Persistence of ectopic pregnancy after intramural ectopic pregnancy surgery: A case report.

Concept and design:Wen-Xiu Yang and Shuai Zhao;data collection and analysis:Ting-Ting Wang;drafting of the article:Wen-Xiu Yang;critical revision of the article for important intellectual content:Shuai Zhao;study supervision:All the authors approved the final article.

Ethical approval for this study was obtained from the Ethics Committee of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine ((2024) Ethical Review No. (133-01- KY)).

This project is funded by the Youth Program of the National Natural Science Foundation of China (82104914).

A 38-year-old patient presented voluntarily to the hospital outpatient clinic(tertiary care hospital), G3A1, who was treated conservatively for an ectopic pregnancy in 2018 and underwent laparoscopic left salpingectomy for an ectopic pregnancy in June 2023, with a history of one clearing of an embryonic arrest. Two cleavage stage embryos were transferred on November 15, 2023, and on December 9, she reported unprovoked vaginal bleeding, slightly less than menstrual flow. On December 11 (27 days after embryo transfer) β-hCG rose to 25,041 mIU/ml. Ultrasonography showed that a 2.1 × 2.3 × 2.1 cm strong echogenic area was detected in the muscular layer of the uterine fundus, and several irregular echogenic areas were seen within the strong echogenic area, rich blood flow signals were seen within and around the strong echogenic area, the strong echogenic area was tightly adherent to the endothelium, and some of the sections were connected to the endothelium, and weak echoes were seen in the area, which were connected to the uterine cavity, so intermuscular pregnancy was considered ( Fig. 1 A, B). MRI: round-like long T1 and long T2 abnormal signals were seen in the muscular layer of the uterine fundus, ranging from 2.0 × 2.0 × 1.9 cm, with uneven internal signals and patchy edges, which seemed to be locally connected with the endothelium, and abnormal signals were seen in the muscular layer of the uterine fundus wall, and an intermuscular gestational sac was considered ( Fig. 2 A, B, C). Subsequent review of blood β-hCG progressively increased. Combined laparoscopic surgery was performed on December 15 to remove the IMP lesion. A few degenerative placental villi, meconium tissue and endometrium in secretory state were seen in the sent tissue. Postoperative β-hCG was discharged when it decreased to 5598 mIU/ml from 41,238 mIU/ml preoperatively, but β-hCG increased again to 10,476 mIU/ml when it was reviewed 1 week postoperatively. Postoperative follow-up ultrasound revealed that abundant blood flow signals were still visible at the lesion site, and arteriovenous fistula formation was suspected ( Fig. 3 A). Methotrexate intramuscular chemotherapy was administered twice on December 26 and 29, and no significant decrease in β-hCG was observed. Transabdominal ultrasound-guided IMP lesion in situ injection of methotrexate 0.05 g was performed on January 2, 2024, and β-hCG gradually decreased to 938 mIU/ml, and again in situ injection of methotrexate was performed on January 29, and β-hCG was decreased to normal, and no elevation was seen in the late follow-up. On ultrasound follow-up the lesion was significantly smaller with blurred borders ( Fig. 3 B). This patient was satisfied with the results of the treatment. Fig. 1 A: Transvaginal ultrasound sagittal (left) and transverse (right) views of an Intramural ectopic pregnancy mass (indicated by arrow). B: Abundant blood flow signal within the Intramural ectopic pregnancy mass (indicated by arrows). Fig. 1 Fig. 2 A: MRI sagittal section of Intramural ectopic pregnancy mass (indicated by arrows). B: MRI transverse view of Intramural ectopic pregnancy mass (indicated by arrows). C: MRI coronal view of the Intramural ectopic pregnancy mass (indicated by arrows). Fig. 2 Fig. 3 A: Patient's postoperative follow-up ultrasound image (rich blood flow signal is still visible at the lesion site, and the arrow indicates a suspected arteriovenous fistula). B: Ultrasound follow-up image after methotrexate in situ injection(indicated by arrows). Fig. 3 A: Transvaginal ultrasound sagittal (left) and transverse (right) views of an Intramural ectopic pregnancy mass (indicated by arrow). B: Abundant blood flow signal within the Intramural ectopic pregnancy mass (indicated by arrows). A: MRI sagittal section of Intramural ectopic pregnancy mass (indicated by arrows). B: MRI transverse view of Intramural ectopic pregnancy mass (indicated by arrows). C: MRI coronal view of the Intramural ectopic pregnancy mass (indicated by arrows). A: Patient's postoperative follow-up ultrasound image (rich blood flow signal is still visible at the lesion site, and the arrow indicates a suspected arteriovenous fistula). B: Ultrasound follow-up image after methotrexate in situ injection(indicated by arrows). This study has been reported in line with the SCARE 2023 criteria [ 4 ].

Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal upon request.

Not applicable.

IMP is a rare but potentially fatal clinical case. There are no typical clinical symptoms and it is difficult to distinguish it from other types of ectopic pregnancy and spontaneous abortion. Early diagnosis is challenging due to its nonspecific clinical presentation. Clinical history, laboratory tests, and imaging are important in accurately determining this particular site of pregnancy. One study summarizes the ultrasound features of IMP: (1) Complete emptying of the uterus and cervical canal. (2) Gestational sac (with/without embryo), partially or surrounded by the myometrium. (3) The gestational sac is thin from the plasma layer of the uterus, usually less than or equal to 3 mm. (4) Asymmetrical enlargement of the uterus with distorted contours. (5) Doppler ultrasound shows a rich blood supply around the gestational sac with low resistance, sometimes described as the “ring of fire” sign [ 5 ]. IMP can be determined with relative accuracy based on the above ultrasound signs. IMP of the mass type combined with the presence of high β-hCG is difficult to differentiate from gestational trophoblastic disease. In gestational trophoblastic disease, the border between the endometrium and the gestational trophoblastic layer is not clear, whereas in IMP is surrounded by the myometrium. In patients with IMP, the chorionic villi erode the muscularis propria tissue and cause defective metamorphosis due to increased syncytiotrophoblast lysing activity, which allows the fetus to implant or penetrate the muscularis propria after external migration, exhibiting a range of non-specific signs and symptoms of rapid invasive dilatation [ 6 ]. In this case, the chorionic tissue is encapsulated in the myometrium expanding peripherally, destroying the myometrium and vascular structures, an invasive process that is similar to the onset of placental implantation. The pathogenesis of IMP is still unclear, but most theories suggest that factors that contribute to the formation of microchannels between the uterine myometrial walls that can be used for the passage of fertilized eggs or gametes can lead to the development of IMP [ 7 ]. These factors include the following: (1) endometrial damage or defects such as a history of uterine manipulation and endometrial adenomyosis; (2) defects in the plasma myometrial layer of the uterus; and (3) in vitro fertilization-embryo transfer. In this case, the patient had a history of clearance of embryonic arrest, which may cause damage to the uterine cavity; the patient had a history of 2 ectopic pregnancies, suggesting that the patient may have pelvic inflammatory disease, which indirectly suggests that the patient's poor endometrial tolerance is not conducive to implantation of fertilized eggs in the uterine cavity; the current pregnancy was a pregnancy after transplantation of 2 oocyte-stage embryos, and there was a possibility of medical endothelial damage, and the factors mentioned above may be the causative factors of IMP. This patient's preoperative β-hCG: 41,238 mIU/ml was significantly higher than that of an ordinary ectopic pregnancy, suggesting strong chorionic villus activity and invasiveness, which posed a challenge for subsequent treatment. The management of IMP is currently controversial, with no corresponding expert consensus or guidelines, and its treatment should follow the principle of individualized therapy. The choice of treatment depends on the clinical presentation, gestational week, location and size of the gestational sac, degree of myometrial involvement, gestational age and blood β-hCG, as well as the expertise of the surgeon [ 8 ]. Commonly used treatment options include expectant, pharmacologic, and surgical treatments [ 9 ]. It has been suggested that after surgical removal of the mass, local or systemic methotrexate administration is recommended to stop the growth of residual trophoblasts [ 10 ]. We found that methotrexate therapy was recommended first after IMP in this patient. However, considering the use of methotrexate in two previous ectopic pregnancies, the patient refused to use methotrexate again and requested mifepristone therapy first. Due to the high serum β-hCG level, the invasive nature of intermuscular pregnancy, the difficulty of conventional drugs to act on the deep trophoblast cells, and the poor efficacy of mifepristone, surgical treatment was performed. In this case, the patient underwent a combined hysterolaparoscopic surgery to remove the lesion, and after the surgery, without further complementary treatment with medication, she presented with a decrease in β-HCG levels followed by a reelevation, and subsequently developed a persistent ectopic pregnancy. Persistent ectopic pregnancy is defined as a patient with ectopic pregnancy who has undergone conservative surgical treatment and whose serum β-hCG level appears elevated or remains unchanged on ≥2 consecutive postoperative monitoring visits [ 11 ]. Serum β-hCG levels reflect trophoblast activity to a certain extent. Under normal circumstances, after trophoblast cells are removed after conservative surgery, serum β-hCG levels should gradually decrease to normal levels. For patients whose postoperative serum β-hCG level increases instead of decreasing, or increases again after decreasing to a certain degree and lasts for a longer period, clinical follow-up should be emphasized to prevent the occurrence of persistent ectopic pregnancy. The probable reason for the presence of persistent ectopic pregnancy after conservative surgery in our patient was the high preoperative serum β-hCG level, IMP chorionic villi are highly invasive and extremely viable, eroding the myometrial vasculature. During the procedure, there is no anatomical pathway through the muscularis propria, the field of view is limited during combined hysterolaparoscopic surgery, the chorionic tissue may be incompletely exposed, the trophoblast cells are incompletely removed and killed, and the remaining portion may continue to grow, resulting in a persistent ectopic pregnancy. The patient presented with a persistent ectopic pregnancy and underwent 2 intramuscular methotrexate injections with no decrease in β-hCG levels, and then 2 focal in situ methotrexate injections guided by abdominal ultrasound resulted in a decrease in serum β-hCG to normal. This suggests that in Intramural ectopic pregnancy, lesion-targeted injections significantly increase the blood concentration at the lesion site relative to intramuscular injections and that local administration is considerably more effective than systemic administration. This case further illustrates the complexity of IMP and the difficulty of treatment. One study [ 12 ] suggested that methotrexate should be injected in situ at a dosage of 1 mg/kg and that a “swirling” sign in the gestational sac should be considered as evidence of successful in situ injection. This may be an effective guide for ultrasound-guided methotrexate in situ injection in patients with ectopic pregnancies at specific sites. IMP with high levels of serum β-hCG is better treated with methotrexate injected in situ at the site of the lesion after surgical removal of the lesion. The strength of this case is that it presents a combined treatment modality for ectopic pregnancies in specific sites, the limitation is that no studies are confirming large-scale applications.

Guarantor:Shan Xiang. First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine.

IMP invades the myometrium in a highly extensive spreading manner, and it is particularly important to choose an appropriate treatment modality based on laboratory tests and imaging manifestations, and methotrexate injection in situ at the site of the lesion after conservative surgery may become a simple and efficacious treatment modality.

Intramural ectopic pregnancy(IMP) is a specific site of ectopic pregnancy in which the gestational sac is deposited and implanted in the myometrium, and its incidence is <1 % of all ectopic pregnancies [ 1 ]. IMP does not have typical clinical symptoms in the early stages; however, as the pregnancy progresses, it faces the risk of uterine rupture, which may even jeopardize the patient's life. Early detection and diagnosis of IMP can prevent uterine rupture and preserve the patient's fertility as long as possible. With the development of ultrasound technology, vaginal ultrasound has become the first-line diagnostic tool for IMP. One study standardized the ultrasound terminology describing normal and ectopic pregnancies and concluded that IMP is located between the myometrial walls of the uterus but disrupts the endometrial-myometrial junction and extends into the myometrium [ 2 ]. IMP is classified as complete or partial according to whether it is located completely independently of the myometrium or partially involves the uterine cavity. Using high-resolution transvaginal ultrasound it may be possible to visualize the exact location of the IMP and even observe the sinus tract connecting the gestational sac to the endometrium to accurately identify the site of the pregnancy. There is no corresponding consensus or expert opinion on the management of IMP, and treatment depends on the extent of myometrial involvement, the patient's status, hemodynamic status, and desire for future fertility [ 3 ]. As with other types of ectopic pregnancies, treatment can be surgical, medication, or expected observation therapy. Here we report a case of IMP detected by transvaginal ultrasonography in early pregnancy, which was corroborated with MRI findings to clarify IMP. Persistent ectopic pregnancy developed after combined hysterolaparoscopic surgery and improved after methotrexate injection in situ at the site of IMP by abdominal ultrasound guidance, suggesting that individualized treatment regimens should be used for the management of IMP. In patients with intermuscular pregnancies with high blood β-hCG, the application of methotrexate in situ at the postoperative lesion site may achieve better clinical outcomes.

The authors declare that they have no conflicts of interests.