Interstitial Pregnancy after Ipsilateral Salpingectomy: Analysis of 46 Cases and a Literature Review

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Interstitial Pregnancy Following Ipsilateral Salpingectomy: Analysis of 46 Cases and Literature Review Meng Yi Gao MD , Hua Zhu PhD , Fei Yun Zheng MD PII: DOI: Reference:

S1553-4650(19)31237-3 https://doi.org/10.1016/j.jmig.2019.04.029 JMIG 3966

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The Journal of Minimally Invasive Gynecology

Received date: Revised date: Accepted date:

4 January 2019 9 April 2019 29 April 2019

Please cite this article as: Meng Yi Gao MD , Hua Zhu PhD , Fei Yun Zheng MD , Interstitial Pregnancy Following Ipsilateral Salpingectomy: Analysis of 46 Cases and Literature Review, The Journal of Minimally Invasive Gynecology (2019), doi: https://doi.org/10.1016/j.jmig.2019.04.029

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Original Article Interstitial Pregnancy Following Ipsilateral Salpingectomy: Analysis of 46 Cases and Literature Review Meng Yi Gao, MD, Hua Zhu, PhD, and Fei Yun Zheng, MD* From the Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China Corresponding author: Feiyun Zheng, MD, Department of Obstetrics & Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. E-mail: [email protected], Telephone: 8613706661062 Facsimile: 86-0577-55578033. Disclosure statement: The authors declare that they have no conflicts of interest and nothing to disclose. Precis Interstitial pregnancy is associated with ipsilateral salpingectomy, and laparoscopic cornuostomy could be selected more widely for patients who wish to preserve fertility. ABSTRACT Study Objective: To investigate the relationship between previous ipsilateral salpingectomy and interstitial pregnancy, and report on our experience of laparoscopic cornuostomy for interstitial pregnancy. Design: A single-center, retrospective review. Setting: A university-based hospital. Patients: Patients who had a previous ipsilateral salpingectomy diagnosed with interstitial pregnancy and treated from July 2010 to September 2018. Interventions: Laparoscopy or laparotomy as treatment for interstitial pregnancy following ipsilateral salpingectomy. Measurement and Main Results: 414 cases of interstitial pregnancy were identified of which 46 (11.1%) were following ipsilateral salpingectomy; 20 of the 46 patients (43.5%) were pregnant by in vitro fertilization and embryo transfer. Ipsilateral

salpingectomy was the result of ectopic pregnancy in 40 patients, hydrosalpinx in 5 patients, and torsion of ovarian tumor in 1 patient. The laparoscopic approach was used to treat 78.3% of patients with history of previous salpingectomy. Patients who underwent previous ipsilateral salpingectomy by laparoscopy had a shorter interval from salpingectomy to interstitial pregnancy (24 months vs. 60 months, p=.038) compared with patients who had ipsilateral salpingectomy managed by laparotomy. Laparoscopic cornuostomy was carried out in 38 cases (82.6%); 12 had fetal cardiac activity, 15 had ruptured, and 16 used prophylactic methotrexate (MTX) intraoperatively. Median size of the ectopic mass was 2.5 cm (1.0–5.0 cm). At the time of laparoscopic cornuostomy, more cases of interstitial pregnancies with intact ectopic mass cases were administered prophylactic MTX (81.3% vs. 45.5%, p =.043). Only 1 patient with a ruptured ectopic mass, high preoperative human chorionic gonadotropin levels, and not administered prophylactic MTX experienced persistent ectopic pregnancy (PEP) . Conclusions: Patients with history of ipsilateral salpingectomy should be cautioned regarding the possibility of interstitial pregnancy. Laparoscopic cornuostomy appears to be an appropriate treatment for interstitial pregnancy in patients wishing to preserve fertility, and the use of concomitant prophylactic MTX may reduce the risk of PEP, especially in patients with ruptured masses and high human gonadotropin levels.

Keywords: Cornuostomy; Laparoscopy; Laparotomy; Methotrexate Introduction Interstitial pregnancy refers to an ectopic pregnancy that is implanted in the tubal segment traversing the muscular wall of the uterus [1], including cases of development of trophoblastic tissue in the tubal stump following salpingectomy [2]. Salpingectomy is the most frequently performed procedure for tubal pregnancy to avoid recurrence of tubal pregnancy on the same side [3]. It is also typically used in

the cases of hydrosalpinx in infertile females scheduled for assisted reproductive technologies [4]. Patients diagnosed with pyosalpinx or isolated fallopian tube torsion can be treated by salpingectomy as well [5]. However, an increasing frequency of interstitial pregnancy following ipsilateral salpingectomy has been reported [6–9], some after in vitro fertilization (IVF) and embryo transfer (ET) [8,9]. Therefore, the aim of the present retrospective study was to investigate the relationship between previous ipsilateral salpingectomy and interstitial pregnancy, possible prevention strategies, and to report on our experience of laparoscopic cornuostomy for interstitial pregnancy. Materials and Methods A retrospective review of medical records was completed of all cases of interstitial pregnancies from July 2010 to September 2018. Four hundred and fourteen patients were diagnosed with interstitial pregnancy; 46 cases (11.1%) of interstitial pregnancies occurred following ipsilateral salpingectomy with histological confirmation, including 26 spontaneous interstitial pregnancies and 20 induced by IVF/ET. The study was approved by the Medical Ethical Committee of the First Affiliated Hospital of Wenzhou Medical University in Zhejiang, China. Laparoscopic cornuostomy was carried out in 38 patients and cornual resection in 8 patients. Intraoperative hemorrhage was controlled by vasopressin (6 international units [IU] diluted in 10 mL normal saline solution) injected into the fundus of the uterus, suturing, and bipolar coagulation. For 16 patients who received laparoscopic cornuostomy, methotrexate (MTX) (50 mg diluted in 2–3 mL distilled water) was injected into the myometrium of the uterocornual region after cornuostomy to prevent persistent ectopic pregnancy (PEP) [10]. Variables selected for analysis included age, body mass index, gravidity, parity, previous ectopic pregnancy, detail surgical history of the previous ipsilateral salpingectomy, the interval from salpingectomy to interstitial pregnancy, symptoms, gestational age at diagnosis, size and fetal cardiac activity of ectopic mass, rupture,

surgical procedures, and outcomes. The statistical analyses were performed using Statistical Package for the Social Sciences (SPSS ver. 17.0; IBM, Armonk, NY). T-tests and Mann-Whitney U-test were used to compare continuous variables. Chi-square test was used for categorical variables. Values of p < .05 denoted significant differences. Results The characteristics of the study population are summarized in Tables 1 and 2. The mean age was 30.7 years (range 19–45 years). A previous laparoscopic ipsilateral salpingectomy was carried out in 36 patients (78.3%), and 10 patients (21.7%) were managed by previous laparotomy. The reason for previous ipsilateral salpingectomy included ectopic pregnancy in 40 cases (87.0%), hydrosalpinx in 5 cases, and torsion of ovarian tumor in 1 case (2.2%). The interval from ipsilateral salpingectomy to interstitial pregnancy varied from 2 to 204 months (median 24 months). Patients who underwent previous laparoscopic ipsilateral salpingectomy had a shorter interval from salpingectomy to interstitial pregnancy compared with patients managed by laparotomy (24 months vs. 60 months, p =.038). There was no significant difference in patient age, rate of interstitial pregnancy induced by IVF/ET, intraoperative pelvic adhesion, and rupture of ectopic mass. The median gestational age at diagnosis was 46.5 days (range, 35–93 days). Laparoscopic cornuostomy was carried out in 38 patients (82.6%); the characteristics of the patients are summarized in Table 3. Median size of the ectopic mass was 2.5 cm (range, 1.0–5.0 cm). Twelve patients (31.6%) had fetal cardiac activity, 15 patients (38.5%) were found with ruptured masses at the time of surgery, and 3 patients (7.9%) had intraperitoneal bleeding > 1,000 mL and required a blood transfusion. Median operative time was 55 minutes (range, 25–90 minutes). Concomitant prophylactic MTX was administered in 16 patients (42.1%) who underwent laparoscopic cornuostomy. More cases of interstitial pregnancies with intact ectopic mass were administered prophylactic MTX at the time of the surgery (81.3% vs. 45.5, p =.043;

Table 4). No significant differences were detected in gestational age, serum human chorionic gonadotropin (hCG), rate of fetal cardiac activity, and size of ectopic mass between patients treated with and without prophylactic MTX. Persistent ectopic pregnancy was detected in 1 patient with ruptured ectopic mass, hCG of 42,248 IU/L, and without prophylactic MTX. Discussion Interstitial pregnancy accounts for 2% to 4% of all tubal gestations [1]. Predisposing factors of interstitial pregnancy include history of previous ectopic pregnancy, in vitro fertilization, and ipsilateral salpingectomy [8,9,11]. Interstitial pregnancy wasreport ed in 4% of ET cycles, and 76.3% of the cases were associated with previous salpingectomy [9]. In the current study, interstitial pregnancy following ipsilateral salpingectomy accounted for 11.1% of all interstitial pregnancies, including 43.5% cases induced by IVF/ET. Approximately 78% of patients with previous ipsilateral salpingectomy underwent laparoscopy in the current study. Patients who had previous ipsilateral salpingectomy managed by laparoscopy experienced a shorter interval from salpingectomy to interstitial pregnancy, a median of 24 months. In some studies of interstitial pregnancy following laparoscopic ipsilateral/bilateral salpingectomy, the interval varied from 3 to 12 months [6,8,11,12]. In addition, no significant differences were found regarding fertility and reproductive performance following salpingectomy between ectopic pregnancy treated by laparoscopy and laparotomy [13,14]. The incidence of interstitial pregnancy after laparoscopic salpingectomy was reported to be 7.24% (27/373) in pregnant patients who underwent IVF [15]. In traditional salpingectomy by laparotomy, the end of the proximal tubal stump is buried within the mesosalpinx or myometrium of the uterus for peritonealization [16]. However, during laparoscopic procedures, the fallopian tube is removed by bipolar electrocoagulation and scissors without suture and peritonealization owing to the possibility of reduced blood supply and delayed healing at the uterocornual region,

possibly inducing a higher frequency of recanalisation or fistula at the tubal stump [17]. Recanalization may allow the ovum to pass on the damaged side into the tubal remnant and result in fertilization and implantation within the interstitial portion of the tube [18,19]. In addition, Ota et al states the possibility of external transperitoneal transmigration of the fertilized egg from serosa to the interstitial portion of the tube prior to local embryonic nidation [20] making it possible that the fertilized egg enters the recanalization part of the tubal stump, resulting in interstitial pregnancy. In addition, aseptic inflammation associated with electrocoagulation-induced injury causes upregulation of inflammatory cytokines and may promote embryo adhesion and invasion in the uterine horn [21]. To reduce the chances for interstitial pregnancy, using less electrocoagulation may reduce the extent of thermal tissue damage, and simple salpingectomy with careful peritonealization extirpating the tube may strengthen the tubal stump. The uterotubal junction can be sutured before removing the proximal part of the fallopian tube to reduce the formation of recanalization or fistulae, and cornual suture at the time of salpingectomy reduces the rate of subsequent interstitial pregnancies [15]. Cornual resection by laparotomy or hysterectomy were historically used as treatment for interstitial pregnancy [1]. Laparoscopic cornual resection was even reported as a feasible approach to treat heterotopic cornual pregnancy with favorable surgical and obstetric outcomes [22]. Laparoscopic cornuostomy has been advocated to better preserve the uterine integrity for future fertility by removing gestational tissue without removing the surrounding myometrium. With no published treatment guidelines for interstitial pregnancy, the radical operation was recommended to be performed when the ectopic mass is >4 cm and/or in cases of visible cardiac activity from the ectopic mass [23]. In the current study, laparoscopic cornuostomy was performed in 82.6% of the surgeries; the largest ectopic mass was 5 cm, and 12 of the gestational masses had visible cardiac activity. Watanabe et al reported successful treatment by laparoscopic cornuotomy of 3 interstitial pregnancies with gestational

masses  50 mm and fetal heartbeats [10]. A larger mass of 60-mm treated by laparoscopic cornuostomy was also reported by MacRae et al with no complications [24]. Persistent ectopic pregnancy is a major complication of the conservative surgical treatment of interstitial pregnancy. Wang et al reported that PEP occurred in 27.3% of ruptured cases after laparoscopic cornuostomy and suggested better use of cornuostomy in interstitial pregnancies with intact ectopic masses [9]. The median level of preoperative hCG in the patients with ruptures was 36,343 IU/L. Watanabe et al reported that none of their cases developed PEP when local MTX injections were used at the time of laparoscopic cornuotomy, including 2 cases of rupture with high preoperative hCG levels [10]. In the current study, prophylactic MTX was used in 42.1% of the laparoscopic cornuostomy cases; more cases of intact ectopic mass were administered prophylactic MTX because invasive microscopic trophoblasts may not be completely removed by cornuostomy under macroscopic observation. Only 1 case of PEP was detected in the current study following ruptured ectopic mass, high hCG levels of 42,248 IU/L, and no treatment with prophylactic MTX. Trophoblastic tissues may be deeply infiltrated in the myometrium in ruptured cases with high preoperative hCG levels. Conclusion In the current study the history of laparoscopic salpingectomy resulted in a shorter interval from salpingectomy to interstitial pregnancy when compared to laparotomy. Careful peritonealization and cornual suture are suggested at the time of laparoscopic salpingectomy to reduce the rate of subsequent ipsilateral interstitial pregnancies. Laparoscopic cornuostomy is suggested for larger interstitial pregnancies with visible cardiac activity in select cases when the patient wishes to preserve fertility. The use of concomitant prophylactic MTX may reduce the risk of PEP, especially in patients who have experienced ruptures and high preoperative hCG levels.

Acknowledgements We thank Xue Qing Wu and Elsevier (http://webshop.elsevier.com) for English language editing of this manuscript.

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Table 1 Patient characteristics Patients Characteristics

(n = 46)

Mean age, y (range)

30.7 (19–45)

Mean body mass index, kg/m2 (range)

21.4 (16.8–26.6)

Abortion, n (%)

28 (60.9)

Reason for ipsilateral salpingectomy, n (%)

0

Ectopic pregnancy

40 (87.0)

Hydrosalpinx

5 (10.9)

Torsion of ovarian tumor

1 (2.1)

Median interval from salpingectomy to interstitial pregnancy, months (range)

24 (2–204)

Clinical manifestations, n (%) Asymptomatic

22 (47.8)

Abdominal pain

18 (39.1)

Vaginal bleeding

11 (23.9)

Median gestational age at diagnosis, days (range)

45 (35–93)

Intraoperative pelvic adhesion, n (%)

24 (52.2)

Surgery procedure, n (%) Laparoscopic cornuostomy

38 (82.6)

Laparoscopic cornual resection

8 (17.4)

ET = embryo transfer; IVF = in vitro fertilization.

Table 2 Patients who underwent previous ipsilateral salpingectomy managed by laparoscopy or laparotomy p

Laparoscopy

Laparotomy

Patients, n

36

10

Mean age, years (range)

30.5 (23–38)

31.5 (19–45)

.718

Pregnancy by IVF/ET, n (%)

17 (47.2)

3 (30.0)

.541

24 (2–204)

60 (2–156)

.038

Intraoperative pelvic adhesion, n (%)

17 (47.2)

7 (70.0)

.359

Rupture of ectopic mass, n (%)

14 (38.9)

1 (10.0)

.179

Median interval from salpingectomy to interstitial pregnancy, months (range)

Value

ET = embryo transfer; IVF = in vitro fertilization.

Table 3 Characteristics of patients who underwent laparoscopic cornuostomy Patients Characteristics

(n = 38)

Mean age, years (range)

30.5 (23–38)

Mean preoperative hCG, IU/L (range)

19,122 (1,301–141,085)

Fetal cardiac activity, n (%)

12 (31.6)

Median size of ectopic mass, cm (range)

2.5 (1.0–5.0)

Median gestational age at diagnosis, days (range)

46.5 (35–93)

Median operation time, minutes (range)

55 (25–90)

Median change in hemoglobin, g/dL (range)

16.5 (1–32)

hCG = human chorionic gonadotropin; IU = international units.

Table 4 Laparoscopic cornuostomy with and without prophylactic MTX With prophylactic

Without

p

MTX

prophylactic MTX

Value

Patients, n

16

22

Mean age, years (range)

31.3 (23–38)

29.5 (23–35)

Mean preoperative hCG, IU/L (range)

19,718

17,314.5

(4,313–141,085)

(1,301–131,687)

5 (31.3)

7 (31.8)

.626

2.0 (1.0–4.0)

.171

47.5 (39–93)

44.5 (35–60)

.258

13 (81.3)

10 (45.5)

.043

.250

.715 Fetal cardiac activity n (%)

Median size of ectopic mass, cm (range) 3.0 (1.5–5.0) Median gestational age at diagnosis, days (range) Intact ectopic mass, n (%)

hCG = human chorionic gonadotropin; IU = international units; MTX= methotrexate.