Review Gynecol Obstet Invest 2014;78:141–149 DOI: 10.1159/000364869

Received: January 27, 2014 Accepted after revision: May 27, 2014 Published online: July 23, 2014

Interstitial Pregnancy: A ‘Road Map’ of Surgical Treatment Based on a Systematic Review of the Literature Gaspare Cucinella a Gloria Calagna a Stefano Rotolo a Roberta Granese b Salvatore Saitta c Gabriele Tonni d Antonio Perino a a

Department of Obstetrics and Gynecology, University Hospital ‘Paolo Giaccone’, Palermo, Departments of Obstetrics and Gynecology, and c Clinical and Experimental Medicine, University Hospital ‘G. Martino’, Messina, and d Department of Obstetrics and Gynecology, Guastalla Civil Hospital, AUSL Reggio Emilia, Guastalla, Italy b

Key Words Angular pregnancy · Cornual pregnancy · Ectopic pregnancy · Interstitial pregnancy

Abstract An electronic search concerning the surgical approach in cases of interstitial pregnancy from January 2000 to May 2013 has been carried out. Fifty three studies have been retrieved and included for statistical analysis. Conservative and radical surgical treatments in 354 cases of interstitial pregnancy are extensively described. Hemostatic techniques have been reported as well as clinical criteria for the medical approach. Surgical outcome in conservative versus radical treatment were similar. When hemostatic techniques were used, lower blood losses and lower operative times were recorded. Conversion to laparotomy involved difficulties in hemostasis and the presence of persistent or multiple adhesions. Laparoscopic injection of vasopressin into the myometrium below the cornual mass was the preferred approach. © 2014 S. Karger AG, Basel

G. Cucinella and G. Calagna are both first authors.

© 2014 S. Karger AG, Basel 0378–7346/14/0783–0141$39.50/0 E-Mail [email protected] www.karger.com/goi

Introduction

Definition Cornual (CP) and interstitial pregnancies (IP) are rare subtypes of ectopic pregnancy (EP) characterized by a gestational sac implanted in the uterine horns or into the proximal portion of the fallopian tube (a relatively thick section averaging 0.7 mm in diameter and 1–2 cm in length), as well as by a significantly greater propensity to expand before rupture as compared with the distal portion [1]. For these reasons, IP may remain asymptomatic until 7–16 weeks’ gestation, at which time tubal rupture may result in catastrophic, life-threatening maternal hemorrhage [2, 3]. CP on the other hand refers to a pregnancy that develops in a horn of a bicornuate uterus, with highly variable clinical outcomes that are particularly related to the size of the uterine horn involved [4]. However, the two terms are often used interchangeably in the medical literature and in clinical practice. Larrain et al. [5] introduced the term ‘proximal ectopic pregnancy’ to encompass these definitions. Note that angular pregnancy (AP) is the term used to identify a viable intrauterine pregnancy implanted in one of the lateral angles of the uterine cavity, medial to the utero-tubal junction, which ends in miscarriage in Dr. Gabriele Tonni, PhD, MD Department of Obstetrics and Gynecology Guastalla Civil Hospital, AUSL Reggio Emilia Via Donatori di Sangue, 1, IT–42016 Guastalla (Italy) E-Mail Tonni.Gabriele @ ausl.re.it

38.5% of cases [1]. Differentiating IP from AP may be clinically challenging, and the diagnosis is usually made at the time of surgery. In this case, AP appears as an asymmetric bulge in one of the uterine angles, which is medial to the round ligament and displaces its reflection laterally, while IP appears lateral to the round ligament itself [6, 7]. However, establishing correct pregnancy location (i.e. CP/IP vs. AP) is essential because of the different methods of clinical management and the different outcomes involved [8]. IPs are estimated to represent approximately 2–4% of all tubal pregnancies occurring in 1/2,500–5,000 of live births [9]. The incidence seems to have increased during the last two decades because of the widespread use of assisted reproductive techniques [10]. Once a diagnosis of IP is suspected, multiple factors should be considered to determine whether surgical or medical treatment, or close observation, is to be selected. These factors include clinical presentation and features of EP, gestational age at diagnosis, contraindications to medical therapy and patient preference. Clinical Diagnosis Early diagnosis may potentially allow conservative treatment for minimizing morbidity and mortality rates. Formerly, treatment options for IP mainly relied upon laparotomy. Today, the use of sensitive β-human chorionic gonadotropin (β-hCG) assay and transvaginal ultrasound permits earlier diagnosis (fig.  1), thus allowing more conservative approaches by either laparoscopy or medical treatment [5]. Different laparoscopic procedures have been proposed, but no clear consensus has been established to date. Since control of bleeding is crucial in such a condition, a wide variety of hemostatic techniques have been employed in laparoscopy, including intramyometrial injection of vasoconstricting agents and suture or device methods. A systematic review of the medical literature on laparoscopic management of IP to evaluate the efficacy and safety of different surgical procedures and of the hemostatic techniques used are reported. Subsequently, clinical recommendations for dealing with IP are suggested.

Methods A computerized search of the PubMed/Medline, EMBASE, Google Scholar and the Cochrane Controlled Trials Register databases to gather information on laparoscopic treatment of IP from January 2000 to May 2013 using the key words ‘interstitial pregnancy’, ‘cornual pregnancy’, ‘ectopic pregnancy’ and ‘laparoscopy’ was performed. All English-language articles were re-

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Fig. 1. Embryo (E) is visible using transvaginal ultrasound.

trieved. Studies published before the year 2000 were excluded, because the vast majority of papers did not provide specific intraoperative and/or postoperative information. The references sections in relevant articles were also examined for eligible studies. Data were extracted by two independent authors from the papers and were then compiled for statistical analysis. Patients were divided into two groups according to surgical treatment: conservative (C) and radical (R). Conservative treatment (C) was defined as the performance of cornuostomy, extended salpingostomy, salpingotomy and/or minicornual excision. Radical treatment (R) was defined as the performance of cornual (wedge) resection and/or salpingectomy. Cornuostomy is analogous to the linear salpingostomy technique commonly used in cases of distal EP [1]. When both conservative and radical laparoscopic management were reported within a single study, they were considered separately for the purposes of statistical analysis. Studies that were included in different case series and which contained neither a description of the surgical procedures nor differentiated between conservative and radical surgical treatments were not revised and were thus excluded from this review. The demographic and clinical variables recorded were as follows: maternal age, parity, previous EP, gestational age at diagnosis, β-hCG titer, presence of embryonic/fetal cardiac activity, size of the ectopic mass and number of ruptured pregnancies. Rate of surgical treatment, operative time, intraoperative blood loss, conversion rate (from laparoscopy to laparotomy), hospital stay, adjuvant medical therapy (methotrexate for persistent trophoblastic activity), return to theater and complications were also considered. Furthermore, reproductive outcome was also reported when available. To compare hemostatic techniques, the current analysis also took into account the injection of local vasoconstricting agents, and hemostatic suture or devices (which include encircling suture, purse-string suture, endoloop device and square suture). The common use of coagulation with bipolar forceps was not considered, as it represents a standard procedure. Data are expressed as mean values. Differences between categories (conservative vs. radical) were analyzed by χ2 test. The statistical analysis was performed with Primer (Software Program for Biostatistics Version 5.0, by Stanton A. Glantz, McGraw-Hill©). The level of statistical significance was set at p < 0.05.

Cucinella/Calagna/Rotolo/Granese/Saitta/ Tonni/Perino

Table 1. Statistical comparison of demographic and clinical data in 156 cases of C versus 198 cases of R group

Maternal age, years

Previous EP, %

Gestational age, weeks

β-hCG value, UI/l

IP size, cm

Ruptured pregnancy, %

CT group RT group

32.2 31.6

19 17

7.8 7.0

19,360 25,655

3.5 4.4

14 23

p

n.s.

0.166

n.s.

n.s.

n.s.

0.221

n.s. = Not significant.

Results

Hemostatic Treatment Hemostatic treatment was used in 183 cases, whereas 167 cases were performed without any specific hemostatic technique. Sutures and/or devices were applied in 29 cases of C versus 21 of the R group. Vasoconstrictive agents were injected locally in 66 and 59 cases in the C versus R group, respectively; both hemostatic techniques were performed in 8 cases. The mean operating time was 31 min when suture/device was the treatment of choice, 43 min following vasopressin injection and 72 min in the absence of specific hemostatic treatment (i.e. only bipolar coagulation). Mean blood loss recorded was 38 ml in case of suture/devices, 41 ml following vasopressin injection cases, and 113 ml in the absence of hemostatic treatment. Based on analysis of the results of previous observations, a clinico-diagnostic flowchart to help clinicians in the decision-making process of this life-threatening event has been developed and proposed in figure 2.

Fifty-three studies were included for statistical analysis. Among these, 27 were single case reports, and 26 were reviews of multiple cases (ranging from 2 to 53 cases). The overall estimated incidence of IP was 3.6% in 8,228 cases of EP. Statistical comparison of demographic and clinical data in 156 cases of C versus 198 cases of R group are shown in table  1. Surgical treatment and type of category, hemostatic technique, intraoperative blood loss and reproductive outcome in 354 previous reported cases of IP are described in table 2. In 4% of the cases in which the IP had ruptured, a blood transfusion was required. Embryo-fetal cardiac activity was present in 42% of all EPs. Conversion rate was 2.2 and 5.4% of C versus R group, respectively (p = 0.3). Adjuvant medical therapy was necessary in 8.4 and 7.0% of C versus R group, respectively (p  = 0.841). Return to theater was 2.6% and observed only in cases within the C group (p = 0.115). Major complications were 0.6% and only occurred in the R group (p = 0.975). When conversion to laparotomy, presence of persistent EP, return to theater and occurrence of major complications were taken into account, the overall success rate was 86.8% in the C versus 87% in the R group, respectively (n.s.). The mean operating time was 42 and 71 min, while mean intraoperative blood loss was 68 and 62 ml in the C versus R group, respectively. The mean hospital stay was 2.7 and 3.8 days in conservative and radical treatment, respectively (n.s.). Pregnancy and live birth rates were found to be similar in both groups, even though clinical observations were limited to small series of patients (26 and 13 patients in each group): specifically, the pregnancy rate was 72% in C group compared with 62% in R group while the live birth rate was higher, although not statistically significant in the R (62%) compared with the C group (48%).

The significance of EP as a public health problem has increased in the last years. Data regarding 1,777,011 pregnancies and 17,028 cases of EP recorded among women resident in Lombardy in a 15-year study period have demonstrated that the proportion of laparoscopic treatment have increased from 25.9% in 1996 to 36.3% in 2010 [60]. Laparoscopic surgery has undergone considerable development and has spread throughout the world. Nowadays, laparoscopy may be considered the ‘gold standard’ in the treatment of certain general and gynecologic diseases [61, 62] and enjoys a clinical success rate of almost 80% when C and R are grouped together. Conservative laparoscopic treatment is now the preferred surgical approach in cases of EP that are not eligible for medical treatment. Even in women with significant hemoperitoneum,

Interstitial Pregnancy: A Road Map of Surgical Treatment

Gynecol Obstet Invest 2014;78:141–149 DOI: 10.1159/000364869

Discussion

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Table 2. Surgical treatment and type of category, hemostatic technique, intraoperative blood loss and reproductive outcome in 354 previous published cases of interstitial pregnancy (IP) References

Cases, Surgical technique n

C/R Hemostatic technique

Intraoperative Note blood loss, ml

Fertility

Delivery

Moon [11]

24

cornuostomy cornuostomy cornuostomy

C C C

endoloop suture vasopressin

32 40 133

12/14 2/2 1/1

9 2 0

Bremner [12]

1

salpingotomy

C

NP

NA

Vicino [13]

1

cornual excision

R

NP

70

Osuga [14]

3

cornual resection

R

cauterization

75

twin IP: 1 case

Sagiv [15]

3

cornuostomy

C

vasopressin

NA

previous IP treated with MTX injection via LPS; vasopressin 0.5 U/ml in 1 case

2/3

1 CS – 1 VD

Vilos [16]

2

cornual resection

R

endoloop/suture

NA

1st case: endoloop 2nd: relapse (same side): suture

Mehra [17]

1

cornuostomy

C

NP

NA

β-hCG ↓ from 180 to 2 mIU/l

Pasic [18]

1

cornuostomy

C

cauterization/Surgicel

200

heterotopic pregnancy

Yoo [19]

4

cornuostomy

C

vasopressin

90

Gezer [20]

1

cornual resection

R

cauterization

NA

Chan [21]

2

cornuostomy cornual resection

C R

cauterization cauterization

NA 100

Coric [22]

1

cornual resection

R

NP

100

Huang [23]

4

cornuostomy

C

suture after resection

350

Grimbizis [24] 1

cornual resection and salpingectomy

R

NP

NA

Tulandi [2]

11

excision cornuostomy

R C

NP NP

NA NA

Takeda [25]

3

cornual resection

R

vasopressin

NA

cornuostomy

C

vasopressin

NA

Ben-Ami [26]

1

cornual resection

R

coagulation

NA

Oliver [27]

1

excision

R

NA

NA

Gunenc [28]

1

hysterotomy

C

NP

NA

hydatidiform mole – 4 courses MTX in 4 weeks

Qin [29]

1

loop ligature procedure C

NP

NA

heterotopic pregnancy

Soriano [30]

16

resection of cornua vicryl loop placement

R C

vicryl loop vicryl loop

NA NA

Ng [31]

53

wedge resection

R

vasopressin

NA

cornuostomy salpingectomy

C R

vasopressin vasopressin

NA NA

cornual resection

R

vasopressin

NA

cornuostomy

C

vasopressin

NA

cornuostomy

C

NP

NA

MacRae [32]

Pluchino [33]

144

11

1

Gynecol Obstet Invest 2014;78:141–149 DOI: 10.1159/000364869

β-hCG ↓ from 10,161 to 92 IU/l

failed aspiration 18 days before

massive hemoperitoneum, autologous blood transfusion 1 relapse of heterotopic pregnancy

conversion due to hemoperitoneum and adhesion; vasopressin 1:40

1 VD

18/53

5 CS – 5 VD

conversion due to hemoperitoneum vasopressin 1:10 vasopressin 1:10

Cucinella/Calagna/Rotolo/Granese/Saitta/ Tonni/Perino

Table 2. (continued) References

Cases, Surgical technique n

C/R Hemostatic technique

Intraoperative Note blood loss, ml

Fertility

4/6 patent tubes at HySG

Choi [34]

8

cornuotomy

C

suture/vasopressin

50

vasopressin 1:250

Moawad [35]

1

mini-cornual excision

C

vasopressin

50

vasopressin 1:10

Casadio [36]

1

conical exeresis

R

NP

200

twin pregnancy

Cheng [37]

1

cornuostomy

C

uterine vessels clamping 80

Sahoo [38]

2

endoloop cornual excision

C R

endoloop NP

NA NA

1st case: relapse 2nd case: relapse

Api [39]

1

cornuotomy

C

NP

500

failed MTX 4 days before

Yan [40]

1

cornual resection

R

vasopressin

NA

Tinelli [41]

3

incision and enucleation C

NP

160

Vignali [42]

3

removal of tubal stump/ R partial cornual resection

NP

50

Pistofidis [43]

1

excision

R

NP

NA

Walid [44]

1

cornual resection

R

vasopressin

NA

Moon [45]

20

cornuostomy cornuostomy

C C

vasopressin vasopressin

NA NA

vasopressin 1:40 vasopressin 1:40

1/3 1/3

Siow [46]

9

cornual wedge resection R

vasopressin

NA

recurrent IP: 5 cases; vasopressin 1:40

2/6

Warda [47]

1

cornuostomy

C

NA

NA

Chachan [48]

1

cornual resection

R

harmonic ace

NA

Yamamoto [49] 1

cornual wedge resection R

vasopressin

NA

Uccella [50]

1

cornual resection

R

uterine and bilateral ovarian vessels ligation

NA

Lee [51]

1

cornual resection

R

NP

NA

0/0

spontaneous rupture at LPS: uterine vessels ligation

2

heterotopic pregnancy

single port

Larrain [5]

64

cornual resection cornuostomy (21), extended salpingostomy (11)

R C

NP NP

NA NA

Hwang [52]

39

cornual resection

R

NP

NA

Lazard [53]

2

cornual resection

R

NP

125

single port

Aust [54]

1

excision

R

suture

NA

heterotopic pregnancy

EndoGIATM

Delivery

Lodhi [55]

3

cornuectomy

R

Multifire stapler

Muglu [56]

1

excision

R

NP

NA

recurrent cornual rupture at 24 and 8 weeks

Cucinella [8]

5

cornual resection

R

suture

47

3/4

3

17

cornual resection evacuation

R C

cauterization cauterization

39 5

3/3

3

Zuo [57]

Interstitial Pregnancy: A Road Map of Surgical Treatment

NA

Gynecol Obstet Invest 2014;78:141–149 DOI: 10.1159/000364869

145

Table 2. (continued) References

Cases, Surgical technique n

C/R Hemostatic technique

Intraoperative Note blood loss, ml

Cai [58]

16

cornuostomy and salpingectomy cornual resection

C

vasopressin

32.5

R

none

120

LPS after cornual perforation during aspiration

cornual resection

R

automatic stapler

100

twin IP

Akhtar [59]

1

Fertility Delivery

C/R = Conservative/radical; HySG = hysterosalpingography; LPS = laparoscopy; MTX = metothrexate; NA = not available; NP = not performed.

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Cucinella/Calagna/Rotolo/Granese/Saitta/ Tonni/Perino

laparoscopic surgery can be safely conducted by experienced laparoscopic surgeons if hemodynamic stability is achieved through perioperative management [63]. Laparoscopic treatment per se offers several advantages over laparotomy. These include lower surgical morbidity, shorter hospital stay, faster return to normal activities, and decreased healthcare cost [64]. Conservative laparoscopic treatment may potentially remove the EP while preserving uterine architecture [65]. It does not appear necessary to routinely monitor serum β-hCG levels postoperatively in women diagnosed with tubal miscarriages, in those undergoing salpingectomy for a ruptured EP or in cases of salpingectomy where there is thought to be spillage of trophoblast [66]. Expectant management of EPs that are located in the distal tube has been shown to be an acceptable approach in the presence of a spontaneously declining serum β-hCG level in an asymptomatic woman [67]. Expectant management may potentially be associated with uterine catastrophic uterine rupture leading to severe maternal morbidity, unpredictable course to resolution (even with declining β-hCG levels) and the need for prolonged hospitalization. Risk of recurrence of IP [68, 69] and risk of uterine rupture during subsequent pregnancy may be also considered. One of the potential limitations of the current review is its limitation to studies published since 2000, which was effected in order to obtain a more objective assessment of the parameters analyzed, because the use of specific laparoscopic techniques has become widespread in response to the development of the required surgical skills only in the last decade. It was observed that the main laparoscopic techniques used were cornuostomy and resection of the affected uterine horn (see table 2). Although cornuostomy is less damaging to the fallopian tubes, it seemed to be indicated only when the ectopic size was 3.5–4 cm in diameter [2]. Alternatively, cornual resection was preferred in cases of advanced gestational age and/or when ectopic size was >4 cm in diameter, a finding that may be associated with increased myometrial invasion, the greater likelihood of persistent products of EP (instead of eradication), and consequent risk of persistence [7, 32]. When cornual resection was considered, only one major complication (bowel injury due to electrocauterization) was reported in 354 laparoscopic treatments [52]. The morphology of the contralateral adnexa was described only by three authors [8, 24, 51] and was referred to as being normal. One of the potential risks of conservative treatment of EP is the persistence of pregnancy. Recently, a rare case of IP extending up to a gestational age compatible with

fetal survival was described [70]. After conservative laparoscopic surgery, the persistence of EP was reported in 5–15% of cases [71]. Second surgery, often as an emergency procedure, may be needed in these patients, with the associated unnecessary risks, hospitalization and suffering. If β-hCG levels are rising or do not decline after surgery, the use of adjuvant MTX can be an alternative to surgery in patients who complain of little or no pain [46, 71, 72]. Combined surgical and systemic MTX treatment has been successfully used in a case of abdominal pregnancy causing hemoperitoneum. Moreover, MTX may avoid the risk of excessive bleeding by surgical resection of the implantation site [73]. Nevertheless, MTX (20 mg intramuscular injection daily for 5 consecutive days) has proved to be successful in nonruptured retroperitoneal EP before operation [74]. Systemic MTX treatment is a reasonable treatment for carefully selected EP [75] with the most important prognosticator for MTX success being the initial β-hCG level [75, 76]. The success rate for systemic MTX therapy of IP was 80% when women with β-hCG levels as high as 106,634 IU/l were treated, even in the presence of fetal cardiac activity [77, 78]. Close follow-up is crucial because approximately 10–20% of patients with IP who are treated with MTX will ultimately require surgery for a rising β-hCG level, continued pain, or evidence of cornual rupture [77, 78]. An international registry of 32 cases included 8 patients who were treated with intramuscular MTX, 3 of whom required surgery because of ‘impending’ rupture or rising serum β-hCG levels [79]. Nonetheless, safety of MTX treatment for IP depends on diligent follow-up and the ability to perform expedient surgery when required. The time from treatment to complete resolution in successful cases ranges from 19 to 129 days [77, 78]. MTX therapy may be a reasonable first-line therapy for the treatment of the asymptomatic patient with an unruptured IP that are diagnosed by ultrasound early in the first trimester [79]. Surgical outcome in both C and R groups were similar. When hemostatic techniques were used, lower blood losses and lower operative times were recorded. Conversion to laparotomy involved difficulties in hemostasis (bleeding from poor visibility) and the presence of persistent and/or multiple adhesions caused by previous abdominal and/or pelvic surgery. Laparoscopic injection of vasopressin into the myometrium below the cornual mass was the preferred method. Alternatively, hemostatic sutures (i.e. pursestring suture) or a hemostatic device (i.e. the endoloop method) to tie off the affected part were also used. Vasoconstrictors are more widely used as compared with methods involving suture/device (125 vs. 50 cases, respectively)

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147

because injection of vasoconstrictors is an easier, faster technique than hemostatic suture and can be administered at no cost in comparison to the use of a hemostatic device.

Conclusion

From an analysis of the medical literature, and based on this review, several clinical conclusions can be made: medical treatment may be considered in cases of early, asymptomatic IP with β-hCG ≤4,000 IU/l and ectopic size 4 cm and the embryo is visible using transvaginal ultrasound and/or when the location of the pregnancy is dubious. To minimize the risk of persistent pregnancy, radical treatment should be performed in cases of IP size >4 cm and/or in cases of visible cardiac activity. Hemostatic techniques may aid controlling intraoperative bleeding and are recommended following surgical treatment. Potential preservation of uterine and tubal anatomy, where applicable, is of great importance and should be discussed with the patient to tailor surgical treatment and allow subsequent treatment with assisted reproductive technology.

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