Objective
To determine the feasibility, safety, and outcomes of an oil-based, iodinated contrast using office-based, ultrasound-imaged hysterosalpingography in women with infertility.
Design
Randomized Controlled Double Blind Clinical Trial.
Setting
Academic health center.
Intervention(s)
Tubal flushing with oil-based contrast medium (Lipiodol UF) versus saline.
Main Outcome Measure(s)
Ongoing pregnancy rate, pain, quality of life, and thyroid function.
Result(s)
Forty-eight patients (24 in each group) were analyzed. The groups were well-matched at baseline. Ongoing pregnancy was noted in 17% (4/24) of the oil-contrast group versus 37% (9/24) in the saline group. Saline group patients more frequently initiated infertility therapy in the six-month follow-up period (saline, 67% vs. oil, 33%), and no serious adverse events in either group. There were no differences in pain from the procedure between groups. There were no differences in thyroid function tests postprocedure between groups, but within the oil-contrast group, there was a slight increase in thyroid-stimulating hormone (post vs. preratio of geometric means: 1.18; 95% confidence interval [CI], 1.02–1.38) and decrease in Free T4 (postdifference vs. predifference in means: 0.08 ng/dL; 95% CI, -0.14 to -0.01). Immediately after the test, the physicians correctly guessed 79% of oil and 71% of saline randomization assignments, whereas patients correctly guessed 63% of oil and 38% of saline.
Conclusion(s)
This pilot study demonstrates the safety and feasibility of giving an oil-based contrast medium during ultrasound-imaged hysterosalpingography. Pregnancies were seen after oil-based administration, and this contrast is associated with minor thyroid function impairment.
Key Words
Hysterosalpingography is a common test in women with primary and secondary infertility to diagnose a normal uterine cavity and tubal patency, and traditionally, in the United States, it has been done under fluoroscopy. However, there is evidence that this test may have therapeutic benefits, as many couples conceive after the female has undergone the test before initiating treatment (
1
). The use of oil-based versus water-based contrast media for hysterosalpingography has been an ongoing subject of debate dating into the 1950s and before (2
). There have been a number of small randomized trials supporting oil-based media compared with water-based agents facilitating a greater benefit on pregnancy in women with infertility after the test (3
, 4
, 5
). This benefit has been confirmed with a large multicenter randomized controlled trial in the Netherlands (H2OIlie study) showing a nearly 40% improvement in live birth rate among patients with infertility randomized to an oil-based contrast medium versus a water-based medium (6
).The major concern about the use of oil-based contrast agents revolves around potential serious adverse events such as the intravasation of oil-based dye and oil embolism (
7
) or possible granuloma formation (7
, 8
). These have not been noted in the recent randomized trials, especially those with longer follow-ups (5
, 6
). Serious adverse events have been noted to be extremely rare after oil-based hysterosalpingography based on a recent systematic review (9
). Other concerns about the limitations of hysterosalpingography under fluoroscopy included limited access to fluoroscopy equipment, the increased expense of facility and multiple physician fees, patient, and provider exposure to ionizing radiation during the test, and the effect of absorption of iodine-containing contrast agents may transiently affect thyroid function. Studies have supported that hysterosalpingography performed using water-based agents or saline as a contrast medium is safe and effective at diagnosing endometrial abnormalities and tubal patency (10
, 11
, 12
). Further studies have shown pregnancy rates after varying types of hysterosalpingography to be comparable between ultrasound-based and fluoroscopy-based tests (13
).We hypothesized that oil-based contrast agents could be used for ultrasound-based hysterosalpingography and that we could potentially see a similar benefit on pregnancy rates and confirmation of safety with longer follow-up. We, therefore, designed and conducted a pilot study to test the efficacy of, as well as the tolerability and safety of, using a lipid-based oil medium for sonographic-based hysterosalpingography (Sono HSG) compared with water-based contrast (ie, normal saline) for women seeking fertility.
Materials and methods
Overview
We conducted a pilot randomized controlled double blind trial comparing an oil-based contrast agent (Lipiodol UF, Guerbet LLC, Princeton, NJ) compared with saline for Sono HSG testing in women with infertility. Patients were randomized in a 1:1 ratio to one of the two treatments using a pseudo-random number-generated algorithm unknown to the study investigators and patients. Patients were first randomized on 1/14/2019 and last randomized on 6/5/2020 into the study, which was conducted at the Penn State Milton S. Hershey Medical Center. The study was overseen by the investigational review board at the Penn State College of Medicine, and all patients gave written informed consent. We were not required to obtain an FDA IND for the study as Lipiodol UF is currently approved in the United States as a contrast medium for hysterosalpingography. The study was investigator-initiated but funded by Guerbet LLC, which also provided the oil-based contrast agent. The sponsor had no role in the design, conduct, or interpretation of the study results. The clinical trial was registered before the enrollment of the first patient (Clinicaltrials.gov: NCT03604549).
Subjects
The inclusion criteria for the study were women with infertility, aged 18–40 years, who were eligible for Sono HSG testing. They were in generally good health, willing to comply with study procedures, ready to undergo fertility treatment immediately after the test, and not planning on in vitro fertilization (IVF) treatment in the next six months. Exclusion criteria were known tubal or endometrial pathology (including polyps), at high risk for tubal disease based on a history of pelvic inflammatory disease, known hypersensitivity to Lipiodol UF or iodine-containing contrast media, unable to tolerate potential pain associated with Sono HSG, requiring IVF because of severe male factor, known pelvic adhesions or another factor suggestive of it. All study subjects who consented and could tolerate the exam underwent an initial Sono HSG with saline to ensure that there were no pelvic pathology or bilateral tubal occlusion, which were also considered to be exclusions from the subsequent tubal flushing by the study agent. As this was the first trial with this contrast medium using Sono SHG, we opted to error on the side of safety by first ensuring no pelvic pathology.
Study Procedures
A screening visit was conducted by telephone or in person to review eligibility for the study and obtain written informed consent. Eligible patients then scheduled their Sono HSG based on their menstrual period, or if anovulatory, based on blood work indicating they were in the follicular phase on the day before the Sono HSG. Randomization was performed at the Investigational Pharmacy at the Penn State Hershey Medical Center, and the study drug was dispensed in an opaque glass syringe to provide blinding and then transported from the hospital to the outpatient office site. The investigational pharmacy was notified of the consented patient’s scheduled Sono HSG on the day before the procedure. Randomization occurred the day of the procedure after contacting the patient by phone to confirm their attendance at visit to avoid wasting the study drug should the subject be unable to attend that day.
On the day of the Sono HSG, blood tests for the study, including thyroid function tests (
14
) and antichlamydial antibodies (15
), were obtained. The antichlamydial antibodies were sent to see if they correlated with any eventual pregnancy outcomes with normal patent tubes, as we have noted in a previous study (15
). Patients filled out the Ferti-QOL, a validated quality of life questionnaire for patients with infertility (16
). After a documented negative pregnancy test, all patients underwent screening transvaginal pelvic sonography followed by Sono HSG using saline as the contrast agent to visualize the endometrial cavity and then use of the FemVue Saline Air device (Femsys, Suwanee GA, 30024) which creates a saline-air contrast (seen as bubbles) through the Sono HSG catheter to allow visualization of tubal patency through transvaginal ultrasonography.As noted above, if the patient was able to tolerate this procedure and did not have any known endometrial pathology, and had at least one patent tube, the study contrast medium was then used to flush the tube(s). The investigational pharmacy pre-loaded 10 mL of the study contrast medium into an opaque glass syringe. We created a device to create bubbles using a three-way stopcock with the study syringe, an empty syringe, and an outlet to the balloon Sono HSG catheter. By passing the study medium back and forth through the two syringes, the attending nurse was able to create turbulence and bubbles, allowing visualization on ultrasound. We then proceeded with the injection of the study medium through the catheter at 2 mL increments. Injecting was stopped on visualization of tubal patency or exhaustion of the 10 mL maximum study dose. On completion of the injection procedure of the study drug, patients ranked their pain from the procedure using a visual analog scale (VAS) on a scale from 0 (no pain) to 10 (severe pain) (
17
). Additionally, both the patient and the provider were asked by the study coordinator to guess the treatment assignment for the study contrast agent.The patients were followed for six months after the procedure for adverse events and pregnancy. The patients returned after 2–4 weeks for follow-up blood thyroid function testing, and patients who did not conceive completed a repeat Ferti-QOL questionnaire at six months. All patients who conceived within the six-month follow-up period were followed till the end of pregnancy. Pregnancy and newborn records were obtained after the written release of the patient to document pregnancy outcomes.
Assays
The serum was tested at the University of Alabama at Birmingham for antiC. trachomatis IgG1 and IgG3 antibodies using a C. trachomatis EB ELISA, which have previously been reported (
15
, 18
). The optical density of reactions was measured at 405 nm (OD405), and cutoff values for positive IgG1 and IgG3 were ≥0.35 and ≥0.1, respectively. The reported serologic responses represent the mean of triplicate determinations of 1/32 diluted serum. Serum thyroid-stimulating hormone (TSH) and Free T4 were run by standardized assays as previously reported (14
).Outcomes
The primary outcome was the ongoing pregnancy rate, defined as an 8-week viable intrauterine pregnancy conceived within six months of Sono HSG. Secondary outcomes included the VAS pain scores after tubal flushing of the study contrast medium and change in Ferti-QOL scores six months after the Sono HSG. In addition to adverse events, we also collected live birth and pregnancy complication data. Exploratory outcomes included the feasibility of conducting a blinded trial, changes in blood thyroid function, and the prevalence of antichlamydial antibodies.
Sample Size Calculation
For pilot studies, it has been suggested that sample sizes ranging from 12 to 60 subjects per group would provide sufficient data to obtain estimates of the primary outcome to power a future definitive clinical trial and provide sufficient evidence to assess feasibility, blinding safety, and regulatory considerations (
19
). A sample size of 50 evaluable subjects (25 per group) was deemed sufficient to satisfy the goals of this pilot study (ie, the feasibility of binding the contrast medium, obtaining estimates for a formal power calculation of a future trial, and evaluating the initial safety of the contrast medium). We projected that 10% of the subjects would either drop out before study completion or be randomized but unable to have a Sono HSG performed because they may change their minds during the procedure and opt out or have endometrial pathology or bilateral tubal occlusion or a hydrosalpinx. Therefore, we targeted a total of 56 subjects to obtain 50 evaluable subjects.Statistical Analysis
Analyses follow a modified intention to treat (mITT) where all evaluable subjects, ie, those able to complete the Sono HSG procedure with injection of study drug, are included. The primary reason for this was based on the logistical limitations of the physical separation (over a mile) of the Investigational Pharmacy in our hospital, where the blinded study contrast medium was prepared from our outpatient site where the study was conducted. We had to randomize patients before they met our eligibility requirements of a normal saline Sono HSG so that we could have the study contrast medium available. In an ideal study, they would have never been randomized until after the normal Sono HSG, assuming we had immediate access to the study drug, which we did not. Descriptive statistics for continuous data are reported as the mean (standard deviation) or as the median (25th percentile, 75th percentile) if the distribution was not normally distributed. Descriptive statistics for categorical data are reported as a frequency and percentage. Pearson’s chi-square tests were used to compare categorical outcomes, eg, ongoing pregnancy, between the oil-based and saline groups; two-sample t-tests were used to compare continuous outcomes, eg, pain score. The effect size of the primary outcome of ongoing pregnancy was quantified with a relative risk and 95% confidence interval (CI). A linear mixed model was used to compare the change from baseline within and between the two study groups with respect to thyroid function tests and Ferti-QOL scores. All hypothesis tests are two-sided, and analyses are conducted using SAS software, version 9.4 (SAS Institute Inc., Cary, NC).
Results
A total of 58 patients were randomized into the study, 29 in each group, of which 24 in each group completed the procedure with study drug injection and were included in the analysis (Supplemental Fig. 1, available online). Reasons for not receiving the study drug injection were related to patient discomfort with the procedure, patients meeting exclusion criteria after the initial Sono HSG with saline or errors in the administration of the study medium as we mastered best practices during the study.
The study groups were well-matched in terms of baseline demographics, Ferti-QOL, and assay measures (Table 1). Patients had at least one patent tube visualized on initial saline Sono HSG, and there were no differences between study groups in the number of patients who had both tubes visualized on this initial test (15 [62.5%] of oil-based group vs. 17 [70.8%] of the saline group). Similarly, there were no differences between study groups in the visualization of fallopian tubes during study medium administration (Table 2). However, both tubes were more likely to be visualized during the initial saline Sono HSG than during the study medium administration. A higher amount of saline (mean = 8.8 mL) was injected compared with oil (mean=6.1mL) (P=.001) (Table 2). There was no difference in pain scores as determined by VAS (Table 2). Physicians were more likely to guess the correct treatment assignment of the study medium than patients. Patients who received saline as their study medium more frequently proceeded with infertility treatment in the six-month follow-up period after the Sono HSG (16 [66.7%] saline vs. 8 [33.3%] oil; P=.02) (Table 2).
Table 1Baseline demographic characteristics, Ferti-QOL and assay results.
| Baseline | Oil-based medium n = 24, (%) | Normal saline (n = 24), (%) |
|---|---|---|
| Demographics | ||
| Age (y) | 31.0 ± 5.4 | 29.6 ± 3.9 |
| BMI (kg/m2) | 31.8 ± 8.9 | 30.3 ± 7.3 |
| Hispanic/Latino Ethnicity | 5 (21.7) | 1 (4.2) |
| White race | 20 (87.0) | 21 (87.5) |
| College graduate | 13 (56.5) | 16 (66.7) |
| Married | 17 (77.3) | 20 (83.3) |
| Nulligravida | 13 (56.5) | 13 (54.2) |
| Nulliparous | 16 (69.6) | 16 (66.7) |
| Thyroid Function Tests | ||
| TSH (U/mL) | 1.8 (1.5, 2.9) | 2.2 (1.6, 3.0) |
| Free T4 (ng/dL) | 1.2 ± 0.1 | 1.2 ± 0.2 |
| Anti-Chlamydial Assay | ||
| CT Seropositive | 8 (34.8) | 9 (37.5) |
| IgG1 Seropositive | 8 (34.8) | 8 (33.3) |
| IgG3 Seropositive | 4 (17.4) | 3 (12.5) |
| Ferti-QOL | ||
| Core emotional | 65.1 ± 18.7 | 62.8 ± 19.0 |
| Core mind-body | 77.4 ± 17.9 | 77.0 ± 11.3 |
| Core relational | 75.5 ± 21.3 | 81.8 ± 9.7 |
| Core social | 75.3 ± 14.2 | 70.7 ± 11.8 |
| Core Ferti-QOL | 73.3 ± 14.0 | 73.0 ± 9.4 |
Data reported as Mean ± SD or frequency (%); TSH reported as median (25th, 75th) percentiles.
BMI = body mass index; QOL = quality of life; TSH = thyroid-stimulating hormone.
Table 2Results of study medium administration and subsequent infertility treatments.
| Baseline | Oil-based medium n = 24 (%) | Normal saline n = 24 (%) |
|---|---|---|
| Study Medium Visualization | ||
| Not visualized in either tube | 8 (33.3) | 8 (33.3) |
| Visualized in both tubes | 10 (41.7) | 8 (33.3) |
| Visualized in one tube | 6 (25.0) | 8 (33.3) |
| Volume infused (mL) | 6.1 ± 2.9 | 8.8 ± 2.2 |
| Pain score | 3.5 ± 2.9 | 3.5 ± 2.7 |
| Correct patient guess of study medium | 15 (62.5) | 9 (37.5) |
| Correct physician guess of study medium | 19 (79.2) | 17 (70.8) |
| Infertility Treatment post procedure | 8 (33.3) | 16 (66.7) |
| Medication | 5 | 9 |
| Medication with IUI | 3 | 4 |
| DIUI | 0 | 1 |
| IVF | 0 | 2 |
Data reported as Mean ± SD or frequency (%)
IVF = in vitro fertilization; IUI = partner intrauterine insemination; DIUI = donor intrauterine insemination.
There was no difference between study groups for the primary outcome of ongoing pregnancy (9 [37.5%] saline vs. 4 [16.7%] oil; relative risk [95% CI] = 2.3 [0.8, 6.3]; P=.10). In each group, there were two additional subjects who conceived but did not have an ongoing pregnancy (one spontaneous abortion and one ectopic pregnancy per group). All ongoing pregnancies resulted in live birth (Table 3). Pregnancy complication rates between the two groups were similar (Table 3).
Table 3Pregnancy rates and outcomes.
| Baseline | Oil-based medium | Normal saline |
|---|---|---|
| n = 24 (%) | n = 24 (%) | |
| Conception | 6 (25.0) | 11 (45.8) |
| Ongoing Pregnancy | 4 (16.7) | 9 (37.5) |
| n = 4 | n = 9 | |
| Delivery Outcomes | ||
| Gestational age at delivery (wks) | 38.5 ± 1.3 | 38.6 ± 1.4 |
| Vaginal delivery | 3 (75.0) | 7 (77.8) |
| Live birth | 4 (100.0) | 9 (100.0) |
| Birthweight (g) | 2979 ± 774 | 3482 ± 420 |
| NICU Admission | 0 (0.0) | 1 (11.1) |
| Pregnancy Complications | ||
| Pre-eclampsia | 1 (25.0) | 0 (0.0) |
| Gestational diabetes | 1 (25.0) | 3 (33.3) |
| IUGR | 1 (25.0) | 0 (0.0) |
| PROM | 0 (0.0) | 1 (11.1) |
| Postpartum infection | 1 (25.0) | 0 (0.0) |
| Postpartum hemorrhage | 1 (25.0) | 1 (11.1) |
Note: Data reported as Mean ± SD or frequency (%)
IUGR = intrauterine growth restriction; NICU = neonatal intensive care unit; PROM = premature rupture of membranes.
There were no differences between groups in the prevalence of seropositivity of the G1 and/or G3 antichlamydial antibody (8/23 or 35% in the lipiodol group vs. 9/24 or 38% in the saline group, Fisher’s exact test P=1.00). Similarly, there was no relationship to ongoing pregnancy based on seropositivity (4/21 or 24% vs. 9/21 or 30% in the seronegative group, P=.74). The presence of antichlamydial antibodies did not affect pregnancy rates (data not shown). There were no significant differences in thyroid function tests post procedure between groups, but within the oil-contrast group, there was a slight increase in TSH and a decrease in Free T4 (Table 4). There was a significant decrease in the Core FertiQOL score on follow-up in the normal saline group, but there were no between-group differences (Table 4). There were no serious adverse events noted during the study drug administration nor in immediate follow-up. One patient in the oil group experienced an adverse event during pregnancy when she was diagnosed with a cervical ectopic pregnancy requiring resection and dilatation, extraction, and curettage.
Table 4Change from baseline in thyroid function and Ferti-QOL questionnaire data.
| Lipiodol UF | Normal Saline | Lipiodol vs. Saline | ||||
|---|---|---|---|---|---|---|
| Difference (95% CI) | P value | Difference (95% CI) | P value | Difference (95% CI) | P value | |
| Thyroid function | ||||||
| Free T4 (ng/dL) | -0.08 (-0.14, -0.01) | .02 | -0.04 (-0.10, 0.03) | .25 | -0.04 (-0.13, 0.05) | .37 |
| TSH | 1.18 (1.02, 1.38) | .03 | 1.00 (0.87, 1.15) | .98 | 1.19 (0.97, 1.46) | .10 |
| Ferti-QOL: subset of subjects who did not conceive | ||||||
| Core emotional | -8.0 (-16.8, 0.8) | .07 | -7.6 (-16.6, 1.4) | .09 | -0.4 (-13.0, 12.2) | .95 |
| Core mind-body | -4.7 (-11.8, 2.4) | .18 | -6.5 (-13.7, 0.7) | .07 | 1.8 (-8.3, 11.9) | .72 |
| Core relational | -4.3 (-14.7, 6.1) | .40 | -9.5 (-20.2, 1.2) | .08 | 5.2 (-9.6, 20.1) | .47 |
| Core social | -7.0 (-14.1, 0.0) | .05 | -4.3 (-11.5, 2.9) | .23 | -2.7 (-12.8, 7.4) | .59 |
| Core FertiQoL | -5.9 (-11.6, -0.1) | .05 | -7.0 (-12.8, -1.1) | .02 | 1.1 (-7.1, 9.3) | .78 |
QOL = quality of life; TSH = thyroid-stimulating hormone.
∗ TSH reported as ratio of geometric means.
Discussion
In this randomized pilot trial, we successfully demonstrated that we could safely and tolerably use a commercially available and FDA-approved oil-based contrast agent for injection for hysterosalpingography in an office-based setting using ultrasonography. Blinding appeared to be more effective for the patients than for the supervising physician. We were able to document ongoing pregnancies and deliveries after the administration of both contrast agents in the study.
We noted a change in thyroid function consistent with the Wolff-Chaikoff effect (
20
). This auto-regulatory event results when an increase in circulating iodine suppresses thyroid hormone production with a subsequent increase in serum TSH. It is considered to exist to prevent excess production of thyroid hormone in the face of iodine excess and is transient. It has been reported often after using iodine-containing radiocontrast agents, including with the proprietary oil-based agent we used in this study (21
). Our changes in thyroid function are consistent with this and other studies of iodine-containing contrast agents for HSG (22
, 23
). We purposely checked thyroid function tests shortly after the exam looking for this effect, but did not repeat the tests to track the time to normalization. Potentially this may be prolonged. There is evidence that after HSG, this may result in neonatal thyroid dysfunction, and it is recommended to use the minimum amount of contrast medium (24
). We did not check thyroid function tests in the neonate, but we did cap the amount of contrast medium used, which tended to be lower with the oil-based medium than saline in our study.There are many limitations to our study. Our study was not powered to detect differences in pregnancy outcomes as it was a pilot study; our safety data are thus derived from a small and select sample. We are not aware of any comparable studies that have used an oil-based contrast medium specifically for Sono HSG. Therefore, we are cautious in comparing our results with other fluoroscopy-based HSG studies, given the potential difference between the two types of tests.
One potential limitation is that the smaller volume of oil-based contrast medium or the lack of a validated device to create turbulence and bubbles in the medium may not, in all cases, allow visualization of the patency of both tubes. We note; however that patency of a single tube is often viewed as adequate to pursue initial therapies of ovulation induction or ovarian stimulation with timed intercourse or insemination (
25
, 26
). Also, we noted that fewer patients in the oil-based treatment group pursued subsequent infertility treatment. Treatment assignment was not revealed to patients during the study, but it is possible that patients in this group may have better guessed their treatment assignment at some time after the test (for there were no differences in rates of correct testing immediately after the test) and deferred initiating treatment hoping that the test was treatment enough given the favorable results from previously published fluoroscopy-based HSG studies.As a pilot study, we also had to troubleshoot the development of equipment and a technique to create a medium/air mixture (ie, bubbles) to visualize the contrast by ultrasound. The oil-based medium we used in the study interacts with specific plastics, and, therefore, we relied on glass syringes or specific plastics that are resistant. Additionally, we learned that the weight of the plunger in glass syringes quickly overcomes the resistance generated by the glass syringe and goes to the ground (along with the contrast agent) if it is held in a dependent position. Our results may not be applicable to all patients, for instance, those who were excluded from our study because of an iodine allergy or a history of pelvic inflammatory disease or pelvic pathology. Because this latter entity is often only discovered at the time of pelvic ultrasound or HSG, our study was designed as a two-step study, first a saline Sono HSG, and then in the absence of pelvic pathology or bilateral tubal occlusion, we proceeded with the second phase, flushing with the randomized study contrast agent and ultrasound visualization. Several patients were excluded after randomization based on pathology discovered during the initial Sono HSG.
The strengths of the study include the design of the study, the double blinding of the study agent with documentation of its accuracy, and the close and long term follow-up of the patients to identify short or long term adverse events. Future directions would be the design and availability of standardized, appropriate equipment for oil-based media that can create turbulence, is easy to use, and is resistant to oil-based medium. The development of an oil-based contrast medium that does not contain iodine would be beneficial in extending the use of this agent to a broader population and allaying concerns about the effects on maternal and fetal thyroid function. Finally, an adequately powered multicenter trial would be necessary to document a greater benefit on ongoing pregnancy and live birth rates while maintaining our initial safe experience with the oil-based medium. Such a trial would best be powered by a projected difference in the risk benefit ratio of the oil-based medium on pregnancy and complication rates after Sono HSG and should likely have a longer period of observation up to a year after the test to capture both spontaneous and treatment-related pregnancies.
Acknowledgments
The authors thank their study coordinators at Penn State for their dedicated work on this project: Patsy Rawa and Amy McMonagle, R.N. They also thank Kanupriya Gupta, Ph.D. at the University of Alabama at Birmingham for her expertise in running the antichlamydial assays for this study. The authors also thank Marie Roman at Guerbet LLC for her collaborative efforts on this study.
Supplementary data
Supplemental Figure 1CONSORT flow chart of the study
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Article info
Publication history
Published online: November 14, 2022
Accepted:
November 10,
2022
Received in revised form:
November 9,
2022
Received:
June 1,
2022
Footnotes
W.C.D. has nothing to disclose. R.S.L. reports research sponsorship from Guerbet LLC for the support of this project; grants or contracts from NIH, Hass Avocado Board, Yale University, Wright State University outside of the submitted work, and consulting fees with Novo Nordisk, Insudd, Bayer, Fractyl and Abbvie outside of the submitted work. C.M.S. reports research sponsorship from Guerbet LLC for the support of this project. A.R.K. reports research sponsorship from Guerbet LLC for the support of this project and Merck stock outside of the submitted work. W.C.D. reports grants or contracts from Hologic Inc. outside of the submitted work and payment or honoraria from Hologic, Inc, and Sanofi outside of the submitted work. S.J.E. reports grants or contracts from Abbvie, Ferring, and Obseva outside of the submitted work and consulting fees from Abbvie outside of the submitted work.
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