Clinical efficacy and safety analysis of different treatment options for Cervical pregnancy

Abstract Objective To compare the efficacy and safety of different treatment options for cervical pregnancy (CP). Materials and methods A total of 74 patients diagnosed with CP at Hunan Provincial Maternal and Child Health Care Hospital between January 2016 and September 2022 were retrospectively analyzed. Among them, 31 were treated with uterine artery embolization (UAE) followed by hysteroscopic curettage, 34 were treated with hysteroscopic curettage alone, and nine were treated with high-intensity focused ultrasound (HIFU) followed by hysteroscopic curettage. Medical records and pregnancy outcomes were analyzed. Results There were no significant differences in age, gravidity, parity, abortion, or preoperative hemoglobin levels among the patients in the three groups; however, significant differences in gestational age, gestational sac diameter, preoperative β-hCG, and presence of cardiac pulsation were observed (p < 0.05). After treatment, there was no conversion to laparotomy, and the uterus was preserved in all patients. Significant differences in blood loss during curettage, hospitalization costs, hospital days, menstrual recovery interval, β-hCG decline rates, retained products of conception, and intrauterine adhesions rate among the three groups were observed (p < 0.05). There were no significant differences in the placement of the uterine Foley balloon, effective curettage rate, pre-and postoperative hemoglobin decline, live birth rate, or proportion of subsequent pregnancies among the three groups. Conclusion Our results showed that hysteroscopic curettage, HIFU, and UAE followed by hysteroscopic curettage are safe and effective for treating patients with CP. Compared with the UAE, HIFU has the advantages of lower hospitalization costs, shorter hospital stays, and shorter menstrual recovery intervals.


Introduction
Cervical pregnancy (CP) is a rare clinical condition in which a fertilized egg implants and develops in the cervical canal, with an incidence of approximately 1/16,000-1/18,000 [1].In recent years, its prevalence has increased due to the widespread application of assisted reproductive technologies [2,3].
The typical clinical manifestation of CP is painless vaginal bleeding following amenorrhea.Physical examination revealed an enlarged cervix with a bluish-purple color.Transvaginal ultrasonography and pelvic magnetic resonance imaging (MRI) were performed to confirm the diagnosis of CP.If curettage is performed because of misdiagnosis or delayed diagnosis of CP, uncontrollable massive bleeding and shock may occur, and hysterectomy may be required to stop bleeding.Therefore, pregnancy termination is recommended once diagnosis is confirmed.Because the cervix is mainly composed of connective tissue with a small number of smooth muscle fibers, blood vessels, and elastic fibers, its contractility is limited.This may lead to difficulties in the natural closure of ruptured blood vessels during miscarriage or curettage, resulting in massive potentially fatal bleeding.Because this disease is rare, there are currently no specific clinical diagnostic or treatment guidelines.Initially, total hysterectomy was the main treatment for CP, resulting in the loss of fertility, which adversely affects the physical and mental health of patients.Later, conservative treatment with drugs, vaginal lesion resection, and curettage after ligation of the descending branches of the uterine artery were gradually explored.Pretreatment before curettage is crucial in clinical practice [4].The most commonly used pretreatment methods include uterine artery embolization (UAE) and medications (methotrexate and mifepristone).Methotrexate (MTX), delivered via systemic or local injection, is an optional drug treatment for women who are clinically stable; however, its curative effect remains uncertain.The estimated failure rate after systemic treatment is high, with a probability of hysterectomy in 10% of cases [5][6][7].UAE is a widely used pretreatment method to treat uncontrollable bleeding in patients with CP and preserve future reproductive function.As a minimally invasive nonsurgical treatment, UAE has been proven effective and safe for the management of CP.However, complications, such as fever, abdominal pain, amenorrhea, infertility, and ovarian dysfunction, may occur after UAE.
Over the last few years, high-intensity focused ultrasound (HIFU) has been used to treat CP [8].By sonicating the implantation site of the gestational sac with HIFU, the local temperature increases, and heat can be used to kill trophoblast cells and destroy blood vessels with diameters of less than 2 mm.Therefore, HIFU can be used to reduce blood perfusion at the implantation site and surrounding areas, facilitate the separation of the gestational sac from the muscle layer, and reduce the risk of bleeding during curettage and postoperative residue.To date, no study has compared the efficacy and safety of direct hysteroscopic curettage, HIFU, or UAE followed by hysteroscopic curettage for CP.This study aimed to compare the efficacy and safety of these three treatment options for CP.

Materials and methods
The protocol for this retrospective study was approved by the ethics committee of our institute (no.2023-S010) and the requirement for informed consent was waived.

Patients
From January 2016 to December 2022, 74 patients with CP treated at Hunan Provincial Maternal and Child Health Care Hospital were enrolled.Among them, 31 were treated with UAE followed by curettage (UAE group), 34 were treated with curettage alone (curettage group), and nine were treated with HIFU followed by curettage (HIFU group).All patients completed the follow-up period.
The inclusion criteria were as follows: (1) a history of amenorrhea, gynecological examination revealing cervical enlargement, congestion, softness, and coloring, with the cervix losing its normal shape and the uterus appearing gourd-shaped; (2) diagnosis of CP made using transvaginal ultrasonography examination or MRI (Figures 1 and 2), b-human chorionic gonadotropin (b-hCG) testing; and (3) postoperative pathological examination showing villi consistent with a diagnosis of CP.The exclusion criteria were as follows: (1) severe cardiovascular or cerebrovascular disease or coagulation dysfunction and (2) incomplete clinical data.

UAE
UAE was performed under local anesthesia with the patients in the supine position.The Seldinger technique was used to access the right femoral artery, at the midpoint of the inguinal ligament.After the successful placement of the vascular sheath, an angiography catheter was inserted through the right external iliac artery and the abdominal aorta, selectively entering the left and right uterine arteries.Angiography revealed tortuous and thickened uterine arteries bilaterally with intense staining.After confirming the presence of the lesion, gelatin sponge particles were used to embolize the uterine arteries.The procedure was terminated after angiography revealed successful embolization.Hysteroscopic curettage was performed 24 h after UAE.

HIFU
HIFU treatment was performed using a JC-200D high-intensity focused ultrasound tumor therapeutic system (Chongqing Haifu Medical Technology Co., Ltd., Chongqing, China) under conscious sedation.Patients were positioned prone on the HIFU table, with the anterior abdominal wall in contact with degassed water.The sagittal ultrasound scanning mode was selected for both pretreatment planning and sonication.The gestational sac and surrounding tissues were identified using ultrasonography.A safe acoustic pathway was established and the targeted gestational sac was divided into several sections with an interlayer spacing of 3 mm using real-time ultrasound.A point scan was used, the power was set between 350-400, watts and the implantation site of the gestational sac was sonicated.The blood flow at the implantation site before and after treatment was compared using a contrast-enhanced ultrasound imaging, and the ablation effect was evaluated.Treatment was terminated when the blood flow signal at the implantation site disappeared.No obvious contrast agent perfusion was observed in the gestational sac or the surrounding tissues after HIFU treatment (Figure 3).The respiratory rate, heart rate, blood pressure, and oxygen saturation were monitored during the procedure.Hysteroscopic curettage was performed 24 h after HIFU.

Hysteroscopic curettage
The patient was placed in the lithotomy position and the procedure was performed under general anesthesia.After disinfecting the vulva and vagina, a speculum was used to expose the cervix, which was fixed using a cervical clamp.Hysteroscopic examination was performed to determine the location and size of the pregnancy tissue.A probe was used to explore the depth and direction of the uterine cavity, followed by a suction curettage of the cervical canal.If residue tissue was detected, further curettage or tissue removal was performed under hysteroscopy.If massive bleeding occurred during curettage, contractions, a uterine Foley balloon, and other hemostasis methods were used to stop the bleeding.Blood loss during the procedure of curettage was counted by the amount of liquid in the negative pressure bottle and the weight of medical gauze.The amount of blood loss was calculated by subtracting the weight of dry gauze from the weight of gauze after blood absorption.
The evaluation criteria for curettage were as follows: the amount of blood loss during curettage less than 100 ml indicated a significantly effective treatment; if the amount of blood loss during curettage was more than 100 ml, but the bleeding was stopped by compressing with balloon, it was defined as effective; and if the amount of blood loss during curettage was greater than 100 ml, but it could not be controlled by compressing balloon and needed to be switched to other treatments, it was defined as ineffectiveness [9].Effective curettage rate ¼ (significantly effective þ effective)/all cases � 100%.

Follow-up
All patients were advised to return to our department for color Doppler ultrasound examination one month after suction curettage.All patients were followed up for at least six months.The following variables were recorded: the presence of any retained products of conception, menstrual recovery interval, the incidence of intrauterine adhesions, and whether patients with fertility requirements became pregnant again.If the patient had a menstrual volume reduction of more than 1/2, then a hysteroscopy was performed.

Statistical analysis
Data were processed using SPSS 22.0.Normally distributed data are expressed as mean ± standard deviation (x ± s), and one-way ANOVA was used for intergroup comparisons.Nonnormally distributed measurement data are expressed as M (P25-P75), and the Kruskal-Wallis H rank-sum test was used for intergroup comparisons, followed by pairwise comparisons using the Mann-Whitney U test.The Bonferroni method was used to adjust test levels.For count data, rates (%) were used, and the v 2 test was used for comparisons among the three groups.Further pairwise comparisons were performed using Fisher's exact probability method and the test level was adjusted.All statistical tests were two-sided, and p < 0.05 indicated a statistically significant difference.

Comparison of baseline characteristics among the three groups
No significant differences were observed among the three groups in terms of age, gravidity, parity, abortion, and preoperative hemoglobin levels (p > 0.05  1).

Evaluation of efficacy and safety
All patients in these three groups underwent curettage; there was no conversion to laparotomy, and the uterus was preserved in all three groups.The effective rate of curettage was 100% (31/31), 97.1% (33/34), 100% (9/9) in the UAE, curettage, and HIFU group, respectively, with no significant difference between the three groups (p > 0.05).The median blood loss during curettage was 15, 20, and 15 ml in the UAE, curettage, and HIFU group, respectively.Significant differences were found among the three groups (p < 0.05), and pairwise comparisons revealed that the patients in the curettage group experienced greater blood loss than those in the UAE group.The probability of using a balloon was 12.9% (4/31), 11.8% (4/34), 0.00% (0/9) in the UAE, curettage, and HIFU group, respectively, with no significant difference between the three groups (p > 0.05).Four patients in the UAE group had bleeding of 200, 500, 220, and 200 ml, respectively, which stopped after placement of the uterine Foley balloon.Four patients in the curettage group had bleeding of 450, 500, 600, and 1500 ml; bleeding stopped after the placement of the uterine Foley balloon for three cases, while emergency UAE was required to stop the bleeding for the case with the bleeding of 1500 ml.Patients in the HIFU group did not receive a uterine Foley balloon and bleeding was < 100 ml.
Statistically significant differences were found among the three groups in terms of hospitalization costs, duration of hospital stay, menstrual recovery intervals, b-hCG decline rates, and retained products of conception (p < 0.05).Pairwise comparisons revealed that the UAE group had the highest hospitalization costs, followed by the HIFU and curettage groups.The UAE group had a longer hospital stay and menstrual recovery interval than the curettage and HIFU groups.The UAE group exhibited a higher proportion of retained products of conception than the direct curettage group, while both the UAE and curettage groups demonstrated a higher b-hCG decline rate than the HIFU group.No statistically significant differences were observed among the three groups in terms of pre-and postoperative hemoglobin decline (p > 0.05) (Table 2).

Follow-up results
The average follow-up time of patients in this study was 46 ± 26 (range: 6-85) months.During the follow-up period, 8 (8/31, 25.80%) patients in the UAE group experienced intrauterine adhesion.Two (2/34, 5.88%) patients in the curettage group experienced intrauterine adhesion and no patient experienced intrauterine adhesion in the HIFU groups.A significant difference was observed in intrauterine adhesion among the three groups (p < 0.05), and pairwise comparisons revealed that the UAE group exhibited a higher proportion of intrauterine adhesion than that in the direct curettage group (Table 2).
Pregnancy outcome was evaluated based on the patient fertility requirements.The UAE group included 25 patients with fertility requirements, and 10 achieved pregnancy, resulting in a pregnancy rate of 40% and a live birth rate of 70%.Three patients experienced preterm deliveries, 4 had full-term deliveries, 1 was in late pregnancy, and two experienced miscarriages.In the curettage group, 28 patients had fertility requirements and 13 patients achieved pregnancy, resulting in a pregnancy rate of 46.42% and a live birth rate of 84.62%.Eleven patients had full-term deliveries, and two patients experienced spontaneous miscarriages.In the HIFU group, 6 patients had fertility requirements, and two patients achieved pregnancy, both resulting in full-term deliveries.No significant difference was observed among the three groups   3).

Discussion
Currently, there are no unified standard guidelines for the treatment of patients with CP [10,11] .In treating CP, clinicians can refer to their experience managing cesarean scar pregnancies (CSP) [2], as the implantation of the pregnancy sac at the uterine incision or the cervix has close anatomical locations and similar effectiveness of hemostasis measures.According to our results, clinicians are making treatment plans for patients according to this rule, which leads to different treatment groups.The results from a cohort study involving 1637 patients with CSP showed that gestational sac diameter, presence of cardiac pulsation, and gestational age were risk factors for CSP [12].Here, we found that patients with older gestational age, larger gestational sac diameter, higher preoperative b-hCG levels, and the presence of cardiac pulsation were more likely to be treated with UAE.Patients with this characteristic have an increased risk of uterine bleeding, and clinicians will choose treatment plans with clear hemostatic effects.UAE is an established treatment for hemostasis because it blocks the uterine artery, reduces blood vessel formation, and degenerates the trophoblast, which reduces the risk of massive bleeding and hysterectomy.UAE is effective in treating and preventing acute uterine hemorrhage [13,14], postpartum hemorrhage, uterine arteriovenous malformation, and the management of CSP and placenta accrete [12,15,16].In our study, patients in the UAE group had less bleeding than those in the curettage group, and none had severe bleeding.Therefore, it is reasonable to consider UAE as a pretreatment option for patients with CP who are at a high risk of massive bleeding during curettage.
HIFU has been used as a noninvasive treatment for the management of patients with CSP [17].However, there are few studies of HIFU treatment for CP, and no criterion of HIFU treatment for CP is available.A retrospective study with a small sample size by Li et al. showed no significant differences between HIFU and UAE groups in terms of intraoperative blood loss, extent of b-hCG decline, intrauterine residuals, or pregnancy outcomes in patients with CP [2].However, some studies have shown that HIFU treatment of CP with a large pregnancy sac is less effective and increases the risk of bleeding during curettage [18].A retrospective study of 58 patients with CSP by Ma et al. found that both gestational age and gestational sac diameter could be used to predict the risk of intraoperative hemorrhage, with the best cutoff values of 51 days and 27 mm, respectively [19].Mu et al. performed a retrospective study of 41 patients with CSP treated with HIFU followed by curettage.Their results showed that the size of the gestational sac in the hemorrhage group (3.80 ± 0.87 cm) was significantly larger than that in the control group (3.39 ± 0.77 cm) (p < 0.05) [20].Therefore, a gestational sac diameter of 3 cm may be suggested as a segmentation point for HIFU or UAE during CSP treatment.In this study, we selected patients with CP for HIFU based on our experience with CSP treatment.For example, the gestational age of HIFU group were 43.89 ± 3.22 days and the diameter of pregnancy sac was 1.30 ± 0.24 cm, while gestational age of the UAE group were 51.77 ± 10.93 days and the diameter of pregnancy sac was 2.89 ± 1.22 cm, which showed statistically significant differences.All nine patients in the HIFU group were treated effectively, and none experienced major bleeding during curettage.
Two patients with high b-hCG (23853 IU/L and 67014 IU/L) and large gestational sac diameter (2.0 cm and 4.0 cm) experienced major bleeding (600 ml and 1500 ml).Bleeding was stopped with a uterine Foley balloon in the first patient, and the second underwent emergency UAE.This is consistent with the results of a previous study [18].However, in two patients with low b-hCG (3872 IU/L and 2514 IU/L) and small gestational sac diameters (1.0 cm and 2.0 cm) who underwent direct curettage, bleed 450 ml and 500 ml, which was stopped with a uterine Foley balloon.This suggests that even if b-hCG is low and the pregnancy sac is small, direct curettage also carries the risk of massive bleeding in the direct curettage group.Although patients had lower hospitalization costs, shorter hospital days and menstrual recovery time, lower probability of intrauterine adhesions, and retained products of conception, the risk of massive bleeding is high.Therefore, direct curettage is not recommended for patients with CP.
Our results showed that the effective rate of curettage in the three groups exceeded 95%; however, further analysis showed that the UAE group had a higher probability of complications, such as a longer menstrual recovery interval, retained products of conception, and intrauterine adhesions, than the curettage group.Among the 31 patients who underwent UAE, eight (25.80%)experienced intrauterine adhesions postoperatively, and four patients required 2-4 additional procedures for adhesion separation, and one experienced premature ovarian failure (POF).Song  Their results showed that 42.1% of women in the UAE group experienced an improvement in menstrual function, which was significantly lower than the rate of 86.0% in the non-UAE group.The UAE group showed a 30% reduction in the American Fertility Society score for intrauterine adhesions, which was significantly lower than the 80% reduction observed in the non-UAE group.The pregnancy and live birth rates in the UAE group (5% and 0%, respectively) were significantly lower than those in the non-UAE group (33% and 25%, respectively).Several studies have shown that the reproductive outcomes of intrauterine adhesions caused by UAE are worse than those caused by non-UAE-related surgical trauma [21].This may be because UAE affects endometrial microvascular density and angiogenesis, thus affecting the repair and tolerance of the endometrium [22]. .Some studies have suggested that UAE may lead to decreased ovarian function.A retrospective analysis of angiographic images before embolization in 92 patients who underwent UAE revealed variations in the blood supply between the uterus and ovaries.Patients with blood flow from the uterus to the ovaries through collateral vessels had a higher incidence of decreased ovarian function after the procedure [23].Therefore, for patients who do not achieve fertility or desire future pregnancy, UAE is not recommended unless there is a severe hemorrhage.
In this study, among the nine patients who underwent HIFU treatment followed by curettage, no significant bleeding occurred during the curettage procedure, and only one patient had postoperative residual products of conception.No intrauterine adhesions or POF were observed in the HIFU group.Among the six patients in the HIFU group who desired fertility, two achieved pregnancy without any occurrence of placenta previa, placental implantation, or postpartum hemorrhage, which is consistent with previous studies that reported the results of HIFU in the treatment of CSP [9].It is speculated that the precise focal ablation of HIFU specifically targets the site of CP implantation without affecting the endometrium or uterine blood flow.Consequently, the incidence of intrauterine adhesions and POF was significantly lower than that of UAE [24].Therefore, HIFU treatment may serve as a potential alternative to UAE, particularly in women who have not completed their fertility journey or have reproductive requirements.
This study is limited because it was retrospective, and the patients were not randomized.In fact, patients with a larger gestational sac diameter, larger gestational age, higher b-hCG levels, and cardiac pulsation were treated with UAE.Therefore, some bias in baseline characteristics occurred, and this study is also limited by its small sample size; in particular, there were only nine cases in the HIFU group.Further prospective randomized controlled studies are required to confirm these findings.In summary, this study showed that hysteroscopic curettage, HIFU, or UAE followed by hysteroscopic curettage are safe and effective for treating patients with CP.Compared with the UAE, HIFU has the advantages of lower hospitalization costs, shorter hospital stays, and shorter menstrual recovery intervals.

Figure 1 .
Figure 1.Ultrasound images obtained from a patient with CP. A. A sagittal of a gestational sac in the cervix.B. Transverse view of a gestational sac in the cervix.

Figure 2 .
Figure 2. MRI from a patient with cervical pregnancy.(A) A sagittal view of T2-Weighted image showing a gestational sac in the cervix (red arrow).(B) A sagittal view of contrast enhanced MRI showing no enhancement in the gestational sac.

Figure 3 .
Figure 3. Contrast-enhanced ultrasound obtained from a patient with CP treated with HIFU.(A) Blood supply around the embedding area of the GS in the previous cervical section (red arrow) before HIFU ablation; (B) No blood supply around the embedding area of the GS in the previous cervical (red arrow) after HIFU ablation.
in the proportion of patients achieving pregnancy and live birth rate (p > 0.05) (Table

Table 1 .
Baseline characteristics among the patients in UAE, curettage, and HIFU groups.

Table 2 .
Comparing treatment and follow-up results among the UAE, curettage, and HIFU groups.
et al. analyzed 26 patients who developed intrauterine adhesions after UAE, 11 of whom had no history of intrauterine procedures, suggesting a correlation between intrauterine adhesions and UAE.Zhou et al. evaluated the reproductive outcomes of 124 patients with a history of UAE who underwent hysteroscopic adhesion lysis for intrauterine adhesions.The results showed a clinical pregnancy rate of 23.4%, live birth rate of 17.7%, full-term live birth rate of 44.8%, and high preterm birth rate of 31%.Most of these patients experienced severe obstetric complications, primarily postpartum hemorrhage, and placental abnormalities, with occurrence rates of 54.5%, 9.1%, and 36.4% for postpartum hemorrhage, placenta previa, and placental adhesion/implantation, respectively.Another retrospective study conducted by Song et al. compared patients with intrauterine adhesions following UAE and those who had intrauterine adhesions but did not undergo UAE.

Table 3 .
Pregnancy proportions among the UAE, curettage, and HIFU groups.