Management of Cesarean Scar Ectopic Pregnancy with Systemic Methotrexate and Ultrasound-Guided Intra-Gestational Sac Injection

Abstract

Background:

Cesarean scar ectopic pregnancy (CSEP) is a rare condition that occurs when an early pregnancy (blastocyst) implants into the fibrous scar tissue of a previous cesarean section hysterotomy. CSEPs are managed on a case-by-case basis as there is not a standardized treatment approach.

Methods:

The authors evaluated the treatment of cesarean scar ectopic pregnancies CSEP using a promising technique of daily alternating methotrexate and leucovorin followed by, if necessary, a minimally invasive approach using ultrasound-guided intra-gestational sac injection of potassium chloride (KCl) through a literature review and cases from our urban community hospital. Data was collected from 22 cases, 17 from our literature review and five from our urban community hospital, where both methotrexate and intra-sac KCl injection were used to treat CSEP.

Results:

19 of the 22 patients (86%) had successful resolution of their CSEP without further intervention.

Conclusion:

We find that daily alternating methotrexate and leucovorin followed by a minimally invasive approach using ultrasound-guided intra-gestational sac injection of KCl is an effective CSEP treatment and is associated with fewer complications and additional required interventions compared to the most commonly reported procedure of administering methotrexate after KCl instillation. Additionally, this procedure is uterine-preserving for future fertility and was found to have minimal maternal adverse effects.

Introduction

Cesarean scar ectopic pregnancy (CSEP) occurs when an early pregnancy (blastocyst) implants into the fibrous scar tissue of a previous cesarean section hysterotomy. This condition is considered very rare, and incidence estimates range from 1 in 1,800 to 1 in 2,500 pregnancies, although CSEP is likely underdiagnosed and underreported.^1,2 However, the incidence is believed to be increasing due to the increased number of cesarean deliveries being performed. Other factors that have contributed to increased reports of CSEP include improved imaging modalities for diagnosis, such as ultrasound and magnetic resonance imaging, and increased physician awareness of cesarean-delivery-associated complications. Different options for the management of CSEP have been reported, including medical, surgical, and minimally invasive therapies, alone or in combination.^3,4 One promising approach is to combine intra-sac instillation of KCl with the administration of systemic methotrexate. However, the order and timing of the two interventions vary both in cases at our urban community hospital and in the literature. Accordingly, we analyzed the outcomes from the cases at our institution and additional literature cases to determine the optimal treatment schedule.

Methods

Cases at our hospital

We performed a retrospective chart review from January 2018 to July 2023 at our urban community hospital. Eight cases of cesarean scar ectopic pregnancies were diagnosed. All eight patients were managed with fixed multiple-dose systemic methotrexate (1 mg/kg) alternating daily with leucovorin (0.1 mg/kg).⁵ If fetal cardiac activity was still seen after administration of one or more doses of systemic methotrexate, then the patient would undergo ultrasound-guided intra-gestational sac injection of 2 mL of KCl using a 20-gauge spinal needle either transabdominally or transcervically. If no fetal cardiac activity was observed, then KCl instillation was not needed. The number of doses of daily alternating methotrexate and leucovorin that were administered before the administration of intra-gestational sac injection of KCl varied based on clinical presentation.⁵ Three patients received four doses of methotrexate (and three doses of leucovorin) prior to KCl instillation on day 7 together with an additional dose of methotrexate, and two patients received only two doses of methotrexate (with two doses of leucovorin) prior to KCl instillation on day 5 with an additional dose of methotrexate. Patients were discharged following KCl instillation following a 15% drop in hCG. This study received an IRB exemption on June 13, 2023, from the Flushing Hospital Medical Center IRB (IRB #2063781-1).

Literature review

The literature review included all publications returned from a search with the keywords “cesarean scar” and (KCl or “potassium chloride”) from MEDLINE (1966-present). We reviewed the protocols and outcomes in 17 cases returned from the search where methotrexate combined with intra-sac injection of KCl was used to treat CSEP (Table 1).

Table 1.

Literature Reports of CSEP Treated with MTX + KCl

Paper	Patient number	Subsequent unplanned intervention	Timing of systemic MTX dosing	Number of MTX doses	Days to hCG baseline	Comments
Grechukhina et al.⁶	1	Yes	After KCl instillation	Unreported	62	Required subsequent hysteroscopic resection
	2	No	After KCl instillation	Unreported	60	Required subsequent hysteroscopic resection
	3	No	After KCl instillation	Unreported	111
Al-Jaroudi et al.⁷	4	No	Together with KCl	One	45
Al-Jaroudi et al.⁷	5	No	Together with KCl	One	35
Agarwal et al.⁸	6	Yes	After KCl instillation	Two	106	AVM Embolization
	7	Yes	After KCl instillation	Two	61	AVM Embolization
	8	No	After KCl instillation	Two	92
Pirjani et al.⁹	9	No	After KCl instillation	Two	63
	10	No	After KCl instillation	Four	56
	11	No	After KCl instillation	Two	77
	12	No	After KCl instillation	Unreported	56
Washburn et al.¹⁰	13	No	Together with KCl	Two	Unreported
	14	No	Together with KCl	One	Unreported
	15	No	Together with KCl	One	Unreported	`
Kelekçi et al.¹¹	16	No	Prior to KCl instillation	One	36
Kelekçi et al.¹¹	17	No	Prior to KCl instillation	Two	56
Our Institution	18	No	Prior to KCl instillation	Four	—^a
	19	No	Prior to KCl instillation	Four	90
	20	No	Prior to KCl instillation	Four	—^a
	21	No	Prior to KCl instillation	Two	120
	22	No	Prior to KCl instillation	Two	—^a

Lost to follow-up or transfer.

Results

Cases at our hospital

Of the eight patients diagnosed with CSEP at our urban community hospital, fetal cardiac activity was absent in three patients after four doses of methotrexate alternating with leucovorin. As such, intra-gestational sac KCl injection was not necessary. For the five patients where fetal cardiac activity remained present after multiple doses of intramuscular methotrexate alternating daily with leucovorin, such patients received direct intra-gestational sac injection of KCl. All the patients reported tolerating systemic methotrexate well without complaints. Total hospital stay ranged from 5 to 9 days, including both the daily alternating methotrexate leucovorin administration, KCl procedure, and 15% drop in hCG necessary for discharge under our hospital’s protocol. All five patients who received KCl instillation were then followed as outpatients, and none were readmitted to the hospital with complications. Three of the five patients were lost to follow-up before full resolution of hCG to baseline; the other two returned to baseline in 120 days and 90 days and had received two and four doses of methotrexate prior to KCl instillation, respectively.

Literature review

Only Kelekçi et. al, report initial dosing with methotrexate followed by intra-sac injection of KCl, which in both cases was successful.¹¹ However, because the intent was to resolve the patient’s CSEP with methotrexate alone, the authors did not use a daily alternating dosing schedule of methotrexate and leucovorin.¹¹ Five cases were reported in which the initial methotrexate dose was administered with KCl (with one case reporting administration of an additional dose of methotrexate post-KCl instillation). All five cases were successful without additional intervention. Ten cases were reported where methotrexate was only administered after KCl injection; in these cases, only seven were successful without further intervention (70%).

Local or intra-gestational sac injection of methotrexate, with or without other modalities, is currently preferred to stand-alone systemic methotrexate.¹² In a literature review by Cheung, 73.9% of CSEP patients were successfully treated after a single intra-gestational sac methotrexate injection, increasing to 88.5% when combined with a single intramuscular methotrexate injection.¹² Although more limited in adoption, intra-gestational sac injection of KCl rather than methotrexate has been used for the treatment of heterotopic CSEP secondary to the desire to preserve the coexisting intrauterine pregnancy. Five cases of heterotopic CSEPs were treated with intra-gestational sac KCl injection with successful result.¹³ All five cases resulted in live births of the coexisting intrauterine pregnancy. Two of the five cases were complicated by postpartum hemorrhage, and one case resulted in hysterectomy for placenta accreta, which the authors did not believe to be associated with the intra-gestational sac KCl injection procedure.

In a review of CSEP treatment outcomes, Agten et al. reported a success rate of 74.5% for intra-sac injection of either KCl or methotrexate and noted that seven cases included a combined treatment with KCl or methotrexate.¹⁴ However, because this study did not report on the effectiveness of the combined treatment or report on the subgroup of KCl versus methotrexate intra-sac injection, we were unable to include these cases in our review. Maheux-Lacroix also performed a literature review of CSEP cases and treatment options, but of the reported cases, only Washburn et al. separately reported outcomes from systemic methotrexate and KCl instillation to treat CSEP.⁴ Maheux-Lacroix concluded that although combination treatments including both systemic methotrexate and either or both of KCl and methotrexate directly injected into the gestational sac increased the success rate from 60% to 77%, the combined treatment also had a statistically significant increase in risk of hemorrhage compared to local instillation (RR: 2.75; 95% CI [1.1–8]).⁴

Aggregate results

Of the 13 cases where the number of doses of methotrexate administered was reported, 38% received one dose, 54% received 2 doses, and 7% received four doses. Ten of those cases also reported the number of days until hCG returned to baseline. The average for patients where one dose of methotrexate was administered was 39 days (95% CI: 28–50 days), and where two doses of methotrexate were administered was 76 days (95% CI: 36.5–115.5 days). Only one patient received four methotrexate doses, with hCG returning to baseline in 56 days. Based on the combined results from the literature reports and our facility, we performed a chi-square test to evaluate if the timing of methotrexate administration in relation to KCl instillation affected treatment effectiveness. Our results indicated that 30% of cases where methotrexate was administered after KCl instillation required further intervention, whereas 0% of cases where methotrexate was administered concurrently with or prior to KCl instillation required further intervention. This difference was statistically significant (p = 0.040).

Discussion

Cesarean scar ectopic pregnancies are rare, but complications can become life-threatening when the CSEP reaches more advanced gestational ages. These complications include placenta accreta spectrum, cesarean hysterectomy, and massive hemorrhage. Because of the high risk of severe maternal morbidity and mortality, expectant management is not recommended.¹⁵ There has been a rise in the number of CSEP cases due to the increase in cesarean deliveries and improved diagnostic modalities. Different options for the management of CSEP have been reported, but the optimal treatment is unknown. Many such treatments are based on the recommended approaches for the treatment of ectopic pregnancies generally, including the daily alternating methotrexate-leucovorin procedure described above and used at our institution.⁵ Medical, surgical, and minimally invasive therapies and various combinations of the previously mentioned treatments have been described in literature.^3,4

In the event the daily alternating procedure or other medical treatment fails to resolve the CSEP, or as a primary intervention, a number of surgical and minimally invasive therapies have been described, including intra-sac injection of methotrexate or KCl. Because methotrexate is a chemotherapeutic agent and widely administered systemically in other settings, the literature reports more cases of injecting methotrexate than KCl for treating a CSEP with good efficacy.¹² However, in heterotopic intrauterine pregnancies where one pregnancy is still desired, the injection of methotrexate creates the risk of reducing all of the intrauterine pregnancies, not just the one desired for reduction, by creating teratogenic conditions. For this reason, KCl injection is more common in those situations.¹³ As seen both in our institution and in some cases reported in the literature, KCl injection has become more common in part because of its better side effect profile and the success shown in heterotopic reductions suggesting efficacy in resolving CSEPs. Our review and experience suggests the use of intrasac KCl instillation and systemic methotrexate is further nuanced based on the dosing schedule. Specifically, our review of literature cases where systemic methotrexate was administered with, or before, KCl injection suggest a very high success rate, and failures can be attributed to either administering systemic methotrexate after injection or other interventions (e.g., intra-sac injection of both methotrexate and KCl). Further investigation is required to determine if our choice of KCl instillation over methotrexate alone or in combination with KCl may explain the increased success of the procedure relative to the results reported in Maheux-Lacroix.⁴

A standardized dosing schedule for the reported approach for managing CSEP using combined systemic methotrexate and local intra-gestational sac instillation of KCl has not been determined. The most commonly reported regimen in our literature review is the administration of methotrexate subsequent to KCl instillation, which had the highest rate of required additional intervention (Table 1). Indeed, the 30% rate of additional intervention tracks the overall efficacy of intra-sac injection reported by Agten et al., suggesting that there may be little benefit in administering methotrexate after KCl instillation.¹⁴ Additionally, based on the results of the literature review, there is no significant difference between the number of doses administered with respect to hCG return to baseline or whether additional intervention was required. Some of the variation may be in part due to different dosing schedules. For instance, our standardized protocol administered daily alternating doses of methotrexate and leucovorin until the minimally invasive KCl instillation, while others administered methotrexate on the first and fourth day.¹¹ Further investigation is needed to determine the optimal number of doses of daily methotrexate prior to performing intra-sac injection of KCl, including correlations with hCG levels.

Further investigation is required to determine whether methotrexate administered prior to KCl instillation is superior to administration concurrently with KCl instillation. In both cases, all reports from our facility and our literature review did not require further surgical intervention. However, we were able to resolve three CSEPs with our 1 week daily alternating methotrexate and leucovorin dosing protocol such that those patients did not need to undergo minimally invasive KCl injection. Although the risks of KCl injection are low, because it is a surgical procedure, it carries some risks such that resolving a CSEP from methotrexate alone may be desirable, in particular in resource-constrained settings. For example, in one case of KCl instillation only, Washburn et al. reported hemorrhage and other complications, and as such, there may be patient safety advantages to our protocol over immediate KCl instillation by limiting the number of patients who need the KCl instillation procedure.¹⁰ In addition to patient safety advantages, this procedure may be performed either in-patient or out-patient, which could provide further cost savings in resource-constrained settings. The daily alternating methotrexate-leucovorin protocol was administered in-patient at our institution based on a review of the patient population and potential risks of complications. However, in a resource-constrained setting the benefits of outpatient administration may outweigh the risks and ultimately demonstrate the flexibility of the protocol.

Conclusion

Based on our review, we find a 100% success rate in the treatment of CSEP without further intervention where systemic methotrexate was injected with, or before, intra-sac KCl instillation. All additional required interventions were attributed to either administering systemic methotrexate after injection or other interventions (e.g., intra-sac injection of both methotrexate and KCl). Further investigation is required to determine whether methotrexate administered prior to KCl instillation is superior to administration concurrently with KCl instillation. In both cases, all reports from our facility and our literature review did not require further surgical intervention. Particularly promising is that we were able to resolve three CSEPs with our one week daily alternating methotrexate and leucovorin dosing protocol such that those patients did not need to undergo minimally invasive KCl injection, and there may be patient safety advantages to our protocol over immediate KCl instillation.¹⁰

Footnotes

Acknowledgments

There are no individuals who contributed to the preparation of this article other than the authors. Certain subject matter included in this article was presented at the American Institute of Ultrasound in Medicine UltraCon Conference on April 6–10, 2024. This conference does not impose any restrictions on publication for accepted or presented abstracts.

Authors’ Contributions

A.H.: Contributed to the conceptualization, data curation, formal analysis, investigation, writing of the original draft and review and editing of this research. H.H. and M.S.: Contributed to the writing, review and editing of this research. I.N.: Contributed to the conceptualization and methodology of this research.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

References

Jurkovic

, Hillaby

, Woelfer

, et al. First trimester diagnosis and management of pregnancies implanted into the lower uterine segment cesarean section scar. Ultrasound Obstet Gynecol, 2003; 21(3):220–227.

Seow

, Huang

, Lin

, et al. Cesarean scar pregnancy: Issues in management. Ultrasound Obstet Gynecol, 2004; 23(3):247–253.

Birch Petersen

, Hoffmann

, Rifbjerg Larsen

, et al. Cesarean scar pregnancy: A systematic review of treatment studies. Fertil Steril, 2016; 105(4):958–967.

Maheux-Lacroix

, Li

, Bujold

, et al. Cesarean scar pregnancies: A systematic review of treatment options. J Minim Invasive Gynecol, 2017; 24(6):915–925.

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin No. 193: Tubal Ectopic Pregnancy. Obstetrics and Gynecology, 2018; 131(3):e91–e103.

Grechukhina

, Deshmukh

, Fan

, et al. Cesarean scar pregnancy, incidence, and recurrence: Five-year experience at a single tertiary care referral center. Obstet Gynecol, 2018; 132(5):1285–1295; doi: 10.1097/AOG.0000000000002940

Al-Jaroudi

, Aboudi

, Baradwan

. Different treatment modalities for cesarean scar pregnancies: A single-center experience and literature review. Arch Gynecol Obstet, 2021; 303(5):1143–1151.

Agarwal

, Gainder

, Chopra

, et al. The management of scar ectopic: A single-center experience. Cureus, 2021; 13(6):e15881.

Pirjani

, Bayani

, Shirazi

. Successful local and systemic medical treatment of cesarean scar pregnancy and a subsequent term pregnancy after treatment: A case series. Iran J Reprod Med, 2015; 13(7):445–450.

10.

Washburn

, Pocius

, Carusi

. Outcomes of nonsurgical versus surgical treatment of cesarean scar pregnancies in the first trimester. Arch Gynecol Obstet, 2017; 296(3):533–541.

11.

Kelekçi

, Aydoğmuş

, et al. Ineffectual medical treatment of cesarean scar ectopic pregnancy with systemic methotrexate: A report of two cases. J Investig Med High Impact Case Rep, 2014; 2(1):2324709614528903.

12.

Cheung

. Local methotrexate injection as the first-line treatment for cesarean scar pregnancy: Review of the literature. J Minim Invasive Gynecol, 2015; 22(5):753–758.

13.

Ugurlucan

, Bastu

, Dogan

, et al. Management of cesarean heterotopic pregnancy with transvaginal ultrasound guided potassium chloride injection and gestational sac aspiration, and review of the literature. J Minim Invasive Gynecol, 2012; 19(5):671–673.

14.

Kaelin Agten

, Jurkovic

, Timor-Tritsch

, et al.; CSP Collaborative Network. First-trimester cesarean scar pregnancy: A comparative analysis of treatment options from the international registry. Am J Obstet Gynecol, 2024; 230(6):669.e1–669.e19.

15.

Rotas

, Haberman

, Levgur

. Cesarean scar ectopic pregnancies: Etiology, diagnosis, and management. Obstet Gynecol, 2006; 107(6):1373–1381.