In this study, we assessed the response to systemic Methotrexate, alone or combined with oral Mifepristone, before D&C, and Foley catheter tamponade in the treatment of CSP. The clinical outcomes of five of the six cases of CSP presented in this case-series collected over a period of three years, were similar, assuming the resolution of pregnancy as successful endpoint of the management. We show that, D&C is a reliable management option in management of CSP if used after inhibition of trophoblast growth and the consequent bleeding after the removal of products of conception is promptly prevented with pressure tamponade. We also found that using Mifepristone in live pregnancies is useful to hasten embryo’s demise. Only one of our patients, who was diagnosed in early second trimester with early placenta accreta, required hysterectomy. Emerging evidence point to first trimester CSP as an entity in the continuum leading to morbidly adherent placenta in the third trimester [2, 16,17,18,19,20]. This finding guided the counselling and management of patients diagnosed with CSP in this case series.
The incidence of CSP is increasing worldwide, following the climbing rate of caesarean deliveries [1, 3, 21, 22]. In Romania, although national statistics data on CS are limited, a recent study suggests that the CS rates could be as high as 60% in urban population, in public maternity hospitals , and may be even higher in private facilities. A trend in increasing rates of CS was also observed in our unit over the past 10 years (unpublished data). Reported to the number of deliveries in our unit from 2017 to 2019, the incidence of CSP was approximately 1/3000, similar to the incidence from other recent reports [24, 25]. Reported to the number of CS deliveries, the frequency of CSP is about 0.05%. There are two reasons for the reported incidence of SCP in our hospital. We are a tertiary university hospital with referrals of rare complications of early pregnancy from eight counties.. In addition, we are an obstetrics & gynaecology training centre, all the gynaecologists in the unit are trained to perform TVUS and Doppler scans and provide care for early pregnancy.
US, transvaginal and transabdominal US, and color Doppler  is first line tool in identifying the markers characteristics of CSP, with a sensitivity of 86.4% . TVUS allowed us positive diagnosis of CSP with high accuracy and characterised the presence, location, and size of gestational sac, presence of the embryo and its cardiac activity, and the relationship between the gestational sac, CS scar, and bladder wall [1, 6, 9]. We used color Doppler functions (i.e impedance, velocity etc) to aid the diagnosis of scar pregnancy, although no clear criteria are yet defined [6, 27]. Only for one women MRI was required to better characterise the trophoblast invasiveness, because of a high clinical suspicion of accreta and/or trophoblastic neoplasia. Our presentation support the use of MRI sparingly, only when other complications are suspected, and should not be routinely employed . The US also proved instrumental for the post therapeutic follow up in all our patients.
Over the past several years an increasing number of publications, reports, and conference presentations on CSP increased the awareness and knowledge on the risks and complications of CSP and its treatment methods. No consensus has been reached and no standard treatment exist to date for CSP . A recent systematic review identified five basic pathways in treatment of CSP: expectant management, medical therapy, surgical intervention, uterine artery embolization, or a combination approach [29,30,31]. Each method has various levels of success and depends on clinical presentation and resources, patient compliance, and surgeon skills and expertise. The management approach devised by us was based on clinical symptoms, gestational age, pregnancy viability, technical means available, while considering patient’s preferences and aiming to preserve fertility.
Among treatment options, medical management with systemically administered methotrexate with or without local administration of the same or another agent are the most common treatment modalities [31, 32]. Methotrexate is largely used in treatment of tubal and cervical ectopic pregnancy, and its use was extended to CSP, using the same criteria to assess the effectiveness of the treatment . To date, however, there is no protocol for the use of methotrexate in CSP. There is no consensus on the dosage, number of doses needed, interval between doses or knowledge about risk factors or predictors of favourable response. There was no correlation between the hCG initial levels and the favourable response to methotrexate in our study, suggesting that systemic methotrexate could be used in CSP with higher levels of hCG. A recent review supports these findings, showing efficacy of the systemic methotrexate treatment in early CSP, with hCG < 12,000 mIU/ml and absent cardiac activity . Because of short half-life of methotrexate, repeated doses were administered to our patients, on alternative days, at a dose of 1 mg/kg, up to five doses. In a study by Kutuk et al. on the effectiveness of systemic multidose methotrexate treatment in CSP, in 13 patients with CSP and initial hCG levels between 2565 and 36,111 mIU/ml, authors report that between 5.3 and 6 dose cycles of methotrexate were needed alternative days to normalise the hCG levels in CSP with and without cardiac activity, respectively . Kalampokas et al. describe a case of CSP where only 3 dose cycles of 75 mg of methotrexate were needed for a CSP case with viable embryo and hCG of 12,072 mIU/ml to achieve resolution of pregnancy . Similar with our protocol, these authors also used mifepristone 600 mg along with methotrexate . There is mass experience with the use of mifepristone in termination of pregnancy, particularly in viable pregnancies [36, 37]. The use of mifepristone along with methotrexate in medical management of unruptured ectopic pregnancy is less known . It has been suggested that mifepristone may reduce the total doses of methotrexate and accelerates the time to embryo death [35, 39]. For this rationale, we also included 600 mg of oral mifepristone as part of the CSP management protocol.
Surgical management with conservation of fertility was done in all our cases but one. The main objective of this management was to remove products of conception while aiming to prevent and contain massive haemorrhage. Retention of products of conception after CSP treatment is a major concern, as it may adversely influence menstruation and future fertility . In addition, the therapeutic approach of D&C with/without immediate haemostatic measures (i.e Foley catheter balloon, uterine/vaginal pack) intended to conserve the uterus and fertility and maintain woman’s health and quality of life . The D&C was practiced shortly after administration of methotrexate, without awaiting the full response to the drug, this management being supported by previous observations. There are individual reports of unsuccessful treatment of scar pregnancy with systemic methotrexate. In a review of 751 CSP cases, 331 (44.1%) had complications requiring further surgical management. Among 32 different treatment modalities, methotrexate was associated with higher complication rate (62.1%). In this study and others, methotrexate was considered to hinder additional embryonic growth. However, as also observed in our study, the increase in hCG after methotrexate administration is more likely due to hormone release after trophoblastic cytolysis induced by methotrexate .
Every method of treatment of CSP carries high risk of excessive haemorrhage. Curettage after medical treatment has a high rate of success and no significant effects on the intraoperative bleeding. The predictors of the risk of bleeding during the procedure are gestational age and the size of gestational sac . The combination of methotrexate and curettage proposed by us is supported by others. For instance, Wang et al. analyses the methotrexate with and without curettage and shows that both therapies could treat the majority of CSP patients successfully, but the combined therapy resulted in a shorter time of therapy and had a more favourable effect . Another study in 45 patients shows that methotrexate administration followed by suction curettage with Foley tamponade was an effective treatment for CSP .
There are several limitations to our study. One limitation is the sample size. This limitation is characteristic to the nature of a case series report. This is explained, however, through the rarity and diagnosis challenges of such presentation. Most of our evidence on CSP diagnosis and management comes from similar case reports and case series reports. The vast majority of the studies were retrospective, the management reported being a reflection of the experience and surgical skills of an individual or a group rather than an evidence-based approach. In contrast, the cases from our study were collected prospectively and a formal management plan was followed, although the plan was individually tailored. The management proposed by us was devised for symptomatic patients, reporting pain and persistent vaginal bleeding, and may not be applied to asymptomatic patients. It is also possible that the incidence of CSP may be higher than reported here. It is likely that among the early pregnancies that end up in miscarriages or pregnancy terminations done in private offices there is a certain number of undiagnosed CSP. That is because most CSP do not cross beyond the first trimester and end up in 1st trimester miscarriage. This and the risk of accreta has led to the common practice of offering termination of pregnancy in CSP, similar to other complications of early pregnancy [44, 45].
Serial hCG and TVUS color Doppler are useful in monitoring the treatment and its success, as it appears to be a good correlation between the hCG values and persistence of the trophoblastic flow at the site of an ectopic pregnancy. Doppler examination showing evidence of persistent functional trophoblast was instrumental for this study in surveillance of the response to treatment and decisions to proceed with surgical management. Previous studies have shown a correlation between the Doppler characteristics such as high-velocity, low-impedance, turbulent flow during the initial follow up and the risk of profuse bleeding . However, these parameters were not systematically measured in our study, thus, it is unclear if this information would have been a warning for the physician to not perform a D&C.
The use of curettage in the management of CSP is rather controversial, and the argument is that the procedure may lead to heavy if not catastrophic bleeding [1, 45]. We were able, however, to contain the bleeding and obtain an efficient haemostasis in all cases by prompt intervention. Also, in all cases but one the drop in Hb levels was enough to grant replacement with blood products. Nonetheless, in this case, the copious spontaneous bleeding came from an accreta led to salvage D&C. None of our D&Cs required salvage hysterectomy to contain the bleeding.
There is little scientific data on the risk of recurrence of the condition in future pregnancy, the role of the interval between the previous caesarean delivery and re-occurrence of caesarean scar pregnancy [7, 46]. Few published studies have reported on the low risks or recurrence of SCP, suggesting that implantation into the CS scar is more likely a chance event, than the result of an affinity of a pregnancy for implanting into the scar . We did not follow up our patients long enough to assess their further fertility. Nonetheless, our patients have been counselled on overall good fertility outcomes following a CSP, while being aware of the low risk of CSP recurrence and need for early surveillance in future pregnancies .
Despite the experience accumulated by us and others in management of CSP, the evidence to date is not strong enough to be translated in a reliable risk scoring system to guide management. Although a standardised clinical protocol for management is yet be developed, this case series contributes our experience to building the evidence for the management of this complex clinical presentation.
Further studies are warranted to deepen our understanding of the CSP pathophysiology and facilitate development of clinical pathways for this presentation. We endorse the project of an international CSP registry  that has been recently proposed with the purpose to collate all the knowledge and produce the best evidence for CSP diagnosis and management.