Successful fertility-preserving management using systemic methotrexate and laparoscopic resection of intramural pregnancy following in vitro fertilization and embryo transfer: a case report

A 39-year-old woman (gravida 4, para 0) was referred to hospital from a fertility clinic 65 days after blastocyst embryo transfer with suspected missed abortion at approximately 5 weeks of gestation, presenting with mild vaginal bleeding. Her history included three prior D&C procedures for abortion. At the first visit, transvaginal ultrasound revealed an empty gestational sac measuring 15.3 mm without a fetus in the uterine cavity ( Fig. 1 a). Color Doppler demonstrated abundant peritrophoblastic blood flow surrounding the sac ( Fig. 1 b). A missed abortion was suspected, and manual vacuum aspiration (MVA) was performed one week later under abdominal ultrasound guidance. However, only blood clots were expelled; no chorionic villi were retrieved. The gestational tissue was inaccessible transcervically and could not be captured by placental forceps. Because an intramural pregnancy was suspected, pelvic magnetic resonance imaging (MRI) was performed the day after the ultrasound-guided D&C to confirm the diagnosis. Fig. 1 Transvaginal sonography shows a longitudinal section of the uterus: grayscale (a) and color Doppler (b) images show an empty gestational sac (GS) and a thin endometrium (arrow). Color Doppler analysis (b) reveals abundant blood flow at the periphery of the gestational sac. Fig. 1 Transvaginal sonography shows a longitudinal section of the uterus: grayscale (a) and color Doppler (b) images show an empty gestational sac (GS) and a thin endometrium (arrow). Color Doppler analysis (b) reveals abundant blood flow at the periphery of the gestational sac. MRI revealed a 42-mm mass within the anterior wall, with low signal intensity on T1-weighted images and high signal intensity on T2-weighted images ( Fig. 2 a–c). Flow voids and marked vascularity were observed around the lesion ( Fig. 2 b); gadolinium-enhanced imaging demonstrated a gestational sac completely embedded within the myometrium and distinct from the endometrium ( Fig. 2 d). The patient's serum β-human chorionic gonadotropin (β-hCG) level was 380.7 mIU/mL on the day of diagnosis; previously, 18 days after the blastocyst ET, the level had been 1443 mIU/mL, indicating nonviability. Histological examination of the evacuated material confirmed only blood clots without chorionic villi. Diagnostic hysteroscopy was subsequently performed to evaluate the uterine cavity and demonstrated that the lesion was not transcervically accessible, confirming the diagnosis of a complete intramural pregnancy. Fig. 2 Pelvic MRI shows a mass (diameter: 42 mm) with a high signal intensity on the T2-weighted images. The conceptus is located in the anterior uterine wall. The arrow shows the flow void. The gestational sac is completely surrounded by the myometrium and is separated from the endometrium (d). (a) T2-weighted image, sagittal plane. (b) T2-weighted image, transverse plane. (c) T2-weighted image, coronal plane. (d) gadolinium-injection T1-weighted image, sagittal plane. Fig. 2 Pelvic MRI shows a mass (diameter: 42 mm) with a high signal intensity on the T2-weighted images. The conceptus is located in the anterior uterine wall. The arrow shows the flow void. The gestational sac is completely surrounded by the myometrium and is separated from the endometrium (d). (a) T2-weighted image, sagittal plane. (b) T2-weighted image, transverse plane. (c) T2-weighted image, coronal plane. (d) gadolinium-injection T1-weighted image, sagittal plane. Given the low serum β-hCG level and nonviability, systemic methotrexate (MTX) (50 mg/m 2 ) was initiated. Because the β-hCG level failed to decline and had in fact slightly increased by day 7, a second MTX dose was administered according to ectopic pregnancy treatment protocols [9] , [10] , followed by weekly MTX injections. After two MTX doses, the gestational sac evolved into a persistent echogenic degenerative mass, despite a gradual decline in serum β-hCG levels ( Fig. 3 ). Marked reduction in vascularity was observed after the fourth course of MTX on Doppler examination. However, because the conceptus demonstrated only limited reduction in size, MTX therapy was continued for a total of seven courses in an attempt to achieve further shrinkage. After seven doses, the mass had only slightly decreased, to 36.5 × 34 mm, with near-complete loss of vascularity ( Fig. 4 a, b); the β-hCG level concurrently declined to 8.4 mIU/mL. As the mass persisted, laparoscopic surgical enucleation was performed 10 weeks after MTX initiation, considering the patient's advanced maternal age, her wish to promptly resume infertility treatment, and the anticipated prolonged resolution with expectant management. Fig. 3 Serial changes in serum β-hCG levels during the course of treatment. Serum β-hCG values showed a gradual decline with each administration of systemic methotrexate (MTX), illustrating the stepwise biochemical response to medical therapy. Thin arrows indicate the timing of MTX administrations while thick arrows represent the timing of manual vacuum aspiration (MVA) and subsequent laparoscopic surgery. Fig. 3 Fig. 4 Transvaginal sonography shows a longitudinal section of the uterus: grayscale (a) and color Doppler (b) images after systemic methotrexate. The degenerative conceptus mass is seen to have persisted (a). The blood flow in the mass is significantly decreased (b). Fig. 4 Serial changes in serum β-hCG levels during the course of treatment. Serum β-hCG values showed a gradual decline with each administration of systemic methotrexate (MTX), illustrating the stepwise biochemical response to medical therapy. Thin arrows indicate the timing of MTX administrations while thick arrows represent the timing of manual vacuum aspiration (MVA) and subsequent laparoscopic surgery. Transvaginal sonography shows a longitudinal section of the uterus: grayscale (a) and color Doppler (b) images after systemic methotrexate. The degenerative conceptus mass is seen to have persisted (a). The blood flow in the mass is significantly decreased (b). Laparoscopic surgery was performed using a standard four-port technique with a 10-mm laparoscope inserted sub-umbilically under carbon dioxide pneumoperitoneum. Intraoperative inspection revealed an enlarged uterus without an obvious protruding mass. The anterior wall appeared slightly swollen ( Fig. 5 a), and both adnexa were normal. Although no distinct bulge was visible, the site of the conceptus in the anterior wall had been localized preoperatively by MRI, which guided the initial incision. After vasopressin infiltration to minimize bleeding, the seromuscular layer of the anterior wall was carefully incised, and a friable, brownish mass was excised ( Fig. 5 b). The degenerative conceptus was successfully removed ( Fig. 5 c). The uterine wall was reconstructed in two layers with absorbable sutures ( Fig. 5 d). Operative time was 67 min with minimal blood loss. Fig. 5 (a) Laparoscopic view shows an enlarged uterus, with no bulging mass on the uterine surface. (b) The uterus is cut with a harmonic scalpel. (c) The product of conception is successfully removed. (d) The wound is repaired with No.1 Monocryl sutures. Fig. 5 (a) Laparoscopic view shows an enlarged uterus, with no bulging mass on the uterine surface. (b) The uterus is cut with a harmonic scalpel. (c) The product of conception is successfully removed. (d) The wound is repaired with No.1 Monocryl sutures. The patient recovered uneventfully and was discharged on postoperative day 3; serum β-hCG became undetectable (<0.5 mIU/mL), and IVF-ET was resumed 3 months after surgery. Histopathological examination confirmed necrotic chorionic villi embedded within the myometrium, consistent with IMP. During follow-up, three subsequent embryo transfer attempts were unsuccessful; the patient continued to have a thin endometrium, which may have contributed to the outcomes.

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Written informed consent was obtained from the patient for publication of the case report and accompanying images.

Intramural pregnancy (IMP) is an extremely rare and potentially life-threatening form of ectopic pregnancy, characterized by implantation of the gestational sac entirely within the myometrium. Risk factors include prior uterine instrumentation and assisted reproductive procedures, both of which were present in this patient. Because of its rarity, atypical imaging findings, and lack of standardized management protocols, both diagnosis and treatment remain clinically challenging [1] , [2] . Accurate diagnosis is often difficult because clinicians are generally unfamiliar with this rare condition. A correct diagnosis was made during the initial ultrasound in only 35.4% (29/82) of cases in one report [2] . Transvaginal ultrasonography serves as the first-line diagnostic tool for IMPs [2] , [5] , [8] , with color Doppler providing important clues by demonstrating abnormal peritrophoblastic vascularity [8] , [11] , [12] . Three-dimensional ultrasonography can further improve accuracy by delineating the endometrial-myometrial junction, which could be helpful in detecting partial IMPs [5] , [8] . In the present case, the markedly thin endometrium resulting from repeated D&C procedures made it difficult to distinguish the border of the sac from the myometrium or endometrial cavity. Color Doppler imaging, however, revealed an atypical elevation in blood flow around the gestational sac, which was a pivotal clue suggesting IMP. MRI is a potentially valuable tool in cases where ultrasound studies prove inadequate or inconclusive [2] . Previous reports have shown that MRI allows precise delineation of the lesion's extent and its relationship to the endometrium and myometrium [12] , [13] , [14] . In the present case, after an unsuccessful attempt at surgical evacuation, MRI confirmed the diagnosis of IMP and guided surgical planning by identifying the precise intramural location, even in the absence of a visible bulge on the uterine surface. This case illustrates the complementary role of MRI in improving diagnostic accuracy and guiding minimally invasive management. Currently, no standardized treatment protocol is available for IMP. Reported management strategies include expectant observation [15] , systemic or local MTX injection [1] , [14] , [16] , uterine artery embolization [13] , laparoscopic or open surgical enucleation [17] , [18] , and hysterectomy in cases complicated by rupture or uncontrollable bleeding [5] . Hysteroscopic excision is feasible in cases of a partial IMP that is accessible transcervically [19] . Treatment should therefore be individualized based on the location, depth, and size of the pregnancy; gestational age at diagnosis; clinical symptoms; serum β-hCG levels; viability status; and, importantly, patient preference regarding fertility preservation [5] . For complete IMPs, some authors recommend conservative medical treatment with systemic or local MTX to avoid further uterine damage or incomplete removal of the pregnancy [5] , [8] , [14] . However, the persistence of non-viable mass despite MTX therapy, as seen in this patient, may necessitate surgical intervention. In the present case, serial color Doppler monitoring demonstrated progressive reduction in vascularity after four MTX sessions, with near-complete avascularity after seven administrations; however, the intramural mass persisted despite continued decline in serum β-hCG levels. The initial intention had been to complete treatment with multidose MTX alone in order to avoid additional surgical trauma to the uterus. However, because reduction in the size of the conceptus remained limited despite repeated therapy, surgical enucleation was ultimately required. This dissociation underscores that anatomic resolution after MTX may lag behind biochemical decline [5] , [14] and highlights the need to integrate imaging findings with β-hCG trends when defining treatment endpoints. Clinically, the earlier reduction in vascularity suggested that surgical intervention could have been undertaken sooner to shorten the time to resumption of infertility treatment. Preoperative systemic MTX reduced trophoblastic activity and vascularity, facilitating safe enucleation with minimal blood loss and avoidance of hysterectomy. Surgical timing was guided by the patient's advanced maternal age, her strong desire to promptly resume infertility treatment, and the anticipated prolonged resolution period associated with expectant management. Importantly, previous reports suggest that MTX does not adversely affect subsequent fertility outcomes [20] , supporting its use in patients undergoing assisted reproduction. This experience indicates that surgical enucleation after adequate medical pretreatment represents a feasible fertility-preserving option for patients with a complete IMP who wish to pursue further ART procedures. While a wait-and-see approach after MTX therapy might eventually achieve spontaneous resolution [14] , the required time frame can extend to several months, which was unacceptable for this patient. Multidose systemic MTX appears to be a practical option for reducing vascularity and ensuring surgical safety, although the optimal regimen and indications remain to be determined [16] . In conclusion, this case highlights the effectiveness of a staged therapeutic approach—systemic MTX followed by laparoscopic resection—in achieving safe resolution of a complete IMP while preserving reproductive potential. It also underscores the diagnostic and therapeutic challenges of IMP and the complexity of clinical decision-making, particularly when biochemical and imaging responses diverge. Future studies are warranted to establish standardized diagnostic criteria and treatment algorithms.

This article was not commissioned and was peer reviewed.

Miwa Sato-Shimizu contributed patient care, conception of the case report, acquiring and interpreting the data, drafting the manuscript, undertaking the literature review and revising the article critically for important intellectual content. Hiroto Tajima contributed to patient care, interpreting the data and revising the article critically for important intellectual content. Shuji Takemoto contributed to patient care and revising the article critically for important intellectual content. Hironori Asada contributed to revising the article critically for important intellectual content. All authors approved the final submitted manuscript.

Intramural pregnancy (IMP) is the rarest form of ectopic pregnancy, constituting less than 1% of all ectopic pregnancies [1] . In IMP, the gestational sac implants entirely within the myometrium, without communication with the uterine cavity or fallopian tubes, rendering both diagnosis and treatment particularly challenging [2] , [3] , [4] . Risk factors include prior intrauterine procedures such as dilatation and curettage (D&C), in vitro fertilization and embryo transfer (IVF-ET), hysteroscopy, and intrauterine device insertion, as well as previous surgical trauma to the uterus, including myomectomy, cesarean section, and salpingectomy [5] , [6] . The increasing use of assisted reproductive technology (ART) has led to more reported cases of IMP [7] , [8] . At present, no standardized diagnostic or therapeutic protocol has been established for IMP; therefore, management should be individualized according to clinical presentation and reproductive goals. This report describes a rare case of complete IMP following IVF-ET that was successfully managed with a staged approach—systemic methotrexate followed by laparoscopic resection—achieving safe resolution while preserving fertility.

The authors declare that they have no competing interest regarding the publication of this case report.