Journal Name: Journal of Case Reports and Images in ... · Authors: Giancarlo Garuti, Stefania Calabrese, Lorenzo Quirino, Marco Di ... 47 to the target ... 120 assuming that its

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Early View Article: Online published version of an accepted article before publication in the

final form.

Journal Name: Journal of Case Reports and Images in Obstetrics and Gynecology

Type of Article: Case Report

Title: Hysteroscopcally-Guided Subchorionic Methotrexate Administration, a New

Technique for Termination of Cesarean Scar Pregnancy

Authors: Giancarlo Garuti, Stefania Calabrese, Lorenzo Quirino, Marco Di Mario

doi: To be assigned

Early view version published: December 2, 2015

How to cite the article: Garuti G, Calabrese S, Quirino L, Mario M D. Hysteroscopcally-

Guided Subchorionic Methotrexate Administration, a New Technique for Termination of

Cesarean Scar Pregnancy. Journal of Case Reports and Images in Obstetrics and

Gynecology. Forthcoming 2015.

Disclaimer: This manuscript has been accepted for publication. This is a pdf file of the

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TYPE OF ARTICLE: Case Report 1

2

TITLE: Hysteroscopcally-Guided Subchorionic Methotrexate Administration, a New 3

Technique for Termination of Cesarean Scar Pregnancy 4

5

AUTHORS: 6

Giancarlo Garuti1, Stefania Calabrese1, Lorenzo Quirino1, Marco Di Mario1 7

8

AFFILIATIONS: 9

1MD, Obstetrics and Gynecology Department, Public Hospital of Lodi, Via Savoia 1, 10

26900-Lodi, Italy 11

12

CORRESPONDING AUTHOR DETAILS 13

Giancarlo Garuti (MD), Obstetrics and Gynecology Department, Lodi Hospital, via 14

Savoia n° 1, 26900-Lodi, Italy 15

Phones: 39.371.372349, 39.338.2702675 16

Email: [email protected] 17

18

Short Running Title: CSP treatment by hysteroscopically-guided MTX 19

administration 20

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Guarantor of Submission : The corresponding author is the guarantor of 22

submission. 23

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TITLE: Hysteroscopcally-Guided Subchorionic Methotrexate Administration, a New 32


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ABSTRACT 35

36

Introduction 37

Cesarean Scar Pregnancy (CSP) is a rare but life-threatening condition, due to the 38

risk of uterine rupture or for the development of placenta previa/accreta. The 39

mainstay of management to spare fertility is early diagnosis and pregnancy 40

termination. Although several conservative treatments have been experienced, no 41

consensus on the best therapeutic approach is currently shared. The medical 42

therapy for CSP termination is based on systemic or local Methotrexate (MTX) 43

administration. Hysteroscopy allows the precise visualization of placental 44

implantation and it can be used to drive MTX injection selectively within the 45

intervillous placental spaces. This procedure increases drug concentration delivered 46

to the target tissue, potentially improving its therapeutic index. 47

48

Case Report 49

A 36-years-old patient with history of cesarean section was admitted to our 50

Department with a diagnosis of viable 7th weeks CSP. The patient gave her consent 51

to pregnancy termination by a hysteroscopically-guided MTX administration within 52

the cervico-isthmic placental implantation site, followed by its resectoscopic removal. 53

In an office setting, 80 mg of MTX were injected through a needle adaptable to the 5-54

Fr operative channel of hysteroscope, under the chorionic membrane of placental 55

implantation site. The duration of the procedure took 3 minutes and it resulted easy, 56

painless and uneventful. An early embryo demise was obtained; the human 57

Chorionic Gonadotropin-beta subunit (beta-hCG) serum trend showed a rapid 58

pregnancy termination and no patient complaints were recorded. After 28 days, a 59

resectoscopic removal of the gestational sac and placenta was safely accomplished. 60

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Conclusion 64

Selective hysteroscopic administration of MTX within intervillous spaces of the 65

ectopic placental implantation is effective and it can be considered for CSP 66

termination. 67

68

Keywords: Cesarean Scar Pregnancy, Methotrexate, Hysteroscopy, Ectopic 69

pregnancy, Office hysteroscopy, Resectoscopy 70

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TITLE: Hysteroscopically-Guided Subchorionic Methotrexate Administration, a New 95


97

INTRODUCTION 98

Cesarean Scar Pregnancy (CSP) is a rare but potentially life-threatening condition, 99

caused by a placental implantation within a retracted scar of cervico-isthmic uterine 100

junction, deriving from a previous Cesarean Delivery (CD) [1]. Firstly described in 101

1978, CSP was more frequently reported in the last decades, due to the increasing 102

rates of CD. In patients with history of CD, the CSP incidence varies from 1:500 to 103

1:1500 [1, 2, 3]. If untreated, CSP exposes the patient to the risk of uterine rupture 104

and hemorrhage during the first pregnancy months or to the development of a 105

placenta previa/accreta near pregnancy termination [4, 5]. The mainstay 106

management aimed to spare fertility and to reduce maternal morbidity, is an early 107

diagnosis and pregnancy termination [6]. The current treatment of CSP is based on 108

case reports and small case series, with more than 30 therapeutic options described 109

[1, 3]. Even if recent studies compared different managements of CSP, no guidelines 110

have been given until now [7, 8]. The dihydrofolate-reductase (DHFR) enzyme 111

inhibitor, Methotrexate (MTX), administered by systemic, loco-regional or 112

intragestational-sac routes, is the cornerstone of medical therapy, followed or not by 113

surgical removal [1, 3, 6, 9]. Due to the reversible and competitive nature of MTX 114

binding to DHFR, drug concentration within target-cell is a major determinant of 115

cytotoxicity [10]. Among the surgical techniques suggested for CSP removal (uterine 116

dilatation and curettage, laparotomy, laparoscopy, vaginal excision and 117

hysteroscopy), hysteroscopy resulted to be effective and showed a low morbidity-118

rate [3, 11, 12]. Based on the knowledge of MTX pharmacokinetics [10] and 119

assuming that its selective administration within the placental intervillous spaces can 120

enhance its cytocidal effects, we report the case of a patient with a viable CSP 121

managed by hysteroscopically-guided sub-chorionic MTX administration, delivered at 122

the placental implantation. The procedure was completed by the resectoscopic 123

removal of the terminated pregnancy. 124

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CASE REPORT 127

In April, 2015, a 36-years-old woman with a positive urine pregnancy test and 8 128

weeks of amenorrhea, was admitted to our Department due to pelvic cramping pain 129

and ultrasound evidences of a viable CSP. No gynecological complaints were 130

recorded; her past obstetric history revealed a CD due to breech presentation and a 131

vaginal delivery 11 and 3 years before, respectively. Pelvic examination detected a 132

movable uterus with a smooth, painless and soft mass measuring about 2.5 cm, 133

arising from the cervico-isthmic area and expanding toward the bladder base. Serum 134

beta-subunit of human Chorionic Gonadotropin (beta-hCG) concentration was of 135

18000 mUI/ml. Transvaginal Ultrasonography revealed empty endometrial cavity and 136

empty cervical canal, the gestational sac measuring 17x14 mm was embedded 137

deep within the uterine wall at the level of the cervico-isthmic junction, bulging 138

ventrally towards the bladder (Figure 1). It contained an embryonic pole showing 139

heart activity and measuring 4.6 mm, corresponding to 7th pregnancy weeks (Figure 140

2). The measurement of myometrial thickness between gestational sac and bladder 141

base was 1.5 mm. Color-Doppler and spectral analysis showed a high blood-flow 142

with low resistances around the cervico-isthmic area. Based on these findings and 143

according to published data, a diagnosis of viable CSP was made [6]. With the 144

assumption that pregnancy termination was indicated and no guidelines were 145

provided to treat CSP, we proposed to the patient local MTX administration through 146

hysteroscopy guidance, followed by the resectoscopic removal of pregnancy. The 147

patient signed an informed consent and an informative chart about the risk of 148

hemorrhage. The first procedure was carried out in an office setting. By the 149

vaginoscopic technique without analgesia or anesthesia, a double-flow 5-mm 150

hysteroscope (Karl Storz, Tuttlingen, Germany) was used to administer 50 mg/m2 of 151

MTX in 2 cc of saline, through a 17-gauge needle adaptable to the 5Fr operative 152

channel. Continuous saline flow was delivered at working pressure set at 60 mm/Hg 153

by an electronic irrigation-suction device. After the visual confirmation of a ventral 154

uterine pregnancy implantation within the cesarean scar, we entered the chorionic 155

sac by using hysteroscopy scissors, opening sequentially capsular decidua, chorion 156

leave and chorionic membrane. After needle insertion within the operative channel, 157

MTX has been injected 2-3 mm deep the chorionic membrane at the level of anterior 158


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implantation of the placenta, i.e. directly within the placental intervillous spaces 159

(Figure 3). The procedure lasted 3 minutes, it was painless, and the patient was 160

discharged after 2 hours of uneventful observation. Clinical, sonographic and beta-161

hCG monitoring were recommended after 4, 7, 14 and 21 days from MTX 162

administration. During the follow-up period a light vaginal bleeding was the only 163

complaint recorded. No embryonic heart activity was found after 4 days while the 164

persistence of gestational sac within the cesarean scar was found until the 21th day. 165

Beta-hCG increased to 29000 mUI/ml after 4 days, decreasing to 18000 mUI/ml, 166

5000 mUI/ml and 3000 mUI/ml after 7, 14 and 21 days, respectively. After 28 days, 167

observing a further drop of beta-hCG to 500 mUI/ml, the hysteroscopy removal of 168

CSP was planned. The intervention was carried-out under conscious sedation, using 169

a 27Fr resectoscope armed with a 4mm bipolar loop (Versapoint Bipolar System, 170

Gynecare, Ethicon Inc., Menlo Park, CA, USA) set at 100w power. Due to the soft 171

consistency of the cervix, its dilatation was avoided. Saline solution was delivered as 172

uterine distension medium at 60 mm/Hg working pressure. After CSP identification 173

(Figure 4 and 5) the intervention was almost entirely managed by using the cold loop 174

to separate villous trophoblast from the cervico-isthmic niche, following a loose 175

cleavage plane maintained between tissues (Figure 6). The application of 176

coagulating current for bleeding control was not necessary. The intervention lasted 8 177

minutes, an uneventful recovery followed and the patient was discharged on first 178

post-operative day. Villous trophoblast and embryonic tissues were found at 179

pathology assessment. After intervention, beta-hCG decreased to a non-pregnancy 180

range after 15 days. The first menstrual period was recorded after 32 days and no 181

abnormalities were found both at physical and ultrasound examination after 40 days 182

from intervention. 183

184

DISCUSSION 185

The main metabolic pathway leading to MTX cytotoxicity is represented by a tight but 186

reversible inhibition of DHFR. The DHFR enzyme plays a key role in maintaining 187

intracellular folate homeosthasis and it is responsible for the conversion of 188

dihydrofolate substrates to tetrahydrofolates. Tetrahydrofolates play an essential role 189

in synthesis of DNA and RNA precursors such as purine and pirimidine rings. With 190


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respect to natural dihydrofolates substrates, the competitive reversible nature of the 191

MTX binding to DHFR, leads to two critical determinants of cytotoxicity: drug cell 192

concentration and duration of drug cell exposure [10]. These pharmacokinetic 193

principles, combined with the short drug half-life and the poor blood supply to scar 194

tissue surrounding a CSP, are the main causes of the low therapeutic index 195

associated with systemic MTX administration [1, 3, 10]. Driving MTX directly to the 196

target tissue may lead to an excess of free drug cell concentration required to fully 197

inhibit the enzyme, potentially enhancing its clinical effectiveness. Accordingly, 198

ultrasound-guided MTX administration within the gestational sac showed an 199

improvement of clinical results with respect to systemic MTX and it is now 200

considered the first choice for CSP conservative treatment [3, 4, 13, 14]. However, 201

as reported in 26%-39% of cases [13, 14] pregnancy absorption takes long time and 202

possible failures require additional treatments. The target tissue of MTX is the villous 203

trophoblast of the blastocyst implantation site, leading to the placental differentiation 204

within the cesarean scar niche. The placental growth inhibition leads to pregnancy 205

termination and it represents the key measure to reduce the risks of uterine wall 206

rupture and hemorrhage. Previous reports related to hystero-embryoscopy settings 207

showed that miniaturized hysteroscopes enable an easy access to the gestational 208

sac [15]. Based on these assumptions, we believed that MTX administration in 209

subchorionic space at placental implantation site (i.e. directly within the intervillous 210

spaces), may optimize the cytotoxicity, enhancing the drug concentrations delivered 211

to the target tissues. In the case here presented, hysteroscopy easily assessed the 212

CSP anatomy and it allowed a selective MTX administration to the underlying villous 213

trophoblast by identifying the placental implantation site. With regard to hysteroscopy 214

guidance, ultrasound techniques of intra-gestational and/or peri-gestational sac MTX 215

administration may be less specific in driving selectively the drug. This is mainly due 216

to the possible difficulty in positioning precisely the needle tip within the placental 217

implantation site [3, 13]. Subchorionic hysteroscopic MTX administration resulted 218

technically easy, quick, painless, safe and effective; moreover, it can be 219

accomplished as outpatient procedure. The effectiveness of this technique was 220

demonstrated by the early loss of embryonic cardiac activity and the early increase 221

of beta-hCG (due to trophoblast cells necrosis) followed by its fast and progressive 222


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fall [6, 13]. In current literature, only one report describes a hysteroscopy-guided 223

MTX administration for treatment of viable CSP. After systemic MTX failure and 224

under hysteroscopy guidance the Authors injected MTX within the gestational sac, 225

obtaining an embryo’s demise but observing a persistent increase of beta-hCG 226

levels [16]. Although no guidelines provided preferential options in CSP 227

management, the recent literature suggests a combined sequential approach. The 228

first measure is aimed to pregnancy termination by MTX administration or by acute 229

reduction of placental blood supply by Uterine Artery Embolization. Subsequently, an 230

appropriate timing for surgical pregnancy removal is advised [7, 8, 9, 17]. Based on 231

literature data, the hysteroscopic CSP removal appears to be the safest surgical 232

therapy. Hysteroscopy allows a precise assessment of pregnancy topography and 233

placental implantation, a bleeding control by use of coagulating current and a 234

selective pregnancy removal under vision [3, 8, 11, 12, 16, 17]. As previously 235

reported, based on the significant decrease of beta-hCG levels after MTX 236

administration and demonstrating the pregnancy termination, we safely removed the 237

CSP by resectoscope, accordingly [11, 12, 16]. 238

239

CONCLUSION 240

A successful and never described technique to manage a viable CSP by the 241

selective administration of MTX under hysteroscopy guidance, within the placental 242

intervillous space of the ectopic implantation, has been reported. An eye-driven MTX 243

administration within the target tissue, leading to high drug cell concentrations, may 244

optimize its cytotoxicity. When hysteroscopy facilities are available, this technique 245

can be considered as an option for CSP termination. 246

247

CONFLICT OF INTEREST 248

All Authors declare no conflict of interest 249

250

AUTHOR’S CONTRIBUTIONS 251

Giancarlo Garuti (MD) 252

Group 1- Conception and design, acquisition of data, analysis and interpretation of 253

data 254


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Group 2- Drafting the article, critical revision of the article 255

256

Stefania Calabrese (MD) 257


data 259

260

Lorenzo Quirino (MD) 261


data 263

264

Marco Di Mario (MD) 265

Group 3- Final approval of the version to be published 266

267

ACKNOWLEDGEMENTS 268

We thank Mrs.Elena Bosoni for language revision of the Manuscript 269

270

REFERENCES 271

1. Ash A, Smith A, Maxwell D. Cesarean scar pregnancy. BJOG 2007;114:253-263 272

2. Larsen JV, Solomon MH. Pregnancy in a uterine scar sacculus: an unusual 273

cause of postabortal haemorrhage. S Afr Med J 1978;53:142-143 274

3. Timor-Tritsch IE, Monteagudo A. Unforeseen consequences of the increasing 275

rate of cesarean deliveries: early placenta accreta and cesarean scar pregnancy. 276

A review. Am J Obstet Gynecol 2012;207:14-29 277

4. Timor-Tritsch IE, Khatib N, Monteagudo A, Ramos J, Berg R, Kovacs S. 278

Cesarean scar pregnancies: experience of 60 cases. J Ultrasound Med 279

2015;34:601-610 280

5. Jurkovic D. Cesarean section scar ectopic pregnancy: a new problem or new 281

name for an old one? Aus J Ultrasound Med 2009;12:22-23 282

6. Timor-Tritsch IE, Monteagudo A, Santos R, Tsymbal T, Pineda G, Arslan AA. The 283

diagnosis, treatment, and follow-up of cesarean scar pregnancy. Am J Obstet 284

Gynecol 2012;207:44e1-13 285


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7. Gao L, Huang Z, Gao J, Mai H, Zhang Y, Wang X. Uterine artery embolization 286

followed by dilatation and curettage within 24 hours compared with systemic 287

methotrexate for cesarean scar pregnancy. Int J Gynaecol Obstet 2014;127:147-288

151 289

8. Li YR, Xiao SS, Wan YJ, Xue M. Analysis of the efficacy of three treatment 290

options for cesarean scar pregnancy management. J Obstet Gynaecol Res 291

2014;11:2146-2151 292

9. Huang Y, Li Y, Xi R, Chen Z, Ying D, Li Z, Yang Y. An application of uterine 293

artery chemoembolization in treating cesarean scar pregnancy. Int J Clin Exp 294

Med 2015;8:2570-2577 295

10. Stika CS. Methotrexate: the pharmacology behind medical treatment for ectopic 296

pregnancy. Clin Obstet Gynecol 2012;55:433-439 297

11. Yang Q, Piao S, Wang G, Wang Y, Liu C. Hysteroscopic surgery of ectopic 298

pregnancy in the cesarean section scar. J Minim Inv Gynecol 2009;16:432-436 299

12. Deans R, Abbott J. Hysteroscopic management of cesarean scar ectopic 300

pregnancy. Fertil Steril 2010;93:1735-1740 301

13. Cok T, Kalayci H, Ozdemir H, Haydardedeoglu B, Parlakgumus AH, Tarim E. 302

Transvaginal ultrasound-guided local methotrexate administration as the first-line 303

treatment for cesarean scar pregnancy. Follow-up of 18 cases. J Obstet Gynecol 304

Res 2015;41:803-808 305

14. Cheung VY. Local methotrexate injection as first-line treatment for cesarean scar 306

pregnancy: review of the literature. J Minim Invasive Gynecol 2015; 22: 753-758 307

15. Ferro J, Martinez C, Love C, Pellicer A, Remohi J, Serra V. Improved accuracy of 308

hysteroembrioscopic biopsies for karyotyping early missed abortions. Fertil Steril 309

2003;80:1260-1264 310

16. Di Spiezio Sardo A, Alviggi C, Zizolfi B, Spinelli M, De Rosa P, De Placido G, 311

Nappi C. Cervico-isthmic pregnancy successfully treated with bipolar resection 312

following methotrexate administration: case report and literature review. Reprod 313

Biomed Online 2013;26:99-103 314

17. Wu X, Xue X, Wu X, Lin R, Yuan Y, Wang Q, Xu C, He Y, Hu W. Combined 315

laparoscopy and hysteroscopy vs uterine curettage in the uterine artery 316


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embolization-based management of cesarean scar pregnancy: a cohort study. Int 317

J Exp Med 2014;7:2793-2803 318

319

FIGURE LEGENDS 320

Figure 1: Gray Scale Transvaginal Sonography showing a 7 weeks gestational sac 321

embedded in the anterior wall of uterine cervico-isthmic junction. Both endometrium 322

and cervical canal are empty 323

324

Figure 2: Gray Scale Transvaginal Sonography showing a viable embryo and yolk 325

sac within the CSP 326

327

Figure 3: Office intervention. Few seconds before MTX injection, with the 328

hysteroscope positioned within the gestational sac we show the tip of the needle 329

(white arrow) inserted few millimeters under the ventral aspect of chorionic 330

membrane of the CSP, i.e. within the intervillous spaces of placental implantation 331

site 332

333

Figure 4: Resectoscopic removal of CSP. A panoramic view of uterine cavity 334

showing an empty endometrial cavity, the upper limit of cervico-isthmic niche and a 335

cranial portion of the CSP capsular decidua (at the top of Figure, on the left, 336

indicated by the arrow) 337

338

Figure 5: Resectoscopic CSP removal. We show the caudal extension of gestational 339

sac demonstrating the break of the capsular decidua resulting from the previous 340

office intervention 341

342

Figure 6: Resectoscopic CSP removal. Using the 4 mm bipolar loop, a cold 343

separation of villous trophoblast from the cervico-isthmic placental bed is in progress 344

345

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FIGURES 349

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Figure 1: Gray Scale Transvaginal Sonography showing a 7 weeks gestational sac 353

embedded in the anterior wall of uterine cervico-isthmic junction. Both endometrium 354

and cervical canal are empty 355

356

357

358

Figure 2: Gray Scale Transvaginal Sonography showing a viable embryo and yolk 359

sac within the CSP 360


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361

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Figure 3: Office intervention. Few seconds before MTX injection, with the 363

hysteroscope positioned within the gestational sac we show the tip of the needle 364

(arrow) inserted few millimeters under the ventral aspect of chorionic membrane of 365

the CSP, i.e. within the intervillous spaces of placental implantation site 366

367

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Figure 4: Resectoscopic removal of CSP. A panoramic view of uterine cavity 376

showing an empty endometrial cavity, the upper limit of cervico-isthmic niche and the 377

cranial portion of the CSP capsular decidua (at the top of Figure, on the left, 378

indicated by the arrow) 379

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396

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Figure 5: Resectoscopic CSP removal. We show the caudal extension of gestational 398

sac demonstrating the break of the capsular decidua resulting from the previous 399

office intervention 400

401

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403

Figure 6: Resectoscopic CSP removal. Using the 4 mm bipolar loop, a cold 404

separation of villous trophoblast from the cervico-isthmic placental bed is in progress 405

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Journal Name: Journal of Case Reports and Images in ... · Authors: Giancarlo Garuti, Stefania Calabrese, Lorenzo Quirino, Marco Di ... 47 to the target ... 120 assuming that its