Advances in Treating Cesarean Scar Pregnancy: A Comprehensive Review of Techniques, Clinical Outcomes, and Fertility Preservation

Introduction

Cesarean scar pregnancy (CSP) is one of the rarest types of ectopic pregnancy; it occurs when an embryo implants at the site of a cesarean section scar [1]. The incidence is estimated to range from 1/1000 to 1/2500 and correlates closely with the number of previous pregnancies terminated by cesarean section [2]. According to He et al, the most important factors influencing the occurrence of CSP are multiparity, number of previously performed abortions, uterus position, and vaginal bleeding [3]. Modern diagnosis is based on ultrasound criteria [4,5]. Two-dimensional (2D) B-mode transvaginal ultrasound (TVS) alone or in conjunction with three-dimensional (3D) ultrasound and color Doppler has been generally considered to be the criterion standard for diagnosis of CSP [6]. Ultrasound can help visualize the gestational sac within the cesarean scar, measure its size, and determine its location and viability [7,8].

Cesarean scar pregnancies can be categorized based on their location within the cesarean scar or niche [8], determined during the first-trimester transvaginal ultrasound examination [7]. There are 2 main categories:

In 2022, a new advanced standardized system for sonographic assessment and reporting of CSP in early pregnancy was created [7]. Depending on the location of the gestational sac (GS), the following types of CSP can be diagnosed:

It is important to note that the type of CSP can change with advancing gestation, meaning that the location of the gestational sac can shift as the pregnancy progresses [9]. The type of CSP and its location can have implications for the management and treatment of the condition, and should be evaluated and monitored by a healthcare provider [7].

Early diagnosis of cesarean scar pregnancy is particularly important in selecting appropriate treatment [10]. Expectant management of a cesarean scar pregnancy has a poor prognosis due to potential complications such as massive bleeding, disseminated intravascular coagulation, and uterine rupture [11]. It has been recommended to terminate the pregnancy in the first trimester soon after diagnosis to improve the prognosis [12]. Hysterectomy was often considered the only treatment option for CSP [13]. However, in recent years, more conservative approaches have been developed and are increasingly being used as an alternative to hysterectomy [14,15]. Contemporary treatment methods include surgical methods such as laparoscopic removal, hysteroscopic evacuation, dilation and curettage, sac aspiration by suction, selective uterine arterial chemoembolization (UAC), and open surgery [16]. Other methods used to treat cesarean scar pregnancy include methotrexate (MTX) administered locally or systemically and potassium chloride, sodium chloride, hyperosmolar glucose, or crystalline trichosanthin under ultrasonography guidance [16].

The choice of treatment approach for CSP depends on various factors, including the size and location of the pregnancy, the patient’s fertility desires, and the presence of any complications or risk factors [17]. At present, there is no universal treatment for CSP. The biggest challenge is to select and carry out the treatment properly, damaging the normal structures of the reproductive organs as little as possible, while effectively allowing fertility preservation [18].

Therefore, we performed a systematic review of the published literature on management of cesarean scar pregnancy and the outcomes, complications, and effects on fertility.

Material and Methods

ETHICS STATEMENT:

Local institutional review board approval was not required for this type of study. The study was conducted in compliance with the Declaration of Helsinki.

SEARCH STRATEGY:

Two independent reviewers (B.K. and K.N.) conducted a comprehensive search in 3 electronic databases (PubMed, Google Scholar, and Web of Science) using the following keywords in combinations: “cesarean scar pregnancy,” “methotrexate,” “systematic,” “chemoembolization,” and “uterine artery embolization.” The search was restricted to articles published in English from 2010 to the present. The search strategy was adapted to each database.

SELECTION CRITERIA:

The inclusion criteria for the studies were: (1) original articles, reviews, and meta-analyses that evaluated the treatment of patients with cesarean scar pregnancy either with systemic methotrexate or uterine artery chemoembolization, and (2) studies published in English.

Results

SEARCH RESULTS:

The baseline search resulted in 413 articles. All of them were initially reviewed on the title and abstract level according to PRISMA guidelines. After the exclusion of 312 irrelevant articles, the abstracts and titles of remaining 91 articles were read for potential inclusion, resulting in the further exclusion of 24 articles. Therefore, the full texts of 67 articles were further investigated. Finally, 60 papers were included in the study.

CHEMOEMBOLIZATION:

Chemoembolization is one of the newest methods used to treat CSP [19]. Embolization of the uterine arteries with intra-arterial infusion of methotrexate is a minimally invasive technique performed endovascularly [20]. This method allows concentrated administration of methotrexate directly into the arteries supplying the gestational foci, while occluding the vessel with occlusive agents such as polyvinyl alcohol and Gelfoam particles administered through a catheter [21].

Indications for chemoembolization for CSP include: presence of a live or viable embryo located in the cesarean scar, gestational age less than 12 weeks, absence of significant maternal symptoms or complications such as heavy vaginal bleeding or signs of hemodynamic instability, and refractory to or contraindications to other treatments such as methotrexate injection or dilation and curettage (D&C) [22]. Many authors have described successful chemoembolization procedures despite the presence of fetal heart activity, so it is not a contraindication to the procedure [23–25].

Uterine artery embolization as a treatment modality is influenced by factors such as high arterial flow associated with GS, uterine myometrial thickness between the sac and bladder less than 2 mm, or serum beta-human chorionic gonadotropin (β-hCG) levels above 10 000 mIU/ml [21].

The chemoembolization procedure is performed by experienced interventional radiologists under local anesthesia from the femoral access. Intraoperative angiography allows effective imaging of the anatomy with special attention to the uterine arteries and the possible presence of anastomoses that could hinder the procedure [23]. The standard dose used in the next step of the procedure is 50 mg of methotrexate, 25 mg in each of the uterine arteries, which directly supply blood to the embryo [26]. After the MTX is administered, occlusive agents such as polyvinyl alcohol and Gelfoam are injected through a delivery catheter to block the feeding vessel, prevent further blood flow to the gestational foci, and MTX migration.

When selecting an embolic agent, it is important to consider various factors, including the patient’s age, their risk for hemorrhage, hemodynamic conditions, and their desire to protect ovarian function and fertility. Ultimately, the selection of an embolic agent should be tailored to the individual needs and preferences, and should involve a comprehensive discussion between the patient and their healthcare provider to weigh the potential benefits and risks of different options [27]. Embolization is continued until complete occlusion of the gestational follicle’s feeding arteries is achieved. This procedure combines chemotherapy with tissue ischemia, which allows for a higher concentration of MTX to target the gestational foci for a longer period of time. This can result in more effective embryocide (destruction of the developing embryo), with fewer systemic toxic effects than other treatments [28].

A prospective observational study by Stępniak et al found that 20/22 (90%) women undergoing chemoembolization followed by suction curettage were successfully treated with this method [1]. The abnormal bleeding that occurred in one patient and the rich vascularization of the CSP originating from the ovarian artery in the other required repeated embolization. Of the 41 patients described by Pyra et al, treatment was successful in 34 patients (83%), and 7 patients required secondary treatment [23]. A retrospective study of 383 patients who underwent chemoembolization showed treatment success in 379 patients (99%) [24]. Treatment efficacy was found to be influenced by size of the gestational mass, presence of fetal heartbeat, and type of CSP. Yu et al evaluated the effectiveness of chemoembolization by comparing it with an injection of methotrexate combined with uterine curettage [26]. They found that the total effective rate was significantly higher in the group of patients treated with chemoembolization (P<0.05). Apart from this, compared to the group of patients treated with methotrexate injection, patients treated with chemoembolization showed better outcomes in terms of intraoperative blood loss, hospitalization period, time to return of menstruation, time to disappearance of the mass, and time to return of normal β-HCG level (P<0.05).

A meta-analysis evaluating the effectiveness of treatment with UAC in China showed that the mean time for β-hCG levels normalization was 29.8 days [14]. As far as the overall mean hospital stay was concerned, the average time hospitalization was 9 days. Authors also evaluated the estimated intraprocedural blood loss which was 41.2 ml. Finally, the counted the overall proportion of severe complication rate which was 0.012

The most commonly reported problems after the procedure are uterine cramping, nausea, and vomiting [1]. However, it is important to note that 5% of patients experience hemorrhage and 3% need a hysterectomy [1]. In a comparative study of UAC followed by curettage (UC) vs patients receiving intra-arterial MTX infusion followed by UAC and curettage (MUC), the use of intra-arterial MTX infusion had a positive impact on treatment outcomes [29]. Patients had a higher success rate (88.9%) without the need for additional medical interventions, and average blood loss during curettage was also lower in patients receiving MTX infusion directly into the arteries. Vaginal bleeding occurred in about 6% of patients.

Chemoembolization also shows similar efficacy as high-intensity focused ultrasound [30]. Wang et al compared the clinical outcome and rate of procedural compilations of high-intensity focused ultrasound (HIFU) vs UAC for the treatment of CSP, and no serious adverse effects were observed in either group. Interestingly, although HIFU was associated with a lower incidence of minor complications, the overall hospital stay was longer compared with patients who underwent endovascular embolization [31]. Overall, the most commonly occurring adverse effect of the treatment was lower abdominal pain [25].

In patients who desire to preserve fertility, performing chemoembolization is debatable because of the risk of ovarian failure and infertility, as well as the increased risk of miscarriage, preterm labor, and postpartum hemorrhage [22,26]. Czuczwar et al compared the effects of treatment with supracervical hysterectomy, ulipristal acetate, and uterine artery embolization on ovarian reserve [32]. The result of treatment was a significant reduction in the values of antral follicle count, anti-Mullerian hormone, and serum inhibin B and E2, while follicle stimulating hormone was significantly increased. They concluded that chemoembolization affects ovarian reserve to the greatest extent and should not be offered to patients who wish to become pregnant in the future. There are also reports of a decrease in menstrual blood volume or lack of menstruation after uterine artery embolization, which can negatively affect patients’ quality of life and subsequent fertility [32,33].

On the other hand, successful pregnancy rates of 30% following the uterine artery chemoembolization have been reported [23]. A large study found a 54% success rate of live births among patients seeking pregnancy [24]. Despite the many reports of successful pregnancies, more research is needed on the effects of UAC on fertility [23,24,32].

Cases of repeat pregnancies in the scar have been reported, which is currently one of the more serious challenges in treating this condition, so patients should always be informed of the risk of recurrence. Recurrent scar pregnancies are influenced by the surgical technique and incision closure technique used in cesarean section. However, based on the current study, the effect of a particular CSP treatment therapy on an episode of recurrence cannot be unanimously confirmed or denied. Most papers indicate that the method of treatment was an independent predictor of the risk of CSP recurrence [34]. CSP recurrence can be successfully treated with chemoembolization [35].

SYSTEMIC METHOTREXATE:

Methotrexate is a medication that works by inhibiting the synthesis of folic acid, which is essential for DNA synthesis and cell proliferation [36]. By disrupting these processes, it can halt the growth of an ectopic pregnancy and promote its absorption by the body. Pharmaceutical treatment with methotrexate is often preferred by patients over surgical treatment for ectopic pregnancy due to its non-invasive nature and lower risk of complications, and it can also be a cost-effective alternative to surgery [37].

There is a risk of treatment failure, which ranges from 22% to 48%, because the success of the treatment depends on several factors, including advanced gestational age, larger gestational sac diameter and crown–rump length, location of the ectopic pregnancy, the level of β-hCG in the blood, the individual patient’s response to the medication, and the presence of embryonic cardiac activity, which were associated with methotrexate failure or need for additional therapy [37,38].

MTX has been shown to be highly effective and safe, despite no exclusion criteria for β-hCG level, gestational sac diameter, or presence of embryonic cardiac activity [38]. Specific indications for treating CSP with methotrexate include contraindications to surgery or general anesthesia, high body mass index (BMI), or previous surgical history [38]. Patients in whom systemic administration of MTX does not have the intended result often undergo second-line surgical management UAE or laparotomy, and, in special cases, hysteroscopic resection [39,40].

Methotrexate in the systemic treatment of CSP is most often administered intramuscularly or intravenously [37]. A single dose of methotrexate was most commonly reported, with a second dose given 1 week apart if necessary [36]. The standard dose administered intramuscularly was 50 mg/m2 body surface area. Tanaka et al administered 100 mg methotrexate IV push over 5–10 min was used, with 200 mg methotrexate in 500 mL normal saline IV infusion over 12 h [38]. The selection of the appropriate treatment dose is influenced by the β-hCG level. If a β-hCG level of less than 1500 IU/L (less than 12 000 mIU/mL) is found, a single-dose regimen is preferred, while a multi-dose regimen is preferred for β-hCG levels under 3000 IU/L [37]. The literature describes the systemic intramuscular administration of MTX at a dose of 25 mg completed successfully in patients with the hCG levels 2781–15 700 milliunits/mL [41].

High efficacy in the treatment of CSP has been reported in patients who received a treatment regimen that included an intravenous bolus dose of methotrexate followed by methotrexate infusion over 12 h [38]. Treatment with high doses of methotrexate was effective and well tolerated by patients, without serious adverse effects. A retrospective cohort study comparing outcome assessment of single-dose methotrexate versus multiple-dose MTX protocols found no significant differences in need for additional surgical treatment [42], and there was no significant difference between the single-dose and multiple-dose groups in blood product administration and total days of hospitalization. On this basis, both single-dose and multiple-dose MTX treatment protocols are considered to have high success rates with relatively low rates of complications. In 2020, a systematic review found that the mean hospital stay was 11.7±1.2 days. The rate of success in pharmacotherapy of ectopic pregnancy by MTX is diverse and ranges from 71% to 100% [37]. In contrast, a systematic review published in 2017 reported a success rate of 56% for MTX treatment alone [43]. Numerous reports have shown that treatment of CSP with systemic MTX monotherapy alone is ineffective, but treatment success can be achieved by combining systemic MTX administration with other described treatment options [43].

The success of systemic treatment with methotrexate is influenced by β-hCG level. Mitsui et al assessed the influence of hCG level and gestational sac size, reporting that in patients who succeeded with treatment, bhCG levels were lower than in those for whom treatment failed [39]. This allowed them to determine that hCG levels less than 17 757.0 mIU/mL and GS sizes less than 10.4 mm are indications that MTX medical treatment is likely to successfully treat CSP patients. Shai et al described an MTX treatment success rate of 61.3% and found that a short time interval from the last cesarean delivery (CD) was a factor that directly influenced treatment outcome [44].

The success of systemic MTX treatment of patients described in a retrospective cohort study by Delplanquea et al was 87.5% (21/24). The remaining patients received second-line surgical treatment due to failure of methotrexate therapy [40]. The risk of failure may be influenced by the time interval between the previous cesarean delivery and CSP [44].

The use of MTX as first-line treatment is controversial, as better efficacy and safety of MTX treatment has been noted only in early pregnancy [42].

Methotrexate, which is a folic acid antagonist, competitively inhibits nucleic acid synthesis in its folate-dependent phase and effectively kills cells and tissues with a high-turnover such as trophoblasts, leading to decreased β-hCG levels [37]. According to a study by Seow et al, the mean time for complete gestational tissue regression after systemic MTX monotherapy is approximately 2 months, but it can take up to 1 year in some cases [45]. This means that even if the patient’s β-hCG levels return to normal relatively quickly after treatment, it may take several months for all of the remaining gestational tissue to be eliminated from the uterus.

Adverse effects occurring during systemic administration of MTX can affect various systems and organs due to the drug’s effects on the entire body, with adverse effects including nausea and vomiting, stomatitis, oral ulceration, vaginal spotting and bleeding, pneumonia, and alopecia [39,46–48].

Complications were more frequent in women with a history of 3 or more cesarean section deliveries and with a myometrial thickness thinner than 2 mm [42,49]. The risk of hemorrhage during MTX treatment was 10% [22]. Genital bleeding was also observed to occur in up to 70% of patients treated with systemic MTX [39]. The advantage of MTX administered directly into the gestational sac is its local action, thus limiting the effect of MTX on the whole body [48]. To date, there are very few reports comparing the adverse effects of CSP treatment using UAC vs systemic MTX. Doses of systemically administered methotrexate are often repeated to achieve an adequate response to treatment; thus, the patient is exposed to higher doses of this drug compared to the chemoembolization procedure [50]. In a study by Li et al compared systemic treatment with MTX as well as chemoembolization, showing that patients treated by chemoembolization had much less bleeding during uterine suction curettage, a shorter time until serum β-hCG resolution, and a shorter hospital stay than those receiving systemic MTX treatment [50]. Moreover, chemoembolization followed by uterine suction curettage was not associated with a higher incidence of complications as compared with MTX treatment.

Successful pregnancies after MTX treatment have been reported, but reliable data confirming the effect of MTX on subsequent female fertility and the incidence of recurrent CSP are still lacking [39,49]. Based on the available publications, conception outcomes are much lower than with chemoembolization treatment or were not analyzed. Tanakaa et al described only 1 healthy birth, which accounted for 3% of all patients [42]. In contrast, Takashi Mitsui et al reported a pregnancy success rate of 30% [39]. Because of these widely varying rates, further analysis is needed of fertility rates in patients treated with systemic MTX.

In patients for whom methotrexate treatment fails or is not appropriate, surgical management may be necessary. The choice of treatment approach will depend on several factors, including the patient’s clinical presentation, their fertility desires, and the potential risks and benefits of each treatment option [37]. In 2020, the Society for Maternal-Foetal Medicine (SMFM) recommended that MTX should not be used alone in the treatment of CSP [51]. Comparing the 2 treatment methods, the administration of systemic MTX is more often associated with the need for patients to undergo additional medical interventions or to repeat the procedure. The highest complication rates were observed with intramuscular methotrexate alone [41]. Additionally, a shorter hospital stay for patients treated with UAC was noted [52].

Discussion

The aim of this study was to systematically review the available literature on the management of cesarean scar pregnancy (CSP) and the outcomes, complications, and effects on fertility, with special attention to comparison of endovascular uterine artery chemoembolization (UAC) vs systemic methotrexate (MTX). We observed that UAC aiming to minimally invasive injection of methotrexate directly into uterine arteries is highly effective, especially if followed by suction curettage, whereas traditional therapy with systemic MTX is associated with a significantly higher risk of failure, increased risk of hemorrhage, and higher post-operative costs connected with longer hospital stays. Our findings agree with results reported by authors of other recent meta-analyses on CSP treatment [14,22,53].

The incidence of cesarean scar pregnancy (CSP) is increasing with the growing number of cesarean sections performed. Some projections show that by 2030 nearly 30% of all deliveries will by cesarean section [54]. Although there are reports of healthy deliveries among patients who received expectant management, it is associated with relatively high morbidity and mortality rates; therefore, termination of CSP is currently recommended [55]. Chemoembolization and systemic methotrexate are both treatments for cesarean scar pregnancy, but UAC might be contraindicated in patients with serious symptoms or complications (eg, vaginal bleeding or hemodynamic instability) [22].

UAC treatment is reported to have 83–99% efficacy [1,23,24]. Factors influencing final outcome include gestational size sac, presence of fetal heartbeat, and type of the cesarean scar pregnancy [24]. Beta-human chorionic gonadotropin (β-hCG) levels usually resolve within 1 month after treatment [24]. In their meta-analysis comparing UAC and systemic MTX in a Chinese population, Qiao et al [56] observed that β-hCG levels normalized significantly faster among patients treated with the endovascular method, with significant differences in hospital stay, blood loss, and rate of adverse events, which confirms the findings of our review. However, systemic methotrexate administration can still be successfully used, especially in patients presenting before 8 weeks’ gestation, with β-hCG levels <12 000 mlU/ml, and without fetal heart beat [43]. There are reports of safe and effective use of a combination of systemic and local administration of MTX for patients with CSP [57,58], but adverse effects (eg, nausea, vaginal spotting, and elevated liver enzymes) were noted. Having had more than 2 previous cesarean section and myometrial thickness <2 mm were independent factors associated with increased risk of complications and treatment failure [42,49].

A concern with any intervention involving the reproductive system in women is the potential impact on future fertility, regardless of their parity. In general, occlusion of uterine arteries carries a risk of ovarian failure and infertility, especially if dangerous utero-ovarian anastomoses are present [59]. Nonetheless, in case of CSP chemoembolization, the occlusion of the arteries is temporary if performed with Gelfoam [23,60]. Reported post-treatment pregnancy rates in patients who underwent UAC due to CSP range from 30% to 54% [23,24]. Interestingly, there are reports of CSP recurrence treated successfully with repeated embolization [35]. Regarding the impact of systemic MTX treatment on fertility, conception outcomes are lower compared with selective chemoembolization and range from 3% to 30% [39,42,49]. However, reliable data confirming the effect of MTX on subsequent female fertility and the incidence of recurrent CSP are still lacking and further research is needed.

Study Limitations

Our study has certain limitations. First, although we tried to include all relevant articles, the number of reviewed databases was limited. Secondly, we included only English language articles, which might be perceived as a potential drawback. Finally, our analysis focused primarily on systemic therapy and uterine artery chemoembolization and only briefly focused on other methods of treatment of cesarean scar pregnancy.

Conclusions

Individualization of treatment after thorough multidisciplinary evaluation remains the key to successful therapy of patients with cesarean scar pregnancy. Results of our review indicate that transarterial chemoembolization appears to be safe and effective method of treatment in patients with CSP and should therefore be considered during multidisciplinary evaluation of these patients. It is associated with higher percentage of successful therapy compared to systemic methotrexate alone, less blood loss, and shorter hospitalization. Nonetheless, due to the small number of randomized control trials included, further research with a larger number of studies and patients is needed.