Conservative management of cervical pregnancy: The utility of methotrexate treatment and uterine artery embolization

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Open Journal of Obstetrics and Gynecology, 2013, 3, 711-716 OJOG

http://dx.doi.org/10.4236/ojog.2013.310131 Published Online December 2013 (http://www.scirp.org/journal/ojog/)

Conservative management of cervical pregnancy: The

utility of methotrexate treatment and uterine artery

embolization

Hisashi Masuyama, Seiji Inoue, Etsuko Nobumoto, Kei Hayata, Tomonori Segawa, Yuji Hiramatsu

Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science,

Okayama, Japan

Email: [email protected]

Received 3 November 2013; revised 24 November 2013; accepted 1 December 2013

cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In

ABSTRACT

The aim of this retrospective case series report is to

evaluate systemic methotrexate therapy in conjunc-

tion with uterine artery embolization (UAE) in the

conservative management of cervical pregnancy. We

examined clinical presentations, treatments, and the-

rapeutic outcomes in fifteen patients with a cervical

pregnancy who wished for preservation of fertility,

treated at Okayama University Hospital between

1998 and 2 012. Twelve pa tients received systemic me-

thotrexate including five treated with UAE. One was

treated with UAE alone. Two patients received nei-

ther UAE nor methotrexate because of a low human

chorionic gonadotropin (hCG) level and poor blood

flow around the gestational sac (GS). An increased

GS size and the elevated hCG level during metho-

trexate therapy might be risk factors for emergent

UAE. Two of six patients treated with UAE had

subsequent confirmed viable pregnancies. In patients

with a cervical pregnancy, methotrexate therapy in

combination with UAE can be considered as an op-

tion before performing a hysterectomy with suitable

counseling about the risk of loss of fertility. Careful

observation of the GS size and hCG level during

methotrexate therapy might be important for mana-

gement.

Keywords: Cervical Pregnancy; Methotrexate; Uterine

Artery Embolization; Dilatation and Curettage; Human

Chorionic Gonadotropin

1. INTRODUCTION

Cervical pregnancy is a rare but potentially life-threatening

medical condition and has been reported at an incidence of

1 in 8000 - 18000 deliveries, but the incidence is increasing

as a result of assisted reproductive technology [1,2]. Thus,

in vitro fertilization and embryo transfer (IVF-ET) has been

associated with an increased incidence of cervical preg-

nancy [3,4]. In the past, 60% of cases of cervical preg-

nancy were diagnosed at an advanced stage in which life-

threatening hemorrhage occurred after a dilatation and

curettage (D&C) or a suspected spontaneous abortion [5].

Such cases often resulted in the need for a hysterectomy

and loss of the patient’s fertility. The use of curettage with a

Foley catheter tamponade or placement of a Shirodkar cer-

clage has also been reported for hemorrhage associated

with a cervical pregnancy [6-9], but these procedures have

not been established as safe.

Recently, the application of first-trimester transvaginal

ultrasonography has led to improvements in the early diag-

nosis of cervical pregnancy, thereby assisting in conser-

vative and fertility-preserving treatment [10,11]. Since

Farabow et al. introduced systemic methotrexate (MTX)

treatment for cervical pregnancy [12], MTX treatment has

become an established alternative to surgical therapy

[13-15]. Moreover, uterine artery embolization (UAE) has

been widely used as a highly effective technique for con-

trolling acute and chronic genital bleeding [16-18]. There

have been sporadic reports of cases of cervical pregnancy

with vaginal bleeding that were controlled by UAE and the

administration of MTX to preserve fertility and control

bleeding [19]. The risks of embolotherapy include uterine

infarction or ischemia and necrosis; however, the majority

of patients tolerate the procedure well [20,21]. Combined

therapy with MTX has also been used and has been

recommended by reports of UAE as an initial therapy to

treat patients with a cervical pregnancy [22,23].

OPEN ACCESS

H. Masuyama et al. / Open Journal of Obstetrics and Gynecology 3 (2013) 711-716

712

Here we report on 15 patients with a cervical pregnancy,

who wished for minimally invasive intervention and/or the

preservation of their fertility. We applied conservative

management with MTX therapy in combination with UAE.

We have examined our reports of clinical presentations,

treatments and therapeutic outcomes to evaluate our con-

servative management for patients with a cervical preg-

nancy. Laboratory values and demographic information

have been compared and follow-up pregnancy information

has been reported, when available. The aim of this re-

trospective case series report is to demonstrate that syste-

matic MTX therapy combined with UAE is a good clinical

option for the conservative management of patients with a

cervical pregnancy.

2. MATERIALS AND METHODS

Seventeen Japanese women with a suspected cervical

pregnancy who were referred to the Department of Obs-

tetrics and Gynecology, Okayama University Hospital,

Japan, from 1998 to 2012 were included in this study.

The study protocol was approved by the institutional

review board of Okayama University Graduate School

of Medicine, Dentistry and Pharmaceutical Science.

Cervical pregnancies were diagnosed by transvaginal

ultrasound as described previously [10]. Data were

collected through paper chart reviews and through a

review of electronic medical records. Clinical data and

ultrasonographic findings were recorded, including

maternal age, reproductive history, gestational age (GA),

mean gestational sac (GS) diameter, size of the embryo,

and fetal heartbeat. Our conservative management for

patients who desire preservation of their fertility is

outlined in Figure 1. Systematic MTX (50 mg/m2) was

administered intramuscularly every 10 days along with

a follow up of serum human chorionic gonadotropin

(hCG) levels and blood flow around the GS. Ultra-

sound-guided injections of MTX (50 mg) into the GS

Cervicalpregnancy

Wishforco nservat i vemanagement

Massivehem o rrhage

‐+

MTXtherapy

Bloodflow–or?? Massivehemorrh ageor

Nochange ofbloodflow

UAE

D&C

Conservative

Informe dco n sen t

Conservative

Informedcho ice

Transvaginalultrasonography

SerumhCG level,(MRI)

Figure 1. Flowchart of the conservative management for cer-

vical pregnancy.

was also considered when there was a positive fetal

heartbeat, a serum hCG level >10000 IU/L, a pregnancy

of >9 gestational weeks or a fetal crown-rump length of

>10 mm.

Uterine artery embolization procedures were per-

formed by qualified interventional radiologists using

gelfoam particles through the right common femoral

artery access and were performed on bilateral uterine

arteries in all cases. The decision to perform UAE was

made on a per-case basis; however, all patients present-

ing with massive hemorrhage were treated in this way.

All values are expressed as the mean ± standard

deviation (SD). Demographic and laboratory data were

compared using Fisher’s exact test for all categorical

variables and mean values were compared using the

Kruskal-Wallis nonparametric analysis of variance and

Mann-Whitney nonparametric U test. Statistical analy-

sis was performed using SPSS software version 20.0

(SPSS Inc., Chicago, IL, USA) and P < 0.05 was con-

sidered statistically significant.

3. RESULTS

Seventeen cases of cervical ectopic pregnancy were

diagnosed at our institution during the study period. One

patient had a heterotopic pregnancy that involved both

cervical and intrauterine gestations. Another patient had

no wish for conservative treatment. The remaining 15

cases were considered for the study (Table 1). Six of

these patients were treated with UAE, and of these, five

also received MTX. One patients had active vaginal

bleeding 67 days after the first UAE was controlled

successfully by additional UAE. The other seven patients

received MTX alone. Two patients received neither UAE

nor MTX because of a low hCG level and poor blood

flow around the GS. Two patients with high serum hCG

levels and positive fetal heartbeats also received local

MTX injection into the GS together with systematic

MTX administration. Forty percent of the study cases

(6/15) had a history of at least one induced abortion and

assisted reproduction techniques were used in eight cases

including six cases of IVF-ET. Six patients were nul-

liparous.

All patients with a cervical pregnancy confirmed by

ultrasound were admitted to our hospital for treatment.

According to our management protocol for cervical

pregnancy (Figure 1), MTX therapy was started imme-

diately except for patients who required emergency UAE

because of a massive hemorrhage. First, we divided the

patients into two groups according to the median GA

value (45 days) to examine whether GA affected the

therapy. There was a significant difference in the serum

hCG level between the two groups and all cases with

massive bleeding were included in the long GA group

(Table 2(a)). The median value of GS size (13 mm) was

H. Masuyama et al. / Open Journal of Obstetrics and Gynecology 3 (2013) 711-716

713

OPEN ACCESS

Table 1. Characteristics of patients with a cervical pregnancy.

Case Age Gravida para antificial

abortion Infertility GA

(days)

(mm)FHM Blood flow

around GS

hGG level

(mIU/mL)

genital

bleeding

No. of

MTX UGE Other

treatment

1 36 1 0 1 – 77 80 + + 64030 Moderate3 + MTX

injection, D&C

2 22 2 0 1 – 42 28 + + 4015 Small 2 + D&C

3 38 1 0 0 IVF-ET 48 9.9– ± 8123 Small 2 - -

4 40 1 0 1 IVF-ET 41 10.6+ + 4133 Small 4 + -

5 23 2 0 1 – 52 18 + ± 16967 - 2 - -

6 34 0 0 0 IVF-ET 42 8.9+ + 4665 - 2 + Aspiration of GS

7 40 0 0 0 – 57 7.5– – 868 - 2 - -

8 28 0 0 0 – 38 11.7+ + 11271 - 2 - MTX injection

9 32 5 1 4 - 56 10.5- + 9897 Heavy0 + -

10 40 2 1 0 AIH 51 21 + ± 16131 - 0 - -

11 37 2 1 0 IVF-ET 52 19 – + 41261 Heavy3 2x D&C

12 30 0 0 0 – 36 17.1– – 6056 Moderate2 - -

13 41 2 0 2 Clomid 41 16 – – 1191 Small 0 - -

14 31 0 0 0 Clomid 38 7 – ± 2095 Small 1 - -

15 39 0 0 0 IVF-ET 45 13 + + 13575 small 8 - D&C

GA: gestational age, GS: gestational sac, FHM: fetal heart movement, hCG: human chorionic gonadotropin, MTX: methotrexate, UAE: uterine artery emboli-

zation, D&C: dilatation and curettage.

Table 2. Comparison between groups with early and late gestational age (GA) (a), small and large gestational sac (GS) (b) and low

and high serum hCG levels (c).

(a)

GA (days) Case number GS(mm) FHM Blood flow around GShCG level (mIU/mL)Massive bleeding MTX UAED&C

<45 7 14.2 ± 7.1 4 5 4775 ± 3288 0 6 3 1

≥45 8 22.4 ± 23.8 4 7 21357 ± 20875* 2 6 3 3

(b)

GS (mm) Case number GA (days) FHM Blood flow around GShCG level (mIU/mL)Massive bleeding MTX UAED&C

<13 7 45.7 ± 8.1 3 6 5864 ± 3962 1 6 3 0

≥13 8 49.5 ± 12.5 5 6 20403 ± 21575* 1 6 3 4

(c)

hCG level (mIU/mL) Case number GA (days) GS (mm)FHM Blood flow around GSMassive bleeding MTX UAED&C

<8123 7 42.4 ± 6.8 13.6 ± 7.53 4 0 6 3 1

≥8123 8 52.4 ± 11.4*22.9 ± 23.45 8* 2 6 3 3

*P < 0.05, mean ± SD, GA: gestational age, GS: gestational sac, FHM: fetal heart movement, hCG: human chorionic gonadotropin, MTX: methotrexate, UAE:

uterine artery embolization, D&C: dilatation and curettage.

also used to divide the patients into two groups. The

serum hCG level was significantly higher and all patients

who required D&C were included in the large GS group

(>13 mm; Table 2(b)). Two groups were also evaluated

using the median value of hCG level (8123 mIU/mL).

There were significant differences in blood flow around

the GS, but there was no significant difference in the

incidence of D&C and the requirement for UAE in the

high hCG group (Table 2(c)). We also examined the

patients who underwent UAE. The GS size and serum

hCG level at admission in the UAE group were higher

than in the group without UAE, but this was not sig-

nificant statistically because some patients with a small

GS and/or low hCG level required UAE because of a

moderate or massive hemorrhage (Table 3(a)). In ad-

dition, clinical data on when UAE was done in the UAE

cases are summarized in Table 3(b). All patients with

emergency UAE except for two with UAE at admission

for massive hemorrhage had an increased and/or large

GS size and/or elevation of serum hCG levels at UAE

compared with those seen at admission.

Of the six patients who underwent UAE, two sub-

sequently had confirmed viable pregnancies. Of these,

one pregnancy resulted in a preterm delivery at 31

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714

Table 3. Comparison between groups with and without UAE (a) and characteristics of cases with UAE (b).

(a)

UAE Case number GA (days) GS (mm) FHMBlood flow around GShCG level (mIU/mL) MTXD&C

- 9 45.1 ± 7.4 [36 - 57] 13.5 ± 4.9 [7.0 - 21.0]4 6 8475 ± 6345 [868 - 16967] 7 1

+ 6 51.7 ± 13.9 [41 - 77] 26.2 ± 27.3 [8.9 - 80.0]4 6 21334 ± 25395 [4015 - 64030] 5 3

(b)

Case GS (mm) FHM Blood flow around GS hCG level (mIU/mL) Bleeding situation

1 80/58 +/− +/− 64030/25 at D&C after MTX 3 courses

2 28/64 +/− +/+ 4015/422 at D&C after MTX 2 courses

4 11/13 +/− +/+ 4133/16055 after MTX 1 course

6 9/50 +/− +/+ 4665/1708 after MTX 2 courses

10 10 − + 9897 at admission

12 19/12 − + 41261/122 at admission and after MTX 3 courses

GA: gestational age, GS: gestational sac, FHM: fetal heart movement, hCG: human chorionic gonadotropin, MTX: methotrexate, UAE: uterine artery emboli-

zation, D&C: dilatation and curettage, GS size: at admisssion/at UAE.

weeks’ gestation because of preterm labor and premature

rupture of membranes and the other patient had a spon-

taneous vaginal term delivery with placenta accreta.

None of the patients required hysterectomy.

4. DISCUSSION

In this study, we analyzed the outcomes for 15 patients

with a cervical pregnancy who wished for minimally

invasive treatment to preserve their fertility under our

protocol of conservative management for cervical

pregnancy (Figure 1). Of this series, 12 patients re-

ceived systemic MTX administration including seven

with MTX alone and five were also treated with UAE.

The other patient was treated with UAE alone. Two

patients received neither UAE nor MTX because of a

low hCG level and poor blood flow around the GS.

Forty percent of the study patients had a history of at

least one induced abortion, and assisted reproductive

techniques were used in eight cases including six cases

of IVF-ET. An increased GS size and an elevated hCG

level during MTX therapy might be risk factors for

emergency UAE. Of the six patients who underwent

UAE, two subsequently had confirmed viable preg-

nancies.

MTX treatment has been used successfully for treat-

ing cervical pregnancies and has become the first line

therapy for stable patients [12-15]. However, additional

therapies were often required for this treatment. We

found here that the group of patients with a high hCG

level (>8123 mIU/mL) included all with a massive

hemorrhage and a higher requirement for D&C, but

there were no significant differences in the requirement

for UAE. This elevated hCG level is consistent with a

previous report [24]. Another report indicated that UAE

should be applied after systematic MTX therapy and—

if a fetal heart beat is present—lethal intraamniotic

KCL injection should be considered in cases with very

high hCG level (>34,000 mIU/mL) [25]. Conversely,

the hCG level at admission could not predict the

requirement for UAE in our study because we observed

that the patients with low hCG level after MTX therapy

as well as with low initial level needed emergency UAE

for a moderate hemorrhage. However, most patients

requiring emergency UAE had a large GS and/or

elevation of serum hCG levels at UAE compared with

at admission, suggesting that careful observation might

be important for conservative management.

Previous reports have suggested that UAE alone may

be insufficient to treat a cervical pregnancy effectively

and that concurrent medical therapy might be indicated

[23,25]. In our study, only one patient had a spon-

taneous abortion after UAE caused by a heavy hemorr-

hage. In all of our patients, UAE was effective in stopp-

ing active vaginal bleeding and preserving the uterus as

reported previously [17,18,26]. However, one of our pa-

tients had active vaginal bleeding 67 days after the first

UAE; this was controlled successfully by additional

UAE and emergency D&C of the cervical canal after

the second UAE.

Viable pregnancies have been reported after UAE

[25,27]. In our study, two patients subsequently had

viable pregnancies although assisted reproduction tech-

niques—one of the risk factors for cervical preg-

nancy—were used in eight cases including six cases of

IVF-ET. Despite these observations, patients seeking

fertility preservation who may undergo UAE should

receive adequate prior counseling according to Ame-

rican college of obstetrics and gynecology (ACOG) re-

commendations [28]. Thus, the use of UAE for cervical

H. Masuyama et al. / Open Journal of Obstetrics and Gynecology 3 (2013) 711-716 715

pregnancy can be considered among patients desiring

future childbearing, but further studies are needed to

elucidate the effect of UAE on pregnancy outcomes.

5. CONCLUSION

In conclusion, MTX therapy in combination with UAE

can be considered as an option before hysterectomy,

with counseling about the risk of loss of fertility in pa-

tients with cervical pregnancy. Careful observations of

GS size and hCG levels during MTX therapy might be

important for management. Because more cases are

being detected earlier with first-trimester ultrasono-

graphy and with the increased incidence with assisted

reproductive technology, cervical pregnancy is becom-

ing a more commonly encountered clinical situation.

The use of MTX in combination with UAE for the con-

servative management of a cervical pregnancy in pa-

tients desiring to preserve their fertility should be con-

sidered strongly.

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