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North American Society for Pediatric and Adolescent Gynecology (NASPAG) Fellows Research ConsortiumProtocol Title: Retrospective review of cases of hematometra in the setting of Depo-provera use in adolescent patients in the the NASPAG Fellows Research Consortium (FRC).Principal Investigator: Kathryn Stambough, MDCo-investigators: Laura Hollenbach, MDBackground/Justification:Depo-provera was originally formulated as a contraceptive injection and contains medroxyprogesterone acetate, a derivative of progesterone, as the active ingredient.1 Standard dosing involves intra-muscular injection of the 150 mg dose every 13 weeks for contraceptive efficacy. Studies have demonstrated contraceptive effectiveness with a failure rate of 6 in 100 women in one year with typical use.2 Mechanism of action includes inhibition of gonadotropin secretion with subsequent prevention of follicular maturation, ovulation and endometrial thinning. Although FDA approved only for the prevention of pregnancy, Depo-provera is also used for non-contraceptive purposes including menstrual suppression, treatment of abnormal uterine bleeding, endometriosis and suppression of ovarian cyst formation particularly in patients who are unable to have estrogen containing methods. Common side effects of Depo-provera include bleeding irregularities. Up to 55% of individuals report amenorrhea after one year of use; the incidence of amenorrhea increases to 68% after 24 months of use1. A subcutaneous formulation of 104 mg of Depo-provera is also available and has demonstrated comparable rates of bleeding irregularities and amenorrhea4. Depo-provera is also associated with a decrease in bone mineral density which appears to be both dose dependent and potentially reversible after discontinuation, although the impact on accrual of peak bone mass in adolescence and implications for bone health long term is not well studied5. Finally unintentional weight gain is one of the more common side effects reported with Depo-provera with an average of 5.4 pounds reported during the first year of use.1 Other adverse reactions which have been reported in more than 5% of subjects included abdominal pain or discomfort, dizziness, headaches, asthenia and nervousness.1 Hematometra is defined as an abnormal intra-uterine collection of blood or clot and is often secondary to outflow obstruction6. Outflow tract obstruction can either be congenital, such as in cases of obstructive Mullerian anomalies, or acquired, often secondary to prior surgical procedures and resultant cervical stenosis, such as cervical conization7. No radiologic guidelines exist for the definition of an endometrial stripe which constitutes hematometra but imaging findings often demonstrate both a thickened lining as well as a possible fluid-fluid level consistent with sedimentation of red blood cells8.There have been several case reports and one small case series which have demonstrated spontaneous hematometra in the setting of Depo-provera use7,9-11. All cases required evacuation of the hematometra in the operating room with dilation and curettage, and in many cases cervical stenosis was not appreciated at the time of evacuation9. Several patients had the concurrent diagnosis of or suspicion for endometriosis as a co-morbid condition which raises concerns for possible concurrent endometriosis as an independent risk factor9,10. Several theories have been postulated as the cause for hematometra in the setting of Depo-provera use, including the formation of decimal cast due to high dose progestin therapy and functional obstruction of the cervix due to inability to spontaneous pass the cast11. Other theories include the effect of progesterone on smooth muscle laxity and impairment of normal uterine contractility with resultant accumulation of blood products9.The NASPAG Fellows Research Consortium is an ideal venue for the collection of a large case series on patients who experience spontaneous hematometra in the setting of Depo-medroxyprogesterone acetate use. We therefore propose to use this consortium to explore characteristics of patients who experience hematometra in the setting of Depo-provera use, including co-morbid conditions such as endometriosis, treatment and recurrence.Hypothesis:We hypothesize that either biopsy confirmed or suspicion for endometriosis will be a common co-morbid finding in individuals with spontaneous hematometra and Depo-provera use. We also hypothesize that most cases with resolve with dilation and curettage and that approximately half of patients will experience a recurrence based on prior case reports. Research Goals and Objectives:Primary Aim:1. Determine the baseline characteristics of patients who experience hematometra while using Depo-provera, including age at onset, cumulative dose of Depo-provera and timing from initiation of Depo-provera to onset of symptoms.2. Determine the most common indications for use of Depo-provera use in patient who experience spontaneous hematometra, including endometriosis3. Determine the incidence of cervical stenosis at the time of dilation and curettage in patients with spontaneous hematometra and Depo-provera useSecondary Aims:1. Determine the most common presentation of spontaneous hematometra in patients using Depo-provera2. Determine ultrasound findings in patients who are diagnosed with hematometra while using Depo-provera3. Determine common treatment strategies for management of hematometra 4. Determine post-treatment strategies for hormonal management after treatment of hematometra5. Determine incidence of recurrence for hematometra after treatment6. Determine any implications of spontaneous hematometra while using Depo-provera on conception rates if possibleMethods:A retrospective chart review through the NASPAG Fellows Research Consortium will completed. Data collection will be completed by each member institution using a standardized data collection form. Demographic information collected will include age at onset of Depo-provera use, race, ethnicity, age of menarche, menstrual characteristics prior to and after the use of Depo-provera (specifically frequency, volume and presence of absence of dysmenorrhea), co-morbidities, medical history, surgical history, allergies, age at menarche, sexual history, symptoms present at initial presentation with hematometra and ultrasound findings, including uterine dimensions, volume and measurements of the endometrial stripe. Data regarding treatment will also be collected, including mode of treatment, time from initial presentation to treatment, presence of absence of cervical stenosis at the time of diagnosis (specifically need for dilation and starting and final dilator size in french) and volume of hematometra evacuated. Finally information on long-term outcomes, including hormonal therapy post-treatment, recurrence and fertility will be collected if known.Data collection sheets will be completed by each member institution and sent to the PI via secure institutional e-mail. The de-identified data will then be entered by the PI into the RedCap database and managed by the Arkansas Children’s Hospital. All data will be de-identified at collection. Data collection sheets will be properly destroyed per Arkansas Children’s Hospital protocol once data is entered into RedCap.Participants: Member institutions of the NASPAG Fellows Research Consortium who choose to participate will obtain local institutional IRB approval for this study in addition to the IRB approval from Arkansas Children’s Hospital and the NASPAG Fellows Research Consortium.Study Design: A retrospective chart reviewInclusion Criteria: All females from birth to 25 years of age who have been diagnosed with hematometra while using Depo-medroxyprogesterone acetate intramuscular or subcutaneous injections in the absence of know congenital risk factors for outflow tract obstruction. Known risk factors for outflow tract obstruction include known obstructive Mullerian anomaly.Exclusion Criteria: Female patients with the diagnosis of hematometra who are not concurrently using Depo-medroxyprogesterone acetate. Females with the diagnosis of hematometra who are using Depo-medroxyprogesterone acetate and have known congenital risk factors for outflow tract obstruction, including known obstructive Mullerian anomaly.Statistical Analysis: This study is a planned multi-site retrospective chart review to include data on patients who experience the spontaneous onset of hematometra in the setting of Depo-medroxyprogesterone acetate use. We are anticipating participation from 10 sites. A preliminary query from possible sites suggest 1 - 3 cases per site. We therefore anticipate 20 - 30 cases in the final case series.After collection of data from participating sites, appropriate statistical analysis will be performed on all data. Given that a majority of the data is qualitative, descriptive statistics will primarily be used.Data Management: Data will be entered into RedCap database and managed by Arkansa Children’s Research Institute in compliance with HIPAA regulation. All data will be de-identified, and no personal identifiers will be collected.Confidentiality of Data: All data collected via retrospective chart review will be de-identified. We will use secure data entry via Research Electronic Data Capture (REDCap) set up through the Arkansas Children’s Research Institute. Data will be exported to institutional password protected computers for data management. No patient identifiers will be collected. Any information exchanged between institutions will be done over secure, institution-based electronic mail and will not contain patient information or identifiers.De-identified data will only be made available to investigators of the study. Site specific data will only be available to individual site investigators. Any additional studies performed using data collected under this protocol will require a separate, IRB approved protocol prior to data evaluation.Paper data collection forms which contain de-identified information will be discarded in a hospital designated bin for shredding of confidential papers which is appropriately HIPAA compliant after entry into REDCap.Consent: Patient consent will be waved given the retrospective nature of this study. Many patients are no longer receiving care at the institutions where diagnosed. Given the retrospective and qualitative nature of the data collection, the risk to patients is negligible and due to anticipated difficulty obtaining consent, patient consent is not a viable option for this study.Risks and Benefits: Breach of data security is an important risk to consider when performing a retrospective chart review. Data de-identification and storage will be performed as outlined above with care to avoid any identifiable information in the standardized data collection form. In addition the data set will be entered into the secure REDCap database, and data management will only occur on a institutional password protected computer.Those patients identified as research subjects on chart review are not likely to benefit directly from this research. However, future adolescent patients will likely benefit, as little is known about this rare but significant finding, and this case series will hopefully form the foundation for prospective clinical and basic research on the association of spontaneous hematometra and Depo-provera use, allowing clinicians to best manage this condition and mitigate pliance: The trial will be conducted in compliance with the written protocol, the mandates of Health and Human Services (HHS) and all applicable institutional, state and local requirements.Feasibility: The completion of this project does not carry any inherent cost, as the REDCap database is available to all Arkansas Children’s Hospital faculty, and no additional research staff are needed to complete the project. We anticipate the IRB approval at participating institutions to be completed by spring 2020. We anticipate overall sample size, data entry and data management/analysis to be completed by fall 2020. We however acknowledge that unanticipated issues surrounding IRB approval and data collection may occur, and the above timeline may need to be adjusted accordingly.References:Pharmacia & Upjohn Company. Depo-provera Contraceptive Injection [package insert]. U.S. Food and Drug Administration website. HYPERLINK ". Revised June 2002. Accessed: September 19, 2019.Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65(No. RR-3):1–104. Schwallie PC, Assenzo JR. Contraceptive use-efficacy study utilizing medroxyprogesterone acetate administered as an intramuscular injection once every 90 days. Fertil Steril. 1973;24:331-339.Arias RD, Jain JK, Brucker C, Ross D, Ray A. Changes in bleeding patterns with depot medroxyprogesterone acetate subcutaneous injection 104 mg. Contraception 2006;74:234–8.Lange HLH, Manos BE, Gothard MD, Rogers LK, Bonny AE. Bone mineral density and weight changes in adolescents randomized to 3 doses of depot medroyprogesterone acetate. J Pediatr Adolesc Gynecol. 2017;30(2):169-175.Dietrich JE, Millar DM, Quint EH. Obstructive reproductive tract anomalies. J Pediatr Adolesc Gynecol. 2014;27:396.Chou B, Bohn JA, Mails R. Acute abdominal pain caused by hematomerta in an adolescent female: a case report. J Med Case Rep. 2016:10:369.Steinkeler JA. Female infertility: a systematic approach to radiologic imaging and diagnosis. RadioGraphics. 2009;29:1353-1370.Thorne JG, Russell EH, Rumboldt D, Jamieson MA. Cause or coincidence? spontaneous hematomatra in young women receiving Depomedroxyprogesterone acetate: a small case series. J Pediatr Adolesc Gynecol. 2018;31(4):416-19.Hernandez AM, Dietrich JE. Recurrent hematomater as a warning sign for endometriosis in a patient with dysmenorrhea on depot Medroxyprogesterone acetate. J Pediatr Adolesc Gynecol. 2018;31:190-91.Singh V, Talib N, Strickland J. Decidual cast in a girl receiving depot medroxyprogesterone acetate—a case report. J Pediatr Adolesc Gynecol. 2007;20:191.Proposed Data Collection for REDCap. To be completed by check-box, numerals or few words answers for ease of useAge at initiation of Depo-proveraAge at diagnosis of hematometraRaceEthnicityBMI at diagnosis of hematometraAge at menarcheMenstrual volume:< 4 pads per day4 - 8 pads per day8 - 10 pads per day> 10 pads per dayDysmenorrhea: Yes or No. If yes:MildModerate SevereMedical history/co-morbiditiesTobacco useAbnormal pap testHistory of STIChlamydiaGonorrheaTrichomonasHSVEndometriosisSuspicion forBiopsy confirmedSurgical historyDilation and curettageDilation and evacuationCervical conization/cold knife coneCervical loop electrical excision procedureHistory of pregnancy? Yes or No. If yes,Age at pregnancy 1? ___________ Outcome of pregnancy 1? _________________Age at pregnancy 2? ___________ Outcome of pregnancy 2? _________________Indication for Depo-provera use:ContraceptionDysmenorrheaEndometriosis, suspicion forEndometriosis, biopsy confirmedAUB - irregular menstrual bleedingAUB - heavy menstrual bleedingSuppression of cyst formationMenstrual suppressionOther: _______________________________________________________________Depo-provera dosing schedule:Dose: ______ mgNumber of doses prior to diagnosis of hematometra: __________Frequency: 4 - 8 weeks9 - 11 weeks11 - 13 weeks> 13 weeksAny other hormonal treatment used WHILE ON Depo-provera? Yes or No? If yes, NoneProgestin only IUSProgestin only subdermal implantProgestin only pill (norethindrone)Progestin only pill (norethindrone acetate)Combined hormonal contraceptive pillCombined hormonal contraceptive patchCombined hormonal contraceptive ringDepo-lupronPresentationAbdominal painNauseaEmesisEarly satietyFever (Tmax > 38.3C)Vaginal dischargeChanges in bowel habitsUrinary urgencyUrinary frequencyUrinary retentionOther ________________________________________________________________Ultrasound findingsUterine lengthUterine widthUterine heightEndometrial stripe (in mm)Presence of fluid-fluid level? Yes or NoPresence of hematosalpinx/hematosalpinges? Yes or NoTreatmentDilation and curettage, sharpDilation and curettage, suctionManual vacuum aspirationObservationCervical dilation, office with use of local anesthesia or no anesthesiaCervical dilation, under anesthesiaOther: _______________________________________________________________Volume of hematometra evacuated (in mL)_____________________________________Cervical dilation needed at the time of treatment? Yes or No. If yes,Size and type of starting dilator (ie 11F Pratt): ________________________________Size and type of final dilator (ie 11F Pratt): __________________________________Hormonal therapy after treatment:NoneDepo-medroxyprogesteroneProgestin only IUSProgestin only subdermal implantProgestin only pill (norethindrone)Progestin only pill (norethindrone acetate)Combined hormonal contraceptive pillCombined hormonal contraceptive patchCombined hormonal contraceptive ringDepo-lupronRecurrence? Yes or NoTime from date of initial treatment to date of recurrence (in months): ________________Use of hormonal therapy at the time of recurrence? Yes or No? If yes,NoneDepo-medroxyprogesteroneProgestin only IUSProgestin only subdermal implantProgestin only pill (norethindrone)Progestin only pill (norethindrone acetate)Combined hormonal contraceptive pillCombined hormonal contraceptive patchCombined hormonal contraceptive ringDepo-lupronPregnancy after treatment? Yes or No? If yes,Time from initial treatment for hematometra to conception (in months)? ______________Pregnancy outcome: _______________________________________________________

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