive pills, 
patches, diaphragms, sponges, cervical caps, spermicidal 
agents, vaginal rings, withdrawal, fertility awareness, 
abstinence, and LAM 
4 and 8 weeks 
 
Vaginal bleeding 
Number of days of any bleeding and spotting in last month  
Estimated at 4 and 8 
weeks 
 
Satisfaction with 
contraception  
Satisfied with method, would recommend method to a friend 
4 and 8 weeks 
 
Pregnancy  
Self-reported new pregnancy, pregnancy intendedness, 
whether planning to continue the pregnancy or not, and 
pregnancy outcome: continued, terminated, pregnancy loss 
4 and 8 weeks 
 
 
 
 
Milk Outcomes 
2 
Composition of 
breastmilk  
Fat, protein, carbohydrate (including oligosaccharide) content 
of milk  
4-week breastmilk 
sample  
 
Maternal 
perception of 
adequate milk 
supply  
Hill and Humenick Lactation Scale 
End of weeks 2-8 
Infant Outcomes  
3 
Change in infant 
growth  
Weight, length, and head circumference 
Change between 
baseline and 4 weeks 

Postpartum Progestin-Only Pill and Breastfeeding Study 
 
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This is a three-arm, placebo-controlled, double-blinded randomized controlled pilot trial that includes 8 
weeks of participation from enrollment to final follow-up.  
 
We hypothesize that the type of progestin used and the timing of progestin initiation will not have 
clinically meaningful effects on breastfeeding continuation, supplementation, the composition of 
breastmilk, or infant growth and body composition. In addition, we hypothesize that the timing of 
progestin initiation will not have a meaningful effect on progestin-only pill (POP) continuation, but that 
women will be more likely to continue d-POPs compared to n-POPs. Findings from this study will support 
more women to use progestin-containing contraceptives to prevent unintended pregnancy in the 
postpartum period with a greater understanding of the safety while breastfeeding. 
 
4.2 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study after she has completed all phases of the study 
including the last visit at 8 weeks postpartum.  
 
5 
STUDY POPULATION 
Postpartum women delivering a baby at University of California, San Diego (UCSD) within the past 7 days 
will be eligible. 30 women will be enrolled. Participants will be screened for eligibility according to the 
below criteria using a screening checklist. If eligible and interested in participating, a consent form will 
be signed.  
 
5.1 
INCLUSION CRITERIA 
There will be a total of 30 postpartum women enrolled in this study. Participants will need to meet the 
following criteria: 
-Are 18 years of age or older 
-Desires to use POPs for 3 months 
-Speak English or Spanish 
-Had a vaginal or cesarean delivery of a singleton full term (≥37 weeks) infant less than 168 hours prior 
-Intends to breastfeed exclusively for 6 months 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
-Desire another pregnancy in less than 6 months 
-Do not intend to exclusively breastfeed 
-Do not have access to a telephone 
-Have any medical contraindication to POPs 
-Have any contraindication to breastfeeding, including maternal illegal drug use, history of breast 
augmentation or reduction, infant with major congenital anomaly  
-Cognitively impaired 
-Currently incarcerated 
 
5.3 
SCREEN FAILURES 
For individuals who do not meet the criteria for participation in this trial (screen failure) due to not 
meeting eligibility requirements, the reason will be documented. Potential participants who decline 

Postpartum Progestin-Only Pill and Breastfeeding Study 
 
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participation will be noted and counted as well. No identifying information will be collected from screen 
failures.   
 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION 
Group 1: Initiation of d-POPs 120-160 hours after delivery (N=10) 
Group 2: Initiation of n-POPs 120-160 hours after delivery (N=10) 
Group 3: Initiation of d-POPs 4 weeks after delivery (N=10) [placebo starting 120-160 hours, continuing 
for 28 days] 
 
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Participants will be randomized to their assigned group by chance with a computer-generated 
randomization scheme. The participant and investigator will both be blinded to the group assignment. 
The investigational pharmacy will be aware of the group assignment of each participant and will 
encapsulate and prepare the blinded medications for the the research coordinator to deliver to the 
participant.  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
If a participant chooses not to move forward with initiation of the study POPs, she will remain in the 
study under observation. Remaining study procedures should be completed as indicated by the study 
protocol. Reasons for choosing another method of contraception will be documented and the 
participant followed for the study duration of 8 weeks.  
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants may withdraw voluntarily from the study at any time. The PI or study team will not 
withdraw anyone from the study without specific request from the participant. Medical care will be 
provided by the patient’s clinician as standard of care in the case of study withdrawal. Research 
participants who sign the informed consent form, and are randomized and receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the study will not be 
replaced. 
 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if she fails to return for any scheduled visits and is 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to respond to surveys or return to the clinic for 
the required study visit: 

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• 
The research coordinator will attempt to contact the participant, re-send surveys and 
reschedule the missed visit within one week and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant, including 3 telephone calls or texts. These contact 
attempts should be documented in the participant’s study file.  
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
This pilot study is a placebo-controlled double-blinded RCT. We will recruit women in the third trimester 
of pregnancy during their routine prenatal care clinical visits and post-partum (PP) during their hospital 
stay. Women will not be enrolled and randomized until after delivery. All women delivering at UCSD 
hospitals are offered comprehensive contraceptive counseling by nurse midwives or physicians during 
prenatal appointments and/or after delivery before discharge from the hospital.  
 
Enrollment Procedures: 
We will assess women who indicate that they desire POPs for contraception for eligibility after they have 
received contraceptive counseling. Research staff will identify postpartum women who are planning on 
utilizing POPs as postpartum contraception via review of medical records of patients receiving inpatient 
obstetrical services at UCSD. Study staff will visit these potential participants during their inpatient 
hospital stay to present the study and administer the pre-screening eligibility form if the patient is 
interested in participation. While only women who intend to use POPs for at least 8 weeks will be 
enrolled, all participants will be told if they are unhappy with POPs at any time, the study team will 
facilitate timely contraceptive counseling and referral to an appropriate provider to ensure that they can 
switch contraceptive methods at any time if they choose. 
 
After enrollment and prior to randomization, participants will be asked to complete a brief self-
administered demographic questionnaire using a private secure tablet that enters data directly into 
REDCap (Research Electronic Data Capture), a secure electronic data collection system. Demographic 
characteristics collected will include maternal age, race, Body Mass Index, gestational weight gain, 
parity, education, previous experience breastfeeding, previous contraceptive use history, breastfeeding 
intentions, delivery type and complications, infant stay in neonatal intensive care unit (and length of 
stay), infant birth weight, race, sex assigned at birth, and gestational age at birth. Participants will 
receive a gift card via text or email link for completing the survey. 
 
Randomization: 
A licensed medical provider on the clinical care team will review eligibility for the method and instruct 
patients on use of POPs prior to discharge from the hospital and will approve a prescription for both 
POPs. Participants will then be randomized to (1) early d-POPs to be initiated at 120-168 hours (5-7 
days) after delivery, (2) early n-POPs to be initiated at 120-168 hours after delivery, or (3) placebo for 28 
days followed by d-POPs initiated at 4 weeks (28-35 days) after delivery, at a 1:1:1 ratio (Figure 2). Study 
staff will then provide participants with written and verbal instructions about when to initiate the 
method and to take the study medications in the order dispensed. Participants, care providers, and 
research staff will be blinded to group assignment. Participants will be instructed on lactational 

Postpartum Progestin-Only Pill and Breastfeeding Study 
 
Protocol 803604 
 
 
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amenorrhea method (LAM), a highly effective form of contraception, and will be counseled that if they 
no longer meet criteria for LAM, then they may be at risk for unintended pregnancy between days 28 
and 33 and should use condoms or abstain from intercourse during that time. Before day 28, the CDC 
Selected Practice Recommendations state that a provider can be “reasonably certain that woman is not 
pregnant” regardless of LAM use and after day 33 all study drugs will be effective contraception 
regardless of group assignment. 
 
The research team will dispense two 28-day pill packs containing either d-POPs, n-POPs, or one placebo 
and one d-POPs, as determined by the randomization scheme, and labeled 1st and 2nd. For participants in 
group 3, the first pack will contain only placebo to facilitate delayed initiation while ensuring blinding. D-
POP packs will include 24 active and 4 placebo tablets per month, and n-POP packs will include 28 active 
tablets, packaged in order of daily use. All d-POP, n-POP, and placebo tablets will be encapsulated by the 
research pharmacies to have an identical appearance. 
 
Figure 2: Outcome Evaluation Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surveys:  
Investigators will send participants hyperlinks via 5 text messages weekly at the end of weeks 2, 3, 5, 6, 
and 7 PP. Hyperlinks will lead to a brief questionnaire that participants can complete through a 
smartphone or tablet. Participants will complete a tablet-based survey in person at their 4 week visit. 
Participants will receive an emailed hyperlink at the end of week 8 which will lead to a longer 
questionnaire. A telephone survey will be available as an alternative to the digital questionnaires if 
desired. Survey questions will address continuation of and satisfaction with breastfeeding, the use of 
supplemental feeding, types of supplemental feeding being used, use of contraception, and satisfaction 
with contraception.  
 
At 8 weeks PP, participants will be emailed and requested to complete a more detailed questionnaire 
eliciting breastfeeding continuation, supplementation amount and type, episodes of lactation support, 
perception of adequate milk supply, vaginal bleeding patterns, satisfaction with breastfeeding and 
Baseline Survey 
Randomization (N=30) 
Group 1: Initiation of d-
POPs 120-160 hours 
after delivery (N=10) 
Group 2: Initiation of n-
POPs 120-160 hours 
after delivery (N=10) 
Group 3: Initiation of d-
POPs 4 weeks after 
delivery (N=10) [placebo 
starting 120-160 hours, 
continuing for 28 days] 
Surveys 
Weekly text survey at weeks 2, 3, 
5, 6 and 7, breastfeeding 
continuation and supplementation 
outcomes (Aim 1) 
-Electronic survey at 4 and 8 
weeks, breastfeeding and 
t
ti
t
(Ai
1)
Milk and Infant growth outcomes  
-Milk sample at 4 weeks, milk 
composition (Aim 2) 
-In-person visit at 4 weeks 
postpartum, infant weight and body 
composition (Aim 3) 
 

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contraceptive use, satisfaction with contraception, infant health and well-being, and any new 
pregnancies and respective pregnancy outcomes if available. Additional potential confounding factors 
will be explored, such as use of nipple shields, pacifiers, breastmilk expression, and other medications 
the participant is using. Participants will receive a gift card via text or email link for each completed 
survey.  
 
Both text and email questionnaires will be sent via a hyperlink that connects to a HIPAA-compliant 
secure platform that will input the data directly into a REDCap database. Participants who do not have 
smartphones or email access will be offered participation instead using phone surveys administered by 
study staff and gift cards will be mailed to these participants.  
 
Breastmilk collection and analysis: 
Women will attend an in-person visit at 4 weeks PP with their infant. Participants will have the option to 
collect a mid-feeding sample at home with all pumping materials and instructions sent to her home or 
collect a sterile sample at the visit using a study-provided breast pump. 10 mLs of breastmilk from the 
collection (either refrigerated sample brought to the visit or collected on-site) will be frozen at the site 
of the visit at the research site. The milk samples will be frozen at -80 degrees onsite. The lab will use 
liquid chromatography to assess the composition of breast milk and compare the concentrations of total 
fat, total protein and carbohydrates including oligosaccharides. 
8.2 
SAFETY AND OTHER ASSESSMENTS 
A Data Safety and Monitoring Board (DSMB) is not planned for this small pilot study. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
The FDA definition of an Adverse event is any untoward medical occurrence associated with the use of 
an intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).  
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events 
that may not result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 

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• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
OR 
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (DE challenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 

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study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
 
8.3.3.3 EXPECTEDNESS  
 
The PI will be responsible for determining whether an adverse event (AE) is expected or unexpected.  An 
AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, by 
communication from the participant to the study team, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured. 
Information to be collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study product (assessed only by those with the training and authority to make a 
diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE. Changes in the severity of an AE will be documented 
to allow an assessment of the duration of the event at each level of severity to be performed. AEs 
characterized as intermittent require documentation of onset and duration of each episode. 
 
At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  
Events will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
All adverse events will be reported to th UCSD IRB. The management of information that is relevant to 
the protection of participants including adverse events, UPRs, protocol violations/deviations, interim 
results and protocol modifications will be the responsibility of the PI. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
All serious adverse events will be reported to th UCSD IRB. The management of information that is 
relevant to the protection of participants including adverse events, UPRs, protocol violations/deviations, 
interim results and protocol modifications will be the responsibility of the PI. 
 

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8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
The UCSD IRB provide guidance to the PI on informing participants regarding AEs and SAEs as needed.  
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
Unanticipated problems involving risks to participants or others to include, in general, any incident, 
experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
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 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigators will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the lead principal investigator (PI). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported to the IRB within reasonable 
timing of the investigator becoming aware of the problem.    
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
The IRB at each site will provide guidance to PIs on informing participants regarding UPs as needed.  
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 

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Comparisons will be made between groups 1 and 2 to assess differences in outcomes by type of 
progestin used, and between groups 1 and 3 to assess differences in outcomes by timing of progestin 
initiation. The primary outcome is the proportion of women exclusively breastfeeding at 8 weeks 
postpartum. Differences in baseline demographic characteristics and in variables between groups will be 
assessed using χ2, Fisher exact, or t-tests as appropriate.  
 
9.2 
SAMPLE SIZE DETERMINATION 
 
The sample size (N=30 in 6 months) was chosen to demonstrate feasibility to enroll 180 women in 36 
months at our site during a larger multi-site trial and to successfully complete follow-up.   
 
9.3 
POPULATIONS FOR ANALYSES 
 
The following datasets will be utilized for analysis: 
 
• 
Intention-to-Treat Analysis Dataset: All participants randomized with known outcomes per the 8 
week follow up survey. 
• 
Per-Protocol Analysis Dataset: Participants who reported taking their assigned POP throughout 
the study period and reported follow up data on the 8 week survey. 
 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
A survival analysis will be conducted to to assess time spent exclusively breastfeeding.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Proportions will be compared using chi-square tests. ANOVAs will be used to calculate means for 
analysis using all 3 groups and t-tests for any pairwise comparisons.  
9.4.4 SAFETY ANALYSES 
 
AEs and SAEs will be recorded by the study team when they become aware. Adverse events leading to 
premature discontinuation from the study intervention and serious treatment-emergent AEs will be 
presented in a table. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Baseline characteristics such as demographic information (age, education level, race, ethnicity and 
employment status) will be collected. At the time of enrollment, questions will also be asked about 
pregnancy history, past use of contraception, use of donor milk and current perception of adequacy of 

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human milk supply. Means and proportions of respondents in each of the two groups will be compared 
to assess for success of randomization.  
 
9.4.6 PLANNED INTERIM ANALYSES  
Interim analyses are not planned during this short pilot study.  
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator and funding agency. 
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform 
study participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for 
the termination or suspension.  Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor and/or IRB. 
 
 
10.1.2 STUDY GOVERNANCE 
The name and contact information of the Principal Investigator: 
Sarah Averbach, MD, MAS, Associate Professor 
University of California, San Diego  
9500 Gilman Drive, La Jolla, CA, 92093 
858-329-4464 
saverbach@health.ucsd.edu 
 
10.1.3 SAFETY OVERSIGHT 
 
Safety oversight will be monitored by the study PI.  
 

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10.1.4 CLINICAL MONITORING 
 
Data verification will take place periodically. This will ensure data completeness and monitor safety of 
participants.  
 
10.1.5 DATA HANDLING AND RECORD KEEPING  
 
10.1.5.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
10.1.5.2 STUDY RECORDS RETENTION  
 
Study documents will be retained for 2 years after the formal completion of the study.  
 
10.1.6 PROTOCOL DEVIATIONS  
It is the responsibility of the PI to use continuous vigilance to identify and report deviations. Protocol 
deviations must be sent to the reviewing Institutional Review Board (IRB) per their policies. The site 
investigator is responsible for knowing and adhering to the reviewing IRB requirements. 
 
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