Pressure Dynamics in the Non-gravid Uterus: Development of an Intrauterine Pressure Threshold to Confirm Tubal Occlusion After Nonsurgical Permanent Contraception
Conditions: Sterilization, Female, Fallopian Tube Occlusion
Sponsor: Oregon Health and Science University

 
 
 
 
Official Title: Development of an Intrauterine Pressure Threshold to Confirm Tubal Occlusion 
 
 
 
 
 
Principal Investigator: Jeffrey Jensen, MD, MPH 
 
 
 
Professor, Department of Obstetrics and Gynecology 
Oregon Health & Science University 
 
 
 
 
 
NCT No. 04071392 
 
 
 
 
Protocol Version Date: 17 February 2016 
 
 

1.3 Design and methodology 
 
1.3.1 Research design and General Methodological Approach  
In order to determine if intrauterine pressure can be used as a screening tool for 
confirmation of tubal occlusion after non-surgical permanent contraception (NSPC), we propose 
a study with two stages:  
First stage: A cross-sectional, descriptive pilot study of intrauterine pressures taken in all 
consenting women presenting for hysterosalpingogram (HSG) for any indication over the 
course of twelve months. This will allow us to measure intrauterine pressure in a wide 
variety of women and to compare pressures in women with patent and occluded fallopian 
tubes. Additionally, we will evaluate the extent to which other factors are associated with 
intrauterine pressures such as BMI or parity. Using the above information, we will 
determine a threshold pressure to serve as a test with acceptably high sensitivity and 
specificity for diagnosing fallopian tube occlusion, using HSG as our gold-standard for 
comparison.  
 
Second stage:  
Recruitment for stage 1 was completed in December 2015 and unfortunately no 
significant difference in uterine pressure was found between women with patent and 
occluded tubes. However, there were many fewer women with occluded tubes recruited. 
Additionally, the majority of women with open tubes had not had prior term pregnancies 
whereas the majority of women with occluded tubes had undergone an Essure® procedure 
for permanent contraception after multiple term pregnancies. Maximum pressures for 
women with occluded and patent tubes were both averaged around 300mmHg. Given this 
novel information and the limitations of the recruited cohorts, the second phase will 
involve recruitment of parous women, 12 with a history of the Essure® procedure and 12 
without. Intrauterine pressure will be measured as in stage 1, both with normal saline and 
again during HSG with contrast. A standard volume will be infused and drawn back to 
see if the amount of volume returned is associated with blocked or open tubes. 
 
The study will be funded by the Society of Family Planning and coordinated through 
Oregon Health & Science University (OHSU) in Portland, Oregon. Study procedures will take 
place with Dr. Amy Thurmond at Women’s Imaging & Intervention (WI&I) in Lake Oswego, 
Oregon. Study procedures will be initiated following approval of the protocol by the institutional 
review board at OHSU. All of the necessary data collection will be performed on the day of the 
procedure, minimizing loss to follow up of study subjects. Of note, Dr. Amy Thurmond is an 
experienced clinician-researcher and international expert in women’s imaging. She is a former 
faculty member in radiology and adjunct professor in OB/GYN at OHSU, and she has an 
ongoing collaborative relationship with the OHSU OB/GYN Family Planning division. She has 
extensive experience as a PI. She has enrolled subjects for numerous studies at her imaging 
center and is familiar with good research practices. 
 
1.3.2: Criteria for the selection of subjects 
The WI&I center is a regional referral center for women’s radiology. Women who need 
evaluation of their uterine cavity and fallopian tubes, either for infertility investigation or 
confirmation of tubal occlusion after Essure®, are referred to the center by their primary 

gynecologist or fertility specialist. We will recruit separate cohorts for each stage. Inclusion and 
exclusion criteria will be the same for subjects in both Stage 1 and Stage 2. 
 
Inclusion criteria: 
1) Literate in English, Spanish, or Chinese  
2) Ages 18-50 
3) Already planning HSG as recommended by their referring physician 
4) Able to understand and sign an IRB-approved informed consent form 
5) Willing to complete a pre-procedure questionnaire 
Exclusion criteria:  
1) Currently pregnant as confirmed by positive high-sensitivity urine pregnancy test  
2) Currently using an intrauterine device (IUD)  
3) Hypersensitive to radio-opaque contrast 
4) History recognized as clinically significant by the investigator, such as symptoms of 
untreated or recent pelvic infection 
Inclusion criteria for Stage 2: 
1) Literate in English, Spanish, or Chinese  
2) Ages 18-50 
3) No history of infertility with current regular menstrual cycles occurring every 24-37 days 
4) At least one term vaginal delivery 
5) Have a negative urine pregnancy test on day of HSG procedure and not be at risk of a luteal 
phase pregnancy 
6) Willing to undergo a single HSG procedure 
7) Able to understand and sign an IRB-approved informed consent form 
8) Willing to complete a pre-procedure questionnaire 
Exclusion criteria for Stage 2:  
1) Currently pregnant as confirmed by positive high-sensitivity urine pregnancy test  
2) Currently using an IUD 
3) Hypersensitive to radio-opaque contrast 
4) History of cesarean section 
5) History recognized as clinically significant by the investigator, such as symptoms of 
untreated or recent pelvic infection 
1.3.3 Subject recruitment and allocation 
Subjects will be enrolled through Dr. Thurmond’s WI&I Center. Patients meeting 
inclusion and exclusion criteria will be recruited for participation either when they call to make 
their appointment or when they arrive for their appointment. Schedulers and receptionists at the 
imaging center will be provided with a pre-scripted recruitment message (Appendix D). Patients 

will be informed they will receive the same care whether or not they choose to participate in the 
study, and that they can remove themselves from the study at any point in time.  
For Stage 2, participants will be recruited from both WI&I and the general population 
using IRB-approved advertisements and from regular visitors to family planning and other 
clinics serving reproductive-aged women for gynecologic care and reproductive health services. 
Previously enrolled Stage 1 subjects who have Essure® devices in place may be contacted to see 
if they would like to participate in Stage 2. Subjects will be selected for the study according to 
the selection criteria detailed above. 
 
1.3.4 Description of the drugs and devices to be studied 
 
We will use a small inline pressure sensor to continuously monitor pressure during the 
HSG procedure. The sensor is a single use sterile device (DPT-100 - Sterile Deltran Disposable 
Blood Pressure Transducer Box, Utah Medical, Midvale, UT). The device has a pressure sensor 
that is sealed and is compatible with inline fluid delivery through a Luer-Lock connector. The 
output cord connects to a pressure sensor (PressureMAT™, PendoTech, Princeton, NJ) for 
continuous monitoring and recording of pressure throughout the procedure. Use of the pressure 
sensor will not inherently change the HSG procedure so subjects will not be at any additional 
risk or undergo additional discomfort if they choose to enroll.  
  
1.3.5 Admission procedure 
 
Subject enrollment: Eligible patients will be offered information about the study when 
they call to schedule their HSG, check-in for their HSG procedure, or contact/are contacted by 
the Women’s Health Research Unit (WHRU). If interested in participating, the potential subject 
will be mailed a copy of the study consent form to review prior to their scheduled appointment. 
On subject arrival for their HSG appointment, the study coordinator or investigator will verify 
that all inclusion criteria are met, review the study in greater detail, answer subject’s questions, 
and obtain informed consent in English or using a translator for both the fully translated consent 
form for Spanish speaking patients or the short form for Chinese speaking patients. Study 
coordinators are employees of the WHRU at OHSU, have completed all required research 
training, and are familiar with the procedures of contraception-related research and use of the 
pressure monitor from an ongoing study.  
Each subject will receive a unique study ID that will be recorded securely in a 
recruitment log. Following completion of informed consent, subjects will then fill out a 
questionnaire in the waiting room to obtain basic demographic data. The survey will be 
administered on a tablet computer using the online data management system RedCap or in paper 
form. Subjects will be weighed. Serum progesterone and estrogen levels will be obtained. Study 
coordinators are well trained in phlebotomy and will collect the samples to be run at the Oregon 
National Primate Research Center (ONPRC) laboratory. 
 

Intrauterine pressure measurement and HSG procedure: An experienced board-certified 
radiologist will conduct the HSG using standard technique. A flexible 5 French balloon catheter 
will be introduced through the cervical os and inflated either in the endocervical canal or in the 
uterine cavity, using 1 cc of air. Iohexol 300mgI/ml 
(Omnipaque; or its equivalent) contrast media will 
be introduced using constant fluoroscopic guidance, 
and images exposed when the tube or tubes first start 
to fill, when contrast agent enters the peritoneal 
cavity, and to document any important finding. The 
contrast medium will be injected via an infusion 
pump set at a constant rate of 2-8 mL/min based on 
prior studies [11]. Usually 5 cc of contrast agent are 
used, up to a maximum of 20 cc of contrast, and 5 
total films. Fluoroscopy time is 1.5 ± 0.7 minutes. 
Occasionally prone and/or 10 minute delayed images will be obtained in an attempt to 
completely visualize the fallopian tubes. We will use a small inline pressure sensor to 
continuously monitor pressure during the HSG procedure. The sensor is a single use sterile 
device (DPT-100 - Sterile Deltran Disposable Blood Pressure Transducer Box, Utah Medical, 
Midvale, UT) (Fig.1). The device has a pressure sensor 
that is sealed and is compatible with inline fluid delivery 
through a Luer-Lock connector. The output cord 
connects to a pressure sensor (PressureMAT™, 
PendoTech, Princeton, NJ) for continuous monitoring 
and recording of pressure throughout the procedure 
(Fig.2). Pressure will be measured continuously but we 
will mark the following points during HSG for uniform 
comparison of pressures during the procedure: 1. 
Catheter in place, balloon is filled; 2. Initial filling of 
cavity with contrast; 3. Initial filling of one tube; 4. 
Complete filling of both tubes; 5. End of filling; 6. 
Balloon deflated. We will mark the pressure at the time 
filling is discontinued if bilateral tubal occlusion is observed and also if the patient is 
repositioned during the procedure. Once the HSG procedure is complete, the radiologist will 
complete a brief survey indicating location of the catheter balloon on inflation, uterine position, 
results of the HSG and whether or not any uterine pathology or Müllerian anomalies were noted.  
 
Validation stage: In stage 2, the exact same enrollment, intrauterine pressure 
measurement and HSG procedure will take place in a second cohort of women. However, after 
the HSG catheter is placed but prior to contrast infusion, infusion of 10cc of normal saline via 
the HSG catheter and infusion pump will be performed. The infusion of saline will be done with 
the infusion pump at a constant rate as in stage 1, and will stop when a full 10cc has been infused 
or when the subject complains of pain or discomfort. After one minute, the radiologist will use 
the attached syringe to draw back the intrauterine fluid. This step has been added to both 
measure intrauterine pressure and the amount of fluid returned. This will provide information 
about the internal reliability of the pressure measurements as well as about the volume of fluid 
that can be recovered in patients with blocked or open tubes. Subjects will specifically be 

recruited according to the above enrollment criteria to undergo the saline infusion, HSG and 
pressure monitoring procedure. 
 
1.3.6 Follow-up procedure 
All of the necessary data collection will be performed on the day of the procedure, 
minimizing loss to follow-up of study subjects. 
 
1.3.7 Criteria for discontinuation 
Patients have the right to withdraw from the trial at any time on their own request for any 
reason; the reason for withdrawal will be recorded in detail. No further data will be obtained 
from the patient once withdrawal occurs. If the HSG and intrauterine pressure readings have not 
been completed by the time of withdrawal, the subject will be excluded from analysis. The Data 
and Safety Monitoring will be conducted by the investigators listed on the first page of the 
protocol. They will meet on an as-needed basis if any serious adverse events related to the study 
protocol are reported by the investigator.  
 
1.3.8 Laboratory and other investigations 
A) Laboratory: Serum estrogen and progesterone levels will be collected at the radiology center, 
then transported and analyzed at the ONPRC endocrine core lab using a validated platform. 
Since many women have irregular cycles and may not be sure of menstrual cycle timing, serum 
hormone levels will confirm whether or not ovulation has occurred at the time of the HSG. The 
results of the blood draw will be entered into the RedCap data management system by a WHRU 
study coordinator. Since blood sampling may be a barrier to recruitment, the hormone samples 
will be optional for women with a history of regular cycles in the early follicular phase, 
However, all women with tubal occlusion will be asked to provide a blood sample. 
B) Demographic and baseline clinical data: These will be self-reported and data will be collected 
on a RedCap computer-based questionnaire. We will ask information about age, height & 
weight, gravidity & parity, pregnancy outcomes, menstrual history including last menstrual 
period and menstrual history, current or recent contraceptive method if any, known uterine 
pathology such as fibroids, prior uterine procedures, surgeries, prior history of sexually 
transmitted infection, and known history of endometriosis or PID. 
C) Intrauterine pressure measurements: These will be continuously collected and stored for each 
subject using the PressureMAT™ software (PendoTech, Princeton, NJ) on a password-protected 
laptop. The study coordinator will record the data points 1-6, time filling is discontinued if 
bilateral tubal occlusion is observed, and whether the patient is repositioned during the procedure 
in the PressureMAT™ software, as indicated by the radiologist during the procedure. Each 
subject’s pressure data will be identified by their study ID and stored on the password-protected 
laptop. 
D) Volume of media infused versus returned: A standard 10cc of saline and subsequently 
contrast will be infused until 10cc is in the uterus or until the patient complains of pain. After 
one minute, the radiologist will use the already attached syringe to draw back the fluid. The 
study coordinator will record the volume infused and the volume returned. 

E) HSG results: The radiologist will complete a brief survey after each procedure on RedCap 
indicating location of the catheter balloon on inflation, uterine position, results of the HSG and 
whether or not any uterine pathology or Müllerian anomalies were noted. HSG images will be 
preserved as source documents for later review if needed. 
1.3.9 Data management 
The PI will manage data collection and monitoring for this study. Study personnel and 
study investigators will collect data at the procedure visit. The subject recruitment log will be 
kept confidential and in a locked office. A unique patient study identification number will be 
used for all RedCap data. Study identifiers kept in a logbook will be assigned to each patient to 
protect confidentiality. No patient names will be included with the study data during statistical 
analysis. Patient identifiers will be stored separately from the data files on the PI’s password-
protected computer. Only the study investigators will have access to this identifier list. Data 
and/or specimens from this study will be kept in a repository (WHRU Repository IRB # 6748) 
and may be shared using the patient study identification number with other investigators for 
future research.  
 
1.3.10 Data analysis 
The primary measurement for this study is the intrauterine pressure reading when filling 
is discontinued for subjects with tubal occlusion compared to the highest pressure obtained at 
data points 1-6 for those with tubal patency. We will refer to these measures as the peak 
intrauterine pressure. Secondary outcomes will include the correlation of subject characteristics 
with intrauterine pressures. 
We will visualize data by plotting each subject’s pressure reading trajectory across the six 
data points. We will characterize the mean, median and range of pressure readings at these data 
points. We will identify the peak intrauterine pressure for each subject to use as a continuous 
variable. A linear regression model will evaluate if other factors such as BMI, parity, uterine 
pathology or anomalies, or serum estrogen and progesterone levels are associated with peak 
intrauterine pressure. We will develop two-by-two tables to compare the various pressure 
thresholds to the gold-standard HSG findings and calculate the sensitivity and specificity of each 
pressure threshold. The sensitivities and specificities will then be used to create a ROC curve 
from which we will determine a pressure threshold value at which the area under the curve 
(AUC) is maximized.   
Stage 1 revealed intrauterine maximum pressures averaging around 300mmHg for both 
subjects with patent and open fallopian tubes. Thus, 300mmHg will be considered the normal 
maximum intrauterine pressure and a clinically relevant increase in pressure for women with 
blocked tubes is considered an increase of 100mmHg. We will also measure the volume of fluid 
medium infused and recovered with the hypothesis that more volume will be recovered in 
subjects with blocked tubes compared to those with open tubes. A difference in volume of 3cc is 
estimated to be clinically relevant. We will recruit cohort of normally cycling parous subjects, 
half who have had Essure® procedures, and half who have not. The uterine pressures and the 
volumes of fluid instilled and recovered from the two cohorts will be analyzed in the same 
manner as Stage 1. 
 
1.3.11 Number of subjects and statistical power 

While this study is hypothesis-driven, an estimate of the effect size is not known. 
Therefore, the initial stage of the study will recruit patients already scheduled to undergo HSG 
for any indication to provide the basis for a follow up validation study with an appropriate 
sample size. The goal of the study will be to establish a “cut-off” pressure measurement at or 
above which fallopian tube patency is not observed. WI&I performed almost 300 HSGs last year, 
of which 90% were infertility evaluations and 10% were post-Essure confirmations. As we do 
not yet know the intrauterine pressure in patients with bilateral tubal occlusion, we will estimate 
pressures of less than 350 mmHg in women with bilaterally patent fallopian tubes [11]. 
Assuming 20% of the infertility population who come to clinic for HSG has blocked tubes based 
on WI&I estimates, and the 98% of success rate of Essure at 3 months, we can estimate the ratio 
of patent and blocked tubes as 72:28. Recruitment of 55 subjects would permit us to see a 300 
mmHg elevation in those with occluded tubes with an alpha of 0.05 and power of 0.8 (Table 1). 
We anticipate an increase in 300 mmHg to be a conservative effect size estimate given abnormal 
(but not occluded tubes) have been reported to have a mean pressure over 800 mmHg [11]. 
However, in case the effect size is less than expected, we will enroll up to 150 subjects in stage 
1; this would allow us to have sufficient power to exclude a 200 mmHg difference.  
 
Table 1: Range of elevations in peak pressure that can be determined from a range of sample 
sizes  
 
 
Data from stage 1 were analyzed, but unfortunately a “cut off” pressure with maximal specificity 
and sensitivity was not identified. To address limitations of the stage 1 cohort, a second cohort of 
parous women will recruited to undergo pressure and volume measurements with a saline 
infusion and at the time of HSG. Given we have set a clinically significant change in pressure as 
100mmHg above the average pressure for women with patent tubes (300mmHg, SD 80mmHg), 
12 subjects (total N=24) will need to be recruited in both the Essure® and no-Essure® groups to 
achieve 80% power and an alpha of 0.05. This sample size will also allow us to detect a 
clinically significant difference of at least 3cc of fluid recovery between subjects with blocked 
and open fallopian tubes with an alpha of 0.05 and power > 80%. The needed number of subjects 
will be recruited from WI&I and WHRU.