The use of methotrexate in the management of placenta accreta spectrum: a narrative review

Abstract

Introduction:

Placenta accreta spectrum (PAS) is a serious pregnancy condition compromising the trophoblastic invasion of the placenta or part of it into the myometrium. It is mainly treated by hysterectomy which may leave many complications on the long term mainly infertility. Nonetheless, the desire to preserve fertility has prompted investigation into fertility-preserving alternatives, most notably the off-label use of methotrexate, despite limited consensus on its efficacy or safety. The aim of this review is to assess the efficacy of methotrexate in treating PAS based on pregnancy trimesters.

Methods:

A search of different databases was performed, extracting the relevant information.

Results and discussion:

This part is divided into two major parts: the use of methotrexate alone and the use of combination therapies including methotrexate. The former was mainly used in the third trimester according to the selected literature, and postpartum while the latter was used in different trimesters. Out of 27 articles, 63% demonstrated a favorable response to methotrexate. However, the outcome has shown no change between different gestational ages.

Conclusion:

Despite guideline recommendations, methotrexate may serve as a viable conservative option in carefully selected hemodynamically stable patients, warranting further investigation. Further large-scale studies stratified by trimester or patient population are needed to assess its safety and efficacy.

Introduction

Placenta accreta spectrum (PAS) encompasses a range of abnormal placental invasions – accreta, increta, and percreta – where the placenta abnormally adheres to or invades the myometrium, leading to increased risks during delivery, particularly hemorrhage[1] (see Fig. 1).

Figure 1.

Types of invasive placenta.

The risk factors for placenta accreta include a history of previous cesarean delivery, uterine surgery, and previous placenta accreta. Having placenta accreta can lead to many clinical complications later during delivery; it can lead to preterm birth which may pose risk to the newborn’s life as well as to the mother’s life. In addition, this abnormal attachment can lead to severe bleeding during delivery in addition to being a risk factor for postpartum hemorrhage. This case may be a life-threatening to the mother where we have uncontrolled bleeding. Placenta accreta is usually diagnosed via ultrasound or MRI during pregnancy. Therefore, early detection and a coordinated medical team are essential for managing this condition effectively to ensure the mother’s and the baby’s safety.

HIGHLIGHTS

• Placenta accreta spectrum (PAS) is a serious pregnancy condition compromising the trophoblastic invasion of the placenta or part of it into the myometrium.

• Hysterectomy is the most known treatment; however, it can be treated conservatively.

• Our focus is on the use of methotrexate which is controversial in PAS.

• Its effectiveness has shown to be independent from gestational age.

Management generally involves a scheduled cesarean delivery followed by hysterectomy to mitigate the risk of severe postpartum hemorrhage and related complications. Expectant and conservative treatments have been explored in order to avoid or reduce the immediate and long-term complications associated with hysterectomy. Conservative management of placenta accreta is increasingly investigated due to the demand for preservation of fertility and reducing maternal morbidity. According to previous studies, methotrexate’s local multi-point injection under the skin instead of IV administration under ultrasound guidance is a better alternative for preserving fertility[2]. Moreover, the use of methotrexate for placenta accreta management during previous case reports showed a decrease in beta-hCG, vascular indices decreased significantly and a decrease in the size of the partial placenta retained^[3,4]. But there is still a lack of on the optimal strategy for the expectant management of PAS due to the limited data.

Therefore, the aim of this research study is to further illustrate the various conservative approaches available for the management of placenta accreta focusing on the use of methotrexate treatment specifically discussing the effects of methotrexate in different trimesters.

Methods

An extensive search through the different databases: PubMed, Lilacs, Scopus, and Grey Literature was done using the following keywords: PAS, placenta accreta, placenta accreta syndrome, conservative management, conservative treatment, methotrexate, MTX. After duplicate removal, we resulted in 107 articles that were screened through RAYYAN for inclusion/exclusion criteria. We included case controls, case series, randomized control trials, cohort studies, and systematic reviews. We excluded narrative reviews, and papers related to invasive management of PAS, and papers related to cesarean scar pregnancies. Only 27 articles about the management of PAS with methotrexate were included, 17 articles about the management of PAS with only methotrexate and 10 articles about combination therapy (see Fig. 2).

Figure 2.

Methods.

The use of methotrexate

Overview of methotrexate and its mechanism of action

Methotrexate is the known drug name for Amethopterin, which is the analog of the unstable aminopterin, discovered in 1948[5]. Initially, it was used in high doses to treat leukemia[6]. However, nowadays, it has a broad spectrum of uses notably, it is used in the conservative treatment of placenta accreta syndrome. On this level, methotrexate induces the necrosis and involution of the placenta by diminishing its vascularity[3]. Nonetheless, methotrexate is focused on dividing cells early in the placenta and not on nondividing ones that are present during the third trimester of gravidarum[7], which limits its efficacy in PAS^[8,9]. As such, it is not recommended by the American College of Obstetricians and Gynecologists, the International Federation of Gynecology and Obstetrics, and the Royal College of Obstetricians and Gynecologists for the treatment of PAS^[7,10].

The use of methotrexate for the treatment of placenta accreta

The use of methotrexate for the cure of placenta accreta syndrome showed success in the reduction of beta-hCG levels and thus resulting in the spontaneous delivery of the placenta residual tissue post-partum. This was well explained in the literature as the use of 50 mg of methotrexate IV for 13 weeks (1 injection/week) resulted in the reduction of beta-hCG levels from 12 656 IU/L at 7 days to undetectable levels (<5 IU/L) at 97 days after the first injection of methotrexate for a woman with placenta percreta, diagnosed at 39 weeks of gestation after an uncomplicated vaginal delivery. And at 117 days, the placental residual tissue was delivered spontaneously[11].

Conservative management of placenta accreta was adopted in a favored case criterion: primigravida without live issue, stable vitals, and absence of active bleeding. As such, the use of IM 50 mg of methotrexate led to a decrease of beta-hCG from 4080 to 1430 mIU/mL in 3 days which facilitated the reduction of placental perfusion in a woman with placenta accreta, diagnosed and delivered her abortus at 26 weeks of gestation. This resulted in the detachment of the affected placental area and resulted in the removal of the placenta without complications under USG[12].

Similarly, MRI showed complete resolution of the uterus at 18 months after cesarean section at 37 weeks of gestation after diagnosis of placenta previa and increta at 33 weeks; and that’s also after treatment for 3 weeks with a 50 mg/m² weekly[13].

Furthermore, Shekhar et al[14] reported the case of a woman whose necrotic placenta diagnosed postnatally was completely manually removed after treatment with a single dose of 60 mg (1 mg/kg) of methotrexate had been administered IM in addition to prophylactic antibiotics.

A paper by Ramoni et al[15] reported four cases of invasive placenta treated by 1 mg/kg methotrexate post-delivery by cesarean section. However, the clinical responses varied significantly, reflecting patient-specific variables: the first case diagnosed with placenta previa in her 27th week of gestation and having undergone C-section in her 37th week achieved spontaneous resolution without surgical intervention after 6 month of the aforementioned treatment taken on a weekly basis for 9 weeks in addition to parenteral antibiotic of fosfomycin and ampicillin/clavulan. In the second case diagnosed with total placenta previa at 32 weeks and where the patient had to undergo urgent C-section at 33 weeks due to extensive vaginal bleeding, vaginal removal of placenta was necessary with insertion of a Bakri balloon although she had been treated by the aforementioned treatment on a weekly basis for 6 weeks. The remaining third (diagnosed with placenta percreta at 32 weeks and delivered at 34 weeks) and fourth (total placenta previa including the bladder wall diagnosed at 28 weeks and delivered at 31 weeks) cases had bleeding necessitating hysterectomy[15].

Besides, the injection of three doses of methotrexate IM demonstrated favorable outcomes in treating a case of placenta accreta in a 33 aged patient with history of placenta accreta: no complication, no infections, and normal separation of the placenta with uneventful postnatal period. As such, Manhendru et al[16] considered that methotrexate not only prevents severe complications but also preserves fertility in hemodynamically stable patients who desire future pregnancies. Even in the case of partial placenta accreta detected post-delivery by CS at 30 weeks after pregnancy prolongation due to premature rupture of membranes (PROM) at 25 weeks, the use of 73 mg of methotrexate IM induced the disposition of placental remnant vaginally after 10 hours with no infection detected[17].

On another hand, two cases have been reported to be nonresponsive to the conservative treatment of placenta accreta with methotrexate: the first case had a total placenta previa in addition to placenta increta revealed post-partum; the second case had C-section at 39 weeks and placenta percreta was diagnosed post-partum. In fact, in both cases a hysterectomy or laparoscopic intervention was needed: no change in the aspect of the adherent placenta nor a reduction in the vascularity, only a decline of beta-hCG was seen. As such, this method was advocated against in these two cases[18] (see Table 1).

Table 1.

Case studies results

Case report ID	Gestational age	Route of administration	Dose	Duration	Clinical outcome
Tamate et al[11]	39 weeks	IV	50 mg	13 weeks (1 injection/week)	Decrease beta-hCG
					Spontaneous delivery of placenta remnant
Senior et al[12]	26 weeks	IM	50 mg	One dose	Drop of beta-hCG
					Decreased perfusion of placenta
					Detachment of the affected area at day 7
Guler et al[13]	37 weeks	IV	50 mg/m2	3 weeks (1 dose weekly)	Complete resolution of the uterus
Shekhar et al[14]	N/A	IM	60 mg (1 mg/kg)	One dose	Successful manual extraction of residual placental tissue
Ramoni et al[15]	27 weeks diagnosed	IM	1 mg/kg	Case 1: 9 courses (weekly) 7 days post cesarean section	Case 1: After 2 months of cesarean section, high fever and CRP
	37 weeks: C-section
					Placenta vanished completely within 6 months
	32–33 weeks: C-section			Case 2: 6 courses (weekly) 7 days post cesarean section	Case 2: 2 months post cesarean section, fever, vaginal bleeding and endometritis
					Intrauterine balloon (Bakri) needed
	32–34 weeks: C-section			Case 3: twice weekly 2 days post-cesarean section	Case 3: severe bleeding and hysterectomy
	28 weeks – C-section: 31 weeks			Case 4: 3 times weekly, 3 days post cesarean section	Case 4: severe bleeding and hysterectomy
Hays et al[18]	35 weeks	IV	50 mg/m2	Case 1: 3 doses at weekly interval	Serum chorionic gonadotropins declined
					Hysterectomy was essential after episode of high fever and hemorrhage
	39 weeks			Case 2: 2 doses at weekly interval
Mahendru et al[16]	Not mentioned	IM	1 mg/kg (50 mg)	Total of 3 doses separated by 72–96 hour interval	Normal placental separation
					Uneventful postnatal period
Morken et al[17]	25 weeks	IM	1 mg/kg (73 mg)	One dose	Placental remnants disposed vaginally after 10 hours

On a broader level, a retrospective study was done with 54 participants having placenta increta divided into two groups: Group 1 that received 50 mg of methotrexate IV for 5 days and Group 2 that received 75 mg of methotrexate at 3 to 4 points at the level of the placenta (Group 1: 35.13 weeks ± 2.43; Group 2: 34.96 weeks ± 4.43). In addition, another course was repeated after 1 month in both groups. The success criteria were a resolution without hysterectomy which occurred in all but four cases in Group 1: two cases had infection, and two cases showed vaginal bleeding. Both methods showed success with minor side effects resolved after treatment[2]. Nonetheless, another prospective study was performed with 24 women (mean gestational age: 28.1 weeks) receiving also methotrexate IM but results only showed that 8 women achieved spontaneous resolution without surgical intervention but the effectiveness of this method, as stated in this study, needed further investigations[3]. It was difficult to assess the efficacy and complications of methotrexate therapy, due to the small number of patients in each group of Matsuzaki et al[19] systematic review. However, no correlation was found between the route of administration and/or total dose of methotrexate and subsequent treatment success and complication rates. Therefore, chemotherapy during conservative treatment of permanent placenta should not be recommended[19].

Safety of methotrexate in breastfeeding

Available data on methotrexate transfer into breast milk remain limited and inconclusive. Baker et al[20], found that the relative infant dose (0.11%) of methotrexate in milk was extremely shallow after the use of 92 mg of methotrexate IM for 5 days for the treatment of placenta accreta, and suggested that levels of methotrexate are low in milk. As such, women could breastfeed their infants with extreme caution after 24 hours of the last dose of methotrexate[20].

Adverse effects of methotrexate use in PAS

Methotrexate is a cytotoxic agent. It has been used in the conservative management of placenta accreta syndrome. It leads to placental vascularity reduction as it targets dividing cells of early placenta. Despite its efficacy in treating PAS, methotrexate has serious side effects. It’s an immunosuppressive agent and can cause hepatotoxicity, nephrotoxicity and pancytopenia which can result in secondary infection[8] and even septicemia[3] and mortality due to myelosuppression in addition. A 30-year-old female patient with methylenetetrahydrofolate reductase deficiency was administered three doses of low-dose methotrexate. She suffered from degree IV myelosuppression, oral ulcerative mucositis, and degree III hepatic injury posttreatment. This adverse effect of the drug could be associated with the patient’s underlying insufficiency. Fortunately, these symptoms were reversed with leucovorin[21].

Patients receiving methotrexate injections need to be regularly monitored for possible complications. Complete blood count, liver function tests, kidney function tests, beta-hCG, USG, and pelvic Doppler can be used to monitor patients on methotrexate and combination therapies[12].

Furthermore, intrauterine infections could happen through the course of therapy[11] and thus, broad-spectrum prophylactic antibiotics could be used to reduce infections.

Conclusion

As noted in our review, the included cases managed with methotrexate only, were majorly detected in the third trimester, some postpartum and some in the second trimester and no case of PAS was detected in the first trimester. Despite the method of administration of chemotherapy with methotrexate and the gestational age, both successful and unsuccessful outcomes, with some cases necessitating hysterectomy, were reported. As such, we can say that gestational age has no association with the result of conservative therapy with methotrexate.

The use of methotrexate in combination with other methods

There have been efforts to manage patients with placenta accreta syndrome using conservative treatments to preserve uterine fertility and avoid postpartum hemorrhage. There is no universal agreement by physicians on the most appropriate method to adopt. The outcomes of different treatments vary between cases. Combination therapies have been employed with varying results.

UAE ± MTX ± MTX/FA

One treatment modality includes occluding uterine arteries and collateral blood vessels using serial uterine artery embolization, combined with a methotrexate regimen.

Chou et al[22] reported the use of UAE with Gelfoam and metallic microcoils followed by weekly methotrexate administration weekly for 2 weeks along with eight 8-day methotrexate and folinic acid regimen at 7 weeks gestation in a 38-year-old G2P0 woman with a history of myomectomy. Methotrexate and folinic acid regimen consisted of four doses of each on alternating days. Patient underwent second UAE due to revascularization of the area. There was a gradual decrease in beta-hCG to normal level with complete resolution of the invasive placenta at 110 days following treatment[22].

A case series of 12 patients with abnormal placental implantation (mean gestational age 29.9 ± 5.5 weeks) treated with UAE and methotrexate were enrolled in a study to explore the outcome of treatment. Seven patients showed full placental expulsion and menstrual resumption. Due to postpartum complications of hemorrhage, sepsis, peritonitis, and intestinal adhesions, five patients ended up with primary or delayed hysterectomy[23].

A case of a placenta percreta managed conservatively till 35 weeks of gestation after diagnosis with low-lying placenta at 19 weeks, was reported by Khan et al[24]. Post-delivery, the placenta was intentionally left in situ to reduce hemorrhagic risk. To prevent post-partum hemorrhage, prophylactic bilateral uterine artery embolization was done. Methotrexate injections were given weekly for 3 weeks. Beta-hCG levels returned to normal after 5 months of treatment, and the patient resumed regular menstrual cycle after 7 months of treatment. This case suggests that conservative management of placenta accreta is a possibility for certain cases. However, patients should be informed of possible risks such as sepsis and delayed hemorrhage. Multidisciplinary efforts are required for uterine conservation[24].

In a single-center retrospective case series, five patients underwent conservative management of placenta accreta syndrome. Four out of five patients had vaginal delivery and one patient had emergency cesarean delivery due to abruption of placenta. All five patients were administered a minimum of one dose of methotrexate (50 mg) around day 17 postpartum. Uterine artery embolization was done in three patients prior to methotrexate. Four out of five patients had successful conservative management. Two out of five patients had methotrexate induced complications[25].

Ramoni et al[15] reported four cases of abnormally invasive placenta treated conservatively with bilateral uterine artery ligation, and bilateral iliac artery ligation in one case, followed by injections of methotrexate of varying courses and timings post-cesarean section. Patients presented with complications including intrauterine infections and delayed hemorrhage requiring antibiotic treatments, intrauterine postpartum balloon insertion, and abdominal hysterectomy. Therefore, outpatient follow-ups should be done consistently for weeks as conservative managements have underlying risks[15].

Selective nutritional vessel embolization ± MTX

Another method of treatment involves selectively embolizing vessels and administering methotrexate as adjuvant therapy.

A case of a 38-year-old woman with placenta accreta (34 weeks of gestation: PROM) was managed conservatively with selective nutritional vessel embolization and methotrexate treatment following manual placenta removal and curettage. The retained placenta mass was expelled 3 days later suggesting this to be a feasible conservative technique[26].

In a case report by Cirpan et al[27], a 34-year-old patient with history of prior cesarean section was diagnosed with placenta previa totalis anteriorly with invasion of bladder at 38 weeks of gestation. Placenta was left in situ to avoid hemorrhage and bladder injury. Internal iliac arteries were ligated, and methotrexate (100 mg) given as adjuvant therapy weekly for five times. Her beta-hCG levels decreased but manual removal of residual placental mass was performed along with a complementary operation. Patient resumed regular menstruation and normal beta-hCG 6 months later[27].

Butt et al[28] reported a case of placenta percreta managed conservatively that resulted in morbidity. The placenta was left in situ post-cesarean at 30 weeks’ gestation, and methotrexate was administered. The patient had postpartum bleeding that was managed by internal iliac balloon catheterization and manual removal of the placental tissue. Ultimately, the patient required hysterectomy and massive transfusion of blood[28].

HIFU ± MTX

A combination of high-intensity focused ultrasound and methotrexate treatment was also explored for managing placenta accreta.

A retrospective study done by Jiang et al[29] included 21 patients with placenta accreta retained postpartum and post abortion. All patients received USgHIFU treatment for 3 days. Those with serum beta-hCG level >100 mIU/mL received additional systemic methotrexate for 3 days and had no myelosuppression. Placental tissue was extracted by USG curettage or hysteroscopic operation. Menstrual cycle resumed normally in 20 patients around 32 days post-operation[29].

MTX ± folic acid ± sequential estrogen and progestin

Mizuno et al[30] reported a case of patient with placenta accreta and history of myomectomy who underwent cesarean delivery at 38 weeks 1 day. Patient received four doses of 50 mg methotrexate IM alternating with four doses of 15 mg folic acid. She also received three courses of sequential conjugated estrogen-progestin therapy. Her beta-hCG returned to normal and necrotic tissue was expelled following treatment. Therefore, a combination of methotrexate with estrogen and progestin is a potential treatment of placenta accreta[30].

MTX ± folinic acid

A combination of methotrexate and folinic acid has demonstrated favorable outcomes in select clinical scenarios. Different doses of methotrexate and folinic acid are given for different periods of time to each patient depending on the case.

IV 50 mg methotrexate combined with IM 5 mg Folinic acid was given to a patient diagnosed with placenta percreta post-delivery at 29 weeks. The patient showed promising results with decreased levels of beta-hCG, small calcified transmural extension of the placenta on MRI, and no blood flow to the area on Color Doppler ultrasonography after more than a year of delivery. Patients also resumed normal menstruation[31].

In a case report by Crespo et al[32], a patient with placenta increta who delivered by C section at 39 weeks, was given four doses of methotrexate IM every other day, and four doses of 15 mg folinic acid on alternative days to reduce placental tissue retained after cesarean delivery. Patient had decreased levels of beta-hCG posttreatment, and expulsion of the retained placental tissue was achieved 7 months later[32].

Lalchandani et al[33] reported two cases of placenta accreta and unruptured interstitial cornual pregnancy where conservative management was implemented. Both patients, 29-year-old woman at 10 weeks’ gestation and 36-year-old woman at 6 weeks gestation, received IV methotrexate (400 mg infusion) followed by 10 doses of folinic acid (15 mg). Beta-hCG gradually returned to normal level and menses resumed regularly in both cases[33].

Conclusion of combination therapy

In conclusion, different combination treatments with methotrexate have been explored over the years. Each combination therapy had varying results among different cases. Methotrexate was combined with UAE, folinic acid, and HIFU for the treatment of cases of abnormal placental invasion. Each combination therapy showed to be effective in the studies and cases mentioned in this review. However, sometimes conservative management with combination therapy could have serious implications. Moreover, there is no optimal treatment modality that can be implemented in all cases. Different dosages and different durations of combined treatments have been used distinctly in different cases, each with varying efficacy and recovery. However, conservative management of placenta accreta with methotrexate combined with varying treatment modalities is to be considered in patients who wish to preserve uterine fertility and reduce the possibility of hemorrhage post-partum. We can note also that the gestational age has no dose-effect relationships with the efficacy of combination therapy with methotrexate.

Conclusion

Numerous studies have demonstrated an efficacy in the use of methotrexate in the conservative treatment of placenta accreta syndrome; while some have also presented risks that may outweigh the benefits. As a conclusion, methotrexate may offer clinical benefit in selected PAS cases, particularly where fertility preservation is prioritized, however further multicenter trials stratified by gestational age, ethnicity, and clinical stability are essential to establish standardized protocols. This paper illustrated outcomes of the treatment with methotrexate in relation with the gestational age, demonstrating that these 2 parameters are independent. While the American College of Obstetricians and Gynecologists, the International Federation of Gynecology and Obstetrics, and the Royal College of Obstetricians and Gynecologists don’t recommend its use in PAS, more research should be done for more relevant evidence.

Ethical approval

Ethics approval was not required for this review.

Consent

Informed consent was not required for this review.

Sources of funding

Not applicable.

Author contributions

Study concept, design, data collection, data analysis and interpretation, writing the paper: L.N.; data collection, writing the paper, compilation: G.N.; data collection, data analysis and interpretation, writing the paper: M.A.; Study concept and design, review, wrote the paper: D.E.C.

Conflicts of interest disclosure

No conflict of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Lea Nohra, Gaelle Nafeh, Dr Maria Assi, Dr Diala El Chbib.

Provenance and peer review

Not invited.

Data availability statement

Data available upon request.