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Caesareans Section Scar Ectopic Pregnancy: An Emerging Challenge

Caesarean scar ectopic pregnancy (CSEP) is an uncommon form of ectopic pregnancy. This review defines types of CSEP, discusses pathophysiology, clinical presentation and diagnosis and compares common treatment options and outcomes. The pathophysiology is not yet fully understood. One third of patient are asymptomatic. In symptomatic patients vaginal bleeding and pelvic pain which is usually misdiagnosed as threatened or missed abortion. The main principles of treatment for CSEP are early diagnose, quick management, and maintain reproductive function as much as possible. Up to date; no consensus or guidelines for the treatment and management of CSEP. Management of CSEP depends on the clinical presentation and gestational age. Significant controversy exists regarding management, for this reason, several factors should be considered including age of the patient, myometrial thickness, clinical symptoms, hemodynamic status, fertility preservation.

It doesn't seem that the number of caesarean deliveries lead to increase in the incidence.
The estimated incidence is 1: 1800 to 1: 2216 pregnancies (0.05-0.04%) and accounting for 6.1% of ectopic pregnancy in women with previous caesarean sections (CS) [5]. A recent data indicates that the incidence of CSEP is 1:3000 among general obstetric population and in the range of 1:2500 to 1:8000 for all caesarean deliveries [6,7]. However, with increase awareness among obstetricians and high index of suspension, the detection and diagnosis of SCEP is increasing.

Pathophysiology:
The pathophysiology is not yet fully understood. The most accepted theory is that the blastocyst invades into the myometrium through a microscopic defect, which may be the consequence of trauma resulted from a previous CS or any prior uterine surgery [8]. In a random population of women with CS scar, the prevalence of this defect is 84% [9]. Roeder et al. studied the histopathology of CS scar wound healing, different thicknesses of the myometrium along the scar with elastosis and adenomyosis were found [10]. It seems that impaired healing of the CS wound may predisposes to the development of CSEP [11]. Ash et al. postulated that when the interval between CS and a subsequent pregnancy is short, the probability of having CSEP and placenta accrete is increased [12]. Timor-Tritsch et al. believe that placenta accreta share a similar histology and pathogenesis of CSEP, he postulated that implantation occurs where there defect of healing process so that trophoblastic tissue invades the myometrium and the surrounding scar tissue [13]. On the other hand, in a study by Flystra, he found that CSEP and placenta accreta are different disease entities. CSEP invade the myometrium and separated from endometrial cavity, while placenta accreta invade the myometrium and completely located in the endometrial cavity [14]. Some researchers suggested that CSEP is even more aggressive than About on third of patients are asymptomatic at diagnosis [23]. In symptomatic patients, vaginal bleeding and pelvic pain in the first trimester are usually misdiagnosed as threatened or missed abortion. This misdiagnosis could result in life-threatening hemorrhage, disseminated intravascular coagulation, shock, uterine rupture, and even death [24].
Generally; vaginal bleeding is the most common presenting symptom [13]. In a study includes 92 cases; vaginal bleeding alone was found in 48% followed by vaginal bleeding and abdominal pain in 23% of patients, Pain alone was found in 10% while 20% where asymptomatic [25].

Diagnosis:
Obstetrician should have high index of suspicion when dealing with women with previous scar. Women with previous CS should have a transvaginal ultrasound (TVU) in the first trimester to exclude CSEP [15]. High accuracy rate in the diagnosis of CSEP can be achieved by combined transabdominal (TAU) and TVU approach [26]. Maymon et al. found that combined approach of both TAU and TVU reduce the risk of a false diagnosis. TAU allows visualization of myometrial thickness, size and location of gestational sac and its relation to the urinary bladder [27]. A sensitivity of 84.6% can be achieved by TAU for detection of CSEP in first trimester [28]. Doppler assessment may help reduce false positive diagnosis.
The majority of CSEP are diagnosed in the first trimester. From a recent systematic review, diagnosis of CSEP was confirmed at 7.2+ 1.1 weeks [26]. In a study included 92 cases, diagnosis was confirmed at mean gestational age of 9 weeks [25]. CSEP can be misdiagnosed as an early pregnancy, cervical or an inevitable abortion.
However; diagnosis of an early CSEP can be very challenging. Delayed diagnosis can lead to massive haemorrhage and uterine rupture [26].

Criteria for the diagnosis of CSEP:
Empty uterus and cervical canal with clearly visible endometrium. Gestational sac or placental tissue present in the anterior wall of the cervical isthmus surrounded by scar tissue of CS.
Diminished myometrium or absent between the bladder and gestational sac with or without fetal pole with positive or absent cardiac activity. Doppler with High velocity with low impedance blood flow of vascular flow around the gestational sac, the "ring of fire" sign.
Absent "sliding sign", an additional confirmatory test as suggested by some investigators, a pressure on the cervix by vaginal probe, the gestational sac will slide against the endocervical canal in cases of miscarriage [30].
Magnetic resonance imaging (MRI) is a helpful tool when TVU and Doppler sonography are inconclusive, when uterine anatomy is distorted by a large fibroid or if the pregnancy has advanced [31]. MRI provides better pelvic soft tissue evaluation and relationship of CSEP to bladder and adjacent pelvic organs, thereby aids in the decision of management.

Treatment:
The main principles of treatment for CSEP are early diagnose, quick management, and maintain reproductive function as much as possible. Up to date; no consensus or guidelines for the treatment and management of CSEP due to limited no of cases and reports. Currently, there is no standard management option for CSEP and no first-line treatment. Treatment options depends on gestational age and presentation, the main aim is removing the gestational sac, preventing hemorrhage and preservation of future fertility.

Expectant management:
For cases with a non-viable CSEP, expectant management might be an option. Ouyang et al. reported 100% success rate among 5 patients with a non-viable CSEP with expectant management [32]. Preservation of CSEP with viable fetus is a challenge. Although several case reports on successful term pregnancy of CSEP have been reported, but expectant management is not without complications [33,34]. Kim  weeks of heterotopic CSEP with expectant management; however, the patient had severe postpartum haemorrhage secondary to placenta accreta which was controlled by excision of the anterior lower uterine segment and bilateral uterine artery ligation [34]. A recent systematic review on expectant management included 11 reports, a total of 44 patients with CSEP with positive fetal heart included. Live births in 73% of patients were achieved, 25% of them before 34 weeks. Seventy percent of patients required hysterectomy to control bleeding. Twelve patients out of 44 pregnancy lost secondary to complications before 24 weeks [35].
In a recent meta-analysis on expectant management of CSEP of 17 studies including 52 patients with CSEP with positive feat heart. Forty patients progressed to third trimester, 39.2% experienced severe bleeding, 74.8% had abnormally adherent placenta, 69.7% found to have placenta percreta. 9.9% of patients had uterine rupture during the first or second trimester and 15.2% of patients needed hysterectomy [36].
In view of high rate of morbidity associated with this condition, termination of pregnancy could be the only therapeutic option offered for women with CSEP. It is still not clear that if the thickness of anterior uterine wall at the gestational sac implantation with viable fetus can determine the decision to allow for expectant management [36][37][38].

Methotrexate (MTX):
It acts by Inhibiting dihydrofolate reductase as a folic acid antagonist, which interferes can be achieved if β -hCG levels <20, 000 mIU/mL and gestational sac less than 3 cm in diameter. It can be given either transabdominal or transvaginal into gestational sac as a single dose, if needed a second dose can be given a week later [40]. In a review by Cheung, a success rate of 73.9 % was achieved by local MTX injection alone, additional local or intramuscular MTX, 88.5% success rate was achieved [41]. On the other hand, Kim [44].
To answer the question, which is more superior? A randomized trial by Peng et al.
including 104 patients with CSEP, both local and systemic MTX administration were compared.
The cure rates were (69.2% vs. 67.3%) for local and systemic treatment, respectively. Patient received systemic MTX experienced prolonged time for β -hCG titer remission and resolution of CSEP mass [40]. Surprisingly, in a systematic review by Kanat-Pektas et al. they found that MTX systemic administration was successful in only 8.7% of cases of CSEP with hysterectomy rate of 4% [45]. Complication rate with systemic MTX according to some reports reached up to 62.1% [46].
The possible explanation is that the effect on placenta and embryo cardiac activity is delayed or no effect when MTX is given systemic. Due to its short half life and limited exposure of trophoblast to MTX when given systemic, the concentration in trophoblastic tissue is blocked by fibrous tissue surrounding the gestational sac [22,44]. Generally, due to low efficacy, more side effects and fertility loss with systemic MTX, it should not be given as a first medical choice when fertility preservation is needed.
Although local MTX is the most commonly used medical treatment, other less commonly used agents such as potassium chloride, mifepristone, ethanol and hyperosmolar glucose have been reported in the literature [47][48][49][50]. Persistent bleeding after medical treatment requires further intervention even though β-hCG may be undetectable. UAE followed by hysteroscopy was found to be the safest and most efficient method. Patients treated by hysteroscopy alone have the shortest length of hospital stay and the lower cost, but high blood loss and slow recovery was noted. They suggested that Patients with a low level of β-hCG, hysteroscopy under sonographic guidance or MTX and hysteroscopy is an option [52].

Combined treatment:
Several combination therapy in the literature, each method has various levels of success and depends on patient presentation, in order of frequency; MTX+D&C, Mifepristone/D&D/UAE followed by hysteroscopy, UAE before D&C, UAE+ local MTX [43,44].

Uterine artery embolization (UAE):
The use of UAE without removal the gestational sac results in gradual decrease of β-hCG levels and irregular vaginal bleeding, so it is considered as an adjuvant treatment in CSEP to minimize bleeding [44,[53][54][55]. UAE minimize haemorrhage by blocking uterine perfusion temporarily, It has been used before or after curettage and D&C [56]. Qiao et al. In a recent meta-analysis included 725 patients treated with MTX+D&C, UAE followed by D&C. Patients treated with UAE followed by D&C had less time for β-hCG normalization (16.7 days) and less time of hospital stay (15 days). In addition, patients who underwent UAE had less blood loss and no side effects of MTX when compared with those treated with MTX plus D&C [57]. It seems that UAE followed by D&C has more advantage and may be a priority option for treatment of patient with CSEP with bleeding. UAE can lead to loss of fertility due to impairment of blood flow in the uterine arteries. UAE should be considered as a treatment option in cases with heavy bleeding or when high vascularity detected by doppler [53].

Hysteroscopy:
Using hysteroscopy with direct visualization of the gestational sac; trophoblastic tissue can be removed precisely without injuring the endometrium. Coagulation of the vascular bed at the implantation site can be done directly to prevent profuse bleeding [55,58].
Depending on the expertise in hysteroscopy, a loop electrode can be used to separate the products of conception from the uterine wall. If bleeding occurs, it can be controlled by electrocoagulation or using an intrauterine Foley balloon [15]. If the myometrium < 3mm, caution should be considered during hysteroscopic resection, it is better to perform hysteroscopy under laparoscopic guidance due to significant risk of perforation of the uterus and injury to the bladder during the procedure [59].  [59]. According to expert opinion hysteroscopy is considered as an optimal approach for type 1 CSEP [46].

Wedge resection:
Occasionally uterine rupture may occur with CSEP. When rupture is confirmed or suspected, wedge excision is mandatory. This can be done by conventional hysterotomy to remove the CSEP and scar repair [27,53]. Nevertheless, this approach is associated with a lot of complications as well. Complications associated with this approach include large surgical wounds, long hospital stay, long recovery time and postoperative adhesions. Furthermore; increase risk of placenta previa and accrete [4,60].

Transvaginal resection:
Transvaginal approach for exogenous type 2 CSEP is an option. The key point of this procedures is that first, the bladder is separated from the lower uterine segment to avoid injury to the bladder and ureters. the gestational product will be completely removed, and the uterine scar tissue is sutured in a continuous 0 absorbable sutures [61]. The post-op recovery using transvaginal approach is rapid. However, this procedure with a narrow operative field, require good experience with transvaginal surgery [61,63]. The β-hCG normalization rate is like that of the abdominal approach [61].

High-intensity focused ultrasound (HIFU):
It acts by converting focused acoustic energy into thermal energy at target tissue, UIFU have been successfully used in ablation of uterine fibroids and adenomyosis [67,68] fewer in the HIFU group. However, longer time for the normalization of β-HCG level and longer time for vaginal bleeding [71]. Similar results obtained by Hang et al. [72].

Conclusion:
CSEP is a challenging life-threatening condition for the gynecologist. Once CSEP is diagnosed, immediate termination is required to prevent massive hemorrhage, uterine rupture and other severe complications. Significant controversy exists regarding management. For this reason, several factors should be considered including age of the patient, myometrial thickness, clinical symptoms, hemodynamic status, fertility preservation. Therapeutic option should be an individualized to treat the CSEP. Generally, any treatment option has advantages and disadvantages, more favorable outcome can be achieved by combination of several methods.

Conflicts of interest:
The author has no conflicts of interest relevant to this article.