{"paper_id":"31fb03cc-8590-4f9c-ba52-1c23b47b188f","body_text":"C A S E R E P O R T Open Access\nA rare case of extensive placenta accreta in\ntwin pregnancy after GnRH agonist\ntreatment of adenomyosis\nShilpi Agrawala 1*, Jeevitha Patil 1, Sukhkamal Campbell 1 and Terri Lynn Woodard 1,2\nAbstract\nBackground: Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to\nsub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth\nrates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).\nCase: Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo\ntransfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size\nfrom 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm.\nSubsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by\nexpansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas\ndemonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.\nConclusions: GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous\nmolecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor\n(GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations\nare needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.\nKeywords: Adenomyosis, GnRH agonist, Placenta accreta, Live birth, Frozen embryo transfer\nBackground\nAdenomyosis is a pathologic condition characterized by\nthe presence of endometrial glands and stroma within\nthe myometrium. While histopathology is the gold\nstandard for diagnostic confirmation, improved ultra-\nsound and MRI technology has led to highly sensitive\nand specific alternative modalities for diagnosis. A recent\nsystematic review showed that the sensitivities for ultra-\nsound and MRI, respectively, were 72 and 77% [ 1]. MRI\nspecificity is slightly higher at 89% compared to 81% for\nultrasound. When diagnosing adenomyosis using either\nimaging modality, physicians focus on the junctional\nzone, the heterogeneity of the uterine wall, and asym-\nmetry in the thickness of the uterine walls [ 2–4].\nThe growing utilization of non-invasive diagnostic im-\naging in patients undergoing infertility workup has led\nto an increased recognition of adenomyosis in this popu-\nlation. Due to its association with sub-fertility and the\ndefinitive treatment being hysterectomy, adenomyosis\nhas presented a clinical dilemma for reproductive endo-\ncrinologists. Thus far, there are no formal guidelines for\nfertility-sparing treatment of adenomyosis, and current\nmethods are largely based on retrospective case series\nand case reports [ 5–9]. Surgical resection, typically re-\nserved for focal lesions, carries an increased risk of uter-\nine rupture [ 6, 9]. Fertility centers can also treat focal\nand diffuse adenomyosis with medical therapy, which\ntypically consists of gonadotropin releasing hormone\n© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,\nwhich permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give\nappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if\nchanges were made. The images or other third party material in this article are included in the article's Creative Commons\nlicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons\nlicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain\npermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nThe Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the\ndata made available in this article, unless otherwise stated in a credit line to the data.\n* Correspondence: Agrawala.Shilpi@gmail.com\n1Department of Obstetrics and Gynecology, Baylor College of Medicine, 1\nBaylor Plaza, Houston, TX 77030, USA\nFull list of author information is available at the end of the article\nAgrawala et al. Fertility Research and Practice             (2021) 7:5 \nhttps://doi.org/10.1186/s40738-021-00097-4\n\nagonist (GnRHa) for 3 to 6 months prior to fresh or fro-\nzen embryo transfer [ 5, 6, 10]. By inducing apoptosis\nand reducing angiogenesis, GnRHa is thought to de-\ncrease the size of the ectopic endometrial glands consti-\ntuting adenomyosis [ 5, 11]. Here we present a successful\ntwin live birth in a 52-year-old patient with three prior\nfailed frozen embryo transfers (FETs) who, after GnRHa\ntherapy, underwent FET and achieved clinical\npregnancy.\nCase description\nThe patient presented to our fertility clinic at age 48 as a\nnulligravida desiring pregnancy. She had a history of fi-\nbroids for which she had undergone a myomectomy at\nan outside institution. The patient reported that the sur-\ngeon removed nine fibroids. Of note, the operative re-\nport was unavailable for review so the type of\nmyomectomy, size of myomas, and depth of myometrial\ninvasion were unable to be confirmed. After surgery, she\nwas told that she would require pre-labor cesarean deliv-\nery if she became pregnant. She reported regular\nmonthly menses and no medical comorbidities. Initial\nevaluation at our clinic included transvaginal ultrasound\n(TVUS), antral follicle count (AFC) as well as anti-\nMullerian hormone measurement (AMH) and assess-\nment for metabolic syndrome. TVUS revealed three\nintramural fibroids (the largest 2.5 cm in diameter), none\nof which appeared to be impacting the endometrial cav-\nity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid func-\ntion and insulin resistance testing were normal.\nAt her follow-up visit, a saline-infused sonohystero-\ngram (SIS) was attempted but only partially successful\ndue to cervical stenosis. A left hydrosalpinx was visual-\nized, and diagnostic laparoscopy was pursued. In the op-\nerating room, cervical dilation was performed.\nSubsequently, chromotubation revealed non-patent fallo-\npian tubes, and due to extensive adhesive disease, bilat-\neral Filshie clips were placed in lieu of salpingectomy.\nNo evidence of endometriosis was seen during her lapar-\noscopy, and the adhesive disease was thought to be due\nto her prior myomectomy. She had a repeat SIS which\nwas successful and a normal endometrial cavity was\nseen. None of the previously seen fibroids were noted to\nhave a submucosal component. A mock embryo transfer\nwas performed without complication.\nIn spite of our recommendation to pursue donor eggs,\nthe patient highly desired a trial of in-vitro fertilization\n(IVF) using autologous oocytes. She underwent ovarian\nstimulation using 450 IU of Bravelle (urofollitopin) and\n150 IU of Menopur (menotropin) daily. GnRH antagon-\nist 0.25 mg was started on stimulation day (SD) 4 to pre-\nvent premature follicle maturation. She was triggered on\nSD8 with 10,000 units of human chorionic gonadotropin\nwhen there were 3 follicles > 17 mm in size and estradiol\npeaked at 922 pg/mL. Four oocytes were retrieved from\nthis cycle, but only one was mature. Intracytoplasmic\nsperm injection (ICSI) was performed on the mature oo-\ncyte; however, there was failed fertilization. After this\noutcome, the patient desired an emotional break from\nthe IVF process.\nFifteen months later, the patient returned to our clinic\nto resume fertility treatment. At this point, she agreed to\nuse fresh donor oocytes and undergo FET. The 24 year-\nold donor underwent an uncomplicated ovarian stimula-\ntion and oocyte retrieval. A total of 45 mature oocytes\nwere retrieved. Following ICSI, there were 39 two pro-\nnuclear embryos that fertilized normally and were cul-\ntured to blastocyst-stage in single step media. Eighteen\nblastocysts were biopsied and vitrified. Fifteen of the 18\nembryos were euploid. The patient underwent another\nSIS and mock ET, both of which were normal. She started\n3 estradiol 0.1 mg patches every other day in preparation\nfor FET. During her ultrasound for a lining check, her\nendometrial stripe (EMS) was 10 mm, so she started 90\nmg of 8% vaginal gel twice daily and 50 mg of intramuscu-\nlar progesterone daily. Six days after progresterone supple-\nmentation, she had her first FET of 1 euploid blastocyst.\nHer pregnancy test 10 days later was negative.\nShe decided to pursue another cycle, and after exten-\nsive counseling regarding the risks associated with twin\npregnancy, the decision was made to proceed with trans-\nfer of 2 euploid blastocysts. This transfer resulted in an\nanembryonic pregnancy, diagnosed by abnormally rising\nB-HCG and ultrasounds done 2 weeks apart which dem-\nonstrated a gestational sac without interval development\nof a fetal pole. Over the next 2 weeks, her B-HCG was\nserially monitored, as patient desired expectant manage-\nment, and her levels were trending downward. The preg-\nnancy failed to evacuate completely after expectant\nmanagement, and she consented to a suction dilation\nand curettage. The pathology results were confirmatory\nof an anembryonic pregnancy.\nThe patient wished to proceed with another embryo\ntransfer. Prior to this transfer, a pelvic MRI was com-\npleted to evaluate if any of her fibroids (described previ-\nously) impacted the endometrial cavity. The MRI only\nshowed evidence of adenomyosis as characterized by\nthickened junction zone (JZ) at 19 mm with multiple 1-\n2 mm myometrial junctional zone cysts (Fig. 1). Since\nthe endometrial cavity was clear on MRI, the patient\nunderwent a third FET of 2 euploid embryos. Her subse-\nquent pregnancy test was negative.\nAfter the third unsuccessful FET, the patient was\ncounseled that her adenomyosis could be contributing\nto the multiple failed FETs. She was counseled on the\noptions of using a gestational carrier vs. medical man-\nagement. She decided to pursue medical management\nusing leuprolide acetate (GnRHa) for 6 months prior to\nAgrawala et al. Fertility Research and Practice             (2021) 7:5 Page 2 of 6\n\nanother FET. She received monthly intramuscular injec-\ntions of 3.75 mg of leuprolide acetate. Three weeks after\nthe last injection, another MRI was completed which\nshowed a decrease in the JZ from 19 to 9 mm. Uterine\nsize also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 ×\n6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the\npatient was counseled on the number of embryos to\ntransfer. While single embryo transfer (sET) was recom-\nmended, we decided to proceed with double embryo\ntransfer due to her history of multiple failed transfers\nand personal preference. The same protocol for FET\npreparation was used, and she underwent her fourth\nFET of 2 euploid blastocysts after an EMS of 10.2 mm\nwas confirmed.\nHer initial B-HCG of 1010.3 collected 10 days after\nFET confirmed pregnancy, and subsequent TVUS sev-\neral weeks later confirmed viable intrauterine twin preg-\nnancy. She was followed by our fertility center until 10\nweeks gestational age (GA) and then transferred to a\ngeneral obstetrician. Her dichorionic-diamniotic preg-\nnancy was complicated by placenta previa in Twin A for\nwhich she had serial ultrasounds. At 27 weeks GA, Twin\nB was noted to have intrauterine growth restriction\n(IUGR) < 5th percentile for which she had weekly bio-\nphysical profiles. At 31 weeks GA, the patient started de-\nveloping elevated blood pressures and was transferred to\na tertiary care center as the estimated fetal weight of\nTwin B was less than 1800 g. She was diagnosed with\npre-eclampsia without severe features and discharged\nhome after receiving betamethasone for fetal lung ma-\nturity. She followed up with the maternal fetal medicine\nspecialists as an outpatient. At 32 weeks, she was admit-\nted for extended maternal fetal monitoring due to wors-\nening pre-eclampsia, IUGR of Twin B < 5th percentile,\nand placenta previa of Twin A. The patient developed\npre-eclampsia with severe features at 33 weeks and was\nexpectantly managed until 34 weeks. She was delivered\nat 34 weeks via planned primary cesarean due to pla-\ncenta previa and history of open myomectomy. Cesarean\ndelivery was complicated by extensive accretas of both\nplacentas, which necessitated a supracervical hysterec-\ntomy. The patient did not sustain any post-operative\ncomplications and has since resumed her daily activities.\nThe neonates also had an uncomplicated hospital stay\nand are currently meeting all their developmental\nmilestones.\nDiscussion and conclusions\nThis case demonstrates that GnRHa therapy for 6\nmonths in patients with adenomyosis may improve\nFig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm\nmyometerial junctional zone cysts (arrowheads) and a thickened\njunctional zone (arrows)\nFig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the\njunctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)\nAgrawala et al. Fertility Research and Practice             (2021) 7:5 Page 3 of 6\n\nimplantation rates after FET, which is consistent with\nprior studies [ 7, 8]. Through pituitary downregulation,\nlong-term GnRHa therapy has been shown to decrease\nthe size of adenomyotic lesions [ 11, 12]. Our patient also\nhad a decrease in her uterine size and a decrease in her\nJZ from 19 mm to 9 mm on MRI. This decrease in JZ\ncould have facilitated implantation as a thickened JZ\nprior to FET has been associated with low implantation\nrates [ 13]. One study showed that a JZ > 12 mm was as-\nsociated with an implantation rate of 5% during FET\nwhereas JZ < 10 mm was associated with a 45% implant-\nation rate [ 14]. Thus, one plausible theory for how\nGnRHa treatment facilitated pregnancy in our patient\nwas through decreasing the JZ.\nThe question remains if GnRHa treatment for 6\nmonths also led to the extensive lack of decidualized\nendometrium, which subsequently led to the develop-\nment of expansive accretas of both placentas. The pa-\ntient did have other risk factors for placenta accreta\nsuch as IVF treatment, advanced maternal age (AMA),\nand prior myomectomy [ 15–19]. The degree of her pla-\ncental disease raises concern for a a global change to the\nendometrial stratum basalis, as opposed to the focal\nchanges often seen with IVF pregnancies and a history\nof myomectomy. The description in the pathology report\nwas that the uterus had no decidualized endometrium\non the implantation site of placenta A and the implant-\nation site of placenta B only had a focal area of decidua-\nlized endometrium. Within the remainder of the uterine\nspecimen, there was only one other focal area of decid-\nualized endometrium, and it was located within the\nmyometrium, consistent with adenomyosis. There was\nno histologic evidence of placental invasion past the\nmyometrium nor was there any histologic evidence of\nendometriosis. Although her prior myomectomy could\nhave contributed to the development of a placenta\naccreta, it is unlikely to be the sole cause as myomecto-\nmies tend to cause focal accretas at the endomyometrial\nincision site [ 18, 19]. While undergoing IVF treatments\nand being of AMA are also risk factors for placenta\naccreta, neither has been associated with an expansive\nplacenta accreta such as this one. The encompassing\nsurface area of affected endometrium indicates a more\nsystemic defect in decidualization.\nAlthough no studies have investigated whether GnRHa\ntherapy can affect endometrial decidualization, molecu-\nlar studies have demonstrated that GnRHa also directly\nexerts anti-proliferative effects on the target organ\nthrough the gonadotropin releasing hormone receptor\n(GnRHR) [ 11, 20]. In these studies, the direct effect of\nGnRHa was highly variable between different samples\nwhich was attributed to the genetic variance in GnRHR\ncapacity and affinity for GnRHa. We hypothesize that\nour patient had a genetic variance in GnRHR that could\nbe associated with an increased response to GnRHa.\nThus, GnRHa downregulated cellular function at the\nlevel of the endometrium so profoundly that it subse-\nquently inhibited or delayed the process of endometrial\ndecidualization. Since this may only affect a small subset\nof the population, it could explain why other studies of\nGnRHa therapy in patients with adenomyosis have not\nshown an increased risk for placenta accreta.\nFurther investigation is necessary since GnRHa ther-\napy is a widely used medication both in IVF protocols,\nin treatment of endometriosis, and more recently in pa-\ntients with adenomyosis. Pregnancies conceived after\nIVF do have an increased risk for subsequent placenta\naccreta [ 15, 16]. These studies did not compare GnRH\nagonist vs GnRH antagonist protocols, but that could be\na potential area of study in the future [ 15, 16, 21, 22].\nAlthough larger studies have shown that endometriosis\nis associated with increased risk for placenta accreta,\nFig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional\nzone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic\nspaces (arrow) and junctional zone have decreased in size\nAgrawala et al. Fertility Research and Practice             (2021) 7:5 Page 4 of 6\n\nsmaller studies did not find an association as it was a\nrare outcome [ 23–25]. None of these studies reported\nwhether the patients were treated with GnRHa prior to\npregnancy. Case literature has reported that adenomyo-\nsis could be a pre-disposing factor for placenta accreta;\nhowever, larger studies have not validated that finding\n[26–29]. Thus, larger studies on patients who receive\nGnRHa therapy prior to conception for any condition\n(endometriosis, adenomyosis, or IVF) may be able to\ndemonstrate that there is an increased risk of abnormal\nplacentation with GnRHa therapy.\nLastly, in patients with adenomyosis who receive\nGnRHa therapy prior to FET, we would recommend sin-\ngle embryo transfer and MFM consultation. We dis-\ncussed with our patient on multiple occasions that sET\nis the standard of care when transferring euploid em-\nbryos. However, given her multiple rounds of IVF and\npersonal preference, a shared decision was made to\ntransfer two euploid embryos. In addition, we would rec-\nommend MFM consultation in patients that achieve\npregnancy after GnRHa therapy to monitor for the de-\nvelopment of abnormal placentation with serial ultra-\nsounds. Targetted monitoring has been shown to\nincrease rates of detection as well as decrease estimated\nblood loss and maternal hospital stay [ 30].\nAbbreviations\nGnRHa: Gonadotropin releasing hormone agonist; FETs: Frozen embryo\ntransfers; JZ: Junctional zone; TVUS: Transvaginal ultrasound; AFC: Antral\nfollicle count; AMH: Anti-Mullerian hormone; SIS: Saline-infused\nsonohysterogram; IVF: In-vitro fertilization; SD: Stimulation day;\nICSI: Intracytoplasmic sperm injection; EMS: Endometrial stripe;\nGA: Gestational age; IUGR: Intrauterine growth restriction;\nGnRHR: Gonadotropin releasing hormone receptor\nAcknowledgements\nWe would like to acknowledge Dr. Popek, Director of Perinatal and Placental\nPathology, who shared her insight and expertise regarding the unique\nfindings of this case. Also, we would like to thank Dr. Jewel Appleton who\nprovided the images for this case report.\nCode availability\nN/A\nAuthors’ contributions\nAll the authors actively participated in the production of this manuscript. The\nauthor(s) read and approved the final manuscript.\nFunding\nNone.\nAvailability of data and materials\nN/A\nEthics approval and consent to participate\nNot applicable in case reports or case series. Our institution only requires\nthat written consent be obtained prior to publication. This consent has been\nobtained.\nInformed consent was obtained for this case report from the participant.\nConsent for publication\nThe participant has consented to the submission of the case report to the\njournal.\nCompeting interests\nThe authors declare that they have no conflict of interest.\nAuthor details\n1Department of Obstetrics and Gynecology, Baylor College of Medicine, 1\nBaylor Plaza, Houston, TX 77030, USA. 2Department of Gynecologic Oncology\nand Reproductive Medicine, M.D. Anderson Cancer Center, 1515 Holcombe\nBlvd, Houston, TX 77030, USA.\nReceived: 5 October 2020 Accepted: 15 February 2021\nReferences\n1. Champaneria R, Abedin P, Daniels J, Balogun M, Khan KS. Ultrasound scan\nand magnetic resonance imaging for the diagnosis of adenomyosis:\nsystematic review comparing test accuracy. Acta Obstet Gynecol Scand.\n2010;89(11):1374–84.\n2. Reinhold C, McCarthy S, Bret PM, Mehio A, Atri M, Zakarian R, Glaude Y,\nLiang L, Seymour RJ. 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Impact of targeted scanning protocols on perinatal outcomes in\npregnancies at risk of placenta accreta spectrum or vasa previa. Am J\nObstet Gynecol. 2018;218(4):443 –e1.\nPublisher’sN o t e\nSpringer Nature remains neutral with regard to jurisdictional claims in\npublished maps and institutional affiliations.\nAgrawala et al. Fertility Research and Practice             (2021) 7:5 Page 6 of 6","source_license":"CC0","license_restricted":false}