From the Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada.
Received June 10, 2003. Received in revised form August 10, 2003. Accepted September 5, 2003.
The authors thank Drs. Jan Bosteels, Mark Damario, Daniel A. Dumesic, Josef Eim, Anatolii Efimenco, Emilio O. Fernandez, Michael Freeman, Jeffrey A. Keenan, Dean Moutos, Petr Novak, Jiri Riegl, Ian Tummon, Marion H. Valkenburg, Bruno Van Herendael, Mary Wood-Molo, and Tamer Yalcinkaya for their participation in this registry.
Address reprint requests to: Togas Tulandi, MD, McGill University, Department of Obstetrics and Gynecology, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada; e-mail: email@example.com.
The interstitial part of the fallopian tube is the proximal portion of the tube that is within the muscular wall of the uterus. It is 0.7 mm wide and approximately 1 to 2 cm long, with a slightly tortuous course, extending obliquely upward and outward from the uterine cavity. A pregnancy implanted in this site is called an interstitial pregnancy. Interstitial pregnancy is a rare entity of ectopic pregnancy, accounting for 2–4% of all tubal pregnancies, but the reported maternal mortality is in the range of 2–2.5%.1
The traditional treatment of interstitial pregnancy was hysterectomy or cornual resection by laparotomy. Recently, several authors have advocated conservative management with methotrexate or laparoscopic treatment.1,2 Laparoscopic techniques involve cornual resection, cornuostomy, salpingostomy, or salpingectomy.1 Hysteroscopic removal of interstitial pregnancy has also been reported.3,4
Because of its low incidence, most authors have published only case reports of small numbers of patients. The purpose of our study was to summarize management of interstitial pregnancy and its outcome among 32 cases in the world.
MATERIALS AND METHODS
A registry of 32 cases from 1999 to 2002 was attained after physicians worldwide answered a five-page questionnaire prepared by the senior author (TT) for the Society of Reproductive Surgeons. Call for participation was advertised in several newsletters, including those of the American Society for Reproductive Medicine, District I of the American College of Obstetricians and Gynecologists, and the International Society for Gynecologic Endoscopy.
The questionnaire asked for information pertaining to patients’ age, previous pregnancies, predisposing factors, such as previous ectopic, previous salpingitis, and pregnancy after in vitro fertilization or induction of ovulation. Information was also noted regarding when and how diagnosis was obtained, including the duration of amenorrhea, the ultrasound diagnosis, largest diameter of ectopic mass, size of gestational sac, whether cardiac activity was present or not, and whether the ectopic mass was intact or had ruptured. Different treatment modalities—methotrexate given locally or systemically, laparoscopic removal of the ectopic mass, or laparotomy—were also recorded. Collection of cases was made after information was obtained from all filled forms in a confidential manner. We also evaluated ultrasound images and operation reports.
A database was set up with Microsoft Excel for Windows (Redmond, WA) to facilitate data entry and retrieval. Statistical analysis was performed with SPSS for Windows 5.0 (SPSS Inc., Chicago, IL). Results are expressed as mean and standard error of the mean, and the differences are considered statistically significant at P < .05.
From 1999 to 2002, 32 cases of interstitial pregnancy were reported: ten from Europe, 21 from North America, and one from Chile. The mean age, duration of amenorrhea, and serum β human chorionic gonadotropin (β-hCG) levels were 32.6 ± 1.0 years, 6.9 ± 0.3 weeks, and 6192.2 ± 2405.6 mIU/mL, respectively. The common predisposing factors for interstitial pregnancy are listed in Table 1. Among those patients with a previous history of salpingectomy, six had ipsilateral salpingectomy, and another six had bilateral salpingectomy. Previous ectopic pregnancy and in vitro fertilization were also predisposing factors. No uterine anomalies were reported.
Diagnosis of interstitial pregnancy was established by transvaginal ultrasound in 23 patients (71.4%), by laparoscopy in five, and by laparotomy in three others. Ultrasound findings revealed a gestational sac in the cornua in 13 patients (40.6%), including a patient with bilateral interstitial pregnancy, and evidence of fetal cardiac activity in five patients. Hyperechoic mass in the cornua was seen in the remaining patients.
Most patients were treated surgically, either by laparotomy or by laparoscopy (Table 2). Laparotomy was performed for tubal rupture in 9 patients and because of severe adhesion in another. In those treated by laparoscopy, tubal rupture was encountered in five patients. The mean hemoperitoneum encountered was 1385.7 ± 978.8 mL in the laparotomy group and 460.0 ± 70.7 mL in the laparoscopy group. Blood transfusion was required for seven patients in the laparotomy group and two in the laparoscopy group. Persistently elevated serum β-hCG levels were found in a patient after laparoscopic cornual excision, and she was successfully treated with methotrexate.
Eight patients were treated with methotrexate: two locally under laparoscopic guidance, two transvaginally, and four with systemic intramuscular methotrexate (50 mg/m2). Two patients treated with systemic methotrexate required surgery: for severe abdominal pain and impending rupture in one and for rising serum β-hCG in another. A laparotomy was also performed in a patient treated by laparoscopic methotrexate injection, owing to severe abdominal pain with impending tubal rupture.
The mean interval between methotrexate administration and resolution of serum β-hCG was 52.7 ± 36.9 days. The diameter of the gestational sac and the serum β-hCG levels in patients who were successfully treated with methotrexate were 1.3–2.1 cm and 1747–9800 mIU/mL, whereas in those who failed the treatment they were 1.4–1.6 cm and 600–13,420 mIU/mL, respectively. Fetal cardiac activity was present in one patient successfully treated and in another unsuccessfully treated with methotrexate treatment.
There were five cases (15.6%) of heterotopic pregnancy;all ruptured at the time of diagnosis. Four had an intrauterine pregnancy concomitant with an interstitial pregnancy ruptured at 5.5, 6.5, 7, and 8 weeks of gestation, respectively, and another had a twin pregnancy along with an interstitial pregnancy ruptured in very early gestation (5 weeks). All heterotopic pregnancies were the result of in vitro fertilization. The interstitial pregnancy was removed by laparotomy in three patients and by laparoscopy in two others. Subsequent pregnancy was reported in ten patients. Despite previous concern that the cornual area might become weak after conservative treatment of interstitial pregnancy, we did not encounter uterine rupture during pregnancy or labor.
Based on our systematic search of the literature completed in July 2003 and conducted with the keywords “interstitial pregnancy,” “cornual pregnancy,” and “ectopic pregnancy” in MEDLINE, EMBASE, and the Cochrane Database of systematic reviews, this is the largest series of interstitial pregnancy reported in the literature.
Despite our advertisements in a few societies’ newsletters, only 32 cases were reported. We believe that this is because of the low incidence of the condition. It could also be that gynecologists were not interested in sharing their experience or did not read our call for participants.
We found that 13 of 32 of patients with interstitial pregnancy had a history of ectopic pregnancy, and 12 of them were treated with ipsilateral salpingectomy. This confirms previous reports that after a total salpingectomy, an ectopic pregnancy can still be encountered and when it occurs it could be in the interstitial part of the ipsilateral tube.5
In vitro fertilization plays an important role in the increased incidence of ectopic pregnancy, including interstitial pregnancy (Table 1). Of the 11 interstitial pregnancies conceived after in vitro fertilization treatment, five were heterotopic pregnancy. More importantly, they were all ruptured at diagnosis. This underscores the need to evaluate the fallopian tubes even after ultrasound visualization of an intrauterine gestation, particularly in pregnancy after in vitro fertilization. The incidence of heterotopic pregnancy after assisted reproductive technology is 1 in 100 pregnancies.6
Because of its unique location, early diagnosis of interstitial pregnancy has historically been difficult.7 The eccentric position of the gestational sac and thinning of the myometrial mantle make differentiation between the eccentric intrauterine pregnancy and interstitial pregnancy sometimes difficult.7 As demonstrated in this study, transvaginal ultrasound facilitates early diagnosis of interstitial pregnancy. Ultrasound revealed a gestational sac in 40.6% of the patients and hyperechoic mass in the cornual region in another 25%. The diagnosis was established in 71.4% of the 32 patients. A sensitivity of 80% and a specificity of 99% have been reported.8 Another diagnostic aid would be the laparoscope. Laparoscopy has the advantage for both diagnosis and treatment.
Traditionally, the treatment of interstitial pregnancy has been hysterectomy or cornual resection by laparotomy. Owing to the thickness of the myometrial wall protecting the interstitial pregnancy, rupture occurs after 12 weeks, leading to catastrophic hemorrhage and even death.9,10 This is because of the abundant blood supply from the uterine and ovarian vessels in this area. In our study, tubal rupture was encountered in 14 patients (Table 2), and all were before 12 weeks. This is in contrast to previous beliefs that rupture of interstitial pregnancy occurs late in pregnancy. Blood transfusion was required in nine patients, but there were no maternal deaths.
In our study, the gestational age at diagnosis was between 5 and 12 weeks (mean, 6.9 weeks). Consequently, interstitial pregnancy can be treated conservatively either medically with methotrexate or by laparoscopy. However, more than one third of the patients treated medically or conservatively by laparoscopy required secondary treatment. Laparoscopic cornual excision was effective: Only one patient had persistently high levels of serum β-hCG. She subsequently responded well to methotrexate injection.
Only eight patients were treated with methotrexate, and three of them required surgery owing to impending tubal rupture or rising serum β-hCG levels. The serum β-hCG levels in the three patients who failed methotrexate were between 600 and 13,420 mIU/mL, which suggests that serum β-hCG levels in interstitial pregnancy might not be predictive of treatment success. However, the diagnosis of impending tubal rupture is subjective. It is possible that surgical treatment might not have been required in some of these patients. In any event, it has been proposed that methotrexate might be less accessible to interstitial pregnancy owing to its location, increased blood supply, and deeper implantation.11
In a review, we previously reported that local, systemic, and combined methotrexate therapy is associated with 83% overall success rate in cases of interstitial pregnancy.1 In the present series, failure occurred in three of eight patients. Accordingly, close follow-up after methotrexate treatment is recommended. The best medical treatment regime for interstitial pregnancy remains unknown.
One of the concerns of pregnancy after an interstitial pregnancy is rupture of the interstitial portion of the tube (uterine rupture). Uterine rupture was described at 20 weeks’ gestation in a patient who had interstitial pregnancy treated by salpingectomy12 and at 24 weeks in another after spontaneous resolution of the interstitial pregnancy.13 In our series, no rupture was encountered during pregnancy or labor.
We conclude that ipsilateral salpingectomy, previous ectopic pregnancy, and in vitro fertilization are predisposing factors for interstitial pregnancy. Ultrasound diagnosis of interstitial pregnancy is accurate in 71.4% of cases, which allows conservative treatment either medically or with laparoscopy. Contrary to previous belief, rupture of interstitial pregnancy occurs relatively early in pregnancy. In selected patients, laparoscopic cornual excision is a viable alternative treatment.
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