Michael J. Heard
John E. Buster
Management of ectopic pregnancy is changing dramatically. Although ectopic pregnancy remains a leading cause of life-threatening first-trimester morbidity, informed clinical suspicion and modern diagnostic procedures now routinely lead to diagnosis and treatment before there are symptoms. Medical therapy with systemic methotrexate, an intervention targeted specifically toward proliferating trophoblasts, is now preferred to surgery as standard first-line therapy. Surgery remains the first choice for hemorrhage, medical failures, neglected cases, and cases where medical therapy is contraindicated. In the wake of these changes, the United States has seen a considerable drop in maternal morbidity and mortality from this disease.
Optimal dosing for methotrexate remains controversial. Rules for timing and technique for surgical intervention during medical failures are empirical. Early diagnosis and selection of optimal therapy are key to prevention of complications, preservation of fertility, control of costs, and elimination of mortality. Using an evidence-based approach to diagnosis and treatment for ectopic pregnancy, this chapter provides a comprehensive examination of the standard of care for this serious gynecologic disease.
INCIDENCE
The incidence of ectopic pregnancy in the United States is not known precisely. Recent attempts at the Centers for Disease Control and Prevention (CDC) to estimate the incidence of this disease have been thwarted, because many cases are treated medically in outpatient facilities and are not recorded in hospital registries. Where hospital records were used, a relentless increase in ectopic pregnancies from 4.5 per 1,000 in 1970 to 16.8 per 1,000 in 1989 to 19.7 per 1,000 (108,000 cases) in 1992 has been reported. The current incidence will probably prove much higher once the CDC is able to make estimates including outpatient records. Certain epidemiologic trends make this likely. First, there is a continued increase in risk factors (Table 5.1) in a society with unprecedented sexual liberties. Second, there is increased ascertainment of ectopics from use of more sensitive and specific diagnostic methods that detect many cases that, in the past, would have resolved spontaneously without diagnosis. Third, with the increasing use of assisted reproductive technology (ART) for treatment of infertility, there is an increase risk of ectopics which comprise up to 5% of pregnancies achieved by using ART. Not surprisingly, heterotopics also are being reported with increasing frequency in ART pregnancies. Between 1979 and 1986, 13% of maternal deaths were secondary to ectopic pregnancy; by 1992, this dropped to 9%. However, ectopic pregnancies continue to be the leading cause of maternal death in the first trimester accounting for 5% to 6% of all maternal deaths in the United States. Ninety percent of these deaths were due to hemorrhagic complications.
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TABLE 5.1. Risk factors associated with ectopic pregnancy |
PATHOGENESIS
Any event that impairs the ability of the tube to transport gametes or embryos will predispose to ectopic implantation. The clinical picture is determined by the site of ectopic implantation. The most common site of ectopic pregnancy is the fallopian tube, which accounts for 98.3% of all ectopic gestations. Implantation in the ampulla is observed in 79.6% of tubal ectopic pregnancies; 12.3% are in the isthmus, 6.2% are in the fimbrial end, and the remaining 1.9% occur in the interstitial (cornual) region. Ectopic nidation outside the fallopian tubes is rare; only 1.4% of ectopic pregnancies are abdominal pregnancies, 0.15% ovarian, and 0.15% cervical (Fig. 5.1).
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FIG. 5.1. Implantation sites for ectopic pregnancy following natural cycles and assisted reproductive technology. |
In most tubal implantations, the proliferating trophoblasts invade the tubal wall. The degree of trophoblastic invasion of maternal tissues, the viability of the pregnancy, and the site of implantation determine the sequence of clinical events. As the trophoblasts proliferate, the growth may extend from the luminal mucosa, into the muscularis and lamina propria, into the serosa and, ultimately, full thickness even into large blood vessels in the broad ligament. With vascular invasion, bleeding takes place which distorts the tube, stretches the serosa, and causes pain. The embryo is abnormal and degenerates in about 80% of cases. Spontaneous tubal abortion occurs in about 50% of tubal ectopic pregnancies and is often clinically silent. Spontaneous tubal abortion with hemorrhage can occur with bleeding that is self-limited. Tubal rupture usually is associated with significant hemorrhage. This complication is most likely to occur in the isthmic part of the tube, which has limited distensibility. Chronic tubal rupture with extension into the broad ligament can produce a pelvic hematoma that can last for several weeks. Unruptured ectopic pregnancies can produce a chronic course, with persistently elevated β-human chorionic gonadotropin (β-hCG) levels that may last for weeks.
RISK FACTORS
Ectopic pregnancy most often is associated with risk factors leading to tubal epithelial damage, which alters gamete and embryo transport. Meta-analyses identify the risk factors listed in Table 5.1 as the most influential.
Tubal Damage and Infection
Documented tubal pathology carries a 3.5-fold common adjusted odds ratio for ectopic pregnancy. Patients with a previous ectopic pregnancy are 6 to 8 times more likely to experience another ectopic pregnancy, and 8% to 14% of patients experience more than one ectopic pregnancy. Patients with a history of tubal surgery have a 21-fold common adjusted odds ratio of ectopic pregnancy.
Tubal pathology frequently results from pelvic infections. Patients with a history of pelvic infections, including gonorrhea, serologically confirmed chlamydia, and nonspecific pelvic inflammatory disease, have a two-fold to four-fold higher risk of developing an ectopic pregnancy. The ectopic pregnancy rate is 4% in women with laparoscopically proven salpingitis, compared with 0.7% in women with normal tubes. In evaluating histologic specimens of ectopic pregnancy, microscopic evidence of inflammatory disease is present in 38% of cases. Recurrent episodes of pelvic infections increase the likelihood of tubal occlusions: 12.8% after one infection, 35.5% after two infections, and 75% in patients with three or more infections.
Salpingitis Isthmica Nodosa
Salpingitis isthmica nodosa is a disease defined by an anatomic thickening of the proximal portion of the fallopian tubes with multiple luminal diverticula. This pattern of tubal pathology increases the incidence of ectopic pregnancy by 52% in age- and race-matched controls.
Diethylstilbestrol
In utero exposure to diethylstilbestrol (DES) alters fallopian tubal morphology, resulting in absent or minimal fimbrial tissue, a small tubal os, and decreased length and caliber of the tube. Abnormal tubal anatomy accounts for the five-fold increase in the risk for ectopic pregnancy.
Cigarette Smoking
Patients who smoke cigarettes are at a slightly increased risk for ectopic pregnancy. It is difficult to conceptualize the link between ectopic pregnancy and cigarettes. Theories include impaired immunity in smokers predisposing them to pelvic infections, alterations in tubal motility, or a representation of certain lifestyles associated with increased risk of tubal injection.
Contraception
Intrauterine devices (IUDs) have been associated with ectopic pregnancy. A multicenter case-control study conducted by the World Health Organization in ten countries found an odds ratio of 6.4 for ectopic pregnancy in current IUD users compared with pregnant controls, whereas the odds ratio was only 0.5 when the comparison was made with nonpregnant controls. Similarly, in the Oxford Study of 17,032 contraceptive users, the proportion of unplanned pregnancies that were ectopic was higher in women using IUDs compared with women taking oral contraceptives. Thus, IUDs effectively prevent pregnancy, but if pregnancy occurs in a woman using an IUD, there is increased likelihood that the pregnancy will be ectopic.
Tubal ligation carries a similar risk for ectopic pregnancy to what is observed with current IUD use. A meta-analysis using case-control studies found the odds ratio for tubal sterilization to be 9.3 when compared with pregnant controls and 0.52 when compared with nonpregnant controls, a finding confirmed by two additional multicenter case-control trials. As with the IUD, tubal ligations effectively prevent pregnancy, but if pregnancy does occur, the suspicion for an ectopic pregnancy should be high.
Electrocoagulation procedures are associated with higher ectopic pregnancy risk than other forms of tubal sterilization, possibly resulting from tubal recanalization or uteroperitoneal fistula formation. Uteroperitoneal fistulas have been found in up to 75% of hysterectomy specimens from women with previous tubal ligations in which the tubes were cauterized flush with the uterus.
Oral contraceptives are associated with a reduced risk of ectopic pregnancy when compared with nonpregnant controls but with elevated risk when compared with pregnant controls. This protection is presumably due to the suppression of ovulation by oral contraceptives. It is therefore not surprising that patients who take emergency contraception, such as oral contraceptives after fertilization, are at substantial risk for an ectopic pregnancy. This has been attributed to altered tubal motility.
Barrier contraception (condoms, spermicides, and diaphragms) also reduces the odds ratio of ectopic pregnancy. An additional advantage may be attributed to the decreased risk of sexually transmitted diseases in women using barrier methods.
Evidence-based Recommendation
Women with a previous ectopic pregnancy, tubal surgery, tubal pathology, or in utero DES exposure are at high risk for ectopic pregnancy. Women who have experienced genital infections, infertility, or more than one sexual partner have a moderate risk of ectopic pregnancy. Previous pelvic or abdominal surgery, smoking, vaginal douching, or an early age of first sexual intercourse have only a slightly increased risk of ectopic pregnancy.
Contraception, if used properly, is an effective way of reducing pregnancy, both intrauterine and extrauterine. If pregnancy occurs in women with an IUD, after tubal ligation, or following emergency contraception, suspicion for ectopic pregnancy should be high. (Strength of recommendation: A.)
SIGNS AND SYMPTOMS
Today, many ectopic pregnancies never produce symptoms; rather, they are timely diagnosed and treated because the patient is identified as high risk. Table 5.1 summarizes and weighs risk factors that should be examined in every woman who has just been identified as being pregnant. If the diagnosis is delayed, some patients may develop the classic triad of amenorrhea, irregular vaginal bleeding, and lower abdominal pain. Early diagnosis, unfortunately, is not always achievable. Sudden, severe, lower abdominal pain is the most common complaint in 90% to 100% of women with symptoms of an ectopic pregnancy. Pain radiating to the shoulder, syncope, and shock as a result of hemoperitoneum occur in up to 20% of patients.
The most common signs are detected upon abdominal examination. Abdominal tenderness is present in 90% of patients and rebound tenderness in 70%. The pelvic examination is usually nonspecific; cervical motion tenderness is present in up to two thirds of patients, while a tender adnexal mass is present in 50%.
DIAGNOSIS
Ectopic pregnancy can be diagnosed as early as 4.5 weeks gestation. Unfortunately, visualizing an ectopic pregnancy this early is frequently not possible. More importantly, traditional laparoscopic visualization (Fig. 5.2,Fig. 5.3,Fig. 5.5) is now rarely necessary. Routine diagnostic tests are serial measurements of β-hCG, ultrasonography, serum progesterone levels, and uterine curettage.
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FIG. 5.2. Laparoscopic visualization of an isthmic ectopic pregnancy. |
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FIG. 5.3. Laparoscopic visualization of an ampullary ectopic pregnancy. |
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FIG. 5.5. Ultrasonogram of free fluid noted under the liver edge above the right kidney. Confirmed to be blood from a ruptured ectopic pregnancy at the time of surgery. (Courtesy of R. Mangal, M.D., Obstetrics/Gynecologic Associates, Houston, TX.) |
Outpatient diagnosis of ectopic pregnancy using various algorithms has been shown to be safe and effective without need for hospitalization even when the diagnosis is equivocal. The clinical algorithm in Figure 5.4 is highly efficacious in diagnosing ectopic pregnancy.
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FIG. 5.4. Diagnostic algorithm for ectopic pregnancy. |
Serial β-Human Chorionic Gonadotropin Determinations
β-hCG determinations used today are based on the enzyme-linked immunosorbent assay (ELISA), detecting low β-hCG concentrations in urine and serum, 20 mIU/mL down to 1 mIU/mL, respectively. The β-hCG, produced by trophoblastic cells in normal pregnancy, rises at least 66% and up to two-fold every 2 days. This generally applies to β-hCG values below 10,000 mIU/mL. Eight-five percent of abnormal pregnancies, whether intrauterine or ectopic, have impaired β-hCG production with a prolonged doubling time. β-hCG levels that plateau or fail to rise normally along with a low serum progesterone value should be considered nonviable. If a viable intrauterine gestation is not visible by transvaginal ultrasonography when the β-hCG is above 2,000 mIU/mL (First International Reference Preparation [IRP]) and no fetal heartbeat can be visualized in the adnexa, uterine curettage can be performed. In this situation, treatment of a nonviable intrauterine pregnancy is performed or ectopic pregnancy is diagnosed when the β-hCG levels do not fall. These β-hCG thresholds are not universal, and each institution must identify its own values to avoid terminating normal intrauterine pregnancies.
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FIG. 5.6. Transvaginal ultrasonographic illustration of tubal ectopic gestation. |
β-hCG determinations are further employed for diagnosis after uterine curettage. If the β-hCG fails to decline by 15% from a level drawn immediately before surgery, the pregnancy is presumed ectopic and treatment should be initiated.
Ultrasonography
Although the uterus and adnexa may be evaluated abdominally or vaginally, transvaginal ultrasonography reliably detects intrauterine gestations when the β-hCG levels are between 1,000 and 2,000 mIU/mL (First IRP), as early as 1 week after missed menses. An intrauterine gestation should almost always be visualized when the β-hCG level is greater than 2,000 mIU/mL.
Diagnosis of an ectopic pregnancy can be made with 100% specificity but with low sensitivity (15%–20%) if an extrauterine gestational sac containing a yolk sac or embryo is identified. A complex adnexal mass without an intrauterine pregnancy improves sensitivity to 21% to 84% at the expense of lower specificity (93.0%–99.5%). In reviewing the literature, the presence of any noncystic, extraovarian adnexal mass in the absence of an intrauterine gestation was diagnostic of an ectopic pregnancy with 98.9% specificity, 96.3% positive predictive value, 84.4% sensitivity, and a 94.8% negative predictive value. Despite the high resolution of transvaginal ultrasonography, an adnexal mass will not be found in 15% to 35% of patients with an ectopic pregnancy, particularly in early stages. Some sonographic images, such as the pseudogestational sac, may mislead even an experienced examiner to falsely diagnose a gestational sac.
Serial β-hCG concentrations and transvaginal ultrasonography predict ectopic pregnancy with a positive predictive value of 95%. Diagnosis is made routinely by the absence of an intrauterine pregnancy (i.e., gestational sac) at a designated β-hCG concentration. The vast majority of viable intrauterine pregnancies can be identified by ultrasonography when the β-hCG is greater than 1,500 mIU/mL (First IRP). However, in those patients with an “indeterminate” ultrasonogram, one fourth have an ectopic pregnancy. Therefore, serial hCG and ultrasonography alone cannot diagnose all ectopic pregnancies.
Uterine Curettage
Uterine curettage is necessary when a transvaginal ultrasonogram and a rising or plateauing β-hCG level below the cutoff value are not sufficient for diagnosis. A decrease in the β-hCG level of 15% or more 8 to 12 hours after curettage is diagnostic of a complete abortion. If the β-hCG titer plateaus or rises and the trophoblast was not removed by curettage, an ectopic pregnancy is likely.
Evidence-based Recommendation
Serial β-hCG determinations, transvaginal ultrasonography, and uterine curettage allow for definitive diagnosis of ectopic pregnancy. A confirmatory laparoscopy is rarely necessary. (Strength of recommendation: A.)
TREATMENT FOR ECTOPIC PREGNANCY
Medical Management
Methotrexate therapy of ectopic pregnancy has been used successfully over the last two decades. A folic acid antagonist, methotrexate inhibits de novo synthesis of purines and pyrimidines, interfering with DNA synthesis and cell multiplication. Rapidly proliferating trophoblasts are particularly vulnerable to methotrexate and this differential sensitivity forms the basis of the therapy. When methotrexate is administered to pregnant women undergoing planned termination, a single dose of 50 mg/m2 significantly blunts the hCG increment over the following 7 days and has been associated with a drop in circulating progesterone and 17α-hydroxyprogesterone concentrations prior to abortion. It appears that methotrexate directly impairs trophoblastic production of hCG with a secondary decrement of corpus luteum progestin secretion. Hemodynamically stable patients with unruptured ectopic pregnancy measuring less than or equal to 4 cm by ultrasonography are eligible for methotrexate therapy. Patients with larger masses or evidence of acute intraabdominal bleeding should undergo surgical treatment. The two commonly employed methotrexate treatment regimens are shown in Table 5.2.
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TABLE 5.2. Methotrexate protocols: single versus multiple |
Multiple-dose Methotrexate
Multiple-dose methotrexate therapy is tailored to the patient's weight and ectopic pregnancy responsiveness. Outcomes of 12 studies comparing multiple-dose systemic methotrexate with laparoscopic salpingostomy are presented in Table 5.3. Between 1982 and 1997, this tabulation shows 325 cases of ectopic pregnancy treated with multiple-dose methotrexate. Of these cases, 93.8% were treated successfully with multiple-dose systemic methotrexate (no subsequent therapy was required), and 78.9% of the women tested had patent fallopian tubes; in addition, of the women desiring pregnancy, 57.9% had a subsequent intrauterine pregnancy and 7.4% developed a repeat ectopic pregnancy. These rates all compare favorably with conservative surgical management.
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TABLE 5.3. Outcome of different treatments for ectopic pregnancy |
There is one randomized clinical trial comparing laparoscopic salpingostomy with systemic multiple dose methotrexate. In it, 100 patients with laparoscopy-confirmed ectopic pregnancy were randomly treated with systemic methotrexate or laparoscopic salpingostomy. In the 51 patients treated with methotrexate, three (8%) required surgical intervention for active bleeding or tubal rupture. An additional course of methotrexate was required in two patients (5%) for persistent trophoblast, basal on β-hCG secretion. Of the 44 patients in the salpingostomy group, two patients (5%) failed and required salpingectomies, and eight patients (22%) required treatment with methotrexate for persistent trophoblast. Tubal patency was present in 67% of the patients in the methotrexate group and in 61% in the salpingostomy group. This randomized study and previous meta-analysis have demonstrated the effectiveness of systemic methotrexate therapy as equal to laparoscopic salpingostomy.
Single-dose Methotrexate
Single-dose methotrexate, although more convenient, is not as efficacious as multiple-dose methotrexate. The high success rates in the initial studies using single-dose methotrexate was most likely due to the inclusion of spontaneously aborting intrauterine pregnancies. Subsequent studies of single-dose methotrexate therapy involving 304 patients are presented in Table 5.3. Although overall success of treatment, measured as no surgical intervention, is 87.2%, 11.5% additional patients required more than one dose of methotrexate. Of the patients considered successfully treated (with one or more doses), tubal patency was found in 81.3% of the women evaluated. The subsequent intrauterine pregnancy rate was 61%, and for ectopic pregnancies 7.8%, in the patients desiring future fertility in the same group (those treated with either one or more doses of methotrexate). Based on the clinical evidence presently available, the routine use of methotrexate as a single-dose intramuscular regimen is probably not as effective as multiple dosage. However, single-dose therapy remains a standard according to publications of the American College of Obstetricians and Gynecologists. With this background, a recent meta-analysis of 26 studies evaluating methotrexate dosing for ectopic pregnancy by Barnhart et al. showed an odds ratio of 1.96 higher likelihood of rupture with use of single-dose methotrexate over multidose therapy. This failure rate was even higher when controlling for baseline β-hCG values.
Safeguards and Counseling
During methotrexate therapy, a patient should be examined by a single examiner only once. The physician and the patient must recognize that transient pain (“separating” or “tearing pain”) is common. Transient pelvic pain from resolution tubal bleeding of the ectopic pregnancy frequently occurs 3 to 7 days after the start of therapy, lasts 4 to 12 hours, and is presumably due to tubal abortion. Perhaps the most difficult aspect of methotrexate therapy is learning to distinguish the transient abdominal pain of successful therapy from that of a rupturing ectopic pregnancy. Isthmic ectopic pregnancies are probably at high risk for rupture, and there is simply no way to identify these in advance. A review of ectopic ruptures after methotrexate therapy revealed a high prevalence of isthmic (47%) ectopic pregnancies that was unexpected. These ectopic pregnancies have an early normal doubling time and rise in β-hCG titers after methotrexate dosing. Physicians must therefore carefully observe for clinical indications that an operation is necessary (Table 5.4 and Table 5.5). Thus, surgical intervention is required when pain is worsening and persistent beyond 12 hours. Orthostatic hypotension or a falling hematocrit should lead to immediate surgery. Sometimes it is necessary to hospitalize the patient with pain for observation (usually about 24 hours). In addition, colicky abdominal pain is common during the first 2 or 3 days of methotrexate therapy, and the woman should avoid gas-producing foods, such as leeks and cabbage. Finally, the patient should avoid exposure to the sun, because photosensitivity can be a complication of methotrexate.
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TABLE 5.4. Treatment with multiple-dose methotrexate |
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TABLE 5.5. Methotrexate failure |
Methotrexate by Direct Injection
In 1987, Feichtinger and Kemeter instilled 1 mL (10 mg) of methotrexate into an ectopic gestational sac under transvaginal ultrasonography, and resolution occurred within 2 weeks. Direct injection delivers concentrations of methotrexate to the site of implantation at higher concentrations than those achieved with systemic administration. Less systemic distribution of the drug should decrease the overall toxicity. However, this approach has the substantial disadvantage of requiring laparoscopic or ultrasound needle guidance.
Outcomes in 21 studies involving direct injection of methotrexate with either laparoscopic or transvaginal ultrasound guidance are presented in Table 5.3. Between 1989 and 1997, 75.1% of 668 cases of ectopic pregnancy were treated successfully with methotrexate by direct injection, and some patients required more than one injection. Tubal patency and subsequent pregnancy rates were comparable to conservative laparoscopic surgery and systemic methotrexate: 80.2% of the women tested had patent oviducts and, of the women desiring pregnancy, 57.2% had a subsequent intrauterine pregnancy and 5.9% developed a recurrent ectopic pregnancy.
Randomized, controlled trials have demonstrated successful treatment with methotrexate by direct injection in 86.2% of the patients. Again, successful therapy included some patients who received more than one injection. Tubal patency was present in 85.1% of the women evaluated, and intrauterine pregnancy occurred in 73.1% of the women desiring subsequent fertility. One of the earlier randomized, controlled trials was discontinued because three of seven patients assigned to laparoscopic injection of methotrexate required additional laparoscopic surgery. Even with the higher success rate in the randomized trials, this technique is more cumbersome than systemic methotrexate.
Side Effects
High doses of methotrexate can cause bone marrow suppression, hepatotoxicity, stomatitis, pulmonary fibrosis, alopecia, and photosensitivity. These side effects are infrequent in the short treatment schedules used in ectopic pregnancy and can be attenuated by the administration of leucovorin (citrovorum factor). The side effects of methotrexate resolve within 3 to 4 days after the therapy is discontinued. Impaired liver function is the most common side effect. Other side effects include stomatitis, gastritis and enteritis, and bone marrow suppression. Local therapy by direct injection of methotrexate into the ectopic gestation resulted in fewer side effects, likely because of less systemic absorption. Even with local injection, impaired liver function tests, gastritis and enteritis, and bone marrow suppression can occur. Additional case reports exist in the literature. Cases of life-threatening neutropenia and febrile morbidity can occur after single or multidose intramuscular methotrexate, requiring hospitalization. Cases of transient pneumonitis from methotrexate therapy for ectopic pregnancy have been observed. Reversible alopecia (a loss of 33–50% of the scalp hair) on two separate occasions following single-dose therapy for an ectopic pregnancy has also been reported. Rarely, hematosalpinx and pelvic hematoceles have been noted as late sequelae of methotrexate following the normalization of β-hCG levels. These patients have pelvic pain, abnormal bleeding, and a pelvic mass, requiring surgical intervention, 3 to 5 months after therapy. Methotrexate remains the first choice before surgical therapy.
Direct Injection of Cytotoxic Agents
Prostaglandins, hyperosmolar glucose, potassium chloride, and saline by direct injection have been tried as therapeutic alternatives to methotrexate. The limited experience with prostaglandins and hypertonic glucose, poor success rates, and the need for laparoscopic or transvaginal aspiration makes these treatment alternatives unattractive.
Evidence-based Recommendation
Multiple-dose systemic methotrexate is the medical treatment of first choice for ectopic pregnancy. (Strength of recommendation: A.)
Surgical Treatment
Since the first successful salpingectomy performed by Tait in 1884, ectopic pregnancies traditionally have been treated by salpingectomy during laparotomy. Historically, ectopic pregnancies were diagnosed at the time of emergency surgery, when concern for the patient's life superseded any concerns for her future fertility. It was not until 1953, when Stromme performed the first conservative procedure (salpingostomy) for ectopic pregnancy, that subsequent successful pregnancy outcomes were reported, confirming the potential for fertility preservation after salpingostomy. Subsequently, other conservative surgical procedures, such as manual fimbrial expression and segmental tubal resection with later reanastomosis, have been performed to preserve fertility. These surgical techniques have been modified for the laparoscope.
Ruptured Ectopic Pregnancy
Early diagnosis and treatment of ectopic pregnancy avoids rupture in most cases. In the 1970s, 13.5% to 17.8% of patients with ectopic pregnancies arrived for treatment in hypovolemic shock, whereas in the early 1980s, only 4.4% of patients arrived in this condition. Today, either laparotomy or laparoscopy with salpingectomy is the first choice for rupture.
Once contraindicated over concern of decreased venous return from intraperitoneal insufflation, laparoscopic salpingectomy is successful in patients in hypovolemic shock. Nearly all patients in hypovolemic shock require blood transfusions. In the hands of a skilled laparoscopist, with adequate cardiac monitoring and anesthesia, laparoscopic salpingectomy is an acceptable alternative to laparotomy. At present, it is the surgeon's choice of laparoscopy or laparotomy for ruptured ectopic pregnancy.
Stable Ectopic Pregnancy
If methotrexate is contraindicated, laparoscopic salpingostomy is the first surgical choice. Salpingectomy can be performed either during laparotomy or laparoscopy using cautery or sutures (laparoscopic or endo-loops). Subsequent to salpingostomy, 53% of patients have intrauterine pregnancies, compared with 49.3% after salpingectomy. Recurrent ectopic pregnancy rates were slightly higher after conservative surgery, 14.8% compared with 9.9%. Laparoscopic salpingectomy is preferred over salpingostomy in cases of uncontrollable bleeding not resolving with conservative measures when extensive tubal damage is present, if the ectopic pregnancy is in the same tube, and if sterilization is desired.
The recommended conservative surgical procedure for an ampullary ectopic pregnancy is linear salpingostomy, because the ectopic nidation typically is located between the endosalpinx and serosa rather than in the tubal lumen. A linear salpingostomy is created through a longitudinal incision by electrocautery, scissors, or laser over the bulging antimesenteric border of the fallopian tube. The products of conception are removed with forceps or gentle flushing or suction. After maintaining hemostasis, the incision is closed primarily or left to heal by secondary intention.
Isthmic pregnancies routinely are treated with segmental excision, followed by intraoperative or delayed microsurgical anastomosis. The tubal lumen is narrower and the muscularis is thicker in the isthmus than in the ampulla, predisposing the isthmus to greater damage after salpingostomy and greater rates of proximal tubal obstruction.
Manual fimbrial expression, also known as milking, should be used only when the trophoblastic tissue is already aborting spontaneously through the fimbriae.
Laparoscopy has several advantages over laparotomy, including less blood loss, decreased need for analgesia, and improved postoperative recovery, as measured by shorter hospitalizations and length of time to resume normal activity. In addition, cost analysis has demonstrated significant savings in randomized trials.
Laparoscopic salpingostomy and fimbrial expression have been evaluated in 32 studies and are presented in Table 5.1. Of the 1,614 patients treated between 1980 and 1997, treatment was successful in 93.4% (required no additional therapy). Of the patients evaluated for tubal patency using either hysterosalpingography or laparoscopy, 77.8% had patent tubes. Of the women desiring subsequent fertility, 56.6% had an intrauterine pregnancy and 13.4% developed another ectopic pregnancy.
When evaluating subsequent fertility, intrauterine pregnancy rates are comparable for laparoscopy and laparotomy, as are rates of recurrent ectopic pregnancy.
PERSISTENT ECTOPIC PREGNANCY FOLLOWING SALPINGOSTOMY
Persistent ectopic pregnancy is diagnosed by a plateauing or rising β-hCG concentration following conservative surgical therapy. Although the number of reported cases is small, women with persistent ectopic pregnancies are treated successfully using single-dose systemic methotrexate.
The increased rate of persistent ectopic pregnancies has been a criticism of conservative laparoscopic therapy when compared with laparotomy. A decision analysis that compared prophylactic methotrexate with linear salpingostomy against no methotrexate in a group of 1,000 women concluded that prophylactic methotrexate at the time of surgery was preferable if certain conditions are met as follows: (a) the incidence of persistent ectopic pregnancy is greater than 9% with observation alone after salpingostomy, (b) the incidence of persistence is less than 5% when prophylactic methotrexate is given, (c) the probability of ectopic pregnancy rupture is greater than 7.3% with a persistent ectopic pregnancy, and (d) the complication rate associated with prophylactic methotrexate is less than 18%. Because the great majority of clinical circumstances meet these recommendations, prophylactic methotrexate administration is recommended.
Evidence-based Recommendation
Due to lower morbidity and equal efficacy, laparoscopic surgery is preferable to laparotomy in the treatment of bleeding or complicated ectopic pregnancy. Salpingectomy by laparotomy is reserved for ectopic ruptures with a hemodynamically unstable patient. (Strength of recommendation: A.)
ECTOPIC PREGNANCY AND ASSISTED REPRODUCTIVE TECHNOLOGY (ART)
Incidence
The risk of ectopic pregnancy is increased in patients undergoing an ART procedure. This increased risk has been attributed to the cause of infertility for which most patients seek treatment, that is, tubal factor infertility. Information on ectopic pregnancies resulting from ART comes from data obtained from institutions in the United States and Canada reporting to the Society for Assisted Reproductive Technology. The rate of pregnancies that resulted in ectopic pregnancies after in vitro fertilization (IVF) in 1999 was 3%. This included outcome of ART cycles using fresh, nondonor eggs or embryos in approximately 53,000 embryo transfers. This lower percentage likely reflected the trend toward performing salpingectomies when hydrosalpinges are present to improve the success of ART.
Location
As in naturally occurring ectopic pregnancies, the fallopian tube is the most common site for ectopic pregnancies following IVF. Data obtained from three case-control studies reveal that 82.2% of ectopic pregnancies were tubal. When tubal location was specified, 92.7% were ampullary and 7.3% interstitial. Extratubal ectopic nidations were as follows: 4.6% ovarian or abdominal, 1.5% cervical, and 11.7% heterotopic pregnancies (see Fig. 5.1).
Tubal Pathology
The most important predisposing factor for ectopic pregnancy in patients undergoing IVF is tubal pathology. Ectopic pregnancies are 4 times higher in patients with tubal factor infertility compared with patients with normal tubes. Hydrosalpinges are associated more commonly with ectopic pregnancy than other types of tubal pathology. Prior tubal reconstructive surgery (salpingostomy) increases the risk of ectopic pregnancy by 10% above that in patients with tubal factor infertility without prior surgery.
Thus, it is not surprising that patients with previous pelvic inflammatory disease have a six-fold increase in ectopic pregnancy after IVF. However, a history of prior ectopic pregnancy does not seem as important a risk factor in IVF cycles as in natural cycles.
Salpingectomy, particularly with hydrosalpinx, has been shown to decrease risks of ectopic pregnancy while increasing pregnancy rates after IVF. Meta-analysis has demonstrated that the presence of hydrosalpinges decreases the chance for viable pregnancy by approximately 50% when compared with patients with tubal disease but without hydrosalpinges.
The implantation rate was also noted to be 50% lower with a higher chance of miscarriage and ectopic gestation. The ultimate conclusion is that when a hydrosalpinx is present there is a decreased pregnancy rate with resultant decreased delivery rate following IVF.
In addition, patients who undergo salpingectomy or proximal tubal occlusion prior to oocyte retrieval and transfer are at decreased risk for pelvic infection as well as future ectopic pregnancy.
Ovulation Induction
Hormone alterations during ovulation induction theoretically alter tubal function. In animal models, estrogen administration results in functional tubal blockage and embryo arrest in the fallopian tube. In humans, steroid hormones alter tubal function and contractility, thus affecting tubal peristalsis. There remains controversy as to whether ovulation-inducing agents, including clomiphene citrate, increase ectopic pregnancy rates.
Embryo Transfer
Knutzen et al. injected 50 µL of radiopaque fluid in mock embryo transfers and found that the material entered the tubes either partially or totally in 44% of subjects, suggesting misplacement of embryos into the fallopian tubes leads to ectopic pregnancy. Embryo catheter placement was implicated also in the increased risk of ectopic pregnancies, which occurred more frequently in patients who underwent deep fundal transfer versus midcavity placement. Although transfer techniques may increase the chances of embryos reaching the fallopian tubes, ectopic pregnancies may result from tubal pathology preventing the embryos from moving back into the uterus.
Heterotopic Pregnancy
Heterotopic pregnancies occur in 1% to 3% of pregnancies following an ART procedure and usually are diagnosed incidentally on routine follow-up ultrasonographic studies. This increased prevalence of heterotopic pregnancies following ART may be related to ovarian hyperstimulation and multiple ovum development. Of 111 reported heterotopic pregnancies following ART, 88.3% were tubal, 6.3% cornual, 2.7% abdominal, 1.8% cervical, and 0.9% ovarian.
Evidence-based Recommendation
Heterotopic and extratubal ectopic pregnancies are more frequent following ART than with natural cycles. Salpingectomy or proximal tubal occlusion of a preexisting hydrosalpinx prior to IVF helps prevent tubal ectopic pregnancies while increasing pregnancy rates following ART. (Strength of recommendation: B.)
EXPECTANT MANAGEMENT
Ectopic pregnancies may resolve spontaneously. In a cavalier experiment in 1955, Lund hospitalized 119 women with ectopic pregnancy for observation. All were at least 6 weeks gestation. Some required multiple blood transfusions, and many were hemodynamically unstable. However, 68 resolved without surgery. Twelve additional studies reported in the literature since Lund's study found similar results (Table 5.3). Of the ectopic pregnancies, 67.2% resolved without surgery. Thus, both conservative medical and surgical therapy overtreats at least 50% of women with ectopic pregnancy. Falling β-hCG levels under 1,000 mIU/mL have been followed with conservative expectant management. Although patients with an equivocal diagnosis of ectopic pregnancy may be treated in this fashion, there are no data to support expectant management in clinical practice.
Evidence-based Recommendation
Expectant management of ectopic pregnancy may be considered an appropriate conservative therapy for some patients with low initial (1,000 mIU/mL) and falling hCG levels.
COST ANALYSIS
In 1990, total costs for ectopic pregnancies were estimated to be $1.1 billion. Direct costs, expenditures for health care, accounted for 77% of the total costs, and the remainder were incurred as a result of lost wages or household responsibilities not performed due to illness (indirect costs). Direct costs from hospital charges were estimated at $6,079 per case, with hospital accommodations (mean length of stay, 3.47 days) and operating room charges accounting for the majority of the hospital expense, 36% and 40%, respectively. An additional $3,254 for professional fees increased inpatient charges to $9,333, and $149 for postoperative follow-up visits increased the total direct cost to $9,482 per case. Indirect costs for a 28-day disability were estimated at $250.5 million, 67% as a result of lost wages and the remainder from lost household duties.
Laparoscopic surgery was less expensive than laparotomy. Surgical management generally has been directed toward laparoscopy. The cost of laparoscopic conservative surgery or salpingectomy was estimated at $2,125 and $1,872, respectively. Costs for conservative treatment or salpingectomy via laparotomy were estimated to be higher, $3,420 and $3,490, respectively. Systemic methotrexate therapy is even more cost efficient.
Charges for patients successfully treated with methotrexate average $1,563 (range, $1,169 to $2,300). Patients requiring laparotomy, due to hemodynamic instability, incur a higher average charge of $8,001 (range, $3,171 to $22,082). The average length of stay following laparotomy was 5.2 days.
A study, undertaken to compare the costs of systemic methotrexate with surgery, concluded that there would be a reduction in overall costs if patients were treated without confirmatory laparoscopy when hCG levels were below 3,000 mIU/mL; otherwise, there was not a substantial cost saving over surgery. Because a confirmatory laparoscopy no longer is required for diagnosis, the lower cost for medical therapy is more realistic. Compared with the cost of a laparoscopic salpingostomy, methotrexate results in a 20% decrease in the cost of treatment.
Evidence-based Recommendation
Systemic methotrexate for unruptured ectopic pregnancy is less expensive than surgery, and direct costs are decreased substantially with methotrexate therapy. In addition to its cost effectiveness, systemic methotrexate does not subject patients to surgery and the complications associated with it. This cost benefit, however, diminishes with higher hCG titers and even disappears with levels greater than 3,000 mIU/mL, because of treatment failures and increased complications. (Strength of recommendation: B.)
RARE TYPES OF ECTOPIC PREGNANCY
Abdominal Pregnancy
The incidence of abdominal pregnancy is estimated at 1 in 8,000 births and represents 1.4% of all ectopic pregnancies. The prognosis is poor, with an estimated maternal mortality rate of 5.1 per 1,000 cases. The risk of dying from an abdominal pregnancy is 7.7 times higher than from other forms of ectopic pregnancy. The high rate of morbidity and mortality from abdominal pregnancy often results from a delay in diagnosis.
Abdominal pregnancies can be categorized as primary or secondary. These ectopic pregnancies may become apparent throughout gestation, from the first trimester to fetal viability. Symptoms may vary from those considered normal for pregnancy to severe abdominal pain, intraabdominal hemorrhage, and hemodynamic instability. Primary abdominal pregnancies are rare and are thought to occur as a result of primary peritoneal implantation. They usually abort early in the first trimester due to hemorrhagic disruption of the implantation site and hemoperitoneum. Secondary abdominal pregnancies occur with reimplantation after a partial tubal abortion or intraligamentary extension following tubal rupture. Historical criteria to distinguish between primary and secondary abdominal pregnancies are moot, because treatment is directed by the clinical picture.
Ultrasonography is the diagnostic tool of choice and usually can identify the empty uterus along with the extrauteral products of conception. If the fetus is near viability, hospitalization is recommended. If time permits, bowel preparation, administration of prophylactic antibiotics, and adequate blood replacement should be made available prior to an operative delivery. Unless the placenta is implanted on major vessels or vital structures, it should be removed. Although complications may occur, including sepsis, abscess formation, secondary hemorrhage, intestinal obstruction, wound dehiscence, amniotic fluid cyst formation, hypofibrinogenemia, and preeclampsia, the placenta can be left in place to prevent further hemorrhage at the time of surgery. In contrast to the typical tubal ectopic pregnancy, methotrexate is unlikely to accelerate retained placental absorption, because the trophoblastic cells are no longer actively dividing.
Ovarian Pregnancy
Ovarian pregnancy, the most common form of abdominal pregnancy, is rare, accounting for less than 3% of all ectopic gestations. Clinical findings are similar to those of tubal ectopic gestations: abdominal pain, amenorrhea, and abnormal vaginal bleeding. In addition, hemodynamic instability as a result of rupture occurs in 30% of patients.
Women with ovarian pregnancies are usually young and multiparous, but the factors leading to ovarian pregnancies are not clear.
The diagnosis usually is made by the pathologist, because many ovarian pregnancies are mistaken for a ruptured corpus luteum or other ovarian tumors. Only 28% of cases were diagnosed correctly at time of laparotomy. The recommended treatment is cystectomy, wedge resection, or oophorectomy during laparotomy, although laparoscopic removal has been successful.
Cornual Pregnancy
Cornual or interstitial pregnancy accounts for 4.7% of ectopic gestations and carries a 2.2% maternal mortality. Almost all cases are diagnosed after the patient is symptomatic. The most frequent symptoms are menstrual aberration, abdominal pain, abnormal vaginal bleeding, and shock, resulting from the brisk hemorrhage associated with uterine rupture. Due to myometrial distensibility, rupture is usually delayed, occurring at 9 to 12 weeks gestation.
A unique risk factor for interstitial pregnancy is previous salpingectomy, present in about 25% of patients.
Only a high index of suspicion and repeated ultrasonographic examination with Doppler flow studies allows early diagnosis. With a timely early diagnosis, alternatives to the traditional cornual resection during laparotomy have been performed successfully. These include laparoscopic cornual resection, systemic methotrexate administration, local injection of methotrexate, potassium chloride injection, and removal by hysteroscopy. Regardless of the initial treatment attempted, if uncontrolled hemorrhage occurs, immediate hysterectomy is warranted.
Cervical Pregnancy
The incidence of cervical pregnancy ranges from 1 in 2,500 to 1 in 12,422 pregnancies. The most common predisposing factor is a prior dilation and curettage, present in 68.6% of patients. Interestingly, 31% of these were performed for termination of pregnancy. Other predisposing factors implicated in cervical pregnancies are previous cesarean delivery and IVF.
The most common initial symptom of cervical pregnancy is painless vaginal bleeding. These ectopics usually are diagnosed incidentally during routine ultrasonography or at the time of surgery for a suspected abortion in progress. In reported cases, 91% of patients sought treatment for vaginal bleeding, and 29.2% had massive bleeding. Not surprisingly, abdominal pain occurred with vaginal bleeding in only 25.8% of cases. The cervix is usually enlarged, globular, or distended. On occasion, it appears cyanotic, hyperemic, and soft in consistency. Sonography and magnetic resonance imaging have improved diagnosis of cervical pregnancy. Up to 81.8% of patients have been diagnosed correctly with ultrasonographic identification of the gestational sac in the cervix below a closed internal cervical os, with trophoblastic invasion into the endocervical tissue.
When the patient is hemodynamically stable, conservative therapy commonly is employed. There are no large studies, only several case series. These have shown that use of methotrexate and uterine artery embolization are safe and effective for treatment in the stable patient with a cervical pregnancy. Systemic and local treatment with various agents carries an overall success rate of 81.3%. Unfortunately, massive hemorrhage may occur despite conservative measures, and hysterectomy is warranted.
Heterotopic Pregnancy
Heterotopic pregnancy is the coexistence of an intrauterine and ectopic gestation. In 1948, the spontaneous heterotopic pregnancy rate was calculated as 1 in 30,000 pregnancies, based on an ectopic pregnancy incidence of 0.37% and dizygous twinning rate of 0.8%. In the 1980s, the calculation rose to 1 in 10,000 due to an increased ectopic pregnancy rate. Today, heterotopic pregnancies occur in 1 in 3,889 to 1 in 6,778 pregnancies. In a review of 66 heterotopic pregnancies by Reece et al., 93.9% were tubal and 6.1% ovarian.
Simultaneous existence of intra- and extrauterine pregnancies poses several diagnostic pitfalls. Heterotopic pregnancies are diagnosed in most cases after clinical signs and symptoms develop, and 50% of patients are admitted for emergency surgery following rupture. The delay in diagnosis is secondary to the finding of an intrauterine pregnancy, with the assumption that any symptoms will be self-limited.
Similar to tubal ectopic pregnancies, the most common complaint is lower abdominal pain. Routine ultrasonography detects only about 50% of tubal heterotopic pregnancies, and the remainder are diagnosed during laparoscopy or laparotomy when patients become symptomatic. Serial levels of the β subunit of hCG are not helpful due to the effect of the intrauterine pregnancy.
If patients are hemodynamically unstable, exploratory laparotomy is warranted. If the diagnosis is suspected or the patient is symptomatic but hemodynamically stable, laparoscopy can be performed. Expectant management is not recommended, because β-hCG levels cannot be monitored adequately. Systemic methotrexate is contraindicated if a viable intrauterine pregnancy is present and desired. Local injection of methotrexate with potassium chloride has been noted successful in a small case series.
SUMMARY POINTS
· In most circumstances, ectopic pregnancy can be diagnosed before symptoms develop and treated definitively with few complications.
· Quantitative β-hCG testing, ultrasonography, and curettage allow early diagnosis of ectopic pregnancy and use of medical therapy as the initial therapy option.
· Conservative surgical therapy and medical therapy for ectopic pregnancy are comparable in terms of success rates and subsequent fertility. Medical therapy is the preferred choice because of the freedom from surgical complications and lower cost.
· Surgery is the treatment of choice for hemorrhage, medical failures, neglected cases, and when medical therapy is contraindicated.
· Multiple-dose methotrexate is preferable to single-dose methotrexate, direct injection, or tubal cannulation and is the first choice for unruptured, uncomplicated ectopic pregnancy.
· Laparoscopic salpingostomy or salpingectomy is favored for cases of intraabdominal hemorrhage, medical failure, neglected cases, and complex cases when medical therapy is contraindicated.
· Prophylactic postoperative systemic methotrexate (a single dose) can prevent virtually all cases of persistent ectopic pregnancy following salpingostomy.
· Salpingectomy prior to IVF decreases ectopic pregnancy incidence while increasing pregnancy rates in select patients with preexisting tubal disease.
REFERENCES
Incidence
Carson SA, Buster JE. Ectopic pregnancy. N Engl J Med 1993;329:1174–1181.
Chow W, Daling JR, Cates W, et al. Epidemiology of ectopic pregnancy. Epidemiol Rev 1987;9:70–94.
National Center for Health Statistics. Advance report of final mortality statistics, 1992. Hyattsville, MD: US Department of Health and Human Services, Public Health Service, CDC. Mon Vital Stat Rep 1994;43[Suppl].
Pathogenesis
Bone NL, Greene RR. Histological study of uterine tube with tubal pregnancy: a search for evidence of previous injection. Am J Obstet Gynecol1961;82:1166.
Budowick M, Johnson TRB, Genadry R, et al. The histopathology of the developing tubal ectopic pregnancy. Fertil Steril 1980;34:169–171.
Westrom L. Effect of acute pelvic inflammatory disease on fertility. Am J Obstet Gynecol 1975;121:707–713.
Risk Factors
Ankum WM, Mol BWJ, Van der Veen F, et al. Risk factors for ectopic pregnancy: a meta-analysis. JAMA 1996;65:1093–1099.
Brenner PF, Benedetti T, Mishell DR. Ectopic pregnancy following tubal sterilization surgery. Obstet Gynecol 1977;49:323–324.
Dubuisson JB, Aubriot FX, Mathieu L, et al. Risk factors for ectopic pregnancy in 556 pregnancies after in vitro fertilization: implications for preventive management. Fertil Steril 1991;56:686–690.
Kranz SG, Gray RH, Damewood MD, et al. Time trends in risk factors and clinical outcome of ectopic pregnancy. Fertil Steril 1990;54:42–46.
Majmudar B, Henderson PH, Semple E. Salpingitis isthmica nodosa: a high-risk factor for tubal pregnancy. Obstet Gynecol 1983;62:73–78.
Mol BWJ, Ankum WM, Bossuyt PMM, et al. Contraception and the risk of ectopic pregnancy: a meta-analysis. Contraception 1995;52:337–341.
Signs and Symptoms
Barnhart K, Mennuti M, Benjamin I, et al. Prompt diagnosis of ectopic pregnancy in an emergency department setting. Obstet Gynecol 1994;84:1010–1015.
Breen JL. A 21-year survey of 654 ectopic pregnancies. Am J Obstet Gynecol 1970;106:1004–1019.
Grimes DA. The morbidity and mortality of pregnancy: still risky business. Am J Obstet Gynecol 1995;170:1489–1494.
Diagnosis
Buster JE, Carson SA. Ectopic pregnancy: new advances in diagnosis and treatment. Curr Opin Obstet Gynecol 1995;7:168–176.
Garcia CR, Barnhart KT. Diagnosing ectopic pregnancy: decision analysis comparing six strategies. Obstet Gynecol 2001;97:464–70.
Goldstein SR, Snyder JR, Watson C, et al. Vaginal sonography versus serum human chorionic gonadotropin in early detection of pregnancy. Am J Obstet Gynecol 1988;158:608–612.
Kim DS, Chung SR, Park MI, et al. Comparative review of diagnostic accuracy in tubal pregnancy: a 14-year survey of 1040 cases. Obstet Gynecol1987;70:547–554.
Lindblom B, Hahlin M, Sjoblom P. Serial human chorionic gonadotropin determinations by fluoroimmunoassay for differentiation between intrauterine and ectopic gestation. Am J Obstet Gynecol 1989;161:397–400.
Shalev E, Yarom I, Bustan M, et al. Transvaginal sonography as the ultimate diagnostic tool for the management of ectopic pregnancy: experience with 840 cases. Fertil Steril 1998;69:62–65.
Stovall TG, Ling FW, Cope BJ, et al. Preventing ruptured ectopic pregnancy with a single serum progesterone. Am J Obstet Gynecol 1989;160:1425–1431.
Timor-Tritsch IE, Meh MN, Peisner DB, et al. The use of transvaginal ultrasonography in the diagnosis of ectopic pregnancy. Am J Obstet Gynecol1989;161:157–161.
Treatment for Ectopic Pregnancy
Medical Management
Buster JE, Heard MJ. Current issues in medical management of ectopic pregnancy. Curr Opin Obstet Gynecol 2000;12:525–527.
Fernandez H, Pauthier S, Sitbon D, et al. Role of conservative therapy and medical treatment in ectopic pregnancy: literature review and clinical trial comparing medical treatment and conservative laparoscopic treatment. Contracept Fertil Sex 1996;24:297–302.
Hajenius PJ, Mol BW, Bossuyt PM, et al. Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev 2000;(2):CD000324.
Kooi S, Kock HC. A review of the literature on nonsurgical treatment in tubal pregnancies. Obstet Gynecol Surv 1992;47:739–749.
Medical Management of Tubal Pregnancy. ACOG Practice Bulletin, Clinical Management Guidelines for Obstetrician-Gynecologists December 1998;3:410–416.
Shalev E, Peleg D, Bustan M, et al. Limited role for intratubal methotrexate treatment of ectopic pregnancy. Fertil Steril 1995;63:20–24.
Stovall TG, Ling FW, Gray LA, et al. Methotrexate treatment of unruptured ectopic pregnancy: a report of 100 cases. Obstet Gynecol 1991;77:749–753.
Stovall TG, Ling FW. Single-dose methotrexate: an expanded clinical trial. Am J Obstet Gynecol 1993;168:759–772.
Surgical Treatment
Brumsted J, Kessler C, Gibson C, et al. A comparison of laparoscopy and laparotomy for the treatment of ectopic pregnancy. Obstet Gynecol 1988;71:889–892.
DeCherney AH, Kase N. The conservative surgical management of unruptured ectopic pregnancy. Obstet Gynecol 1979;54:451–455.
Gracia C, Brown H, Barnhart K. Prophylactic methotrexate after linear salpingostomy: a decision analysis. Fertil Steril 2001;76:1191–1195.
Lundorff P, Thorburn J, Hahlin M, et al. Laparoscopic surgery in ectopic pregnancy: a randomized trial versus laparotomy. Acta Obstet Gynecol Scand1991;70:343–348.
Murphy AA, Nager CW, Wujek JJ, et al. Operative laparoscopy versus laparotomy for the management of ectopic pregnancy: a prospective trial. Fertil Steril1992;57:1180–1185.
Pouly JL, Mahnes H, Mage G, et al. Conservative laparoscopic treatment of 321 ectopic pregnancies. Fertil Steril 1986;4:1093–1097.
Seifer DB, Guttmann JN, Grant WD, et al. Comparison of persistent ectopic pregnancy after laparoscopic salpingostomy versus salpingostomy at laparotomy for ectopic pregnancy. Obstet Gynecol 1993;81:378–382.
Silva PD, Schaper AM, Rooney B. Reproductive outcome after 143 laparoscopic procedures for ectopic pregnancy. Obstet Gynecol 1993;81:710–715.
Vermesh M, Silva PD, Rosen GF, et al. Management of unruptured ectopic gestation by linear salpingostomy: a prospective, randomized clinical trial of laparoscopy versus laparotomy. Obstet Gynecol 1989;73:400–404.
Ectopic Pregnancy and Assisted Reproductive Technology
Abusheikha N, Salha O, Brinsden P. Extra-uterine pregnancy. Assisted reproductive technology in the United States and Canada: 1994 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 1996;66:697–705.
Camus E, Poncelet C, Goffinet F, et al. Pregnancy rates after in-vitro fertilization in cases of tubal infertility with and without hydrosalpinx: a meta-analysis of published comparative studies. Hum Reprod 1999;14:1243–1249.
Abusheikha N, Salha O, Brinsden P. Extra-uterine pregnancy following assisted conception treatment. Hum Reprod Update 2000;6:80–92.
Marcus SF, Brinsden PR. Analysis of the incidence and risk factors associated with ectopic pregnancy following in vitro fertilization and embryo transfer. Hum Reprod 1995;10:199–203.
Martinez F, Trounson A. An analysis of factors associated with ectopic pregnancy in a human in vitro fertilization program. Fertil Steril 1986:45:79–87.
Expectant Management
Fernandez H, Lelaidier C, Baton C, et al. Return of reproductive performance after expectant management and local treatment for ectopic pregnancy. Hum Reprod 1991;6:1474–1477.
Garcia AJ, Aubert JM, Sama J, et al. Expectant management of presumed ectopic pregnancies. Fertil Steril 1987;48:395–400.
Shalev E, Peleg D, Tsabari A, et al. Spontaneous resolution of ectopic tubal pregnancy: natural history. Fertil Steril 1995;63:15–19.
Ylöstalo P, Cacciatore B, Korhonen J, et al. Expectant management of ectopic pregnancy. Eur J Obstet Gynecol Reprod Biol 1993;49:83–84.
Cost Analysis
Alexander JM, Rouse DJ, Varner E, et al. Treatment of the small unruptured ectopic pregnancy: a cost analysis of methotrexate versus laparoscopy. Obstet Gynecol 1996;88:123–127.
Mol BW, Hajenius PJ, Engelsbel S, et. al. Treatment of tubal pregnancy in the Netherlands: an economic comparison of systemic methotrexate administration and laparoscopic salpingostomy. Am J Obstet Gynecol 1999;181:945–951.
Mol BWJ, Hajenius PJ, Engelsbel S, et al. An economic evaluation of laparoscopy and open surgery in the treatment of tubal pregnancy. Acta Obstet Gynecol Scand 1997;76:1–5.
Stovall TG, Bradham DD, Ling FW, et al. Cost of treatment of ectopic pregnancy: single-dose methotrexate versus surgical treatment. J Womens Health1994;3:445–450.
Washington AE, Katz P. Ectopic pregnancy in the United States: economic consequences and payment source trends. Obstet Gynecol 1993;81:287–292.
Yao M, Tulandi T, Kaplow M, et al. A comparison of methotrexate versus laparoscopic surgery for treatment of ectopic pregnancy: a cost analysis. Hum Reprod 1996;11:2762–2766.
Rare Types of Ectopic Pregnancy
Atrash HK, Friede A, Hogue CJR. Abdominal pregnancy in the United States: frequency and maternal mortality. Obstet Gynecol 1987;69:333–337.
Goldenberg M, Bider D, Oelsner G, et al. Treatment of interstitial pregnancy with methotrexate via hysteroscopy. Fertil Steril 1992;58:1234–1236.
Grimes HG, Nosal RA, Gallagher JC. Ovarian pregnancy: a series of 24 cases. Obstet Gynecol 1983;61:174–180.
Hallatt JG. Primary ovarian pregnancy: a report of twenty-five cases. Am J Obstet Gynecol 1982;143:55–60.
Reece EA, Petrie RH, Sirmans MF, et al. Combined intrauterine and extrauterine gestations: a review. Am J Obstet Gynecol 1983;146:323–330.
Timor-Tritsch IE, Monteagudo A, Mandeville EO, et al. Successful management of viable cervical pregnancy by local injection of methotrexate. Am J Obstet Gynecol 1994;170:737–739.
Ushakov FB, Elchalal U, Aceman PJ, et al. Cervical pregnancy: past and future. Obstet Gynecol 1996;52:45–59.
