Accepted Manuscript Transvaginal methotrexate injection for the treatment of cesarean scar pregnancy: Efficacy and subsequent fecundity Munekage Yamaguchi, M.D., Ph.D. Ritsuo Honda, M.D., Ph.D. Kikuko Uchino, M.D. Hironori Tashiro, M.D., Ph.D. Takashi Ohba, M.D., Ph.D. Hidetaka Katabuchi, M.D., Ph.D. PII:
S1553-4650(14)00243-X
DOI:
10.1016/j.jmig.2014.03.024
Reference:
JMIG 2291
To appear in:
The Journal of Minimally Invasive Gynecology
Received Date: 4 February 2014 Revised Date:
25 March 2014
Accepted Date: 25 March 2014
Please cite this article as: Yamaguchi M, Honda R, Uchino K, Tashiro H, Ohba T, Katabuchi H, Transvaginal methotrexate injection for the treatment of cesarean scar pregnancy: Efficacy and subsequent fecundity, The Journal of Minimally Invasive Gynecology (2014), doi: 10.1016/ j.jmig.2014.03.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Transvaginal methotrexate injection for the treatment of cesarean scar pregnancy:
2
Efficacy and subsequent fecundity
3
Munekage Yamaguchi, M.D., Ph.D. , Ritsuo Honda, M.D., Ph.D., Kikuko Uchino, M.D.,
4
Hironori Tashiro, M.D., Ph.D., Takashi Ohba, M.D., Ph.D., and Hidetaka Katabuchi,
5
M.D., Ph.D.
6
Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto
7
University, 1-1-1 Honjo, Chuo-Ku, Kumamoto-City, Kumamoto 860-8556, Japan
8
Corresponding author contact information: M. Yamaguchi
9
Department of Obstetrics and Gynecology, Faculty of Life Science, Kumamoto
10
University, 1-1-1 Honjo, Chuou-Ku, Kumamoto-City, Kumamoto 860-8556, Japan. Tel
11
+81-96-363-5269, Fax +81-96-363-5164.
12
E-mail address: [email protected]
13
Key words: Cesarean scar pregnancy, Fecundity, Human chorionic gonadotropin, MTX,
14
Transvaginal methotrexate injection
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Abstract
16
OBJECTIVES: Cesarean scar pregnancy (CSP) is an extremely rare type of ectopic
17
pregnancy. There is still no consensus on the appropriate treatment method for this
18
abnormal pregnancy, and little data are available on the risk of subsequent pregnancies.
19
The aim of the present study was to investigate the efficacy of local methotrexate
20
(MTX) injections under transvaginal ultrasound guidance for the treatment of CSP and
21
to assess post-treatment fecundity.
22
METHODS: We retrospectively reviewed eight CSP cases treated with local MTX
23
injection under transvaginal ultrasonography. In all cases, serum human chorionic
24
gonadotropin (hCG) levels were monitored and the gestational sac was evaluated using
25
ultrasonography after the treatment. Magnetic resonance imaging was performed, as
26
necessary. The patients’ clinical characteristics and clinical course after treatment,
27
treatment efficacy, and post-treatment fecundity in patients desiring subsequent
28
pregnancies were evaluated.
29
RESULTS: All eight cases were successfully treated without the need for blood
30
transfusions or surgical procedures, although two cases required additional MTX
31
treatments via local injection or systemic administration. The mean time required for
32
hCG normalization was 78.5 ± 37.7 days (range, 42−166 days). Four out of five patients
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2
ACCEPTED MANUSCRIPT
desiring subsequent pregnancies after the treatment had uneventful parturitions, and one
34
was diagnosed with recurrent CSP.
35
CONCLUSIONS: In the present study, we found that transvaginal MTX injection was
36
effective and safe as a sole treatment for the management of CSP. Although the
37
treatment course tended to be long, this method can be considered as the first choice of
38
treatment for patients desiring future pregnancies, but careful attention should be paid to
39
the possibility of CSP recurrence.
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3
ACCEPTED MANUSCRIPT
Introduction:
41
Cesarean scar pregnancy (CSP) is a rare ectopic pregnancy that develops in a previous
42
cesarean scar and occurs in approximately 1 in 2,000 pregnancies [1]. In women with a
43
history of at least one cesarean section, CSP accounts for 6.1% of all ectopic
44
pregnancies, and this incidence is likely to increase with the recent increase in cesarean
45
rate worldwide [2]. Because CSP can now be diagnosed at earlier stages of pregnancy,
46
correspondingly, treatment methods of CSP have shifted away from surgical approaches
47
towards more conservative treatment modalities. Although a wide variety of
48
management approaches have been reported, there is still no consensus on the
49
appropriate treatment for CSP. Viable intrauterine pregnancies and recurrent CSP have
50
been also documented after conservative treatment of CSP; however, thus far, there are
51
little data on complications during pregnancy subsequent to CSP treatments [3].
EP
TE D
M AN U
SC
RI PT
40
In 2001, we successfully preserved an intrauterine gestation with a
53
simultaneous cervical pregnancy through the use of an ultrasound-guided local
54
methotrexate (MTX) injection to the cervical gestation [4]. Since then, we have applied
55
a local MTX injection as the initial treatment for both cervical pregnancies and CSPs.
56
Other CSP studies combined local MTX injections with systemic MTX administration
57
or other treatments [5, 6]; therefore, little is known about the efficacy and prognosis of a
AC C
52
4
ACCEPTED MANUSCRIPT
single local MTX injection. Accordingly, here, we investigated the efficacy of a local
59
MTX injection under transvaginal ultrasound guidance to treat CSP; in addition, we
60
followed-up patients to assess post-treatment fecundity.
AC C
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TE D
M AN U
SC
RI PT
58
5
ACCEPTED MANUSCRIPT
Methods:
62
We retrospectively reviewed eight CSP cases treated at Kumamoto University Hospital
63
between June 2005 and March 2012. Diagnosis was based on medical history, clinical
64
examination, serum human chorionic gonadotropin (hCG) levels, transvaginal
65
ultrasonography, and magnetic resonance imaging (MRI). Serum levels of intact hCG
66
were measured using automated electrochemiluminescence immunoassays (TOSOH,
67
Tokyo, Japan). Ultrasound was performed using a 5−7.5 MHz mechanical sector probe
68
(Mochida, Tokyo, Japan) with the following criteria for diagnosis: 1) an empty uterine
69
cavity, 2) an empty cervical canal, 3) the presence of the gestation sac in the anterior
70
part of the uterine isthmus, and 4) the absence of or a defect in the myometrial tissue
71
between the bladder and the sac [7]. MRI was performed as an adjunct to
72
ultrasonography when an implantation site remained obscure or when the clinical course
73
was eventful [3].
SC
M AN U
TE D
EP
AC C
74
RI PT
61
After diagnosis, a patient’s baseline blood count and liver and kidney statuses
75
were assessed, followed by treatment with an ultrasound-guided transvaginal local
76
injection of 50 mg of MTX dissolved in 2 ml of distilled water. Specifically, a 21-gauge
77
percutaneous transhepatic cholangiography needle (Hakko, Tokyo, Japan) was attached
78
to a transvaginal prove, and the needle was thereafter introduced into the gestational sac
6
ACCEPTED MANUSCRIPT
via the vaginal fornix under transvaginal ultrasound guidance. When the amniotic sac
80
was large enough to allow aspiration, amniotic fluid was first aspirated. Next, a total of
81
50 mg of MTX was injected into the gestational sac and the muscular layer surrounding
82
it. In cases where the flow around the gestational sac could be visualized by color
83
Doppler, MTX was administered into the region of flow. The procedure was performed
84
in an operating room under general anesthesia in order to prevent patient movement and
85
to prepare for potential serious bleeding. We used the same procedure on cases with or
86
without fetal cardiac activity and with any initial hCG levels.
M AN U
SC
RI PT
79
The treatment date was defined as day 0, and serum hCG levels were
88
monitored until they became negative. The ratios of serum hCG levels to those on day 0
89
were also evaluated during the first 2 weeks after the treatment. An additional local
90
MTX injection was administered when serum hCG levels increased again after a first
91
rise within two weeks of the initial therapy. Systemic MTX administration was
92
performed when serum hCG levels increased again following a downward trend after
93
the third week. The gestational sac was also observed by ultrasonography until the sac
94
completely resolved. The patient was adviced to avoid pregnancy until the cesarean scar
95
was evaluated using hysteroscopy six months after treatment. During the follow-up
96
period, the mean time required for hCG normalization, the duration until menses
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87
7
ACCEPTED MANUSCRIPT
97
resumed, the treatment success rate, and the rate of subsequent parturition in patients
98
desiring pregnancy were analyzed. All CSP cases were numbered in serial order. Descriptive statistics are
100
presented as mean ± SD or percentages. This study was approved by Kumamoto
101
University Hospital Review Board, and all the patients provided written informed
102
consent.
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99
8
ACCEPTED MANUSCRIPT
Results:
104
Clinical characteristics
105
Eight cases, including one recurrent case, were diagnosed with CSP at our institution
106
during the study period. The case characteristics are summarized in Table 1. All patients
107
were referred to our hospital by their primary physicians. The mean age of the patient at
108
the time of diagnosis was 32.3 ± 4.1 years old (range, 25−38 years old). Three of the
109
women had a history of uterine curettage. Two had experienced a single previous
110
cesarean delivery, while five had undergone two previous cesarean deliveries. Five
111
women had required emergency cesarean sections. The mean interval from the last
112
cesarean section to the initial CSP therapy was 52.3 ± 29.7 months (range, 6−108
113
months). Seven cases were untreated at the first visit, and one case was referred owing
114
to a poor outcome after two courses of systemic MTX administration.
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103
All pregnancies were spontaneously conceived. The mean estimated gestational
116
age at the time of the first injection was 8w0d ± 1w3d (range, 6w5d−10w5d). Five cases
117
presented with vaginal bleeding. Fetal cardiac activity was present in five cases at
118
presentation. The mean serum hCG level at initial treatment was 45,823 ± 34,495
119
mIU/ml (range, 4,890−95,707 mIU/ml). After CSP diagnosis, all eight cases were
120
treated with a transvaginal ultrasonography-guided local MTX injection as the initial
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ACCEPTED MANUSCRIPT
121
therapy.
123
The pattern of hCG level resolution and additional treatments
RI PT
122
Changes in serum hCG ratio in CSP cases during the first 2 weeks after MTX
125
injection are presented in Figure 1a. The increase in hCG levels was less than 40% over
126
the first 6 days in all cases. We did not regard an initial increase in serum hCG levels
127
after MTX injection as a poor prognostic factor; however, the treatment in Case 5 was
128
considered ineffective owing to a second increase in serum hCG level. Therefore, an
129
additional local MTX injection into other muscle layers in the presence of blood flow
130
was required on day 6. The hCG levels in the seven other cases reduced by more than
131
60% over 2 weeks. The trend of changes in serum hCG levels until resolution is
132
demonstrated in Figure 1b. Four courses of additional MTX intramuscular injection
133
were given in Case 2 because of a sudden increase in hCG levels on day 49. Six of the 8
134
cases were successfully treated with a single local MTX injection.
136
M AN U
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EP
AC C
135
SC
124
Recurrent in a patient
137
Recurrent CSP was diagnosed in one patient (Cases 4 and 6) in whom a niche
138
was observed in the anterior lower uterine segment myometrium. The patient was first
10
ACCEPTED MANUSCRIPT
diagnosed with CSP (Fig. 2a, hCG: 6897.7 mIU/ml). She was in a stable condition with
140
no symptoms after the local MTX injection; however, a residual sac was observed
141
although the patient’s hCG levels continued to decrease. Accordingly, the sac was
142
evaluated using MRI on day 83 (Fig. 2b, hCG: 6.4 mIU/ml). Thereafter, the patient was
143
observed by ultrasonography and was advised to avoid conception after the evaluation
144
of the previous uterine scar by hysteroscopy and MRI (Fig. 2c, hCG:
S1553-4650(14)00243-X
DOI:
10.1016/j.jmig.2014.03.024
Reference:
JMIG 2291
To appear in:
The Journal of Minimally Invasive Gynecology
Received Date: 4 February 2014 Revised Date:
25 March 2014
Accepted Date: 25 March 2014
Please cite this article as: Yamaguchi M, Honda R, Uchino K, Tashiro H, Ohba T, Katabuchi H, Transvaginal methotrexate injection for the treatment of cesarean scar pregnancy: Efficacy and subsequent fecundity, The Journal of Minimally Invasive Gynecology (2014), doi: 10.1016/ j.jmig.2014.03.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Transvaginal methotrexate injection for the treatment of cesarean scar pregnancy:
2
Efficacy and subsequent fecundity
3
Munekage Yamaguchi, M.D., Ph.D. , Ritsuo Honda, M.D., Ph.D., Kikuko Uchino, M.D.,
4
Hironori Tashiro, M.D., Ph.D., Takashi Ohba, M.D., Ph.D., and Hidetaka Katabuchi,
5
M.D., Ph.D.
6
Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto
7
University, 1-1-1 Honjo, Chuo-Ku, Kumamoto-City, Kumamoto 860-8556, Japan
8
Corresponding author contact information: M. Yamaguchi
9
Department of Obstetrics and Gynecology, Faculty of Life Science, Kumamoto
10
University, 1-1-1 Honjo, Chuou-Ku, Kumamoto-City, Kumamoto 860-8556, Japan. Tel
11
+81-96-363-5269, Fax +81-96-363-5164.
12
E-mail address: [email protected]
13
Key words: Cesarean scar pregnancy, Fecundity, Human chorionic gonadotropin, MTX,
14
Transvaginal methotrexate injection
AC C
EP
TE D
M AN U
SC
RI PT
1
1
ACCEPTED MANUSCRIPT
Abstract
16
OBJECTIVES: Cesarean scar pregnancy (CSP) is an extremely rare type of ectopic
17
pregnancy. There is still no consensus on the appropriate treatment method for this
18
abnormal pregnancy, and little data are available on the risk of subsequent pregnancies.
19
The aim of the present study was to investigate the efficacy of local methotrexate
20
(MTX) injections under transvaginal ultrasound guidance for the treatment of CSP and
21
to assess post-treatment fecundity.
22
METHODS: We retrospectively reviewed eight CSP cases treated with local MTX
23
injection under transvaginal ultrasonography. In all cases, serum human chorionic
24
gonadotropin (hCG) levels were monitored and the gestational sac was evaluated using
25
ultrasonography after the treatment. Magnetic resonance imaging was performed, as
26
necessary. The patients’ clinical characteristics and clinical course after treatment,
27
treatment efficacy, and post-treatment fecundity in patients desiring subsequent
28
pregnancies were evaluated.
29
RESULTS: All eight cases were successfully treated without the need for blood
30
transfusions or surgical procedures, although two cases required additional MTX
31
treatments via local injection or systemic administration. The mean time required for
32
hCG normalization was 78.5 ± 37.7 days (range, 42−166 days). Four out of five patients
AC C
EP
TE D
M AN U
SC
RI PT
15
2
ACCEPTED MANUSCRIPT
desiring subsequent pregnancies after the treatment had uneventful parturitions, and one
34
was diagnosed with recurrent CSP.
35
CONCLUSIONS: In the present study, we found that transvaginal MTX injection was
36
effective and safe as a sole treatment for the management of CSP. Although the
37
treatment course tended to be long, this method can be considered as the first choice of
38
treatment for patients desiring future pregnancies, but careful attention should be paid to
39
the possibility of CSP recurrence.
AC C
EP
TE D
M AN U
SC
RI PT
33
3
ACCEPTED MANUSCRIPT
Introduction:
41
Cesarean scar pregnancy (CSP) is a rare ectopic pregnancy that develops in a previous
42
cesarean scar and occurs in approximately 1 in 2,000 pregnancies [1]. In women with a
43
history of at least one cesarean section, CSP accounts for 6.1% of all ectopic
44
pregnancies, and this incidence is likely to increase with the recent increase in cesarean
45
rate worldwide [2]. Because CSP can now be diagnosed at earlier stages of pregnancy,
46
correspondingly, treatment methods of CSP have shifted away from surgical approaches
47
towards more conservative treatment modalities. Although a wide variety of
48
management approaches have been reported, there is still no consensus on the
49
appropriate treatment for CSP. Viable intrauterine pregnancies and recurrent CSP have
50
been also documented after conservative treatment of CSP; however, thus far, there are
51
little data on complications during pregnancy subsequent to CSP treatments [3].
EP
TE D
M AN U
SC
RI PT
40
In 2001, we successfully preserved an intrauterine gestation with a
53
simultaneous cervical pregnancy through the use of an ultrasound-guided local
54
methotrexate (MTX) injection to the cervical gestation [4]. Since then, we have applied
55
a local MTX injection as the initial treatment for both cervical pregnancies and CSPs.
56
Other CSP studies combined local MTX injections with systemic MTX administration
57
or other treatments [5, 6]; therefore, little is known about the efficacy and prognosis of a
AC C
52
4
ACCEPTED MANUSCRIPT
single local MTX injection. Accordingly, here, we investigated the efficacy of a local
59
MTX injection under transvaginal ultrasound guidance to treat CSP; in addition, we
60
followed-up patients to assess post-treatment fecundity.
AC C
EP
TE D
M AN U
SC
RI PT
58
5
ACCEPTED MANUSCRIPT
Methods:
62
We retrospectively reviewed eight CSP cases treated at Kumamoto University Hospital
63
between June 2005 and March 2012. Diagnosis was based on medical history, clinical
64
examination, serum human chorionic gonadotropin (hCG) levels, transvaginal
65
ultrasonography, and magnetic resonance imaging (MRI). Serum levels of intact hCG
66
were measured using automated electrochemiluminescence immunoassays (TOSOH,
67
Tokyo, Japan). Ultrasound was performed using a 5−7.5 MHz mechanical sector probe
68
(Mochida, Tokyo, Japan) with the following criteria for diagnosis: 1) an empty uterine
69
cavity, 2) an empty cervical canal, 3) the presence of the gestation sac in the anterior
70
part of the uterine isthmus, and 4) the absence of or a defect in the myometrial tissue
71
between the bladder and the sac [7]. MRI was performed as an adjunct to
72
ultrasonography when an implantation site remained obscure or when the clinical course
73
was eventful [3].
SC
M AN U
TE D
EP
AC C
74
RI PT
61
After diagnosis, a patient’s baseline blood count and liver and kidney statuses
75
were assessed, followed by treatment with an ultrasound-guided transvaginal local
76
injection of 50 mg of MTX dissolved in 2 ml of distilled water. Specifically, a 21-gauge
77
percutaneous transhepatic cholangiography needle (Hakko, Tokyo, Japan) was attached
78
to a transvaginal prove, and the needle was thereafter introduced into the gestational sac
6
ACCEPTED MANUSCRIPT
via the vaginal fornix under transvaginal ultrasound guidance. When the amniotic sac
80
was large enough to allow aspiration, amniotic fluid was first aspirated. Next, a total of
81
50 mg of MTX was injected into the gestational sac and the muscular layer surrounding
82
it. In cases where the flow around the gestational sac could be visualized by color
83
Doppler, MTX was administered into the region of flow. The procedure was performed
84
in an operating room under general anesthesia in order to prevent patient movement and
85
to prepare for potential serious bleeding. We used the same procedure on cases with or
86
without fetal cardiac activity and with any initial hCG levels.
M AN U
SC
RI PT
79
The treatment date was defined as day 0, and serum hCG levels were
88
monitored until they became negative. The ratios of serum hCG levels to those on day 0
89
were also evaluated during the first 2 weeks after the treatment. An additional local
90
MTX injection was administered when serum hCG levels increased again after a first
91
rise within two weeks of the initial therapy. Systemic MTX administration was
92
performed when serum hCG levels increased again following a downward trend after
93
the third week. The gestational sac was also observed by ultrasonography until the sac
94
completely resolved. The patient was adviced to avoid pregnancy until the cesarean scar
95
was evaluated using hysteroscopy six months after treatment. During the follow-up
96
period, the mean time required for hCG normalization, the duration until menses
AC C
EP
TE D
87
7
ACCEPTED MANUSCRIPT
97
resumed, the treatment success rate, and the rate of subsequent parturition in patients
98
desiring pregnancy were analyzed. All CSP cases were numbered in serial order. Descriptive statistics are
100
presented as mean ± SD or percentages. This study was approved by Kumamoto
101
University Hospital Review Board, and all the patients provided written informed
102
consent.
AC C
EP
TE D
M AN U
SC
RI PT
99
8
ACCEPTED MANUSCRIPT
Results:
104
Clinical characteristics
105
Eight cases, including one recurrent case, were diagnosed with CSP at our institution
106
during the study period. The case characteristics are summarized in Table 1. All patients
107
were referred to our hospital by their primary physicians. The mean age of the patient at
108
the time of diagnosis was 32.3 ± 4.1 years old (range, 25−38 years old). Three of the
109
women had a history of uterine curettage. Two had experienced a single previous
110
cesarean delivery, while five had undergone two previous cesarean deliveries. Five
111
women had required emergency cesarean sections. The mean interval from the last
112
cesarean section to the initial CSP therapy was 52.3 ± 29.7 months (range, 6−108
113
months). Seven cases were untreated at the first visit, and one case was referred owing
114
to a poor outcome after two courses of systemic MTX administration.
EP
TE D
M AN U
SC
RI PT
103
All pregnancies were spontaneously conceived. The mean estimated gestational
116
age at the time of the first injection was 8w0d ± 1w3d (range, 6w5d−10w5d). Five cases
117
presented with vaginal bleeding. Fetal cardiac activity was present in five cases at
118
presentation. The mean serum hCG level at initial treatment was 45,823 ± 34,495
119
mIU/ml (range, 4,890−95,707 mIU/ml). After CSP diagnosis, all eight cases were
120
treated with a transvaginal ultrasonography-guided local MTX injection as the initial
AC C
115
9
ACCEPTED MANUSCRIPT
121
therapy.
123
The pattern of hCG level resolution and additional treatments
RI PT
122
Changes in serum hCG ratio in CSP cases during the first 2 weeks after MTX
125
injection are presented in Figure 1a. The increase in hCG levels was less than 40% over
126
the first 6 days in all cases. We did not regard an initial increase in serum hCG levels
127
after MTX injection as a poor prognostic factor; however, the treatment in Case 5 was
128
considered ineffective owing to a second increase in serum hCG level. Therefore, an
129
additional local MTX injection into other muscle layers in the presence of blood flow
130
was required on day 6. The hCG levels in the seven other cases reduced by more than
131
60% over 2 weeks. The trend of changes in serum hCG levels until resolution is
132
demonstrated in Figure 1b. Four courses of additional MTX intramuscular injection
133
were given in Case 2 because of a sudden increase in hCG levels on day 49. Six of the 8
134
cases were successfully treated with a single local MTX injection.
136
M AN U
TE D
EP
AC C
135
SC
124
Recurrent in a patient
137
Recurrent CSP was diagnosed in one patient (Cases 4 and 6) in whom a niche
138
was observed in the anterior lower uterine segment myometrium. The patient was first
10
ACCEPTED MANUSCRIPT
diagnosed with CSP (Fig. 2a, hCG: 6897.7 mIU/ml). She was in a stable condition with
140
no symptoms after the local MTX injection; however, a residual sac was observed
141
although the patient’s hCG levels continued to decrease. Accordingly, the sac was
142
evaluated using MRI on day 83 (Fig. 2b, hCG: 6.4 mIU/ml). Thereafter, the patient was
143
observed by ultrasonography and was advised to avoid conception after the evaluation
144
of the previous uterine scar by hysteroscopy and MRI (Fig. 2c, hCG:
