Early vs. Interval Postpartum IUD Insertion: A Multi-site Randomized Controlled Trial
Phase: NA
Conditions: Contraception
Sponsor: University of California, San Diego

 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol: Early vs. Interval Postpartum IUD Insertion:  
A Multi-Site Randomized Controlled Non-Inferiority Trial 
Protocol Number: 172101 
National Clinical Trial (ClinicalTrials.gov) Identifier Number: NCT03462758   
Principal Investigator: Dr. Sarah Averbach, MD, MAS 
Funded by: Society of Family Planning 
Version: 03.01.2018 
 

 
 
  
 
ii 
Table of Contents 
1 
PROTOCOL SUMMARY .................................................................................................................................. 1 
1.1 
Synopsis .................................................................................................................................. 1 
2 
INTRODUCTION .............................................................................................................................................. 2 
2.1 
Study Rationale ....................................................................................................................... 2 
2.2 
Background ............................................................................................................................. 2 
2.3 
Risk/Benefit Assessment   ....................................................................................................... 3 
2.3.1 
Known Potential Risks ........................................................................................... 3 
2.3.2 
Known Potential Benefits ...................................................................................... 4 
2.3.3 
Assessment of Potential Risks and Benefits .......................................................... 4 
3 
OBJECTIVES AND ENDPOINTS ........................................................................................................... 4 
4 
STUDY DESIGN .................................................................................................................................. 5 
4.1 
Overall Design ......................................................................................................................... 5 
4.2 
Scientific Rationale for Study Design ...................................................................................... 5 
4.3 
End of Study Definition ........................................................................................................... 5 
5 
STUDY POPULATION ......................................................................................................................... 5 
5.1 
Inclusion Criteria ..................................................................................................................... 5 
5.2 
Exclusion Criteria ..................................................................................................................... 5 
5.3 
Screen Failures ........................................................................................................................ 6 
6 
STUDY INTERVENTION ...................................................................................................................... 6 
6.1 
Study Interventions ................................................................................................................. 6 
6.2 
Measures to Minimize Bias: Randomization and Blinding ...................................................... 6 
7 
STUDY INTERVENTION DISCONTINUATION/PARTICIPANT DISCONTINUATION/WITHDRAWAL ........ 6 
7.1 
Discontinuation of Study Intervention .................................................................................... 6 
7.2 
Participant Discontinuation/Withdrawal from the Study ....................................................... 6 
7.3 
Lost to Follow-Up .................................................................................................................... 7 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................................................................. 7 
8.1 
Efficacy Assessments ............................................................................................................... 7 
8.2 
Safety and Other Assessments ................................................................................................ 9 
8.3 
Adverse Events and Serious Adverse Events ........................................................................... 9 
8.3.1 
Definition of Adverse Events (AE) ......................................................................... 9 
8.3.2 
Definition of Serious Adverse Events (SAE) ........................................................... 9 
8.3.3 
Classification of an Adverse Event ........................................................................ 9 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 11 
8.3.5 
Adverse Event Reporting ..................................................................................... 11 
8.3.6 
Serious Adverse Event Reporting ........................................................................ 11 
8.3.7 
Reporting Events to Participants ......................................................................... 11 
8.4 
Unanticipated Problems ....................................................................................................... 12 
8.4.1 
Definition of Unanticipated Problems (UP) ......................................................... 12 
8.4.2 
Unanticipated Problem Reporting ...................................................................... 12 
8.4.3 
Reporting Unanticipated Problems to Participants ............................................. 12 
9 
STATISTICAL CONSIDERATIONS ................................................................................................................. 12 
9.1 
Statistical Hypotheses ........................................................................................................... 12 

 
 
  
 
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9.2 
Sample Size Determination ................................................................................................... 13 
9.3 
Populations for Analyses ....................................................................................................... 13 
9.4 
Statistical Analyses ................................................................................................................ 13 
9.4.1 
General Approach ............................................................................................... 13 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ....................................................... 13 
9.4.3 
Analysis of the Secondary Endpoint(s) ................................................................ 14 
9.4.4 
Safety Analyses .................................................................................................... 14 
9.4.5 
Baseline Descriptive Statistics ............................................................................. 14 
9.4.6 
Planned Interim Analyses .................................................................................... 14 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................................... 14 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ..................................................... 14 
10.1.1 
Study Discontinuation and Closure ..................................................................... 15 
10.1.2 
Study Governance ............................................................................................... 15 
10.1.3 
Safety Oversight .................................................................................................. 15 
10.1.4 
Clinical Monitoring .............................................................................................. 15 
10.1.5 
Data Handling and Record Keeping ..................................................................... 15 
10.1.6 
Protocol Deviations ............................................................................................. 16 
11 
REFERENCES .......................................................................................................................... 16 
12 
Abbreviations ........................................................................................................................ 18 
 

Early vs. Interval Postpartum IUD Insertion 
 
Protocol 172101 
 
 
1 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title:  
Early vs. Interval Postpartum IUD Insertion: A Multi-Site Randomized 
Controlled Non-Inferiority Trial 
Study Description: 
This is a randomized controlled non-inferiority trial comparing the 
expulsion rate of early postpartum IUDs (intrauterine devices) inserted 
between 2-4 weeks postpartum to the standard interval placement at 6-8 
weeks postpartum 
 
 
Objectives: 
Primary Objective: Complete IUD expulsion at 6 months postpartum 
Secondary Objectives: Partial IUD expulsion at 6 months postpartum, IUD 
utilization, IUD removal, IUD perforation, pelvic infection, pain, vaginal 
bleeding, and user satisfaction at 6 months postpartum 
Endpoints: 
Primary Endpoint: Speculum and ultrasound evaluation 
Secondary Endpoints: Speculum, ultrasound and x-ray evaluation, self-
reported outcomes (survey results) 
Study Population: 
Postpartum women who delivered an infant within the previous 10 days 
Phase: 
N/A 
Description of 
Sites/Facilities Enrolling 
Participants: 
Academic medical centers: the University of California, San Diego (UCSD); 
University of New Mexico (UNM); University of Illinois, Chicago (UIC); and 
Naval Medical Center, San Diego (NMCSD) 
Description of Study 
Intervention: 
Postpartum insertion of IUDs at 2-4 weeks after delivery vs. 6-8 weeks 
after delivery 
Study Duration: 
2 years 
Participant Duration: 
6 months (with optional 12-month participation offered) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Early vs. Interval Postpartum IUD Insertion 
 
Protocol 172101 
 
 
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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Intrauterine devices (IUDs) provide highly effective contraception and are historically placed at the 
interval six-week PP visit for women who desire intrauterine contraception. Since ovulation can occur as 
early as 25 days postpartum, there is a risk that women could become pregnant between 4-6 weeks 
postpartum. 
The early postpartum (EPP) period, 2-4 weeks postpartum, could be a convenient time for women to 
receive contraception, including IUDs. Women can’t become pregnant in the first 25 days postpartum. 
The visit can be co-located with other health care visits, such as well baby visits, that occur in this time 
frame.  
Offering women EPP IUDs may decrease the risk of undesired pregnancy and rapid repeat pregnancy. 
 
2.2 
BACKGROUND  
 
Intrauterine devices (IUDs) provide highly effective contraception and are historically placed at the 
interval six-week postpartum visit for women who desire intrauterine contraception. Since ovulation can 
occur 25 days postpartum, there is a risk that women could become pregnant between 4-6 weeks 
postpartum. 
Immediate postpartum (IPP) IUD placement, within 10 minutes of delivery, is safe and effective as well 
as convenient for providers and patients (ACOG, 2016). Despite the benefits of IPP IUD insertion, there 
are significant barriers to widespread implementation, most importantly a lack of reimbursement 
mechanisms and training. Although efforts are currently in place to increase access to IPP IUDs, they are 
developing slowly, and additional strategies are urgently needed to allow for flexibility and multiple 
options for provision of highly effective contraception in the postpartum period.  
Both immediate and interval IUD insertion carry unique risks. IPP IUD insertion is associated with an 
increased risk of expulsion (IUD being pushed out of the uterus) with rates as high as 24-38% (Chen, 
2011; Goldwaithe, 2017) compared to IUDs placed at 6 weeks PP 3-5% (Chen, 2011). However, interval 
IUD insertion at 6 weeks postpartum is associated with a small increase in the risk of uterine perforation 
(IUD going through the uterine wall), particularly among breastfeeding women (Heinemann, 2015) and 
there is a risk that women will become pregnant by 6 weeks postpartum leading to undesired 
pregnancies and rapid repeat pregnancies.  
The early postpartum (EPP) period, 2-4 weeks postpartum, could be a convenient time for women to 
receive contraception, including IUDs. Women can’t become pregnant in the first 25 days postpartum. 
The visit can be co-located with other health care visits, such as well baby visits, that occur in this time 
frame.  
Three studies have shown that EPP IUD placement is feasible and acceptable (Baldwin 2016, Zerden 
2017, Chen 2017). There were no perforations among participants in these studies and no complete 
expulsions. Partial IUD expulsion rates were low (2-5% at 6 months). However, these studies were not 
powered to determine IUD expulsion. The purpose of this study is to compare the expulsion rate of EPP 
IUDs inserted between 2-4 weeks postpartum to the standard placement timing at 6-8 weeks 
postpartum. This trial will provide a key piece of missing data that will allow women to be counseled 
appropriately about the benefits and risks of EPP IUD insertion and potentially allow women access to all 
methods of contraception, including the most effective methods of contraception, at time points earlier 
than the traditional six-week postpartum visit. 

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2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
1. Loss of confidentiality: there is risk of stress, emotional distress, inconvenience, and possible loss of 
privacy associated with participating in a research study. There will be a need for medical record 
access to assess patient demographics and clinical outcomes. Most study data will be stored in the 
HIPAA-secure online REDCap database. Any printed study data (such as consent forms) will be 
secured in a locked cabinet/filebox, and only those directly involved in the study will have access to 
these including the investigators who will process the data. Data will only be saved under a secure 
file on a computer requiring a log-in password. Data will be shared between institutions and UCSD 
using REDCap, which is a secured HIPAA-compliant web application (https://redcap.ucsd.edu). 
NMCSD is not able to enter data directly into REDCap. NMCSD will, instead, use paper copies of all 
study instruments and share them via secure fax to UCSD; UCSD staff will enter data into REDCap. 
Once data is entered into REDCap, UCSD will shred the paper copies. Shared patient identifiers 
include: patient initials, date of service, baby delivery date. Consent will be obtained in the patient’s 
private postpartum room, in the private clinical space where participant can ask questions without 
feelings of embarrassment or discomfort, and/or over the phone from a private office. The physical 
exam will be conducted in a private examination room. 
2. IUD expulsion or uterine perforation risk: there is a risk that IUD expulsion and uterine perforation 
could be greater than in the study group (EPP) compared to the standard of care group. Currently 
available data suggest that the risk of expulsion and perforation will be less than or equal to the risk 
of expulsion and perforation associated with the standard of care. There have been over 200 
women who have had documented EPP IUDs placed and the risks of expulsion have been low (<4%) 
and there have been no documented perforations (Baldwin 2016, Zerden 2017, Chen 2017). In 
addition, ultrasound studies have shown that approximately two-thirds of uterine involution occurs 
by 14 days PP which could be protective against expulsion (Belachew, 2012) In the EPP period the 
uterine wall is thicker than 6 weeks postpartum, which could be protective against perforation 
(Watanagara, 2015). The practice of inserting IUDs at this time is approved and considered to be a 
category 2 practice (benefits outweigh the risks) from the CDC Medical Eligibility Criteria (CDC, 
Medical Eligibility Criteria, 2016). However, the data on this practice are minimal and thus there are 
potential risks to IUD insertion at this time which is why this study is urgently needed.  
All patients will be informed of possible IUD expulsion and uterine perforation (known and 
unknown). Clinicians may also use ultrasound guidance for placement if they feel that ultrasound 
will mitigate the risk of expulsion or perforation. Participants will be assessed at a follow-up visit for 
IUD expulsion and uterine perforation. A study clinician will conduct a bimanual pelvic exam and a 
transvaginal ultrasound at this visit and provide any care clinically required to address any IUD side 
effects or complications.  
3. There is a risk that an IUD could be placed when a woman is already pregnant. This is true only 
during the standard of care and it is a potential benefit of the EPP that women cannot yet be 
pregnant so soon after delivery (ovulation can’t occur until at least 25 days postpartum). Any 
woman who is > 25 days postpartum who has an IUD placed will be assessed for the risk of new 
pregnancy (will be asked if she has had unprotected intercourse and will be assessed for lactational 
amenorrhea). If > 25 days postpartum and at risk for pregnancy, then a urine pregnancy test will be 
done prior to IUD placement and an IUD will not be placed if a urine pregnancy test is positive until 
new pregnancy has been excluded. A clinician will see the patient and evaluate whether the positive 

Early vs. Interval Postpartum IUD Insertion 
 
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pregnancy test represents a new pregnancy or residual positive pregnancy test from the recently 
delivered pregnancy. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Patients may not experience a direct benefit from participation in this study. However, this study will 
help determine if IUDs can be provided during the early postpartum period with low expulsion rates and 
high patient satisfaction rates. There may be a benefit to women in the EPP group to avoid unplanned 
early repeat pregnancies. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The potential benefit of early postpartum contraception (the potential for decreased unwanted 
pregnancies, possible decrease in expulsion, and possible decrease in perforation) outweighs the 
potential risks of increase in expulsion and/or uterine perforation. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To determine if the risk of 
complete expulsion of EPP IUDs is 
non-inferior to interval PP IUDs 
 
 
Diagnosis of IUD expulsion by 
speculum and ultrasound exam at 
6 months postpartum. Expulsion 
defined as no IUD within the 
uterus by ultrasound or x-ray. 
   
 
We propose that greater 
than or equal to a 6% 
difference in expulsion at 
6 months postpartum 
between the two arms is 
clinically meaningful (6% 
non-inferiority margin). 
Secondary 
 
 
To assess the proportion of 
participants utilizing the IUD at 6 
months 
Transvaginal and speculum exam 
to confirm presence of the IUD at 
6 months. 
From a public health 
perspective, the duration 
of IUD use is important for 
pregnancy prevention. 
To determine if the risk of partial 
expulsion of EPP IUDs is non-
inferior to interval PP IUDs 
 
Diagnosis of IUD expulsion by 
speculum and ultrasound exam at 
6 months postpartum. Partial 
expulsion defined as IUD 
protruding from the external 
cervical os on speculum exam or 
any part of the IUD seen below 
the internal cervical os on 
transvaginal ultrasound. 
We propose that greater 
than or equal to a 6% 
difference in partial 
expulsion and perforation 
at 6 months postpartum 
between the two arms is 
clinically meaningful (6% 
non-inferiority margin). 
Tertiary/Exploratory  
 
 
To assess the risk of perforation 
after EPP IUD compared to interval 
postpartum IUDs 
IUD not visible in uterus on 
transvaginal ultrasound, but 
visible on pelvic x-ray at 6 months. 
 
 
 

Early vs. Interval Postpartum IUD Insertion 
 
Protocol 172101 
 
 
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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This is a multi-site, two-arm, non-blinded randomized controlled non-inferiority trial that includes 6 
months of participation from enrollment to final follow-up.  
 
Hypothesis: We hypothesize that the EPP IUD expulsion rate at 6 months postpartum will be lower than 
the reported expulsion rate for IPP IUDs (24%) and non-inferior at a 6% margin to the expulsion rate for 
interval postpartum IUDs (previously reported at 3-5%). 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Traditionally, IUDs are placed at 6-8 weeks postpartum, therefore the standard of care will serve as the 
control condition. We are using a 6% non-inferiority assuming a 4% expulsions rate in the interval group 
according to prior research. This difference is presumed to be clinically meaningful. 
 
4.3 
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 6 months postpartum or the optional 12-month postpartum phone call.  
 
 
5 
STUDY POPULATION 
Postpartum women delivering a baby at one of the 4 study sites are eligible: University of California, San 
Diego (UCSD); University of New Mexico (UNM); University of Illinois, Chicago (UIC),  and the Naval 
Medical Center, San Diego (NMCSD). 404 women will be enrolled between the 4 different study sites.  
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 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1) Gave birth less than or equal to 10 days ago 
2) Desires to use an IUD for contraception (either copper or levonorgestrel-containing)  
3) Willing and able to sign an informed consent  
4) Willing to comply with the study protocol 
5) Age greater than or equal to 18 years 
6) English or Spanish speaking  
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1) Uterine anomaly or leiomyomata which would not allow placement of an IUD 
2) Desire for repeat pregnancy in less than 6 months  
3) Evidence of intra-uterine infection (chorioamnionitis or postpartum endometritis) treated with 
antibiotics 
4) Ruptured uterus at the time of delivery 

Early vs. Interval Postpartum IUD Insertion 
 
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5) Received a postpartum tubal ligation or immediate postpartum IUD or implant at delivery 
6) Incarcerated women or women with significant cognitive impairment prohibiting consent 
7) 4th degree perineal laceration at delivery  
8) Any medical contraindication to IUD per the US CDC Medical Eligibility Criteria 
9) Any suspicion of new pregnancy  
 
 
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 
participation will be noted and counted as well. No identifying information will be collected from screen 
failures.   
 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION 
Control: IUD placed 6-8 weeks postpartum (standard of care, interval placement) 
Intervention: IUD placed 2-4 weeks postpartum (early postpartum placement, EPP) 
 
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Participants will be randomized to receiving EPP or Interval IUD placement by chance with a computer-
generated randomization scheme in alternating blocks of 4 and 6 stratified by IUD type and site. The 
group assignment will be in opaque sealed envelope that will be opened by the research assistant. The 
participant will not be blinded to the group assignment. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
If a participant chooses not to move forward with placement of an IUD, 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 6-12 months.  
 
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. 
 
 

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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 return to the clinic for a required study visit: 
• 
The sites will attempt to contact the participant 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  
a. Admission/Enrollment Procedure 
All women in the 4 study health centers are educated about postpartum contraception during antenatal 
care. All postpartum women who do not receive an IPP IUD or tubal ligation will be asked if they are 
interested in the IUD for contraception while on the postpartum floor. If they plan to choose an IUD 
they will be asked for verbal assent to be pre-screened for the study. If a woman gives verbal consent to 
be pre-screened, a research assistant will administer the Pre-Participation Questionnaire/Eligibility 
Checklist. Women who meet inclusion criteria, meet no exclusionary criteria, and want to participate, 
will be formally consented to participate in the study. Signed informed consent forms will be collected. 
Subjects will be given copies of the consent document and a copy of the “Experimental Subject’s Bill of 
Rights,” and a HIPAA Authorization form for medical data to be released for research purposes. Enrolled 
participants will then be randomized to EPP or Interval PP IUD placement within 10 days of delivery. The 
Research Assistant (RA) will open the sealed envelope with the appropriate randomization envelope for 
the assigned participant number to unblind the participant to her assigned group. Participant numbers 
are assigned sequentially by each site. Participants will then be asked to complete the Baseline 
questionnaire.  
For women who believe they want an IUD postpartum but are unsure whether or not they would like to 
be part of the study, study staff will provide them with our contact information, an informed consent 
form, a Subject’s Bill of Rights, and a HIPAA Authorization form for medical data to be released for 
research purposes. If they decide they are interested in participating while they are still in the hospital, 
the RA will go to their postpartum floor within 24 hours and will pre-screen/enroll as outlined above. For 
interested women who are being discharged from the hospital, staff will ask them to call us to discuss 
the study. Over the phone, the RA will ask for verbal consent to pre-screen for the study. If a woman 
gives verbal consent to be pre-screened, the RA will administer the Pre-Participation 
Questionnaire/Eligibility Checklist. For women who meet inclusion criteria, meet no exclusionary 
criteria, and want to participate, the RA will review the Informed Consent and HIPAA Authorization 
forms and then ask the woman to sign the forms and bring the signed copies to their first study visit. The 
woman will be officially enrolled in the study at that point. The RA will then open the randomization 
envelope and schedule the first study visit at either 2 weeks or 6 weeks postpartum once the consent is 

Early vs. Interval Postpartum IUD Insertion 
 
Protocol 172101 
 
 
8 
signed. The RA will administer the Enrollment Survey either over the phone or in person before the first 
research visit. 
b. Two Week Postpartum Visit 
All women randomized to EPP will be scheduled to have an IUD placement visit with their designated 
prenatal care provider between 14 and 28 days. Women will be scheduled to see a nurse midwife or 
physician based on their obstetrical history and prenatal care. IUDs will be placed by the patient’s usual 
prenatal provider or any provider that the patient would normally be referred to for IUD placement. 
Whether ultrasound guidance is used for placement will be at the discretion of the clinician. Participants 
will be compensated with a $20 gift card for their time and participation after completing the IUD 
Insertion survey. If a patient in the interval group is seen by her provider at 2 weeks postpartum for 
other reasons an IUD will not be placed at that visit. Providers will be compensated with a $5 gift card 
for their time completing a brief questionnaire for every patient seen at 2 weeks who is participating in 
the study.  
c. Six Week Postpartum Visit 
All women will be scheduled to have a routine postpartum visit with their designated prenatal care 
provider between 42-56 days postpartum according to the standard of care at the health centers.  
Women will be scheduled to see a nurse midwife or physician based on their obstetrical history and 
prenatal care. Women in the interval group will be assessed for IUD placement at this visit per the 
standard of care at the center. IUDs will be placed by the patient’s usual prenatal provider or any 
provider that the patient would normally be referred to for IUD placement. Whether ultrasound 
guidance is used for placement will be at the discretion of the clinician. Participants will be compensated 
with a $20 gift card for their time and participation. Participants will be asked to complete either the 
insertion visit questionnaire or the string check questionnaire depending on their assignment group. 
Providers will be compensated with a $5 gift card for their time completing a brief questionnaire for 
every patient seen at six weeks postpartum. 
D. Optional String Check Visit: 
Whether a follow-up string check visit is scheduled after six weeks will be at the discretion of the 
clinician according to standard practice of the clinic. String checks are not recommended by the CDC but 
are common practice. If a string check is scheduled by the clinician at any time (according to their 
personal practice or participant needs) then the participant will be asked to complete the string check 
questionnaire at that time.  
e. Six Month Follow Up Visit 
All women will be scheduled for a 6-month follow up study visit to assess for IUD expulsion, perforation, 
pregnancy, IUD removals and acceptability. A study clinician will conduct a bimanual pelvic exam, a 
speculum exam, and a transvaginal ultrasound at this visit. Women will also be asked to complete the 6-
month study questionnaire and will be compensated with a $20 gift card for their time and 
participation. The clinician will attempt to stay blinded to the participant’s group assignment by not 
reviewing the medical chart prior to the visit. 
f. 12 Month Optional Follow Up Call 

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9 
During baseline survey data collection, all women will be asked if they consent to a 12-month follow up 
phone call to assess for IUD expulsion, perforation, pregnancy, IUD removals and acceptability. 
8.2 
SAFETY AND OTHER ASSESSMENTS 
We will convene a Data Safety and Monitoring Board (DSMB) to review adverse events if any of the 
following occur: 
• 
At the midpoint of enrollment  
• 
If there is 1/3rd the expected enrollment at 6 months 
• 
More than four serious adverse events at any time deemed definitely, probably, or potentially 
related to the intervention   
• 
Rate of any serious adverse events is greater than 1% (including blood transfusion, 
hospitalization related to IUD, surgery related to IUD, death, IUD perforation, venous 
thromboembolism)   
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.  
 
• 
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. 

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• 
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 
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. 

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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 all three IRBs in a timely fashion (UCSD, UNM, UIC, and NMCSD) 
regardless of where the adverse event occurred. The on-site PI at each site will be responsible for 
monitoring adverse events and report any adverse events to each PI who will, in turn, report to their 
associated 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 each local PI at each site (Dr. Averbach- UCSD, Dr. Hofler -
UNM, Dr. Stortz – NMCSD, Dr. Hinz – UIC). 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
All serious adverse events will be reported to all three IRBs in a timely fashion (UCSD, UNM UIC, and 
NMCSD) regardless of where the adverse event occurred. The on-site PI at each site will be responsible 
for monitoring adverse events and report any adverse events to each PI who will, in turn, report to their 
associated IRB. 
 

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8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
The IRB at each site will provide guidance to PIs 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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• 
Primary Efficacy Endpoint: Complete expulsion of IUDs placed in the early postpartum is non-
inferior to IUDs placed at the standard interval time, assuming a 6% non-inferiority margin. 
 
• 
Secondary Efficacy Endpoints: 
o The proportion of participants utilizing the IUD at 6 months postpartum will be greater 
in the EPP group compared to the interval group.  
o Partial expulsion of IUDs placed in the early postpartum is non-inferior to IUDs placed at 
the standard interval time, assuming a 6% non-inferiority margin. 
o There will not be a clinically or statistically significant difference in the proportion of 
participants diagnosed with a pelvic infection. 
o Proportion of participants agreeing or strongly agreeing that they are satisfied with the 
IUD, and the timing of IUD placement, will be similar between groups. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
We hypothesize that EPP IUD expulsion will be non-inferior to interval insertion. We propose that 
greater than or equal to a 6% difference in expulsion at 6 months postpartum between the two arms is 
clinically meaningful (6% non-inferiority margin). Therefore, we estimate that 404 women will be 
needed [202 in each arm] to achieve an 80% power to detect a difference of 6% in expulsion at 6 
months at a significance level of .05 (two-sided alpha), assuming a 15% loss to follow up and that 5% of 
IUDs would not be placed after randomization (due to patient preference or new medical 
contraindication or inability to place the IUDs) and assuming a 4% expulsion rate in the interval group. 
We estimate that enrolling 404 patients allows us to achieve an 80% power to detect a difference of 6% 
or more between groups with a 1-sided type 1 error of 0.25%. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
The following datasets will be utilized for analysis: 
 
• 
Intention-to-Treat Analysis Dataset: All participants randomized with known outcomes at the 6 
month follow up visit*. 
• 
Modified Intention-to-Treat Analysis Dataset: Participants who received an IUD within 6 months 
of delivery with known outcomes at the 6 month follow up visit*. 
• 
Per-Protocol Analysis Dataset: Participants who received an IUD within the specified timeframe 
as designated by their group assignment with known outcomes at the 6 month follow up visit 
(14-28 days in the early group and 42-56 days in the interval group)*.  
 
*participants known to have an IUD outcome by ultrasonography, pelvic examination, or a contact up to 
240 days postpartum will be included. 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 

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Our primary outcome, the proportion of women with complete IUD expulsion at 6 months after delivery 
in the two groups, will be compared in the modified intention-to-treat (MITT) cohort using the Wald 
test. Women who change their mind about receiving the IUD after randomization, choose to receive the 
IUD after 6 months, or women who choose not to participate in the study any time after randomization, 
will be excluded from analysis for the MITT analysis. In addition, we will present a per-protocol analysis. 
The per-protocol analysis will include women who received their treatment according to the timeframe 
in which they were randomized. For the early IUD insertion group, per-protocol analysis will include 
women with documented receipt of the IUD insertion between 14 and 28 days postpartum. For the 
interval IUD insertion group, the per-protocol analysis will include only women with documented receipt 
of a postpartum IUD between 42-56 days postpartum. In both the MITT and per-protocol analyses IUD 
expulsion rates will be compared using the 2-sided test of noninferiority. If the CI for the risk difference 
does not cross the prespecified 6% margin, noninferiority will be confirmed. 
 
We will consider imputing missing data. However, if one group had no or few expulsion outcomes the 
model may not converge. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Partial IUD expulsion and perforation will be analyzed with the same methods as the primary outcome. 
IUD discontinuation over the six-month study period will also be analyzed using survival analysis.  Data 
will be censored either (1) at the last date of contact if a participant is lost to follow up or (2) time of IUD 
removal.  The Log-rank test will be used for an unadjusted comparison of the two survival functions. This 
will be presented graphically using Kaplan-Meier curves.   
For other secondary outcomes, normally distributed, continuous variables will be compared using 
Student’s t-tests as appropriate. The Mann-Whitney U test will be used to compare other continuous 
variables that are not normally distributed. Proportions will be compared using chi-square tests.  For 
small cell sizes, Fisher’s exact test will be used as appropriate.  
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, breastfeeding status and future fertility desires. 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 will be carried out only when the conditions to convene a DSMB are met.  
 
 

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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 under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including statistics and clinical. Members of the DSMB will be 
independent from the study conduct and free of conflict of interest, or measures should be in place to 
minimize perceived conflict of interest.  The DSMB will meet if the study meets the pre-specified 
conditions described in section 8.2. The DMSB will operate under the rules of an approved charter that 
will be written and reviewed at the organizational meeting of the DSMB. At this time, each data element 
that the DSMB needs to assess will be clearly defined. The DSMB will provide its input to the research 
team and IRBs as required.  
 

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10.1.4 CLINICAL MONITORING 
 
Data verification will take place every 6 months by site PIs, who will report to the study PI at UCSD. 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 site 
investigator. 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 site investigator 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. 
 
11 REFERENCES 
 
1) ACOG committee opinion 670, Immediate postpartum long acting reversible contraception. 
2016 
2) Baldwin M, Edelman A, Lim J, Nichols M, Bednarek P, Jensen J. Intrauterine device placement at 
3 versus 6 weeks postpartum: a randomized trial. Contraception 2016: (93) 356-63. 
3) Chen B, Reeves M, Hayes J, Hohmann H, Perriera L, Creinin M. Postplacental or delayed insertion 
of the levonorgestrel intrauterine device after vaginal delivery. Obstet and Gynecology 2011; 
116(5) 1979-1087. 
4) Chen MJ, Hou MY, Hsia JK, Cansino CD, Melo J, Creinin MD. Long-Acting Reversible 
Contraception Initiation With a 2- to 3-Week Compared With a 6-Week Postpartum Visit. Obstet 
Gynecol. 2017;130(4):788-794. 
5) Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 
2016. MMWR Recomm Rep. 2016;65(3):1-103. 
6) Belachew J, Axelsson O, Mulic-Lutvica A, Eurenius K. Longitudinal study of the uterine body and 
cavity with three-dimensional ultrasonography in the puerperium. Acta Obstet Gynecol Scand. 
2012;91(10):1184-90. PMID: 22497320. 
7) Goldwaithe L, Hyer J, Sheeder J, Tocce K, Teal S. Postplacental levonorgestrel and copper 
intrauterine device insertion after vaginal delivery and expulsion by 12 weeks postpartum: a 
prospective cohort study 

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8) Heinemann K, Reed S, Moehner S, Minh TD. Risk of uterine perforation with levonorgestrel-
releasing and copper intrauterine devices in the European Active Surveillance Study on 
Intrauterine Devices. Contraception 2015: 91(4)274-9 
9) Wataganara T, Phithakwatchara N, Komoltri C , et al. Functional three-dimensional sonographic 
study of the postpartum uterus. J Matern Fetal Neonatal Med 2015:28(18)2221-7. 
10) Zerden M, Steward G, Charm S, Bryant A, Garrett J, Morse J. Two week postpartum intrauterine 
contraception insertion: a study of feasibility, patient acceptability and short-term outcomes. 
Contraception 2017: (95) 65-70. 
 

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12 ABBREVIATIONS 
 
AE 
Adverse Event 
DSMB 
Data Safety and Monitoring Board 
EPP 
Early Postpartum 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IPP 
Immediate Postpartum  
MITT 
Modified Intention-To-Treat 
NMCSD Naval Medical Center, San Diego 
N/A 
Not applicable 
OHRP 
The Office for Human Research Protections 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
UCSD 
University of California, San Diego 
UIC 
University of Illinois, Chicago 
UNM 
University of New Mexico