The incidence of interstitial pregnancy is rising. Traditional treatment with laparotomy, hysterectomy, or cornual wedge resection is associated with high morbidity and detrimental effects on future fertility. A diverse array of alternate treatments has been introduced over the last 3 decades, with the common goal of achieving a minimally invasive, standardized management strategy. This has been facilitated by impressive strides towards prompt diagnosis, both radiologically and chemically. In this review, we explore the current state of the art diagnostic criteria and the clinically significant diverse therapeutic options with supporting literature. Finally, we propose a structured, best-practice management plan for the once-lethal interstitial pregnancy, based on the current literature.
The ectopic gestational sac is an important source of pregnancy-related morbidity and mortality. Interstitial pregnancy refers to an ectopic pregnancy that is implanted in the interstitial portion of the fallopian tube, which is defined as the tubal segment traversing the muscular wall of the uterus. This segment originates at the tubal ostium and follows a tortuous course superiorly and laterally away from the uterine cavity to the point at which the isthmic portion of the tube arises from the fundus. Averaging 0.7 mm in diameter and 1-2 cm in length, this relatively thick section of the tube has a significantly greater capacity to expand before rupture than do the distal tubal segments. For this reason, the interstitial pregnancy may remain asymptomatic until 7-16 weeks of gestation in rare cases, at which time rupture can result in catastrophic hemorrhage. This is accentuated by the rich vascular anastomosis of the uterine and the ovarian arteries in this region. Thus, early detection and a high index of suspicion are crucial to reducing morbidity and mortality.
Interstitial pregnancies account for only 2-4% of tubal pregnancies or approximately 1 in 2500-5000 live births. However, because of the factors discussed earlier and diagnostic difficulties, the mortality rate is as high as 2.5%, a rate that is 7 times greater than that of ectopic pregnancies in general.
Interstitial pregnancy sometimes is mistakenly referred to as cornual pregnancy and frequently confused with angular pregnancy. A strict distinction among the 3 conditions is clinically important because their behavior, management, and outcomes are different. In contrast to interstitial pregnancy, an angular pregnancy refers to a viable intrauterine pregnancy that is implanted in 1 of the lateral angles of the uterine cavity, medial to the uterotubal junction. Angular pregnancies lead to asymmetric and symptomatic enlargement of the uterus and end in miscarriage in 38.5% of cases. Persistent pelvic pain or recurrent vaginal bleeding during pregnancy, retention of the placenta during the third stage of labor, and rarely uterine rupture are among the potential complications of angular pregnancy, although the symptoms resolve and a normal pregnancy may follow in a significant number of women. During laparoscopy, angular pregnancy appears as an asymmetric bulge in 1 of the uterine angles, medial to the round ligament and displacing its reflection laterally. On the other hand, interstitial pregnancy appears lateral to the round ligament.
Cornual pregnancy refers to a pregnancy in a horn of a bicornuate uterus. The clinical outcome of cornual pregnancy varies greatly, depending on the size and expansile nature of the affected horn.
Traditional treatments for interstitial ectopic pregnancy have ranged from exploratory laparotomy with cornual wedge resection to total abdominal hysterectomy. However, the development of high-resolution ultrasound evaluation and rapid quantitative β human chorionic gonadotropin (β-hCG) assays has fostered the detection of interstitial gestations before rupture, which, in turn, has made possible more conservative treatment options for the patient whose condition is hemodynamically stable. Conservative options include methotrexate administration (local and systemic) and minimally invasive surgical techniques that include resection of the involved tube and pregnancy alone with preservation of the uterine architecture. Hysteroscopic removal of interstitial pregnancy has also been described.
Despite the advent of conservative strategies, the most appropriate technique for treatment of interstitial pregnancy and treatment of these patients during subsequent pregnancies remains controversial. Two important considerations that are related to optimal treatment include the extent of uterine wall trauma and the patient’s desire for future pregnancy.
This article will review modern methods for the diagnosis and management of interstitial pregnancies and strategies for management of subsequent pregnancies.
Diagnosis
The single most important facet of caring for women with interstitial pregnancy is early diagnosis. Diagnosis before rupture makes conservative treatment possible and minimizes morbidity and mortality rates that are associated with interstitial gestation and with surgical intervention.
Since the introduction of high-resolution transvaginal ultrasonography (TVUS) and the highly sensitive quantitative β-hCG assays, early and accurate diagnosis has become possible. With recent advances, interstitial pregnancy is diagnosed at a gestational age of 6.9-8.2 weeks. The higher the index of suspicion for interstitial pregnancy, the earlier the diagnosis is made. The index of suspicion should be very high when the characteristic risk factors are elicited.
Risk factors
Factors that increase the risk of interstitial pregnancy are similar to those for ectopic pregnancy that is located in the more distal tube. In a series of 32 interstitial pregnancies, the most common risk factors were tubal damage from previous ectopic pregnancy (40.6%), previous ipsilateral or bilateral salpingectomy (37.5%), conception after in vitro fertilization (34.4%), and history of sexually transmitted disease (25.0%).
Another series of 27 patients with interstitial pregnancy showed that 54% of the patients had a history of salpingectomy or tubal ligation, that 54% had had a previous ectopic pregnancy, that 29.7% had had in vitro fertilization, and that only 12.5% had a history of pelvic inflammatory disease. No single risk factor clearly differentiates patients with an interstitial pregnancy from those with an ampullary or isthmic ectopic pregnancy.
Presentation
Contrary to common belief, current evidence dispels a long-standing myth that interstitial pregnancies present and rupture at a much later gestational age than other forms of ectopic pregnancy. The gestational age at presentation of interstitial pregnancy ranged from 6.9 ± 0.3 weeks in 1 series to 8 ± 2 weeks in another. Similarly, a series of 119 ectopic pregnancies (noninterstitial) reported the gestational age at diagnosis to range from 6.8-8.8 weeks. Regarding the gestational age at rupture, 1 series reported 14 cases of ruptured interstitial pregnancies all at <12 weeks. Similarly, Sindos et al reported the average gestational age at rupture of ectopic pregnancy to be 53.9 ± 4.7 days (7.7 ± 0.7 weeks of gestation).
Symptoms and signs
The most common symptoms of interstitial pregnancy are abdominal pain and vaginal bleeding in the first trimester of pregnancy. The clinical evaluation of patients with interstitial pregnancy has changed over the years because of recent advances in early diagnosis and a higher index of suspicion with the significant increase in incidence of ectopic pregnancy. Although Felmus and Pedowitz reported in 1953 that 71% of patients were in shock when evaluated, Soriano et al reported in 2007 that, of 27 patients at a mean gestational age of 8.2 ± 2 weeks, only 22.2% presented with ruptured interstitial pregnancy and hemorrhagic shock, while 48% presented with abdominal pain, 29% presented with vaginal bleeding, and 33.3% were asymptomatic at the time of diagnosis.
Vaginal bleeding appears to be less common in interstitial pregnancy than in other forms of ectopic pregnancy. In the series of Soriano et al, only 8 of 27 women (29.6%) with an interstitial pregnancy experienced vaginal bleeding before treatment vs 50-79% of women with ampullary or isthmic ectopic pregnancies. This decreased incidence of first-trimester bleeding may contribute to the occasionally delayed presentation of interstitial pregnancies.
On physical examination, the classic signs of a tender adnexal mass and cervical motion tenderness may be elicited. An asymmetric uterine enlargement may be palpable. Signs of acute abdomen may be elicited in cases of cornual rupture and hemoperitoneum; in severe cases, tachycardia and subsequent hypotension may be evident.
TVUS
TVUS is the primary method of diagnosis of interstitial pregnancies before surgery. Interstitial pregnancies are often discovered in asymptomatic patients during TVUS that is performed in the first trimester. One case series reported that TVUS was diagnostic of interstitial pregnancy in 15 of 27 patients (56%) at a mean gestational age of 8.2 weeks. In another series, TVUS established the diagnosis in 23 of 32 patients (71%) at a mean gestational age of 6.9 weeks. Three-dimensional TVUS may offer an advantage over conventional 2-dimensional sonography.
However, interstitial pregnancy may often be challenging to differentiate from angular pregnancy. The differentiating ultrasonographic feature of an interstitial pregnancy is the paucity of myometrium around the superolateral portion of the sac; conversely, the intrauterine angular pregnancy will be surrounded on all sides by at least 5 mm of myometrium.
Multiple authors helped establish TVUS criteria for diagnosing interstitial pregnancy ( Figure 1 ). Jafri et al report an eccentric gestational sac surrounded by an asymmetric myometrial mantle and an empty uterine cavity as the most common ultrasonographic findings with interstitial pregnancy. Timor-Tritsch et al delineated 3 ultrasonographic criteria for diagnosis: (1) an empty uterine cavity, (2) a chorionic sac separate and at least 1 cm from the lateral edge of the uterine cavity, and (3) a thin (<5 mm) myometrial layer surrounding the gestational sac. These parameters were found to have a specificity of 88-93% but carried a sensitivity of only 40%. Ackerman et al described the interstitial line sign, which refers to the visualization of an echogenic line that runs from the endometrial cavity to the cornual region, abutting the interstitial mass or gestational sac. This echogenic line has been reported to be 80% sensitive and 98% specific for the diagnosis of interstitial pregnancy.
Magnetic resonance imaging
Although TVUS with color-flow mapping is the first choice in the early diagnosis of interstitial pregnancy, magnetic resonance imaging may be used if ultrasound is inconclusive in ruling out the diagnosis of interstitial pregnancy and, particularly, in differentiating it from an angular or intrauterine pregnancy. In clinical practice, this can be particularly useful when fetal cardiac activity is present and the pregnancy is highly desired. Bourdel et al suggested 3 magnetic resonance imaging criteria for the diagnosis of interstitial pregnancy: (1) eccentricity of the gestational sac, (2) presence of a myometrial tissue that surrounds the entire gestational sac with a thickness of <5 mm, and (3) detection of an interstitial line sign that connects the endometrium to the trophoblast. However, further studies are needed to characterize the sensitivity and specificity of such criteria.
Surgical diagnosis
Many interstitial pregnancies are not diagnosed before surgery, either because ultrasonography was not performed in the first trimester or the pregnancy was mistaken for other types of ectopic pregnancy. In 1 series, only 23 of 32 patients (71%) were diagnosed before surgery. In another series, only 56% of 27 patients were diagnosed before surgery.
At the time of laparoscopy or laparotomy, an unruptured interstitial pregnancy will appear as an asymmetric bulge in the cornual region.
Treatment
Treatment options depend on the gestational age at diagnosis, whether rupture has occurred and the patient’s desire for future fertility. If the diagnosis is made before rupture, minimally invasive surgery and nonsurgical treatment options can be used. A ruptured interstitial pregnancy is a medical emergency that requires surgical intervention with either laparoscopy or laparotomy, depending on the patient’s condition and available surgical assets.
Nonsurgical treatment
Several authors have reported the use of nonsurgical treatment for interstitial pregnancies that are diagnosed by ultrasonography in the first trimester ( Table 1 ). The potential advantage of conservative therapy is the avoidance of a surgical scar on the uterus and the risks that are associated with surgery. The risks of nonsurgical treatment include subsequent cornual rupture and life-threatening hemorrhage. Because of this possibility, nonsurgical therapy should be attempted only with the 24-hour availability of anesthesia and physicians with adequate surgical expertise.
| Approach | Considerations |
|---|---|
| Expectant management | Close follow-up evaluation necessary |
| Most appropriate when serum beta-human chorionic gonadotropin levels spontaneously decline in asymptomatic patient | |
| Few cases reported, mostly inpatient | |
| Risk of rupture | |
| Systemic methotrexate | Most widely reported nonsurgical treatment for interstitial pregnancies |
| Close follow-up evaluation necessary | |
| Risk of subsequent rupture | |
| Local injection | Methotrexate most commonly studied agent |
| Special expertise and added procedure/cost |
Expectant management
Spontaneous miscarriage is a common pregnancy outcome, whether the pregnancy is intrauterine or ectopic in location. Expectant management of ectopic pregnancies 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. Successful expectant treatment of 3 patients with interstitial pregnancy has been reported. In this case series, however, 1 patient was observed in the hospital for 2 weeks. Subsequent ultrasound examination 5 months later revealed no evidence of the interstitial pregnancy. Another case of attempted expectant treatment eventually required laparoscopic treatment 2 months later because of persistent pain.
Avoiding chemotherapy and surgical risks are among the proposed benefits of expectant management. Another potential benefit is preserved fertility; however, limited data are available regarding tubal patency and subsequent pregnancy outcomes after expectant management.
Obviously, potential disadvantages of expectant management may include the potential catastrophic rupture and associated maternal morbidity and death, the unpredictable course to resolution (even with declining β-hCG levels), and the need for prolonged hospitalization and the resultant cost and disability. Other potential drawbacks include the risk of recurrence of interstitial pregnancy, partly because of the persistence of the tubal factors that have led to the ectopic implantation of the gestational sac and the risk of uterine rupture during subsequent pregnancy. Downey and Tuck reported uterine rupture at 24 weeks gestation after the spontaneous resolution of interstitial pregnancy. With the availability of several minimally invasive surgical and medical therapies for interstitial pregnancy, the isolated reports of successful expectant management of this potentially life-threatening condition do not outweigh the documented and theoretical disadvantages.
Systemic methotrexate
Systemic methotrexate treatment is well established as a reasonable treatment for carefully selected ectopic pregnancies. Methotrexate is a folinic acid antagonist that interferes with DNA synthesis in the rapidly proliferating trophoblast. The most important prognosticator for methotrexate success in ectopic pregnancy is the initial β-hCG level.
Tanaka et al reported the first successful treatment of interstitial pregnancy with systemic methotrexate. Lau and Tulandi reviewed 40 other cases, with an overall success rate of 83%, that used systemic or local methotrexate or a combination of both.
The success rate for systemic methotrexate therapy of interstitial pregnancy 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. Close follow up is crucial because approximately 10-20% of patients with interstitial pregnancies who are treated with methotrexate will ultimately require surgery for a rising β-hCG level, continued pain, or evidence of cornual rupture. An international registry of 32 cases included 8 patients who were treated with intramuscular methotrexate, 3 of whom required surgery because of “impending” rupture or rising serum β-hCG levels. Barnhart et al, in 1997, reported 3 unsuccessful cases of medical treatment of interstitial pregnancy.
Hospitalization is rarely necessary for patients whose condition is stable, except in cases of diagnostic uncertainty when brief observation is prudent or for patients with limited access to a tertiary care facility.
Jermy et al reported the successful treatment of unruptured interstitial pregnancies in 16 of 17 patients (94%). All patients with an initial β-hCG level of <5000 IU/L were treated successfully with a single intramuscular dose of 50 mg/m 2 body surface area, which was the protocol that was used commonly to treat extrauterine tubal pregnancies ( Table 2 ). A second dose was given to 6 patients in whom β-hCG levels dropped <15% between days 4 and 7. Four patients had evidence of fetal cardiac activity, and all patients were treated successfully with methotrexate. The mean duration of amenorrhea in this series was 51.5 days; the median baseline β-hCG level was 6452 IU/L (range, 32–31,381 IU/L). However, inpatient treatment was used, and the median duration of hospital stay was 7 days (range, 0–40 days). Dilbaz et al reported the successful treatment of 3 interstitial pregnancies with the same single-dose regimen of methotrexate.
| Day | Therapy |
|---|---|
| 0 | β-hCG, CBC, AST, Cr, blood type, and Rh |
| Administer rho D immune globulin (RhoGAM), if indicated | |
| Methotrexate 50 mg/m 2 body surface area, intramuscular single dose | |
| 4 | β-hCG |
| 7 | β-hCG |
| Second dose of methotrexate, given if β-hCG decreased <15% from days 4-7 |
Several other regimens of systemic methotrexate have been described in the literature, with comparable success rates. The systemic use of a multidose regimen of methotrexate has been described in several reports with a cumulative success rate of 89% (16/18 cases). Up to 3 courses were used in some series if β-hCG levels plateaued without evidence of rupture or hemodynamic instability. The multidose regimen is detailed in Table 3 .
| Day | Therapy |
|---|---|
| 0 | β-hCG, CBC with differential, AST, Cr, blood type and Rh; administer rho D immune globulin (RhoGAM), if indicated |
| Intramuscular methotrexate 1 mg/kg body weight | |
| 1 | Oral folinic acid 0.1 mg/kg body weight |
| 2 | Intramuscular methotrexate 1 mg/kg body weight |
| 3 | Oral folinic acid 0.1 mg/kg body weight |
| 4 | Intramuscular methotrexate 1 mg/kg body weight |
| β-hCG | |
| 5 | Oral folinic acid 0.1 mg/kg body weight |
| 6 | Intramuscular methotrexate 1 mg/kg body weight |
| 7 | Oral folinic acid 0.1 mg/kg body weight |
| β-hCG | |
| Weekly | β-hCG, CBC, and TVUS, if clinically indicated; repeated course of methotrexate may be required |
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