Sequential intramural pregnancies in the right uterine cornu after the transfer of two embryos in a single cycle: a case report and literature review.

The patient was a 37-year-old woman of childbearing age with no previous pregnancies or deliveries and a 3-year-and-5-month history of infertility. In 2021, she underwent hysteroscopy and laparoscopic tubal irrigation to assess the function of both fallopian tubes. The surgical results revealed obstruction at the proximal end of both fallopian tubes. The patient underwent in vitro fertilization embryo transfer (IVF-ET) at another hospital, and two fresh embryos were transferred to the patient’s uterine cavity using a flexible tube under ultrasound guidance. The embryo transfer went smoothly. After embryo transfer, patients have no obvious symptoms and only occasionally experience a small amount of vaginal bleeding. Five days after surgery, the patient developed lower abdominal pain and discomfort without obvious cause, which gradually worsened, accompanied by vomiting the stomach contents once, dizziness, fatigue, and anal distension. Emergency ultrasound revealed mixed echo masses in the right adnexium area, massive pelvic effusion, an HCG level of 7507 IU/L, and a progesterone concentration of 30.14 ng/ml, and an ectopic pregnancy was considered. Hysteroscopy and laparoscopic exploration (Fig.  1 ) were performed. Fig. 1 Laparoscopic field of view for the first surgery. The lesion of the ectopic pregnancy protruded from below the right uterine horn, and a tear was seen on the surface of the mass. The black arrow indicates the location of the lesion at the time of the first surgery. The yellow arrow indicates the location of the second surgery to be performed. As shown in the figure, during the first operation, no obvious bulge was observed in this area Laparoscopic field of view for the first surgery. The lesion of the ectopic pregnancy protruded from below the right uterine horn, and a tear was seen on the surface of the mass. The black arrow indicates the location of the lesion at the time of the first surgery. The yellow arrow indicates the location of the second surgery to be performed. As shown in the figure, during the first operation, no obvious bulge was observed in this area During the operation, a massive pelvic hemorrhage of approximately 1000 ml was found, and no purple blue nodules were found in either fallopian tube. The uterus was enlarged as if the pregnancy was 40 + days, and a 1.5 cm diameter mass was found below the right corner of the uterus, which was purple blue, with a tear on the surface and active bleeding. Laparoscopic removal of the lesion muscle during intramural uterine pregnancy was performed. On the first day of postoperative monitoring, the HCG level was 4476 IU/L, and the progesterone concentration was 7.25 ng/ml; on the fourth day, the HCG level was 3592 IU/L; on the sixth day, the HCG level was 3344 IU/L; on the eighth day, the HCG level was 3615.3 IU/L; and on the tenth day, the HCG level was 2919.5 IU/L. Due to the patient’s poor postoperative decline in HCG levels, she was given oral mifepristone and traditional Chinese medicine to help terminate the pregnancy. Two days later, the HCG level was 3324.5 IU/L. On intrauterine ultrasound, the exact gestational cyst was not visible, and a 1.3 cm heterogeneous echo area was observed angled slightly to the right, with a 0.6 cm dark bubble surrounded by rich blood flow (Fig.  2 ). Fig. 2 Transvaginal ultrasound images. No definite gestational sac echo was observed in the uterine cavity. On the right side of the uterine horn, a cystic anechoic area protruded outward from the uterus and did not communicate with the endometrial echo (the places indicated by the yellow arrow ). The muscular layer in this area was very thin, with the thinnest part being approximately 0.2 cm. A cystic echo located below the uterus was considered to indicate a corpus luteum. Transvaginal ultrasound images. No definite gestational sac echo was observed in the uterine cavity. On the right side of the uterine horn, a cystic anechoic area protruded outward from the uterus and did not communicate with the endometrial echo (the places indicated by the yellow arrow ). The muscular layer in this area was very thin, with the thinnest part being approximately 0.2 cm. A cystic echo located below the uterus was considered to indicate a corpus luteum. MRI (Fig.  3 ) revealed uneven signal intensity in the right uterine horn, small cystic lesions in the lower part, and uneven enhancement in the right uterine horn. In the uterus right next to the insufflation site, local vascular enlargement, circuity, and a few hemorrhages were observed. Fig. 3 Pelvic and abdominal magnetic resonance imaging. The right uterine horn showed heterogeneous enhancement with a cystic mass protruding outwardly into the pelvis (the places indicated by the yellow arrow). The mass appeared to be wrapped by the myometrium and had no communication with the fallopian tubes or uterine cavity. Pelvic and abdominal magnetic resonance imaging. The right uterine horn showed heterogeneous enhancement with a cystic mass protruding outwardly into the pelvis (the places indicated by the yellow arrow). The mass appeared to be wrapped by the myometrium and had no communication with the fallopian tubes or uterine cavity. Because the patient had two embryos transferred at a time via assisted reproductive technology and the HCG level did not decrease to normal but rather increased, and considering the imaging results, we believed that the patient could have a persistent or ectopic pregnancy. The decision was made to perform another hysteroscopy and laparoscopy. Hysteroscopy revealed a thickened endometrium, an inverted triangular uterine cavity, visible openings of both fallopian tubes, and no abnormal protrusions or masses in the uterine cavity. Because there was no obvious abnormality, this hysteroscopy operation was only an observation operation without special treatment, and no invasive manipulation of the endometrium was performed. During laparoscopic exploration, the uterus was slightly enlarged (Fig.  4 a). The posterior wall of the right uterine horn shows the surgical wound and sutures from the previous surgery. A purple–blue protrusion with a diameter of approximately 2 cm was visible on the anterior wall of the right uterine horn (Fig.  4 b). The surface tension is high, and no other abnormal protrusions are observed. No obvious abnormalities were detected in the bilateral fallopian tubes or ovaries. Blood accumulation was low in the Douglas cul-de-sac. During the operation, adhesions in the pelvic cavity and intestinal adhesions were first separated to restore the normal anatomical organization of the pelvic cavity. Both fallopian tubes were subsequently removed according to the surgical approach discussed with the patient and their family prior to surgery. Pituitary posterior lobe extract (3U) was diluted and administered via intramuscular injection in the right uterine horn to prevent bleeding. An ultrasonic scalpel was used to incise the surface mass on the right uterine horn, after which the uterine serosa layer was incised to reach the uterine muscle layer (Fig.  4 c). The mass was encapsulated by the uterine muscle layer and did not connect to the uterine cavity or the fallopian tubes. The mass was then bluntly dissected and completely removed. The procedure did not penetrate the uterus or touch the endometrium. Upon examination of the removed mass, villous tissue was observed inside. The wound was closed with continuous barbed sutures, restoring the uterus to its normal shape. A subsequent examination of the uterine surface revealed no other abnormal protrusions. Fig. 4 Images from the second laparoscopic exploration. ( A ) There was a convex mass above the right uterine horn without surface laceration or active bleeding (indicated by the yellow arrow). There was a small amount of pelvic hemorrhage and local adhesion of the greater omentum to the fundus of the uterus. ( B ) After separation of the adhesions, the incision and suture of the first operation could be seen, and the location of the two ectopic pregnancies was identified (indicated by the black arrow). ( C ) Incision of the mass revealed the gestational sac, which was wrapped in the muscular layer, and the villi were floating inside (indicated by the red arrow) Images from the second laparoscopic exploration. ( A ) There was a convex mass above the right uterine horn without surface laceration or active bleeding (indicated by the yellow arrow). There was a small amount of pelvic hemorrhage and local adhesion of the greater omentum to the fundus of the uterus. ( B ) After separation of the adhesions, the incision and suture of the first operation could be seen, and the location of the two ectopic pregnancies was identified (indicated by the black arrow). ( C ) Incision of the mass revealed the gestational sac, which was wrapped in the muscular layer, and the villi were floating inside (indicated by the red arrow) Histopathological examination of the myometrial villus tissue (Fig.  5 ) revealed evidence of IMP, and the pathological report did not suggest that the patient was suffering from uterine adenomyosis. The postoperative patient recovered well, with serum HCG levels of 1008.3 IU/L on the first postoperative day and 6.8 IU/L on the 16th day, which decreased significantly. The changes in HCG levels are shown in Fig.  6 . Fig. 5 Results of pathological examination. The villi (indicated by black arrows) were seen to be surrounded by muscle tissue, confirming an intramural pregnancy in this patient Results of pathological examination. The villi (indicated by black arrows) were seen to be surrounded by muscle tissue, confirming an intramural pregnancy in this patient Fig. 6 Changes in HCG levels. The horizontal axis represents the date Changes in HCG levels. The horizontal axis represents the date

Ectopic pregnancy refers to the implantation of a fertilized egg in a location other than the uterine cavity. Nearly 95% of heterotopia originates in fallopian tubes, and 5% in non-fallopian tubes [ 1 ]. The incidence of ectopic pregnancy is approximately 1.5 to 2.0%. After assisted reproductive technology (ART), the incidence is as high as 2.1–8.6% [ 2 ]. Intramural pregnancy (IMP) is among the rarest types of ectopic pregnancy. This condition was first reported in the literature in 1965 by Mcgowa, who reported two cases secondary to induced abortion [ 3 ]. It refers to the implantation and development of fertilized eggs in the myometrium, in which the invasion of trophoblasts exceeds the junction of the endometrium and myometrium, is surrounded by the myometrium, and does not communicate with the uterine cavity, fallopian tube cavity, pelvic cavity, etc. The incidence is approximately 1/30,000, and the incidence of ectopic pregnancy is less than 1% [ 4 ]. Its clinical manifestations are nonspecific and include irregular vaginal bleeding, abdominal pain, secondary amenorrhea or elevated human chorionic gonadotropin (HCG) levels [ 5 ]. Thinning of the myometrium due to the growth of the gestational sac during pregnancy can easily lead to uterine rupture. Ectopic pregnancy accounts for 2.7% of all pregnancy-related deaths [ 6 ]. IMP mostly occurs in patients with a history of uterine trauma, such as in those who have undergone myomectomy, salpingectomy, uterine dilatation and curettage, assisted reproductive technology, and adenomyosis. The early diagnosis of IMP is difficult and involves more intraoperative or postoperative diagnoses [ 7 ]. Imaging examination and hysteroscopy play important roles in early diagnosis. Liu et al. summarized the key points of ultrasound diagnosis of IMP [ 8 ]: the gestational sac is completely wrapped by the muscle layer and has no connection with the uterine cavity and fallopian tube; the yolk sac, germ or fetal heart beat can be seen; and color Doppler ultrasound shows rich blood flow and low resistance. However, it is difficult to distinguish early IMP from cornual pregnancy on ultrasound images [ 7 ]. In this case report, we describe a patient who underwent sequential intramural pregnancies in the right uterine cornu after the transfer of two embryos in a single cycle. Approval was obtained from the Ethics Committee of Chengdu Women and Children’s Central Hospital. The patient provided consent for the report to be published.

Here, we report a case in which a patient presented two IMPs after embryo transfer, and our diagnosis was difficult because of the atypical presentation and the multitude of disorders that could be differentiated. Ultimately, hysteroscopy and laparoscopy were used to confirm the diagnosis, and timely intervention was performed to preserve the patient’s fertility. In this case report, the causes, early diagnosis and treatment of IMP, especially among women of child-bearing age, are discussed to provide reference data for clinical diagnosis and treatment. The etiology of IMP is still unclear and may include the following risk factors [ 9 – 11 ]: (1) Damage to or defects in the endometrium, such as injury sustained during uterine surgery (abortion, hysteroscopy surgery, diagnostic curettage surgery, etc.) or the formation of tiny channels in the myometrium, which promotes fertilized egg implantation in the myometrium. (2) Damage to or defects in the uterine serosal layer, such as injury sustained from pelvic or abdominal surgery (myomectomy, cesarean section, etc.), pelvic inflammation or pelvic endometriosis, which may lead to embryo implantation from the serosal layer to the myometrium. (3) Adenomyosis, in which ectopic endometrium in the myometrium undergoes decidual-like changes under the action of estrogen and progesterone and becomes a potential site of implantation of fertilized eggs. (4) An embryo used for ART having excessively strong viability and high invasiveness or being implanted at a time not synchronized with endometrial development, which would allow the embryo to penetrate the entire thickness of the endometrium and implant into the uterine myometrium, increasing the risk of intramural pregnancy. Although embryo transfer in ART is usually performed under ultrasound guidance, with the goal of placing the embryo in the middle or lower part of the uterine cavity, excessively deep insertion or an abnormal angle of the transfer catheter may push the embryo to areas near the uterine cornua or fundal myometrium, increasing the probability of the embryo invading the myometrium. In addition, if the volume of fluid injected during transfer is excessive or if the injection pressure is too high, it may cause a sudden increase in intrauterine pressure, forcing the embryo to deviate from the normal implantation area and even squeeze into the uterine myometrium through tiny breaks in the endometrium, resulting in abnormal implantation. Furthermore, ovulation-inducing drugs (e.g., gonadotropins) used in ART may alter endometrial receptivity and indirectly affect the blood supply and elasticity of the uterine myometrium. Although they do not directly cause intramural pregnancy, they may reduce the success rate of normal implantation and indirectly increase the probability of abnormal implantation. In this case report, the patient denied a history of previous pelvic or abdominal surgery, pelvic inflammatory disease, abortion, or endometriosis. This pregnancy was assisted by IVF-ET, and two fresh embryos were transferred at one time, which was a high-risk factor. During IVF-ET, the high-estrogen environment can enhance the contraction of uterine smooth muscle and increase the probability of ectopic pregnancy [ 12 ]. Fresh embryo transfer, excessive transfer fluid during the operation, a transfer site that is too deep, an injection speed that is too fast, the transfer of multiple embryos at one time and other factors may lead to the occurrence of IMP [ 13 ]. However, the two intramural pregnancies in this patient were located at different positions in the right uterine horn, which is worthy of discussion. If the transplanted embryos are implanted into the endometrium or muscle layer and the sinus tract is formed and if the two embryos have different activities and wander in the sinus tract, they may eventually form IMP at different times and at different locations. Cases of IMP are rare, and its clinical manifestations are similar to the common symptoms of ectopic pregnancy and lack specificity. Sometimes the only indication is the serum HCG level not matching the gestational age or rupture of a lesion leading to hemorrhagic shock, which can be diagnosed by retrospective analysis after emergency surgery. Therefore, the clinical diagnosis of this condition is difficult, and the misdiagnosis rate is high [ 14 ]. IMP is often misdiagnosed as intrauterine pregnancy, abortion, fetal membrane residue, other ectopic pregnancy, and trophocyte diseases. Vaginal ultrasound in the diagnosis of IMP is the main auxiliary examination, and the accuracy of ectopic pregnancy diagnosis is as high as 90.9% [ 15 ]. Many scholars have summarized typical IMP under sonographic findings [ 8 ] into 3 types: gestational cyst type, mass type, and uterine rupture type, with the most common gestational cyst type, observed intraoperatively after it develops. Our patient had two consecutive intramural pregnancies in the right cornual region, and the embryo was implanted in the muscle wall of the cornual region, which is easily confused with interstitial tubal pregnancy, a major problem in differential diagnosis. Ackerman et al.’s “transvaginal ultrasound interstitial line signs” theory for imaging provides a meaningful reference [ 16 ]: The embryo of interstitial pregnancy was implanted in the lumen of the interstitial part of the fallopian tube. The pregnancy mass interrupted the interstitial line and connected with the uterine cavity through the interstitial line. However, in intramural pregnancy embedded in the muscular layer of the cornual region, the blastocyst is not in contact with the uterine cavity and fallopian tube, and the pregnancy mass pushing against the interstitial line causes its displacement, and the interstitial line is not interrupted (Fig. 7 ). Fig. 7 Schematic representation of the interstitial line sign on transvaginal ultrasound. ( A ) Pregnancy in the interstitial part of the fallopian tube, the gestational mass interrupts the “interstitial line” and contacts the uterine cavity through the “interstitial line”. ( B ) The gestational sac is embedded in the wall of the uterine muscle in the cornual region, and the gestational mass pushes the “interstitial line” to displace it. The “interstitial line” is not interrupted Schematic representation of the interstitial line sign on transvaginal ultrasound. ( A ) Pregnancy in the interstitial part of the fallopian tube, the gestational mass interrupts the “interstitial line” and contacts the uterine cavity through the “interstitial line”. ( B ) The gestational sac is embedded in the wall of the uterine muscle in the cornual region, and the gestational mass pushes the “interstitial line” to displace it. The “interstitial line” is not interrupted MRI can reveal lesions in, or intrude into, a muscular layer depth and surrounding tissue [ 17 ], as well as unique residual ectopic pregnancy fetal placental tissue with a fibrous protein chain structure, making early diagnosis convenient [ 7 , 18 ]. More foreign scholars believe that MRI is the gold standard for the preoperative diagnosis of IMP [ 19 ]. Typical IMP cases can be identified early on the basis of medical history, HCG level and imaging characteristics. However, the clinical manifestations of some IMP patients are very similar to those of trophoblastic tumors, which makes IMP difficult to identify. In this case, three-dimensional ultrasound, high-resolution endovenous ultrasound and transvaginal intravenous contrast-enhanced ultrasound can be used to more intuitively show the relationship between the mass and the uterine cavity and myometrium, as has been demonstrated with a retrospective study [ 20 ]. Although the above method is still difficult to identify, some scholars believe that surgical exploration is safe and effective, is helpful for guiding clinical diagnosis and treatment planning, and can avoid complications; moreover, IMP is still diagnosed worldwide mainly by surgical exploration and postoperative pathological analysis [ 21 , 22 ]. In this study, the final diagnosis of this patient was also confirmed using surgical exploration and postoperative pathological analysis. At present, there is no single universal treatment for IMP, and the development of treatment requires consideration of many factors, such as the location of the gestational sac, the extent of myometrial involvement, the gestational age at diagnosis, and the patient’s future reproductive plans. Treatment includes surgical, pharmaceutical, and interventional treatment [ 23 , 24 ]. If the patient’s condition is stable and an early and accurate diagnosis is made, pharmaceutical treatment can be selected [ 25 ]. E Kucera et al. demonstrated that conservative management is the preferred treatment modality for complete intramural pregnancy, with a preference for local injection of methotrexate and strict adherence to follow-up [ 26 ]. However, pharmaceutical treatment may not be complete. If conservative treatment fails, surgery is still needed, and histopathological results are needed to confirm the final diagnosis. In recent years, the incidence of uterine rupture and hemorrhagic shock secondary to IMP has decreased, and the surgical methods are mainly laparoscopic and hysteroscopic surgery, resulting in less damage and quick recovery [ 21 ]. Hysteroscopy is preferred for IMP with a gestational sac connected to the uterine cavity through a sinus tract or for cases where cornual pregnancy needs to be excluded. In addition to facilitating early diagnosis, laparoscopic surgery is a safe and effective treatment. In this patient, the gestational sac ruptured during the first ectopic pregnancy, resulting in massive intra-abdominal hemorrhage. In the second ectopic pregnancy, the patient’s HCG levels continued to increase. To avoid other ruptures and blood loss, we did not prioritize methotrexate treatment but chose carefully timed surgical exploration. Due to the careful timing of the operation at 8 weeks of gestation, abdominal hysteroscopy detection and successful lesion resection, the patient’s fertility was preserved, and adverse hysterectomy outcomes such as focal rupture hemorrhage and uncontrolled hemorrhagic shock were avoided. This patient has never successfully conceived a full-term pregnancy before, and preserving her fertility was particularly important. This case is worthy of a retrospective analysis. The primary reason for the nonsimultaneous diagnosis of the two intramural pregnancies was the “masking effect of a dominant lesion overshadowing a covert lesion”. Initially, one pregnancy site on the uterine serosa presented as a surgical emergency due to acute rupture and hemorrhage, causing classic acute abdomen symptoms. This became the immediate focus of clinical attention. The emergency laparoscopy was rightly directed at controlling this active bleeding. In contrast, the second pregnancy, which was embedded deep within the myometrium, was clinically occult, being small, nonruptured, and asymptomatic, making it easy to miss during both the initial surgery and ultrasonography. The pivotal clue was the suboptimal decline in HCG levels postoperatively, which indicated the presence of residual viable trophoblastic tissue. This prompted further investigation with more sophisticated imaging, MRI, which ultimately localized the second lesion. This case highlights the critical importance of serial HCG monitoring in the management of ectopic pregnancies following ART to rule out rare cases of multiple and cryptic ectopic gestations. After discharge, the patient was followed up at our hospital. On July 3rd, the serum HCG level had decreased to 6.8 IU/L, and the patient had mild anemia. There was no postoperative discomfort, such as abdominal pain or vaginal bleeding, and no abnormalities were found on the rechecked ultrasound. The patient resumed normal menstruation on August 17th. Currently, the patient is taking medication to correct anemia and is taking care of her health. In the future, she plans to continue with IVF for assisted pregnancy. In conclusion, the diagnosis of IMP is very difficult; this condition is sometimes misdiagnosed, leading to incorrect treatment, such as repeated uterine cavity operations or chemotherapy, for example, which can cause uterine rupture or uncontrolled hemorrhagic shock requiring life-threatening surgery. Early recognition and diagnosis of IMP are particularly important; therefore, we need to increase awareness of this condition among gynecologists, fertility physicians, and imaging physicians. Atypical clinical symptoms, when considered in combination with a patient’s medical history and imaging data, are important for correct and timely diagnosis. In ART, the risk of IMP can be somewhat reduced by closely monitoring endometrial thickness and morphology via ultrasound, optimizing embryo transfer techniques (e.g., precise positioning and controlled fluid volume and pressure) and evaluating the patient’s previous uterine surgical history.