Berek and Novak's Gynecology 15th Ed.

20 Early Pregnancy Loss and Ectopic Pregnancy

Amy J. Voedisch

Carrie E. Frederick

Thomas G. Stovall

• Spontaneous pregnancy loss is common, occurring in up to 20% of recognized conceptions.

• Following an ectopic pregnancy, approximately 15% of women will have a subsequent ectopic pregnancy.

• Single-dose methotrexate appears to be the treatment of choice if medical therapy is indicated and selected.

• Surgical management and medical therapy appear to be equivalent in a randomized comparison.

An abnormal gestation can be either intrauterine or extrauterine. Extrauterine or ectopic pregnancy occurs when the fertilized ovum becomes implanted in tissue other than the endometrium. Although 70% of ectopic gestations are located in the ampullary segment of the fallopian tube, such pregnancies may also occur in other sites (Fig. 20.1) (1). Abnormal intrauterine pregnancy often results in pregnancy loss early in gestation. Such losses can be related to a number of factors such as age, previous pregnancy loss, and maternal smoking (Table 20.1). With both abnormal intrauterine and extrauterine gestation, early recognition is key to diagnosis and management.

Table 20.1 Potential Causes of Spontaneous Pregnancy Loss

Increased maternal age

Previous spontaneous abortion

Maternal smoking

Maternal systemic disease (diabetes mellitus, infection, thrombophilia, etc.)

Maternal alcohol consumption (moderate to high)

Increasing gravidity

Amphetamine use

Chromosomal or other embryologic abnormalities

Anembryonic gestation

Uterine anomalies

Intrauterine device in place

Placental anomalies

Severe maternal trauma

Extremes of maternal weight

Figure 20.1 Common sites of ectopic pregnancy. (Adapted from Seeber BE. Suspected ectopic pregnancy. Obstet Gynecol 2006;107:399–413.)

Abnormal Intrauterine Pregnancy

Spontaneous Abortion

Spontaneous abortion is a pathologic process resulting in unintentional termination of the pregnancy prior to 20 weeks' gestation. About 8% to 20% of known pregnancies terminate in spontaneous abortion (2,3). About 80% of spontaneous pregnancy losses occur in the first trimester; the incidence decreases with each gestational week (4–6). In women who had one prior spontaneous abortion, the rate of spontaneous abortion in a subsequent pregnancy ranges from 13% to 20%; in women who had three consecutive losses, the rate is 33% (7). Patients should be reassured that, in most cases, spontaneous abortion does not recur. In women less than 36 years of age, when fetal cardiac activity is confirmed by ultrasound, the risk of spontaneous abortion is less than 4.5%. For women older than 36, the risk of spontaneous abortion rises to 10%, and above 40 years may approach 30% (8). Risk factors for spontaneous abortion include increasing maternal age, closely spaced pregnancies (less than 3 to 6 months apart), history of previous spontaneous abortion, maternal diabetes, and maternal smoking during pregnancy (9–13).

With pelvic ultrasound, spontaneous abortion can be differentiated into various categories, based on examination findings and ultrasound findings. Missed abortion is defined as a nonviable intrauterine pregnancy in the presence of a closed cervix and little or no abdominal cramping or vaginal bleeding and can be subdivided into anembryonic gestation and embryonic demise. Anembryonic gestation is a pregnancy where the embryo failed to develop and is confirmed when the mean gestational sac diameter measured by transvaginal ultrasound is greater than 20 mm and no embryonic pole is present. When an embryo is present with crown-rump length greater than 5 mm and no cardiac activity, this is classified as embryonic demise, and the pregnancy is nonviable (14).

Threatened Abortion

Threatened abortion is defined as vaginal bleeding before 20 weeks of gestation. It occurs in at least 20% of all pregnancies (15). The distinction from missed or inevitable abortion requires ultrasound documentation of an intrauterine embryo or fetus with cardiac activity. The bleeding is usually light and may be associated with mild lower abdominal or cramping pain. The differential diagnosis in these patients includes consideration of possible cervical polyps, vaginitis, cervical carcinoma, gestational trophoblastic disease, ectopic pregnancy, trauma, and foreign body. On physical examination, the abdomen usually is not tender, and the cervix is closed. Bleeding can be seen coming from the os, and usually there is no cervical motion or adnexal tenderness.

In the vast majority of cases, threatened abortion does not result in a pregnancy loss, but may be associated with poor outcomes later in pregnancy. In a study of 347 patients with a first-trimester pregnancy documented by ultrasonography, the overall rate of pregnancy loss was 6.1% to 4.2% in patients without bleeding and 12.4% in patients with bleeding (4). In a review of over 800 women presenting with first trimester vaginal bleeding or abdominal pain, nearly 14% with bleeding had spontaneous abortion compared with 2.5% in patients without bleeding (5). There is no effective therapy for a threatened intrauterine pregnancy. Bed rest and progesterone treatment, although often advocated, are not effective (16–18). Women with first trimester vaginal bleeding who do go on to have continuing pregnancies have nearly three times the risk of preterm birth between 28 and 31 weeks as women without bleeding, and a 50% higher likelihood of preterm birth between 32 to 36 weeks (19). First trimester bleeding may predict higher risk for intrauterine growth restriction, preterm premature rupture of membranes, and placental abruption (20). Bacterial vaginosis, if present, should be treated, as this is associated with increased risk for spontaneous abortion (21).

Inevitable Abortion

With an inevitable abortion, the volume of bleeding is often greater than with other types of abortion, and the cervical os is open and effaced, but no tissue has passed. Most patients have crampy lower abdominal pain, and some have cervical motion or adnexal tenderness. When it is certain that the pregnancy is not viable because the cervical os is dilated or excessive bleeding is present, the patient should be offered medical or surgical management. Blood type and Rh determination and a complete blood count should be obtained if there is any concern about the amount of bleeding. Rh₀(D) immune globulin (RhoGAM) should be given if the patient’s blood is Rh negative(22). It is acceptable to give a dose of 50 μg [MB2]until 12 completed weeks; if this dose is not available, the standard 300 μg dose may be given.

Incomplete Abortion

An incomplete abortion is a partial expulsion of the pregnancy tissue. Although most patients have vaginal bleeding, only some have passed tissue. Lower abdominal cramping is invariably present, and the pain may be described as resembling labor. On physical examination, the cervix is dilated and effaced, and bleeding is present. Often, clots are admixed with products of conception. If the bleeding is profuse, the patient should be examined promptly for tissue protruding from the cervical os; removal of this tissue with a ring forceps may reduce the bleeding. A vasovagal bradycardia may occur and responds to removal of the tissue. A complete blood count, maternal blood type, and Rh determination should be obtained; Rh-negative patients should receive RhoGAM. If the patient is febrile, broad-spectrum antibiotic therapy should be administered.

Management of Spontaneous Abortion

In women with stable vital signs and mild vaginal bleeding, three management options exist: expectant management, medical treatment, and suction curettage. Despite a wide range (25% to 76%) of success cited in the literature, expectant management may remain a desirable option for a stable and carefully counseled patient (23,24). Medical management with 800 μg of misoprostol placed vaginally can be up to 84% effective in achieving complete abortion (25). For incomplete abortion, the misoprostol dose can be reduced to 600 μg orally or 400 μg sublingually, with efficacy greater than 90% (26). Suction curettage should be performed in women with excessive bleeding, unstable vital signs, or in whom reliable follow-up is a concern.

Ectopic Gestation

Incidence

The most comprehensive data available on ectopic pregnancy rates were collected by the Centers for Disease Control and Prevention (CDC). The incidence of ectopic pregnancy increased significantly in the past century. In 1992, the latest year for which statistics are published, there were an estimated 108,800 ectopic pregnancies at a rate of 19.7 ectopic pregnancies per 1,000 reported pregnancies. This represents a sixfold increase compared with 1970 rates. The observed increase may represent an increase in detection and diagnosis resulting from more sensitive ultrasound technology, and a rise in sexually transmitted illnesses and assisted reproductive technologies (27). As Figure 20.2 demonstrates, while the absolute number of ectopic pregnancies continues to rise, the number of hospitalizations declined since the late 1980s, likely because of increasing outpatient management of this condition. Precise estimation of the true incidence of ectopic pregnancy is difficult, but the most recent estimate by the CDC is 2% of reported pregnancies (28). The data on demographic trends indicate that the highest rates occurred in women aged 35 to 44 years (27.2 per 1,000 reported pregnancies). When the data are analyzed by race, the risk for ectopic pregnancy among African Americans and other minorities (20.8 per 1,000) is 1.6 times greater than the risk among whites (13.4 per 1,000) (29). In 1992, 9% of all maternal deaths were attributable to ectopic pregnancy, down from 15% in 1988. The risk for death is higher for African Americans and other minorities than for whites. For all races, teenagers have the highest mortality rates, but the rate for African American and other minority teenagers is almost five times that of white teenagers (28,29). After an ectopic pregnancy, there is an 8% to 15% chance of recurrent ectopic pregnancy, with single-dose methotrexate conferring the lowest risk, while linear salpingostomy is associated with the highest risk (30). Many variables make accurate assessment of risk difficult (e.g., size and location of the ectopic pregnancy, status of the contralateral adnexa, treatment method, and history of infertility).

Figure 20.2 Estimation of the number of ectopic pregnancies (United[MB5]States, 1970–1992). (Adapted from MMWR 1995;44:46–48.)

Etiology and Risk Factors

Ectopic pregnancy results from various factors that interrupt the successful migration of the conceptus to the endometrium. The most important risk factors for ectopic pregnancy are a history of tubal surgery, including tubal ligation, prior ectopic pregnancy, in utero diethylstilbestrol (DES) exposure, and history of pelvic inflammatory disease (31,32). Intrauterine device (IUD) use and infertility are associated with increased risk for ectopic gestation, but these relationships are complex. Up to half of women with ectopic pregnancy will have no identifiable risk factors (33–35). Many other risk factors, including smoking and multiple lifetime sexual partners, are weakly associated with ectopic pregnancy (32).

Myoelectrical activity is responsible for propulsive activity in the fallopian tube (36). This activity facilitates movement of the sperm and ova toward each other and propels the zygote toward the uterine cavity. Estrogen increases smooth muscle activity, and progesterone decreases muscle tone. Aging results in progressive loss of myoelectrical activity along the fallopian tube, which may explain the increased incidence of tubal pregnancy in perimenopausal women (36). Hormonal control of the muscular activity in the fallopian tube may explain the increased incidence of tubal pregnancy associated with failures of the morning-after pill, minipill, progesterone-containing IUDs, and ovulation induction. There is no increase in the incidence of chromosomal abnormalities in ectopic pregnancies (37).

Tubal Surgery

As would be expected, factors that disrupt normal tubal anatomy are the primary etiology for ectopic pregnancy. Women with prior tubal surgery have a more than 20-fold increased risk of subsequent ectopic pregnancy (32). Tubal repair or reconstruction may be performed to correct an obstruction, lyse adhesions, or evacuate an unruptured ectopic pregnancy. Although it is clear that tubal surgery is associated with an increased risk for ectopic pregnancy, it is unclear whether the increased risk results from the surgical procedure or from the underlying problem. A four- to fivefold increased risk is associated with salpingostomy, neosalpingostomy, fimbroplasty, anastomosis, and lysis of complex peritubal and periovarian adhesions (38). After tubal surgery, the overall rate of ectopic pregnancy is 2% to 7%, and the viable intrauterine pregnancy rate is 50% (38).

Though tubal sterilization remains one of the most effective forms of contraception, failures do occur; when they do, they are more likely to result in ectopic gestation. The 10-year cumulative incidence of pregnancy after any form of tubal sterilization is 18.5 per 1,000 woman-years and the likelihood of sterilization failure does not decrease with time since the procedure (39). Despite a greater proportion of poststerilization failures resulting in ectopic pregnancy, the absolute rate of ectopic pregnancy is decreased after sterilization (40). Calculating cumulative lifetime risk for ectopic pregnancy according to method of contraception, sterilized women have a lower cumulative risk for ectopic pregnancy than IUD users or nonusers of contraception, and women using barrier methods or oral contraceptives have the lowest risk (40).

The 10-year cumulative incidence of tubal pregnancy after any sterilization procedure is 7.3 per 1,000 procedures (41). The risk depends on the sterilization technique and the woman’s age at the time of sterilization: postpartum partial salpingectomy and unipolar coagulation have the lowest rates of ectopic pregnancy (1.5 and 1.8 per 1,000 procedures), while bipolar coagulation techniques had the highest incidence (17.1 per 1,000 procedures). Spring clip and band application techniques have 10-year ectopic rates similar to the general incidence, 8.5 and 7.3 per 1,000 procedures, respectively (41). Women younger than 28 years at the time of sterilization are more likely to have a failure than women over 34 years.

Sterilization reversal increases risk for ectopic pregnancy. The exact risk depends on the method of sterilization, site of tubal occlusion, residual tube length, coexisting disease, and surgical technique. In general, the risk for reanastomosis of a cauterized tube is up to 17%, and it ranges from 6% to 9% for reversal of Pomeroy and 5% to 11% for reversal of ring procedures (42–47).

Prior Ectopic Pregnancy

A previous history of ectopic pregnancy is a risk factor for another occurrence. The likelihood of recurrence exists because of the factors that led to an initial ectopic implantation and may be affected by the type of treatment the patient received with the first episode. There is concern that conservation of the tube at the time of removal of an ectopic pregnancy would increase the risk for recurrent ectopic pregnancy (27,48). The rates for intrauterine pregnancy (40%) and ectopic pregnancy (15%, range 4% to 28%) are similar after tubal removal or conservation (49). In a series of 54 patients with conservative surgical procedures for management of ectopic pregnancy, the incidence of future ectopic pregnancy could be predicted by the status of the contralateral tube: normal (7%), abnormal (18%), or absent (25%) (50). In a later study of pregnancy outcomes of 200 patients treated with tubal conservation for ectopic pregnancy, preservation of the tube did not increase the incidence of repeat ectopic pregnancy, but it did improve overall fertility rates (51). The risk of recurrence after methotrexate treatment is similar to that encountered with salpingectomy (52,53). The risk of recurrent ectopic pregnancy after two prior episodes may be as high as 30% (54).

Pelvic Infection

The relationship of pelvic infection, tubal obstruction, and ectopic pregnancy is well documented. In a study of 2,500 women with suspected pelvic inflammatory disease (PID) who underwent diagnostic laparoscopy, the incidence of ectopic pregnancy in the subsequent pregnancy for those with laparoscopically confirmed disease was 9.1% compared with 1.4% in the women with normal laparoscopy (55). In a study of 415 women with laparoscopically proven PID, the incidence of tubal obstruction increased with successive episodes of PID: 13% after one episode, 35% after two, and 75% after three (56).

Chlamydia is an important pathogen causing tubal damage and subsequent tubal pregnancy. Chlamydia was cultured from 7% to 30% of patients with tubal pregnancy (57,58). A strong association between chlamydia infection and tubal pregnancy was shown with serologic tests for chlamydia (59–62). Conception is three times as likely to be tubal in women with anti–Chlamydia trachomatistiters higher than 1:64 than in those women whose titers were negative (63). The number of episodes of chlamydia is directly associated with risk for ectopic pregnancy. In a retrospective cohort study of 11,000 women, those with two chlamydial infections were more than twice as likely to develop ectopic pregnancy as those with one, and women with three or more were at greater than four times higher risk (64). Women at risk for chlamydia infections should be diligently tested, treated when infection is present, and counseled about the risk of ectopic pregnancy.

Diethylstilbestrol

Women exposed to DES in utero who subsequently conceive are at increased risk for ectopic pregnancy. In a review by Goldberg and Falcone, the pooled risk of ectopic pregnancy in DES-exposed women was nine times that of nonexposed women (65). Structural tubal abnormalities were found in DES-exposed women, including foreshortening, constrictions, and distortions (66). The Collaborative Diethylstilbestrol-Adenosis Project, which monitored 327 DES-exposed women, found that about 50% had uterine cavity abnormalities. In DES-exposed women, the risk for ectopic pregnancy was 13% in those who had uterine abnormalities compared with 4% in those who had a normal uterus. No specific type of defect was related to the risk for ectopic pregnancy (67).

Contraceptive Use

It is not surprising that by reducing the overall likelihood of pregnancy, contraceptive use reduces the risk of ectopic pregnancy. There is concern that because of the various mechanisms of action of contraceptives, if a pregnancy were to occur, it might be more likely to be ectopic. In a meta-analysis of 13 studies examining the relationship between contraception and the risk of ectopic pregnancy, there was no increased risk in users of oral contraceptives or barrier methods compared with pregnant controls (40). There is no demonstrated increased risk in users of depomedroxyprogesterone injections, emergency contraceptive pills, or etonogestrel implants (68–70).

Hormonal and copper-containing IUDs are highly effective at preventing both intrauterine and extrauterine pregnancies. Women who conceive with an IUD in place are more likely to have a tubal pregnancy than those not using contraceptives. For women using the levonorgestrel intrauterine device, half of pregnancies will be ectopic, and 1 in 16 pregnancies in women with a copper IUD in place will be ectopic (71). The baseline risk of ectopic pregnancy in women not contracepting is 1 in 50. In a meta-analysis of studies investigating risk of ectopic pregnancy in IUD users compared with nonpregnant controls, IUD use had a protective effect with the exception of one study that showed no effect of IUD use (40). In the same meta-analysis, when IUD users were compared with pregnant controls, IUD use was associated with a significantly increased risk for ectopic pregnancy; the odds ratios ranged from 4.2 to 45. A common odds ratio could not be calculated because of heterogeneity between studies. The study with the most precise point estimate was a multinational case-control study conducted by the World Health Organization involving more than 2,200 women, which found an odds ratio of 4.2 (95% confidence interval, 2.56.9) (72). This suggests that while the intrauterine device decreases the risk of pregnancy overall, if a failure does occur, the device is more successful at preventing intrauterine pregnancy than tubal pregnancy. Past IUD use may slightly increase the risk of ectopic pregnancy. It should be noted that many of the studies that demonstrated this finding were conducted in the 1970s and 1980s, when women may have been using the Dalkon Shield, an IUD strongly associated with PID and ectopic pregnancy (73). The IUDs on the market in recent years are not associated with PID after the immediate insertion period (74).

Other Causes

Prior Abdominal Surgery

Many patients with ectopic pregnancies have a history of previous abdominal surgery. The role of abdominal surgery in ectopic pregnancy is unclear. In one study, there appeared to be no increased risk for cesarean delivery, ovarian surgery, or removal of an unruptured appendix (75). Other studies showed that ovarian cystectomy or wedge resection increases the risk for ectopic pregnancy, presumably because of peritubal scarring (76,77). Although there is agreement that an increased risk for ectopic pregnancy is associated with a ruptured appendix, one study did not confirm this finding (75).

Infertility

The incidence of ectopic pregnancy increases with age and parity, and there is a significant increase in nulliparous women undergoing infertility treatment (27,32,49). For nulliparous women, conceptions after at least 1 year of unprotected intercourse are 2.6 times more likely to be tubal (78). Additional risks for infertile women are associated with specific treatments, including reversal of sterilization, tuboplasty, ovulation induction, and in vitrofertilization (IVF). Various studies examining risk factors for ectopic pregnancy found that infertility increased the odds of tubal pregnancy at least 2.5 times and perhaps as much as 21 times (32).

Hormonal alterations characteristic of clomiphene citrate and gonadotropin ovulation-induction cycles may predispose to tubal implantation. About 1.1% to 4.6% of conceptions associated with ovulation induction are ectopic pregnancies (78–80). In many of these patients, the results of hysterosalpingography are normal, and there is no evidence of intraoperative tubal pathology. Hyperstimulation, with high estrogen levels, may play a role in tubal pregnancy; however, not all studies showed this relationship (81–83).

When the first pregnancy obtained with IVF was a tubal pregnancy; about 2% to 8% of the conceptions are tubal (84). Tubal factor infertility is associated with a further increased risk of 17% (85–88). Predisposing factors are unclear but may include placement of the embryo high in the uterine cavity, fluid reflux into the tube, and a predisposing tubal factor that prevents the refluxed embryo from returning to the uterine cavity.

Smoking

Cigarette smoking is associated with an increased risk for tubal pregnancy in a dose-dependent fashion. A case-control study showed a dose relationship: smokers of more than 20 cigarettes a day had a relative risk of 3.5 compared with nonsmokers, whereas smokers of up to 10 cigarettes had a risk of 2.3 (89). A case-control study in France found similar relative risk estimates (90). Alterations of tubal motility, ciliary activity, and blastocyst implantation are associated with nicotine intake.

Abortion

Multiple studies suggest an association between ectopic pregnancy and spontaneous abortion (79,91). With recurrent spontaneous abortion the risk may be increased up to four times (92). This may reflect a shared risk factor, such as with luteal phase defect. Substantial evidence found no increased risk with elective abortion; one study did find a slightly increased risk, particularly with multiple abortions (93–96).

Salpingitis Isthmica Nodosa

Salpingitis isthmica nodosa (SIN) is a noninflammatory pathologic condition of the tube in which tubal epithelium extends into the myosalpinx and forms a true diverticulum. The incidence in healthy controls is 6% to 11%, but this condition is found more often in the tubes of women with an ectopic pregnancy than in nonpregnant women (97). In one study, 46% of women with isthmic tubal pregnancy were found to have SIN (98). Myometrial electrical activity over the diverticula is abnormal. Whether tubal pregnancy is caused by SIN or whether the association is coincidental is unknown.

Endometriosis or Leiomyomas

Endometriosis or leiomyomas can cause tubal obstruction. Neither is commonly associated with ectopic pregnancy.

Histologic Characteristics

Chorionic villi, usually found in the lumen, are pathognomic findings of tubal pregnancy (99). Gross or microscopic evidence of an embryo is seen in two-thirds of cases. An unruptured tubal pregnancy is characterized by irregular dilation of the tube, with a blue discoloration caused by hematosalpinx. The ectopic pregnancy may not be readily apparent. Bleeding associated with tubal pregnancies is mainly extraluminal but may be luminal (hematosalpinx) and may extrude from the fimbriated end. A hematoma is frequently seen surrounding the distal segment of the tube. Patients who have tubal pregnancies that spontaneously resolved and those treated with methotrexate frequently have an enlargement of the ectopic mass associated with blood clots and extrusion of tissue from the fimbriated end. Hemoperitoneum is nearly always present but is confined to the cul-de-sac unless tubal rupture occurred. The natural progression of tubal pregnancy is either expulsion from the fimbriated end (tubal abortion), involution of the conceptus, or rupture, usually around the eighth gestational week. Some tubal pregnancies form a chronic inflammatory mass that is associated with involution and reestablishment of menses and thus is difficult to diagnose. Extensive histologic sampling may be required to disclose a few ghost villi.

Histologic findings associated with tubal gestation include evidence of chronic salpingitis and SIN. Inflammation associated with salpingitis causes adhesions as a result of fibrin deposition. Healing and cellular organization lead to permanent scarring between folds of tissue. This scarring may allow transport of sperm but not the passage of the larger blastocyst. About 45% of patients with tubal pregnancies have pathologic evidence of prior salpingitis (56).

The cause of SIN is unknown but is speculated to be an adenomyosis-like process or, less likely, inflammation (100). This condition is rare before puberty, indicating a noncongenital origin. Tubal diverticula are identified in about one-half of patients who have ectopic pregnancies, as opposed to 5% of women who do not have ectopic pregnancies (101).

Histologic findings include the Arias-Sella reaction, which is characterized by localized hyperplasia of endometrial glands that are hypersecretory. The cells have enlarged nuclei that are hyperchromatic and irregular (102). The Arias-Sella reaction is a nonspecific finding that can be seen in patients with intrauterine pregnancies (Fig. 20.3).

Figure 20.3 The Arias-Stella reaction of the endometrium. The glands are closely packed and hypersecretory with large, hyperchromatic nuclei suggesting malignancy.

Diagnosis

The diagnosis of ectopic pregnancy is complicated by the wide spectrum of clinical presentations, from asymptomatic cases to acute abdomen and hemodynamic shock. The diagnosis and management of a ruptured ectopic pregnancy is straightforward; the primary goal is achieving hemostasis. If an ectopic pregnancy can be identified before rupture or irreparable tubal damage occurs, consideration may be given to optimizing future fertility.With patients presenting earlier in the disease process, the number of those without symptoms or with minimal symptoms increased. There must be a high degree of suspicion of ectopic pregnancy, especially in areas of high prevalence. History and physical examination identify patients at risk, improving the probability of detection of ectopic pregnancy before rupture occurs.

History

Patients who have an ectopic pregnancy have an abnormal menstrual pattern or the perception of a spontaneous pregnancy loss. Pertinent points in the history include the menstrual history, previous pregnancy, infertility history, current contraceptive status, risk factor assessment, and current symptoms.

The classic symptom triad of ectopic pregnancy is pain, amenorrhea, and vaginal bleeding. This symptom group is present in about 50% of patients and is typical in patients with a ruptured ectopic pregnancy. Abdominal pain is the most common presenting symptom, but the severity and nature of the pain vary widely. There is no pathognomonic pain that is diagnostic of ectopic pregnancy. Pain may be unilateral or bilateral and may occur in the upper or lower abdomen. The pain may be dull, sharp, or crampy and either continuous or intermittent. With rupture, the patient may experience transient relief of the pain, as stretching of the tubal serosa ceases. Shoulder and back pain, thought to result from hemoperitoneal irritation of the diaphragm, may indicate intra-abdominal hemorrhage.

Physical Examination

The physical examination should include measurements of vital signs and examination of the abdomen and pelvis. Frequently, the findings before rupture and hemorrhage are nonspecific, and vital signs are normal. The abdomen may be nontender or mildly tender, with or without rebound. The uterus may be slightly enlarged, with findings similar to a normal pregnancy (103,104). Cervical motion tenderness may or may not be present. An adnexal mass may be palpable in up to 50% of cases, but the mass varies markedly in size, consistency, and tenderness. A palpable mass may be the corpus luteum and not the ectopic pregnancy. With rupture and intra-abdominal hemorrhage, the patient develops tachycardia followed by hypotension. Bowel sounds are decreased or absent. The abdomen is distended, with marked tenderness and rebound tenderness. Cervical motion tenderness is present. Frequently, the findings of the pelvic examination are inadequate because of pain and guarding.

History and physical examination may or may not provide useful diagnostic information. The accuracy of the initial clinical evaluation is less than 50% (105). Additional tests are frequently required to differentiate early viable intrauterine pregnancy or suspected ectopic or abnormal intrauterine pregnancy.

Laboratory Assessment

Quantitative β-human chorionic gonadotropin (β-hCG) measurements are the diagnostic cornerstone for ectopic pregnancy. The hCG enzyme immunoassay, with a sensitivity of 25 mIU/mL, is an accurate screening test for detection of ectopic pregnancy. The assay is positive in virtually all documented ectopic pregnancies.

Reference Standards

There are three reference standards for β-hCG measurement. The World Health Organization introduced the First International Standard (1st IS) in the 1930s. Testing for hCG and its subunits improved over the years. The Second International Standard (2nd IS), introduced in 1964, has varying amounts of β-hCG and β subunits. A purified preparation of β-hCG is now available. Originally referred to as the First International Reference Preparation (1st IRP), the test standard is now referred to as the Third International Standard (3rd IS). Although each standard has its own scale, the 2nd IS is about one-half of the 3rd IS. For example, if a level is reported as 500 mIU/mL (2nd IS), it is equivalent to a level of 1,000 mIU/mL (3rd IS). The assay standard used must be known to interpret hCG results correctly (106). In several recent articles, attention was drawn to a problem known as phantom hCG, in which the presence of heterophile antibodies or proteolytic enzymes causes a false-positive hCG result. Because the antibodies are large glycoproteins, significant quantities of the antibody are not excreted in the urine. In the patient with hCG levels less than 1,000 mIU/mL, a urine pregnancy test should be performed and confirmatory positive results obtained before instituting treatment (107,108).

Doubling Time

The hCG level correlates somewhat with the gestational age (109). During the first 6 weeks of amenorrhea, serum hCG levels increase exponentially. During this period, the doubling time of hCG is relatively constant, regardless of the initial level. After the sixth week of gestation, when hCG levels are higher than 6,000 to 10,000 mIU/mL, the hCG rise is slower and not constant (110).

The hCG doubling time can help to differentiate an ectopic pregnancy from an intrauterine pregnancy—a 66% rise in the hCG level over 48 hours (85% confidence level) represents the lower limit of normal values for viable intrauterine pregnancies (111). About 15% of patients with viable intrauterine pregnancies have less than a 66% rise in hCG level over 48 hours, and a similar percentage with an ectopic pregnancy have more than a 66% rise. If the sampling interval is reduced to 24 hours, the overlap between normal and abnormal pregnancies is even greater. Patients with normal intrauterine pregnancies usually have more than a 50% rise in their hCG levels over 48 hours when the starting level is less than 2,000 mIU/mL. The hCG pattern that is most predictive of an ectopic pregnancy is one that has reached a plateau (a doubling time of more than 7 days). For falling levels, a half-life of less than 1.4 days is rarely associated with an ectopic pregnancy, whereas a half-life of more than 7 days is most predictive of ectopic pregnancy.

Serial hCG levels are usually required when the results of the initial ultrasonography examination are indeterminate (i.e., when there is no evidence of an intrauterine gestation or extrauterine cardiac activity consistent with an ectopic pregnancy). When the hCG level is less than 2,000, doubling time helps to predict viable intrauterine gestation (normal rise) versus nonviability (subnormal rise). With normally rising levels, a second ultrasonography examination is performed when the level is expected (by extrapolation) to reach 2,000 mIU/mL. Abnormally rising levels (less than 2,000 mIU/mL and less than 50% rise over 48 hours) indicate a nonviable pregnancy. The location (i.e., intrauterine versus. extrauterine) must be determined surgically, either by laparoscopy or dilation and curettage. Indeterminate ultrasonography results and an hCG level of less than 2,000 mIU/mL is diagnostic of nonviable gestation, either ectopic pregnancy or a complete abortion. Rapidly falling hCG levels (50% over 48 hours) occur with a completed abortion, whereas with an ectopic pregnancy levels rise or plateau.

Single Human Chorionic Gonadotropin Level

A single hCG measurement has limited usefulness because there is considerable overlap of values between normal and abnormal pregnancies at a given gestational age. The ectopic pregnancy site and hCG level do not correlate (112). Many patients in whom the diagnosis of ectopic pregnancy is being considered are uncertain about their menstrual dates. A single hCG level may be useful when measured by sensitive enzyme immunoassays that, if negative, exclude a diagnosis of ectopic pregnancy. Measurement of a single level may be helpful in predicting pregnancy outcome after timed conceptions using advanced reproductive technology. If the hCG level is more than 300 mIU/mL on day 16 to 18 after artificial insemination, there is an 88% chance of a live birth (113). If the hCG level is less than 300 mIU/mL, the chance of a live birth is only 22%. A single hCG level may facilitate the interpretation of ultrasonography when an intrauterine gestation is not visualized. An hCG level greater than the ultrasound discriminatory zone indicates a possible extrauterine pregnancy. Determination of serial hCG levels may be needed to differentiate an ectopic pregnancy from a completed abortion. Further tests are required for patients in whom ultrasonography examination results are inconclusive and hCG levels are below the discriminatory zone.

Serum Progesterone

The mean serum progesterone level in patients with ectopic pregnancies is lower than that in patients with normal intrauterine pregnancies (114,115). However, in studies of more than 5,000 patients with first-trimester pregnancies, a spectrum of progesterone levels was found in patients with both normal and abnormal pregnancies (35,116,117). About 70% of patients with a viable intrauterine pregnancy have serum progesterone levels higher than 25 ng/mL, whereas only 1.5% of patients with ectopic pregnancies have serum progesterone levels higher than 25 ng/mL, and most of these pregnancies exhibit cardiac activity (35,116,117).

A serum progesterone level can be used as an ectopic pregnancy screening test for both normal and abnormal pregnancy, particularly in settings in which hCG levels and ultrasonography are not readily available. A serum progesterone level of less than 5 ng/mL is highly suggestive of an abnormal pregnancy, but it is not 100% predictive. The risk of a normal pregnancy with a serum progesterone level of less than 5 ng/mL is about 1 in 1,500 (118). Serum progesterone measurements alone cannot be used to predict pregnancy nonviability.

Other Endocrinologic Markers

In an effort to improve early detection of ectopic pregnancy, various endocrinologic and protein markers were studied. Estradiol levels increase slowly from conception until 6 weeks of gestation and then rise rapidly as placental production of estradiol increases (119). Estradiol levels are significantly lower in ectopic pregnancies when compared with viable pregnancies. However, there is considerable overlap between normal and abnormal pregnancies and between intrauterine and extrauterine pregnancies (120,121).

Maternal serum creatinine kinase was studied as a marker for ectopic pregnancy diagnosis (122). Maternal serum creatine kinase levels were significantly higher in all patients with tubal pregnancy when compared with those in patients who had missed abortions or normal intrauterine pregnancies. No correlation was found between the creatine kinase level and the clinical presentation of the patient, and there was no correlation with the hCG levels. Schwangerschafts protein 1 (SP₁), also known as pregnancy-associated plasma protein C (PAPP-C) or pregnancy-specific β-glycoprotein (PSBS), is produced by the syncytiotrophoblast (120). The main advantage of SP₁ level assessment may be in the diagnosis of conception after recent hCG administration. A level of 2 ng/L might be used for the diagnosis of pregnancy; however, it is doubtful that a diagnosis can be established before delay of menses. Although the level of SP₁ increases late in all patients with a nonviable pregnancy, a single SP₁ level assessment does not have prognostic value (123).

Relaxin is a protein hormone produced solely by the corpus luteum of pregnancy. It appears in the maternal serum at 4 to 5 weeks of gestation, peaks at about 10 weeks of gestation, and decreases until term (124). Relaxin levels are significantly lower in ectopic pregnancies and spontaneous abortions than in normal intrauterine pregnancies. Prorenin and active renin levels are significantly higher in viable intrauterine pregnancies than in either ectopic pregnancies or spontaneous abortions, with a single level of more than 33 pg/mL excluding the diagnosis of ectopic pregnancy (125). The clinical utility of relaxin, prorenin, and renin levels in diagnosing ectopic pregnancy is not yet determined.

CA125 is a glycoprotein, the origin of which is uncertain during pregnancy. Levels of CA125 rise during the first trimester and return to a nonpregnancy range during the second and third trimesters. After delivery, maternal serum concentrations increase (126,127). Levels of CA125 were studied in an effort to predict spontaneous abortion. Although a positive correlation was found between elevated CA125 levels 18 to 22 days after conception and spontaneous abortion, repeat measurements at 6 weeks of gestation did not correlate with outcome (128). Conflicting results were reported—one study showed a higher serum CA125 level in normal pregnancies than in ectopic pregnancies 2 to 4 weeks after a missed menses, whereas another study found higher CA125 levels for ectopic pregnancies compared with normal pregnancies (129,130).

Maternal serum α-fetoprotein (AFP) levels are elevated in ectopic pregnancies; however, the use of AFP measurements as a screening technique for ectopic pregnancy was not studied (131,132). A combination of AFP with three other markers—β-hCG, progesterone, and estradiol—has 98.5% specificity and 94.5% accuracy for the prediction of ectopic pregnancy (133,134). Serum placental growth factor may prove to be a diagnostic biomarker for ectopic pregnancy because it was shown to be undetectable in ectopic and nonviable pregnancies.

C-reactive protein is an acute-phase reactant that increases with trauma or infection. Levels of this protein are lower in patients with ectopic pregnancy than in patients with an acute infectious process. When an infectious process is part of the differential diagnosis, measurement of C-reactive protein may be beneficial (135).

Ultrasonography

Improvements in ultrasonography resulted in the earlier diagnosis of intrauterine and ectopic gestations (136). The sensitivity of the β-hCG assay allows the diagnosis of pregnancy before direct visualization by ultrasonography.

The complete examination should include both transvaginal and transabdominal ultrasonography. Transvaginal ultrasonography is superior to transabdominal ultrasonography in evaluating intrapelvic structures. The closeness of the vaginal probe to the pelvic organs allows use of higher frequencies (5–7 mHz), which improves resolution. Intrauterine pregnancy can be diagnosed 1 week earlier with transvaginal than with transabdominal ultrasonography. Evidence of an empty uterus, detection of adnexal masses and free peritoneal fluid, and direct signs of ectopic pregnancy are more reliably established with a transvaginal procedure (137–142). Transabdominal ultrasonography permits visualization of both the pelvis and abdominal cavity and should be included as part of the complete ectopic pregnancy evaluation to detect adnexal masses and hemoperitoneum.

The earliest ultrasonographic finding of an intrauterine pregnancy is a small fluid space and the gestational sac, surrounded by a thick echogenic ring, located eccentrically within the endometrial cavity. The earliest normal gestational sac is seen at 5 weeks of gestation with transabdominal ultrasonography and at 4 weeks of gestation with transvaginal ultrasonography (143,144). As the gestational sac grows, a yolk sac is seen within it, followed by an embryo with cardiac activity.

The appearance of a normal gestational sac may be simulated by intrauterine fluid collection, the pseudogestational sac, which occurs in 8% to 29% of patients with ectopic pregnancy (145–147). This ultrasonographic lucency, centrally located, probably represents bleeding into the endometrial cavity by the decidual cast. Clots within this lucency may mimic a fetal pole.

Morphologically, identification of the double decidual sac sign (DDSS) is the best method of ultrasonographically differentiating true sacs from pseudosacs (148). The double sac, believed to be the decidua capsularis and parietalis, is seen as two concentric echogenic rings separated by a hypoechogenic space. Although useful, this approach has some limitations in sensitivity and specificity—the DDSS sensitivity ranges from 64% to 95% (147). Pseudosacs may occasionally appear as the DDSS; intrauterine sacs of failed pregnancies may appear as pseudosacs.

The appearance of a yolk sac within the gestational sac is superior to the DDSS in confirming intrauterine pregnancy (149). The yolk sac is consistently visible on transabdominal ultrasonography with a gestational sac size of 2 cm and on transvaginal ultrasonography with a gestational sac size of 0.6 to 0.8 cm (150,151). Intrauterine sacs smaller than 1 cm on transabdominal ultrasonography and smaller than 0.6 cm on transvaginal ultrasonography are considered indeterminate. Larger sacs without DDSS or yolk sac represent either a failed intrauterine or ectopic pregnancy.

The presence of cardiac activity within the uterine cavity is definitive evidence of an intrauterine pregnancy. This finding essentially eliminates the diagnosis of ectopic pregnancy because the incidence of combined intrauterine and extrauterine pregnancy is 1 in 30,000.

The presence of an adnexal gestational sac with a fetal pole and cardiac activity is the most specific but least sensitive sign of ectopic pregnancy, occurring in only 10% to 17% of cases(135,152,153). The recognition of other characteristics of ectopic pregnancy improves ultrasonographic sensitivity. Adnexal rings (fluid sacs with thick echogenic rings) that have a yolk sac or nonliving embryo are accepted as specific ultrasonographic signs of ectopic pregnancy (154). Adnexal rings are visualized in 22% of ectopic pregnancies using transabdominal ultrasonography and in 38% using transvaginal ultrasonography (137). Other studies identified adnexal rings in 33% to 50% of ectopic pregnancies (135,153). The adnexal ring may not always be apparent because bleeding around the sac results in the appearance of a nonspecific adnexal mass.

Complex or solid adnexal masses are frequently associated with ectopic pregnancy; however, the mass may represent a corpus luteum, endometrioma, hydrosalpinx, ovarian neoplasm (e.g., dermoid cyst), or pedunculated fibroid (4,155–157). The presence of free cul-de-sac fluid is frequently associated with ectopic pregnancy and is no longer considered evidence of rupture. The presence of intra-abdominal free fluid should raise concern about tubal rupture (158,159).

Accurate interpretation of ultrasonography findings requires correlation with the hCG level (discriminatory zone) (146,151,154,160). All viable intrauterine pregnancies can be visualized by transabdominal ultrasonography for serum hCG levels higher than 6,500 mIU/mL; none can be seen at 6,000 mIU/mL. The inability to detect an intrauterine gestation with serum hCG levels higher than 6,500 mIU/mL indicates the presence of an abnormal (failed intrauterine or ectopic) pregnancy. Intrauterine sacs seen at hCG levels below the discriminatory zone are abnormal and represent either failed intrauterine pregnancies or the pseudogestational sacs of ectopic pregnancy. If there is no definite sign of an intrauterine gestation (the empty uterus sign) and the hCG level is below the discriminatory zone, the differential diagnosis includes the following considerations:

1. Normal intrauterine pregnancy too early for visualization

2. Abnormal intrauterine gestation

3. Recent abortion

4. Ectopic pregnancy

5. Nonpregnant patient

The discriminatory zone is lowered progressively with improvements in ultrasonography resolution. Discriminatory zones for transvaginal ultrasonography are reported at levels from 1,000 to 2,000 mIU/mL(146,151,154,160). Discriminatory zones vary according to the expertise of the examiner and capability of the equipment.

Although the discriminatory zone for intrauterine pregnancy is well established, there is no such zone for ectopic pregnancy. Levels of hCG do not correlate with the size of ectopic pregnancy. Regardless of how high the hCG level may be, nonvisualization does not exclude ectopic pregnancy. An ectopic pregnancy may be present anywhere in the abdominal cavity, making ultrasonographic visualization difficult.

Doppler Ultrasonography

A Doppler shift occurs whenever the source of an ultrasound beam is moving. The usual sources of Doppler-shifted frequencies are red blood cells. The presence of intravascular blood flow, flow direction, and flow velocity can be determined (161). Pulsed Doppler provides ultrasonographic control over which vessels are sampled. The vascular information is provided both by the shape of the time-velocity waveform (high- or low-resistance flow) and by its systolic, diastolic, and mean velocities (or Doppler frequency shifts) (162). Color flow Doppler ultrasonography analyzes very low amplitude signals from an entire ultrasound tomogram; the Doppler shift is then modulated into color. This information is used to gauge generalized tissue vascularity and to guide pulsed Doppler vascular sampling of specific vessels.

The waveform in the uterine arteries in the nongravid state and in the first trimester of pregnancy shows a high-resistance (little or no diastolic flow), low-velocity pattern. Conversely, a high-velocity, low-resistance signal is localized to the area of developing placentation (163–165). This pattern, seen near the endometrium, is associated with normal and abnormal intrauterine pregnancies and is termed peritrophoblastic flow. Whereas transvaginal ultrasonography requires a well-developed double decidual sac (or possibly cardiac activity) to localize an intrauterine gestation, the use of Doppler techniques allows detection of an intrauterine pregnancy at an earlier date. The combined use of Doppler and two-dimensional imaging allows the differentiation of pseudogestational sacs and true intrauterine gestational sacs and the differentiation of the empty uterus sign as either the presence of an intrauterine pregnancy (normal and abnormal) or absence of an intrauterine pregnancy (with an increased risk for ectopic pregnancy) (158,166).

A similar high-velocity, low-impedance flow characterizes ectopic pregnancies. The addition of Doppler to the ultrasonographic evaluation of suspected ectopic pregnancy improves diagnostic sensitivity for individual diagnoses: from 71% to 87% for ectopic pregnancy, from 24% to 59% for failed intrauterine pregnancy, and from 90% to 99% for normal intrauterine pregnancy (154,158,166). Transvaginal color Doppler ultrasonography did not increase overall detection rates (167). Magnetic resonance imaging (MRI) was studied for its possible uses in the diagnosis of ectopic pregnancy. The role of MRI in the detection of ectopic pregnancy is inconclusive. It was 96% accurate in detecting fresh hematoma associated with ectopic pregnancy. Further studies need to be done to assess its predictive value (168).

Dilation and Curettage

Uterine curettage is performed when the pregnancy is confirmed to be nonviable and the location of the pregnancy cannot be determined by ultrasonography. The decision to evacuate the uterus in the presence of a positive pregnancy test must be made with caution to avoid the unintentional disruption of a viable intrauterine pregnancy. Although suction curettage traditionally was performed in the operating room, it can be accomplished under local anesthesia on an outpatient basis. Endometrial sampling methods (e.g., a Novak curettage or Pipelle endometrial sampling device) are accurate in diagnosing abnormal uterine bleeding, but their reliability for intrauterine pregnancy evacuation was not studied. These devices might miss intrauterine villi and falsely suggest the diagnosis of ectopic pregnancy.

It is essential to confirm the presence of trophoblastic tissue as rapidly as possible so that therapy may be instituted. After tissue is obtained by curettage, it can be added to saline, in which it will float (Fig. 20.4). Decidual tissue does not float. Chorionic villi are usually identified by their characteristic lacy frond appearance. The sensitivity and specificity of this technique are 95% when the tissue is examined with the aid of a dissecting microscope. Because flotation of curettage sample tissue is not 100% accurate in differentiating an intrauterine from extrauterine gestation, histologic confirmation or serial β-hCG level measurement is required. The presence of chorionic villi may be assessed rapidly with frozen section analysis, which avoids the waiting period of at least 48 hours for permanent histologic evaluation. Immunocytochemical staining techniques are used to identify intermediate trophoblasts that are not normally identified by light microscopy (169).

Figure 20.4 When floated in saline, chorionic villi are often readily distinguishable as lacy fronds of tissue. (From Stovall TG, Ling FW. Extrauterine pregnancy: clinical diagnosis and management. New York: McGraw-Hill, 1993:186, with permission.)

When frozen section analysis is not available, serial assessment of hCG levels permits rapid diagnosis. After evacuation of an abnormal intrauterine pregnancy, the hCG level decreases by greater than 15% within 12 to 24 hours. A borderline fall may represent interassay variability. A repeat level should be obtained in 24 to 48 hours to confirm the decline. If the uterus is evacuated and the pregnancy is extrauterine, the hCG level will plateau or continue to increase, indicating the presence of extrauterine trophoblastic tissue.

Culdocentesis

Culdocentesis was used widely as a diagnostic technique for ectopic pregnancy. With the use of hCG testing and transvaginal ultrasonography, culdocentesis is rarely indicated. The purpose of the procedure is to determine the presence of nonclotting blood, which increases the likelihood of ruptured ectopic pregnancy. After exposing the posterior vaginal fornix with a bivalve vaginal speculum, the posterior lip of the cervix is grasped with a tenaculum. The cul-de-sac is entered through the posterior vaginal wall with an 18- to 20-gauge spinal needle with a syringe attached. As the cul-de-sac is entered, suction is applied, and the intraperitoneal contents are aspirated. If nonclotting blood is obtained, the results are positive. If serous fluid is present, results are negative. A lack of fluid return or clotted blood is nondiagnostic.

Historically, if the culdocentesis results were positive, laparotomy was performed for a presumed diagnosis of ruptured tubal pregnancy. The results of culdocentesis do not always correlate with the status of the pregnancy.Although about 70% to 90% of patients with ectopic pregnancy have a hemoperitoneum demonstrated by culdocentesis, only 50% of patients have a ruptured tube (170). About 6% of women with positive culdocentesis results do not have an ectopic gestation at the time of laparotomy. Nondiagnostic taps occur in 10% to 20% of patients with ectopic pregnancy and are not definitive of the diagnosis. A study concludes that culdocentesis is an obsolete tool in the diagnosis of suspected ectopic pregnancy (171).

Laparoscopy

Laparoscopy is the gold standard for the diagnosis of ectopic pregnancy. The fallopian tubes are easily visualized and evaluated, but the diagnosis of ectopic pregnancy is missed in 3% to 4% of patients who have very small ectopic gestations. The ectopic gestation is seen distorting the normal tubal architecture. With earlier diagnosis, the possibility increases that a small ectopic pregnancy may not be visualized. Pelvic adhesions or previous tubal damage may compromise assessment of the tube. False-positive results occur when tubal dilation or discoloration is misinterpreted as an ectopic pregnancy, in which case the tube can be incised unnecessarily and damaged.

Diagnostic Algorithm

The presenting symptoms and physical findings of patients with unruptured ectopic pregnancies are similar to those of patients with normal intrauterine pregnancies (35). History, risk-factor assessment, and physical examination are the initial steps in the management of suspected ectopic pregnancy. Patients in a hemodynamically unstable condition should undergo immediate surgical intervention. Patients with a stable, relatively asymptomatic condition may be assessed as outpatients.

If the diagnosis of ectopic pregnancy can be confirmed without laparoscopy, several potential benefits result. First, both the anesthetic and surgical risks of laparoscopy are avoided; second, medical therapy becomes a treatment option. Because many ectopic pregnancies occur in histologically normal tubes, resolution without surgery may spare the tube from additional trauma and improve subsequent fertility. An algorithm for the diagnosis of ectopic pregnancy without laparoscopy proved to be 100% accurate in a randomized clinical trial (172,173) (Fig. 20.5). This screening algorithm shows the combined use of history and physical examination, serial hCG levels, serum progesterone levels, vaginal ultrasonography, and dilation and curettage. When hCG levels and transvaginal ultrasonography are available in a timely fashion, serum progesterone screening is not required. Serial hCG levels are used to assess pregnancy viability, correlated with transvaginal ultrasonography findings, and measured serially after a suction curettage. For patients in a stable condition, a treatment decision is never based on a single hCG level. After the initial evaluation, the patient is seen again at 24 to 48 hours for a repeat hCG level. At this time, transvaginal ultrasonography often is repeated so the findings can be correlated with the two hCG levels.

Figure 20.5 Nonlaparoscopic algorithm for diagnosis of ectopic pregnancy. hCG, human chorionic gonadotropin; IUP, intrauterine pregnancy; USG, urine specific gravity; D&C, dilation and curettage.

In this algorithm, transvaginal ultrasonography is used as follows:

1. The identification of an intrauterine gestational sac or pregnancy effectively excludes the presence of an extrauterine pregnancy. If the patient has a rising hCG level of more than 2,000 mIU/mL, and no intrauterine gestational sac is identified, the patient is considered to have an extrauterine pregnancy and can be treated without further testing.

2. Adnexal cardiac activity, when seen, definitively confirms the diagnosis of ectopic pregnancy.

3. A tubal mass as small as 1 cm can be identified and characterized. Masses greater than 3.5 cm with cardiac activity or larger than 4 cm without cardiac activity should not be treated with medical therapy.

Suction curettage is used to differentiate nonviable intrauterine pregnancies from ectopic gestations (less than 50% rise in hCG level over 48 hours, an hCG level of less than 2,000 mIU/mL, and indeterminate ultrasonography findings). Performance of this procedure avoids unnecessary use of methotrexate in patients with abnormal intrauterine pregnancy that can be diagnosed only by evacuating the uterus. An unlikely potential problem with suction curettage is missing either an early nonviable intrauterine pregnancy or combined intrauterine and extrauterine pregnancies.

Treatment

Ectopic pregnancy can be effectively treated medically or surgically. Traditionally, exploratory laparotomy with unilateral salpingectomy was used for diagnosis and treatment for ectopic pregnancies. With techniques available that allow for early detection, including serum quantitative hCG levels and ultrasound, more conservative treatment options are available. Minimally invasive surgical techniques and medical management with methotrexate are the commonly used treatment options for ectopic pregnancies. The treatment approach depends on the clinical circumstances, the site of the ectopic pregnancy, and the available resources.

Surgical Treatment

Operative management is the most widely used treatment for ectopic pregnancy. The surgical approach (laparotomy versus. laparoscopy) and procedure (salpingectomy versus. salpingostomy) used to treat ectopic pregnancies depend on the clinical circumstances, available resources, and provider skill level. Each approach and procedure has associated risks and benefits, and the treatment employed must be individualized to best meet the needs of the patient and provider.

Laparotomy versus Laparoscopy

Treatment of an ectopic pregnancy can be accomplished by laparoscopy or laparotomy. The hemodynamic stability of the patient, size and location of the ectopic mass, and the surgeon’s expertise all contribute to determining the appropriate surgical approach. Laparotomy is indicated when the patient becomes hemodynamically unstable and an expedited abdominal entry is required. A ruptured ectopic pregnancy does not necessarily require laparotomy. If the hemoperitoneum cannot be evacuated in a timely manner, laparotomy should be considered. Surgeon’s experience with laparoscopy and the availability of laparoscopic equipment will determine the surgical approach. Cornual or interstitial pregnancies traditionally were treated with laparotomy, although laparoscopic management was described and is becoming common among skilled surgeons (174). Laparotomy is chosen for the management of most abdominal pregnancies. In some cases, the patient may have extensive abdominal or pelvic adhesive disease, making laparoscopy difficult and laparotomy more feasible.

Laparoscopy has advantages over laparotomy for management of ectopic pregnancy. In a case-control study of 50 patients comparing the use of laparoscopy and laparotomy for ectopic pregnancy management, hospital stay was significantly shorter (1.3 ± 0.8 versus. 3.0 ± 1.1 days), operative time was shorter (78 ± 26 versus. 104 ± 27 minutes), and convalescence was shorter (9 ± 8 versus. 26 ± 16 days) in the laparoscopy group (175). Laparoscopic management was associated with significant cost savings when compared with laparotomy (more than $5,528 ± $1,586 versus. more than $6,793 ± $155[MB3]). Using a prospective analysis, 105 patients with tubal pregnancy were stratified with regard to age and risk factors and randomized to undergo either laparoscopic management or laparotomy (176). Subsequently, 73 patients underwent second-look laparoscopy to assess the degree of adhesion formation. Patients treated by laparotomy had significantly more adhesions at the surgical site than those treated by laparoscopy, but tubal patency rates were similar. A recent Cochrane review confirmed these findings and laparoscopic salpingostomy was associated with decreased cost, operative time, blood loss, and hospital stay when compared to salpingostomy at the time of a laparotomy (177).

An alternative to laparoscopy is the use of a minilaparotomy incision. This approach has the advantage of not requiring laparoscopic equipment and utilizes a smaller incision that should result in decreased postoperative pain and shorter recovery times for patients. A randomized control trial comparing minilaparotomy to laparotomy showed decreased complication rates and reduced costs associated with the minilaparotomy incision with similar success rates in the treatment of the ectopic pregnancy (177,178).

Salpingectomy versus Salpingostomy

There is debate about which surgical procedure is best. Salpingo-oophorectomy was once considered appropriate because it was theorized that this technique would eliminate transperitoneal migration of the ovum or zygote, which was thought to predispose to recurrent ectopic pregnancy (179). Ovarian removal results in all ovulations occurring on the side with the remaining normal fallopian tube. Subsequent studies have not confirmed that ipsilateral oophorectomy increases the likelihood of conceiving an intrauterine pregnancy; therefore, this practice is not recommended (180). Whether to treat the ectopic pregnancy with a salpingostomy or salpingectomy is strongly debated and multiple studies investigated this issue. If one surgical technique resulted in higher treatment efficacy, lower rates of recurrent ectopic pregnancies, and higher rates of future intrauterine pregnancies, the decision would be clear. Studies have not demonstrated a clear advantage of either salpingectomy or salpingostomy. The decision to chose one technique over the other depends on the condition of the affected and contralateral fallopian tubes, history of a previous ectopic pregnancy in the affected tube, and the patient’s desire for future fertility.

Linear salpingostomy can be considered when the patient has an unruptured ectopic pregnancy, wishes to retain her potential for future fertility, and the affected fallopian tube appears otherwise normal. If the contralateral tube appears damaged, a salpingostomy should be considered.

In a salpingostomy, the products of conception are removed through an incision made into the tube on its antimesenteric border. The procedure can be accomplished with needle-tip cautery, laser, scalpel, or scissors. It can be done with operative laparoscopic techniques or via a laparotomy. Contraindications to a salpingostomy include ruptured fallopian tube, use of extensive cautery to obtain hemostasis, severely damaged tube, and a recurrent ectopic pregnancy in the same tube. The main risk factor of salpingostomy is a persistent ectopic pregnancy resulting from failure to remove the entire pregnancy from the fallopian tube. This was reported in 5% to 20% of cases, and the rate appears to be higher in laparoscopic cases as compared to salpingostomies at the time of a laparotomy (181–184). Patients with high starting β-hCG levels, early gestations, and small ectopic pregnancies (<2 cm) are at greater risk of having a persistent pregnancy after a salpingostomy (185). Because of this risk, it is recommended to follow weekly β-hCG levels to ensure complete resolution of the ectopic pregnancy. β-hCG levels that persist or plateau can usually be treated successfully with a single dose of methotrexate, as described below (26).

Milking the tube to effect a tubal abortion was advocated; if the pregnancy is fimbrial, this technique may be effective. When milking was compared with linear salpingostomy for ampullary ectopic pregnancies, milking was associated with a twofold increase in the recurrent ectopic pregnancy rate (186).

Reproductive Outcome

Reproductive outcome after ectopic pregnancy is evaluated by determining tubal patency by hysterosalpingography, the subsequent intrauterine pregnancy rate, and the recurrent ectopic pregnancy rate. Pregnancy rates are similar in patients treated by either laparoscopy or laparotomy. Tubal patency on the ipsilateral side after conservative laparoscopic management is about 84% (187).

In a study of 143 patients followed after undergoing laparoscopic procedures for ectopic pregnancy, the overall intrauterine pregnancy rates for laparoscopic salpingostomy (60%) and laparoscopic salpingectomy (54%) were not significantly different (188). If the patient had evidence of tubal damage, pregnancy rates (42%) were significantly lower than in those women who did not have tubal damage (79%). In another study, the reproductive outcome of 188 patients followed for a mean of 7.2 years (range 3–15 years) was reported after conservation by laparotomy for ectopic pregnancy (189). An intrauterine pregnancy occurred in 83 (70%) patients, with a recurrent ectopic pregnancy rate of 13%, suggesting that reproductive outcome after an ectopic pregnancy treated by laparotomy is similar to that of patients undergoing laparoscopic or medical management. A recent Cochrane review showed no difference in tubal patency rate, future intrauterine pregnancy rates, and recurrent ectopic pregnancy rates in those patients treated with salpingostomy by either laparoscopy or laparotomy approach (177).

Medical Treatment

The drug most frequently used for medical management of ectopic pregnancy is methotrexate, although other agents were studied, including potassium chloride (KCl), hyperosmolar glucose, prostaglandins, and RU-486. These agents may be given systemically (intravenously, intramuscularly, or orally) or locally (laparoscopic direct injection, transvaginal ultrasonographically directed injection, or retrograde salpingography). Other agents besides methotrexate are not recommended for the treatment of ectopic pregnancy because their safety and efficacy are not well documented.

Methotrexate

Methotrexate is a folic acid analogue that inhibits dehydrofolate reductase and thereby prevents synthesis of DNA. Methotrexate affects actively growing cells including trophoblastic tissues, malignant cells, bone marrow, intestinal mucosa, and respiratory epithelium (190). It is used extensively in the treatment of gestational trophoblastic disease (see Chapter 39). Initially, methotrexate was used for the treatment of trophoblastic tissue left in situ after exploration for an abdominal pregnancy (191). In 1982, Tanaka et al. treated an unruptured interstitial gestation with a 15-day course of intramuscular methotrexate(192). Multiple studies documented the safety and efficacy of methotrexate therapy for the management of ectopic pregnancies, and this is the first-line treatment for many providers. Approximately 35% of patients with ectopic pregnancies are candidates for primary therapy with methotrexate (193). Methotrexate is appropriate for primary treatment and may be given for the treatment of persistent ectopic pregnancies that failed surgical management.

Candidates for Methotrexate

Medical management of ectopic pregnancies with methotrexate is safe and effective, however, not all patients are candidates for this medical therapy. According to American College of Obstetricians and Gynecologists (ACOG) guidelines, methotrexate therapy can be considered for those patients with confirmed, or high suspicion for, ectopic pregnancy who are hemodynamically stable with no evidence of rupture. Table 20.2 documents the absolute contraindications to methotrexate therapy including breastfeeding, hepatic, renal, or hematologic disorders and known sensitivity to methotrexate. A patient who is unable to comply with the follow-up protocol should not be offered medical management. Relative contraindications to methotrexate therapy include gestational sac greater than or equal to 3.5 cm and embryonic cardiac motion (Table 20.2). Prior to the administration of methotrexate, a patient should have a complete blood count, blood type, liver function tests, electrolyte panel including creatinine, and a chest x-ray if there is any history of pulmonary disease. These studies are usually repeated 1 week after administration of methotrexate to evaluate for any potential complications from the therapy (190).

Table 20.2 Contraindications to Medical Therapy

Absolute Contraindications

Hemodynamically unstable

Ruptured ectopic pregnancy

Unable to comply with medical management follow-up

Breastfeeding

Immunodeficiency

Alcoholism, alcoholic liver disease or chronic liver disease

Preexisting blood dyscrasias

Known sensitivity to methotrexate

Active pulmonary disease

Peptic ulcer disease

Hepatic, renal, or hematologic disorder

Relative Contraindications

Gestational sac larger than 3.5 cm

Embryonic cardiac motion

Adapted from ACOG Practice Bulletin Medical Management of Ectopic Pregnancy, 2008.

Methotrexate Dosing Regimens

Methotrexate is usually given via intramuscular injection but can be administered orally or by intravenous infusion. Methotrexate traditionally was administered using a multidose regimen, but single dosing protocols were developed that are easier for patient compliance (194).

The multidose regimen is outlined in Table 20.3. Patients receive 1 mg/kg of methotrexate intramuscularly on days 1, 3, 5, and 7 with leucovorin 0.1 mg/kg intramuscular administered on days 2, 4, 6, and 8. As a result of the repeat dosing of methotrexate, side effects are more common. The leucovorin helps reduce these side effects and increases patients' tolerance of the treatment. A patient may not require all four doses of methotrexate and her β-hCG levels should be monitored on days 1, 3, 5, and 7. If the β-hCG level drops 15% between two measurements, the regimen can be stopped and weekly β-hCG monitoring initiated. If the methotrexate is discontinued early, the patient should receive leucovorin after her final dose of methotrexate to help reduce potential side effects. If a patient’s β-hCG level plateaus or increases, a second round of methotrexate and leucovorin can be given 1 week later. Earlier studies indicated approximately 19% will require all four doses, and 17% of women will require only one dose with this regimen (195,196). A more recent meta-analysis showed 10% of women require only one dose, while nearly 54% will require all four doses.

Table 20.3 Methotrexate Treatment Regimens

Multidose Regimen

Administer MTX 1 mg/kg IM days 1, 3, 5, 7

Administer leucovorin 0.1 mg/kg days 2, 4, 6, 8

Measure β-hCG levels on days 1, 3, 5, 7 until 15% decrease between two measurements.

Once β-hCG levels drop 15%, stop MTX and monitor β-hCG weekly until nonpregnant level

Single-Dose Regimen

Administer MTX 50 mg/m2 on day 0

Measure β-hCG level on days 4 and 7

If levels drop by 15%, monitor β-hCG weekly until nonpregnant level

If levels do not drop by 15%, repeat dose of MTX and measure β-hCG on days 4 and 7

Two-Dose Regimen

Administer MTX 50 mg/m2 on days 0 and 4

Measure β-hCG level on days 4 and 7

If levels drop by 15%, monitor β-hCG weekly until nonpregnant level

If levels do not drop by 15%, repeat dose of MTX on days 7 and 11 and measure β-hCG on days 7 and 11. If levels drop 15%, monitor β-hCG weekly until nonpregnant level

MTX, methotrexate; IM, intramuscular; β-hCG, β-human chorionic gonadotropin;

Adapted from ACOG Practice Bulletin Medical Management of Ectopic Pregnancy, 2008.

Methotrexate Single-Dose Regimens

Single-dose regimens were designed to increase patient compliance and simplify the administration of methotrexate. This regimen is well studied and safe and effective in the treatment of ectopic pregnancies. The single-dose regimen is detailed in Table 20.3.

Approximately 15% to 20% of patients in the single-dose regimen will require a second dose of methotrexate due to persistent β-hCG levels (194,197). The β-hCG level at the time of treatment appears to predict the subsequent success rate of single-dose therapy. Patients with β-hCG levels greater than 5,000 mIU/mL have a 14.3% chance of treatment failure compared to only 3.7% for women with levels less than 5,000 mIU/mL (198).

Compared with the multidose protocol, single-dose methotrexate is less expensive, patient acceptance is greater because less monitoring is required during treatment, and the treatment results and prospects for future fertility are comparable (194).

Methotrexate Two-Dose Regimen

The two-dose regimen was described as a cross between the single and multidose regimens. Because only 54% require all four doses of the multidose regimen, and 15% to 20% will require a second dose in the single-dose regimen, it is reasonable to consider a two-dose regimen of methotrexate. The protocol is outlined in Table 20.3 and involves the administration of methotrexate on day 0 and day 4 with monitoring of β-hCG levels on days 4 and 7. If there is less than a 15% drop between the two measures, a repeat administration of methotrexate is given on days 7 and 11 and β-hCG levels drawn accordingly. A single study showed an 87% success rate with low complication rates and high patient satisfaction (199).

Effectiveness of Methotrexate

The overall effectiveness of methotrexate therapy ranges from 78% to 96% (200). A meta-analysis in 2003 of 26 observational studies including 1,300 women revealed a significantly higher rate (93% versus. 88%) of successful treatment with multidose therapy (194). A meta-analysis comparing two randomized controlled trials showed no difference in success rates between the two regimens; however, the β-hCG levels in both of these studies were less than 3,000 mIU/mL (184,201,202).

When comparing methotrexate to laparoscopic salpingostomy, the multidose regimen has similar success rates. The single-dose regimen has lower initial success rates. After women receive additional doses as needed, the success rates are comparable between laparoscopic salpingostomy and single-dose methotrexate protocols (184).

Initiating Methotrexate

Outlined in Table 20.4 is a checklist that should be followed by the physician before initiating methotrexate. It includes instructions that are helpful to the patient.

Table 20.4 Initiation of Methotrexate: Physician Checklist and Patient Instructions

Physician Checklist

Obtain hCG level.

Check CBC, liver function tests, creatinine, and blood type

Administer RhoGAM if patient is Rh-negative.

Identify unruptured ectopic pregnancy smaller than 3.5 cm (relative contraindication)

Obtain informed consent

Prescribe FeSO4 325 mg PO bid if hematocrit is less than 30%.

Schedule follow-up appointment on days 4 and 7.

Patient Instructions

Refrain from alcohol use, multivitamins containing folic acid, NSAID use, and sexual intercourse until hCG level is negative.

Call your physician if:

You experience prolonged or heavy vaginal bleeding.   The pain is prolonged or severe (lower abdomen and pelvic pain is normal during the first 10–14 days of treatment).   You use oral contraception or barrier contraceptive methods.

About 4%–5% of women experience unsuccessful methotrexate treatment and require surgery.

hCG, human chorionic gonadotropin; SGOT, serum glutamic-oxaloacetic transaminase; BUN, blood urea nitrogen; CBC, complete blood count; Rho-GAM, Rh0(D) immune globulin; NSAIDs, nonsteroidal anti-inflammatory drugs; WBC, white blood cell; PO, by mouth; bid, twice daily.

Patient Follow-Up

After intramuscular administration of methotrexate, regardless of the dose regimen used, patients are monitored on an outpatient basis with weekly β-hCG levels. These levels need to be monitored until the β-hCG reaches nonpregnant levels. It is possible that tubal rupture may occur even if β-hCG levels are falling. Signs of a tubal rupture include severe pain, hemodynamic instability, and a drop in hematocrit. Patients who report severe or prolonged pain should be evaluated by measuring hematocrit levels and performing transvaginal ultrasonography. The ultrasonography findings during follow-up, although usually not helpful, can be used to provide reassurance that the tube is not ruptured (203). Cul-de-sac fluid is a common finding, and the amount of fluid may increase if a tubal abortion occurs. It is not necessary to intervene surgically, unless the patient has a precipitous drop in hematocrit levels or she becomes hemodynamically unstable.

Side Effects

Side effects of methotrexate therapy are dose and frequency dependent. The most commonly reported side effects are the gastrointestinal symptoms of nausea, vomiting, stomatitis, and abdominal pain. Because of these potential effects, women are cautioned against using alcohol and nonsteroidal anti-inflammatory medications while being treated with methotrexate (190). Other side effects include bone marrow suppression, hemorrhagic enteritis, alopecia, dermatitis, elevated liver enzyme levels, and pneumonitis (204). These side effects are usually mild and self-limited; few life-threatening side effects are reported with methotrexate treatment for ectopic pregnancy. The risk of these side effects does not appear to differ between single-dose and multidose regimens when adjusting for starting level of β-hCG at initiation of treatment. The frequency of reported side effects ranges from 30% to 40% (194). For those patients on prolonged therapy, leucovorin can reduce the incidence of these side effects and is included in the “multidose” regimen. Long-term follow-up of women treated with methotrexate for gestational trophoblastic disease shows no increase in congenital malformations, spontaneous abortions, or tumors recurring after chemotherapy (205). Treatment of ectopic pregnancy differs from that of gestational trophoblastic disease in that a smaller total dose of methotrexate is required and shorter treatment duration is used.

Although surgical management of ectopic pregnancy remains the mainstay of treatment worldwide, methotrexate treatment is appropriate in those patients who meet the treatment criteria previously detailed.

Reproductive Outcome

Reproductive function after methotrexate treatment can be assessed on the basis of repeat ectopic pregnancy rates, tubal patency, and pregnancy outcome. The risk of subsequent ectopic pregnancy is approximately 10% following either methotrexate or salpingostomy (52,53). The tubal patency rates are reported to be higher than 80% in those patients treated with either single-dose or multidose regimens with no difference in rates compared with women treated with salpingostomy (52,53). A randomized trial comparing methotrexate to laparoscopic salpingostomy showed no difference in tubal patency rates among the two groups, although in this trial patency rates were lower than previously reported at 66% in the salpingostomy group (206).

Subsequent spontaneous intrauterine pregnancy rates are similar between those women treated with methotrexate versus salpingostomy, with rates ranging from 36% to 64% (207,208). Comparison of laparoscopically treated patients with methotrexate-treated patients indicates that the two methods have similar reproductive outcomes.

Other Drugs and Techniques

Salpingocentesis is a technique in which agents such as KCl, methotrexate, prostaglandins, and hyperosmolar glucose are injected into the ectopic pregnancy transvaginally using ultrasonographic guidance, transcervical tubal cannulization, or laparoscopy. Agents injected under ultrasonographic guidance included methotrexate, KCl, combined methotrexate and KCl, and prostaglandin E₂ (162,209–215). The potential advantages of salpingocentesis include a one-time injection with the potential avoidance of systemic side effects. Reproductive function after this form of treatment was not reported. Because of the limited experience, this treatment cannot be recommended until there is further study.

Agents injected into the amniotic sac at laparoscopy included prostaglandin F_2a, hyperosmolar glucose, and methotrexate (216–218). This method has the obvious disadvantage of requiring laparoscopy, but it can be used if laparoscopy is performed for diagnosis. Other agents reported for the treatment of ectopic pregnancy include RU-486 and anti-hCG antibody (219,220).

Types of Ectopic Pregnancy

Spontaneous Resolution

Some ectopic pregnancies resolve by resorption or by tubal abortion, obviating the need for medical or surgical therapy (221–225). The proportion of ectopic pregnancies that resolve spontaneously and the reason they do so while others do not are unknown. There are no specific criteria for patient selection that predict successful outcome after spontaneous resolution. A falling hCG level is the most common indicator used, but tubal rupture can occur even with falling hCG levels. Patients with low initial levels of β-hCG are generally the best candidates for expectant management, and there is a reported 88% success rate of spontaneous remission with an initial β-hCG level less than 200 mU/mL (226). These patients should be followed with serial β-hCG levels and active management initiated if these levels plateau or rise or the patient develops abdominal pain or signs of tubal rupture (190).

Persistent Trophoblastic Tissue

Persistent ectopic pregnancy occurs when a patient underwent conservative surgery (e.g., salpingostomy, fimbrial expression) and viable trophoblastic tissue remains. Histologically, there is no identifiable embryo, the implantation usually is medial to the previous tubal incision, and residual chorionic villi are confined to the tubal muscularis. Peritoneal trophoblastic tissue implants may be responsible for persistence (182,183,227–230).

The incidence of persistent ectopic pregnancy increased with the increased use of surgery that conserves the tubes. Persistence is diagnosed when the β-hCG levels plateau after conservative surgery. Risk factors for persistent ectopic pregnancy are based on the type of surgical procedure, the initial β-hCG level, the duration of amenorrhea, and the size of the ectopic pregnancy. Patients treated with laparoscopic salpingostomy have a higher rate of persistent ectopic pregnancies compared to those treated with salpingostomy at the time of a laparotomy, with an incidence of persistence after laparoscopic linear salpingostomy ranging from 4% to 15% (49,177). Other risk factors for persistent ectopic pregnancies include very early gestations (amenorrhea less than 7 weeks' duration), ectopic pregnancies less than 2 cm, and those with high starting β-hCG levels (183,185,229).

Persistent ectopic pregnancy can be treated surgically or medically; surgical therapy consists of either repeat salpingostomy or, more commonly, salpingectomy. Methotrexate offers an alternative to patients who are hemodynamically stable at the time of diagnosis. Methotrexate may be the treatment of choice because the persistent trophoblastic tissue may not be confined to the tube and, therefore, not readily identifiable during repeat surgical exploration (231–233).

Chronic Ectopic Pregnancy

Chronic ectopic pregnancy is a condition in which the pregnancy does not completely resorb during expectant management. The condition arises when there is persistence of the chorionic villi with bleeding into the tubal wall, which is distended slowly and does not rupture. It may arise from chronic bleeding from the fimbriated end of the fallopian tube with subsequent tamponade. In a series of 50 patients with a chronic ectopic pregnancy, pain was present in 86%, vaginal bleeding was present in 68%, and both symptoms were present in 58% (234). Ninety percent of the patients had amenorrhea ranging from 5 to 16 weeks (mean, 9.6 weeks). Most patients develop a pelvic mass that usually is symptomatic. The β-hCG level usually is low but may be absent; ultrasonography may be helpful in the diagnosis; rarely, bowel involvement or ureteral compression or obstruction exists (234,235).

This condition is treated surgically with removal of the affected tube. Often, the ovary must be removed because there is inflammation with subsequent adhesion development. A hematoma may be present secondary to chronic bleeding.

Nontubal Ectopic Pregnancy

Cervical Pregnancy

The incidence of cervical pregnancy in the United States ranges from 1 in 2,400 to 1 in 50,000 pregnancies and accounts for less than 1% of ectopic pregnancies (236,237). The cause of cervical ectopic pregnancies is unknown and the rare occurrence prevents identification of known risk factors. The incidence does appear to be higher with in vitro fertilization procedures, accounting for 3.7% of IVF-related ectopic pregnancies (238).

The clinical criteria for diagnosing a cervical pregnancy include the following findings (239):

1. Uterus is smaller than the surrounding distended cervix;

2. External os may be open;

3. Visible cervical lesion often blue or purple in color;

4. Profuse bleeding on manipulation of cervix.

Patients classically present with painless vaginal bleeding, but reports of associated cramping and pain are published (240).

When a cervical pregnancy is suspected, imaging studies are useful in confirming the diagnosis. Ultrasonographic diagnostic criteria are described that are helpful in differentiating a true cervical pregnancy from an ongoing spontaneous abortion (Table 20.5). MRI of the pelvis is used in this situation (241). Other potential diagnoses that must be differentiated from cervical pregnancy include cervical carcinoma, cervical or prolapsed submucousal leiomyomas, trophoblastic tumor, placenta previa, and low-lying placenta.

Table 20.5 Ultrasound Criteria for Cervical Pregnancy

1. Gestational sac or placental tissue visualized within the cervix 2. Cardiac motion noted below the level of the internal os 3. No intrauterine pregnancy 4. Hourglass uterine shape with ballooned cervical canal 5. No movement of the sac with pressure from transvaginal probe (i.e., no “sliding sign” that is typically seen with incomplete abortions) 6. Closed internal os

Adapted from Kung FT, Lin H, Hsu TY, et al. Differential diagnosis of cervical ectopic pregnancy and conservative treatment with the combination of laparoscopy-assisted uterine artery ligation and hysteroscopic endocervical resection. Fertil Steril 2004;81:1642–1649.

Management of cervical ectopic pregnancies includes medical treatment with methotrexate and surgical dilation and curettage. The ideal regimen for medical management is unknown and success is reported with both the single- and multidose regimens, as previously described. More advanced gestations, especially with fetal cardiac activity, may require a combination of multidose methotrexate and intra-amniotic/intrafetal injection of PCl. These injections require skill to avoid rupture of membranes during the procedure (240). As with tubal ectopic pregnancies, medical management is appropriate only for those patients who are hemodynamically stable.

If the patient and physician elect to proceed with surgical management, the preoperative preparation should include blood typing and cross-matching, establishment of intravenous access, and detailed informed consent. This consent should include the possibility of hemorrhage that may require transfusion or hysterectomy.

The diagnosis may not be suspected until the patient is undergoing suction curettage for a presumed incomplete abortion and hemorrhage occurs. In some cases, bleeding is light, whereas in others, there is hemorrhage. Various techniques that can be used to control bleeding include uterine packing, lateral cervical suture placement to ligate the lateral cervical vessels, placement of a cerclage, and insertion of an intracervical 30-mL Foley catheter in an attempt to tamponade the bleeding. Alternatively, angiographic artery embolization can be used. If laparotomy is required, an attempt can be made to ligate the uterine or internal iliac arteries (242–244). When none of these methods is successful, hysterectomy is required.

Ovarian Pregnancy

A pregnancy confined to the ovary accounts for up to 3% of all ectopic pregnancies and is the most common type of nontubal ectopic pregnancy (1). The incidence ranges from 1 in 40,000 to 1 in 7,000 deliveries (245,246). The diagnostic criteria were described in 1878 by Spiegelberg (Table 20.6) (247). Unlike tubal gestation, ovarian pregnancy is associated with neither PID nor infertility. The risk of ovarian ectopic pregnancies in patients using IUDs is controversial.

Table 20.6 Criteria for Ovarian Pregnancy Diagnosis

1. The fallopian tube on the affected side must be intact. 2. The fetal sac must occupy the position of the ovary. 3. The ovary must be connected to the uterus by the ovarian ligament. 4. Ovarian tissue must be located in the sac wall.

From Spiegelberg O. Casusistik der ovarialschwangerschaft. Arch Gynaecol 1878;13:73.

Patients have symptoms similar to those of ectopic pregnancies in other sites. Misdiagnosis is common because it is confused with a ruptured corpus luteum in up to 75% of cases (245). As with other types of ectopic pregnancy, an ovarian pregnancy was reported after hysterectomy (248). Ultrasonography makes preoperative diagnosis possible in some cases (249).

The treatment of ovarian pregnancy has changed. Whereas oophorectomy was advocated in the past, ovarian cystectomy and/or wedge resection is now utilized with success (250–252). Successful treatment with methotrexate is reported (253–255).

Abdominal Pregnancy

Abdominal pregnancies are classified as primary and secondary. Listed in Table 20.7 are criteria for classifying a primary abdominal pregnancy. Secondary abdominal pregnancies are the most common and result from tubal abortion or rupture or, less often, from subsequent implantation within the abdomen after uterine rupture. The incidence of abdominal pregnancy varies from 1 in 372 to 1 in 9,714 live births and accounts for 1.4% of ectopic pregnancies (1,256). Risk factors for abdominal pregnancy include PID, multiparity, endometriosis, assisted reproductive techniques, and tubal damage (257,258). Abdominal pregnancy is associated with high morbidity and mortality, with the risk for death seven to eight times greater than from tubal ectopic pregnancy and 50 times greater than from intrauterine pregnancy (256). There are scattered reports of term abdominal pregnancies. When this occurs, perinatal morbidity and mortality are high, usually as a result of growth restriction and congenital anomalies such as fetal pulmonary hypoplasia, pressure deformities, and facial and limb asymmetry. The incidence of congenital anomalies ranges from 20% to 40% (259,260).

Table 20.7 Studdiford’s Criteria for Diagnosis of Primary Abdominal Pregnancy

1. Presence of normal tubes and ovaries with no evidence of recent or past pregnancy 2. No evidence of uteroplacental fistula 3. The presence of a pregnancy related exclusively to the peritoneal surface and early enough to eliminate the possibility of secondary implantation after primary tubal nidation

The presentation of patients with an abdominal pregnancy varies and depends on the gestational age. In the first and early second trimesters, the symptoms may be the same as with tubal ectopic gestation; in advanced abdominal pregnancy, the clinical presentation is more variable. The patient may report painful fetal movement, fetal movements high in the abdomen, or sudden cessation of movements. Physical examination may disclose persistent abnormal fetal positioning, abdominal tenderness, a displaced uterine cervix, easy palpation of fetal parts, and palpation of the uterus separate from the gestation. The diagnosis may be suspected when there are no uterine contractions after oxytocin infusion. Other diagnostic aids include abdominal radiography, abdominal ultrasonography, CT, and MRI (261–263).

Because the pregnancy can continue to term, the potential maternal morbidity and mortality are very high. As a result, surgical intervention is recommended when an abdominal pregnancy is diagnosed.At surgery, the placenta can be removed if its vascular supply can be identified and ligated, but hemorrhage can occur, requiring abdominal packing that is left in place and removed after 24 to 48 hours. Angiographic arterial embolization was described (264). If the vascular supply cannot be identified, the cord is ligated near the placental base, and the placenta is left in place. Placental involution can be monitored using serial ultrasonography and assessment of β-hCG levels. Potential complications of leaving the placenta in place include bowel obstruction, fistula formation, and sepsis as the tissue degenerates. There are concerns regarding the use of methotrexate treatment in abdominal pregnancies. Specifically, there is theoretically an increased risk of infection and sepsis resulting from the rapid tissue necrosis that occurs following methotrexate administration (265). There are reports of successful treatment of abdominal pregnancies with methotrexate in patients not considered to be optimal surgical candidates (266).

Interstitial Pregnancy

Interstitial pregnancies represent about 2.4% of ectopic pregnancies (1). This section of the fallopian tube is relatively thick with an increased capacity to expand prior to rupture. This ability may allow these types of ectopic pregnancies to remain asymptomatic for 7 to 16 weeks of gestation (267). Late presentations are rare and these patients typically present between 6 to 8 weeks of gestation, similar to other types of ectopic pregnancies (268,269). The diagnosis of an interstitial ectopic pregnancy can be difficult, because this area has a relatively high level of vascular supply. Interstitial pregnancies represent a disproportionately large percentage of fatalities from ectopic pregnancy with a 2.5% mortality rate (268,270).

Treatment classically was a cornual resection by laparotomy, but early detection allows for a more conservative management approach in hemodynamically stable patients without evidence of rupture. Medical management with methotrexate is well described, with both the single- and multidose regimens. Approximately 10% to 20% of patients treated medically will ultimately require surgery and close follow-up, as is warranted with all medically managed ectopic pregnancies (271).

Although cornual wedge resection by laparotomy is an acceptable surgical option, minimally invasive techniques were described, including cornual excision, minicornual excision, and cornuostomy. Laparoscopic approaches are more widely used and are dependent on surgical skill. Transcervical suction evacuation under laparoscopic or ultrasound guidance is reported (271). The appropriate surgical technique and approach depends on the individual patient presentation and the surgeon’s expertise.

Interligamentous Pregnancy

Interligamentous pregnancy is a rare form of ectopic pregnancy that occurs in about 1 of 300 ectopic pregnancies (272). An interligamentous pregnancy usually results from trophoblastic penetration of a tubal pregnancy through the tubal serosa and into the mesosalpinx, with secondary implantation between the leaves of the broad ligament. It can occur if a uterine fistula develops between the endometrial cavity and the retroperitoneal space. As in abdominal pregnancy, with interligamentous pregnancy the placenta may be adherent to the uterus, bladder, and pelvic side walls. If possible, the placenta should be removed; when this is not possible, it can be left in situ and allowed to resorb. Cases of live birth are reported with this type ectopic gestation (272).

Heterotropic Pregnancy

Heterotropic pregnancy occurs when intrauterine and ectopic pregnancies coexist. The reported incidence varies widely from 1 in 100 to 1 in 30,000 pregnancies (273). Patients who underwent assisted reproduction have a much higher incidence of heterotropic pregnancy than those who have a spontaneous conception (274,275). An intrauterine pregnancy is seen during ultrasonography examination, and an extrauterine pregnancy may be overlooked, delaying diagnosis. Serial β-hCG levels are not helpful because the intrauterine pregnancy causes the β-hCG level to rise appropriately.

The ectopic pregnancy is treated surgically if the intrauterine pregnancy is desired. When the ectopic pregnancy is removed, the intrauterine pregnancy continues in most patients. The rate of spontaneous abortion is higher with approximately one in three ending in miscarriage (276,277). It may be possible to treat the ectopic pregnancy using nonchemotherapeutic medical treatment, such as KCl, by transvaginal or laparoscopically directed injection; however, a reported 55% may require additional surgical treatment (278).

Multiple Ectopic Pregnancies

Twin or multiple ectopic gestations occur less frequently than heterotropic gestations and may appear in a variety of locations and combinations. Multiple ectopic pregnancies are thought to be rare, but with the advent of assisted reproductive technologies the incidence appears to be rising. A recent review of bilateral tubal pregnancies reported 242 cases between 1918 and 2007, with 42 cases in the past 10 years alone. Fifty percent of these twin tubal pregnancies were associated with assisted reproductive technologies (279). Another review of 163 cases of tubal ectopic pregnancies had a reported rate of twin tubal pregnancies of 2.4% (280). Although most reports are confined to twin tubal gestations, ovarian, interstitial, and abdominal twin pregnancies were reported. Twin and triplet gestations were reported following partial salpingectomy and IVF (281,282). Management is similar to that of other types of ectopic pregnancy and is somewhat dependent on the location of the pregnancy.

Pregnancy after Hysterectomy

The most unusual form of ectopic pregnancy is one that occurs after vaginal or abdominal hysterectomy (283,284). Such a pregnancy may occur after supracervical hysterectomy because the patient has a cervical canal that may provide intraperitoneal access. Pregnancy may occur in the perioperative period with implantation of the already fertilized ovum in the fallopian tube. Pregnancy after total hysterectomy probably occurs secondary to a vaginal mucosal defect that allows sperm into the abdominal cavity.

References

1. Bouyer J, Coste J, Fernandez H, et al. Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases. Hum Reprod 2002;17:3224–3230.

2. Wilcox AJ, Weinberg CR, O'Connor JF, et al. Incidence of early loss of pregnancy. N Engl J Med 1988;319:189–194.

3. Wang X, Chen C, Wang L, et al. Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. Fertil Steril 2003;79:577–584.

4. Hill LM, Guzick D, Fries J, et al. Fetal loss rate after ultrasonically documented cardiac activity between 6 and 14 weeks, menstrual age. J Clin Ultrasound 1991;19:221–223.

5. Juliano M, Dabulis S, Heffner A. Characteristics of women with fetal loss in symptomatic first trimester pregnancies with documented fetal cardiac activity. Ann Emerg Med 2008;52:143–147.

6. Wyatt PR, Owolabi T, Meier C, et al. Age-specific risk of fetal loss observed in a second trimester serum screening population. Am J Obstet Gynecol 2005;192:240–246.

7. Stirrat GM. Recurrent miscarriage. Lancet 1990;336:673–675.

8. Deaton JL, Honore GM, Huffman CS, et al. Early transvaginal ultrasound following an accurately dated pregnancy: the importance of finding a yolk sac or fetal heart motion. Hum Reprod 1997;12:2820–2823.

9. Nybo Andersen AM, Wohlfahrt J, Christens P, et al. Maternal age and fetal loss: population based register linkage study. BMJ 2000;320:1708–1712.

10. Kleinhaus K, Perrin M, Friedlander Y, et al. Paternal age and spontaneous abortion. Obstet Gynecol 2006;108:369–377.

11. Buss L, Tolstrup J, Munk C, et al. Spontaneous abortion: a prospective cohort study of younger women from the general population in Denmark. Validation, occurrence and risk determinants. Acta Obstet Gynecol Scand 2006;85:467–475.

12. Chatenoud L, Parazzini F, di Cintio E, et al. Paternal and maternal smoking habits before conception and during the first trimester: relation to spontaneous abortion. Ann Epidemiol 1998;8:520–526.

13. Nielsen A, Hannibal CG, Lindekilde BE, et al. Maternal smoking predicts the risk of spontaneous abortion. Acta Obstet Gynecol Scand 2006;85:1057–1065.

14. Perriera L, Reeves MF. Ultrasound criteria for diagnosis of early pregnancy failure and ectopic pregnancy. Semin Reprod Med 2008;26:373–382.

15. Makrydimas G, Sebire NJ, Lolis D, et al. Fetal loss following ultrasound diagnosis of a live fetus at 6–10 weeks of gestation. Ultrasound Obstet Gynecol 2003;22:368–372.

16. Sotiriadis A, Papatheodorou S, Makrydimas G. Threatened miscarriage: evaluation and management. BMJ 2004;329:152–155.

17. Gerhard I, Gwinner B, Eggert-Kruse W, et al. Double-blind controlled trial of progesterone substitution in threatened abortion. Biol Res Pregnancy Perinatol 1987;8:26–34.

18. Harrison RF. A comparative study of human chorionic gonadotropin, placebo, and bed rest for women with early threatened abortion. Int J Fertil Menopausal Stud 1993;38:160–165.

19. Lykke JA, Dideriksen KL, Lidegaard O, et al. First-trimester vaginal bleeding and complications later in pregnancy. Obstet Gynecol 2010;115:935–944.

20. Weiss JL, Malone FD, Vidaver J, et al. Threatened abortion: a risk factor for poor pregnancy outcome, a population-based screening study. Am J Obstet Gynecol 2004;190:745–750.

21. Leitich H, Bodner-Adler B, Brunbauer M, et al. Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol 2003;189:139–147.

22. American College of Obstetrics and Gynecology. ACOG Practice Bulletin. Prevention of Rh D alloimmunization. Number 4, May 1999 (replaces educational bulletin Number 147, October 1990). Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet 1999;66:63–70.

23. Ballagh SA, Harris HA, Demasio K. Is curettage needed for uncomplicated incomplete spontaneous abortion? Am J Obstet Gynecol 1998;179:1279–1282.

24. Jurkovic D, Ross JA, Nicolaides KH. Expectant management of missed miscarriage. Br J Obstet Gynaecol 1998;105:670–671.

25. Zhang J, Gilles JM, Barnhart K, et al. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med 2005;353:761–769.

26. Blum J, Winikoff B, Gemzell-Danielsson K, et al. Treatment of incomplete abortion and miscarriage with misoprostol. Int J Gynaecol Obstet 2007;99(Suppl 2):S186–S189.

27. Seeber BE, Barnhart KT. Suspected ectopic pregnancy. Obstet Gynecol 2006;107:399–413.

28. Anonymous. Ectopic pregnancy—United States, 1990–1992. MMWR Morb Mortal Wkly Rep 1995;44:46–48.

29. Anonymous. Ectopic pregnancy—United States, 1988–1989. MMWR Morb Mortal Wkly Rep 1992;41:591–594.

30. Yao M, Tulandi T. Current status of surgical and nonsurgical management of ectopic pregnancy. Fertil Steril 1997;67:421–433.

31. Murray H, Baakdah H, Bardell T, et al. Diagnosis and treatment of ectopic pregnancy. CMAJ 2005;173:905–912.

32. Ankum WM, Mol BW, Van der Veen F, et al. Risk factors for ectopic pregnancy: a meta-analysis. Fertil Steril 1996;65:1093–1099.

33. Buckley RG, King KJ, Disney JD, et al. History and physical examination to estimate the risk of ectopic pregnancy: validation of a clinical prediction model. Ann Emerg Med 1999;34:589–594.

34. Dart RG, Kaplan B, Varaklis K. Predictive value of history and physical examination in patients with suspected ectopic pregnancy. Ann Emerg Med 1999;33:283–290.

35. Stovall TG, Kellerman AL, Ling FW, et al. Emergency department diagnosis of ectopic pregnancy. Ann Emerg Med 1990;19:1098–1103.

36. Pulkkinen MO, Talo A. Tubal physiologic consideration in ectopic pregnancy. Clin Obstet Gynecol 1987;30:164–172.

37. Coste J, Fernandez H, Joye N, et al. Role of chromosome abnormalities in ectopic pregnancy. Fertil Steril 2000;74:1259–1260.

38. Lavy G, Diamond MP, DeCherney AH. Ectopic pregnancy: its relationship to tubal reconstructive surgery. Fertil Steril 1987;47:543–556.

39. Peterson HB, Xia Z, Hughes JM, et al. The risk of pregnancy after tubal sterilization: findings from the U.S. Collaborative Review of Sterilization. Am J Obstet Gynecol 1996;174:1161–1170.

40. Mol BW, Ankum WM, Bossuyt PM, et al. Contraception and the risk of ectopic pregnancy: a meta-analysis. Contraception 1995;52:337–341.

41. Peterson HB, Xia Z, Hughes JM, et al. The risk of ectopic pregnancy after tubal sterilization. U.S. Collaborative Review of Sterilization Working Group. N Engl J Med 1997;336:762–767.

42. Rock JA, Guzick DS, Katz E, et al. Tubal anastomosis: pregnancy success following reversal of Falope ring or monopolar cautery sterilization. Fertil Steril 1987;48:13–17.

43. Henderson SR. The reversibility of female sterilization with the use of microsurgery: a report on 102 patients with more than one year of follow-up. Am J Obstet Gynecol 1984;149:57–65.

44. Spivak MM, Librach CL, Rosenthal DM. Microsurgical reversal of sterilization: a six-year study. Am J Obstet Gynecol 1986;154:355–361.

45. DeCherney AH, Mezer HC, Naftolin F. Analysis of failure of microsurgical anastomosis after midsegment, non-coagulation tubal ligation. Fertil Steril 1983;39:618–622.

46. Hulka JF. Spring clip technique for sterilization. Obstet Gynecol 1982;60:760.

47. Vasquez G, Winston RM, Boeckx W, et al. Tubal lesions subsequent to sterilization and their relation to fertility after attempts at reversal. Am J Obstet Gynecol 1980;138:86–92.

48. Hajenius PJ, Mol BW, Ankum WM, et al. Suspected ectopic pregnancy: expectant management in patients with negative sonographic findings and low serum hCG concentrations. Early Pregnancy 1995;1:258–262.

49. Farquhar CM. Ectopic pregnancy. Lancet 2005;366:583–591.

50. Langer R, Bukovsky I, Herman A, et al. Conservative surgery for tubal pregnancy. Fertil Steril 1982;38:427–430.

51. Hallatt JG. Tubal conservation in ectopic pregnancy: a study of 200 cases. Am J Obstet Gynecol 1986;154:1216–1221.

52. Stovall TG, Ling FW, Buster JE. Reproductive performance after methotrexate treatment of ectopic pregnancy. Am J Obstet Gynecol 1990;162:1620–1624.

53. Stovall TG. Medical management should be routinely used as primary therapy for ectopic pregnancy. Clin Obstet Gynecol 1995;38:346–352.

54. Tulandi T. Reproductive performance of women after two tubal ectopic pregnancies. Fertil Steril 1988;50:164–166.

55. Westrom L, Joesoef R, Reynolds G, et al. Pelvic inflammatory disease and fertility. A cohort study of 1,844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results. Sex Transm Dis 1992;19:185–192.

56. Westrom L. Effect of acute pelvic inflammatory disease on fertility. Am J Obstet Gynecol 1975;121:707–713.

57. Diquelou JY, Pia P, Tesquier L, et al. [The role of Chlamydia trachomatis in the infectious etiology of extra-uterine pregnancy]. J Gynecol Obstet Biol Reprod (Paris) 1988;17:325–332.

58. Berenson A, Hammill H, Martens M, et al. Bacteriologic findings with ectopic pregnancy. J Reprod Med 1991;36:118–120.

59. Coste J, Job-Spira N, Fernandez H, et al. Risk factors for ectopic pregnancy: a case-control study in France, with special focus on infectious factors. Am J Epidemiol 1991;133:839–849.

60. Svensson L, Mardh PA, Ahlgren M, et al. Ectopic pregnancy and antibodies to Chlamydia trachomatis. Fertil Steril 1985;44:313–317.

61. Brunham RC, Binns B, McDowell J, et al. Chlamydia trachomatis infection in women with ectopic pregnancy. Obstet Gynecol 1986;67:722–726.

62. Miettinen A, Heinonen PK, Teisala K, et al. Serologic evidence for the role of Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma hominis in the etiology of tubal factor infertility and ectopic pregnancy. Sex Transm Dis 1990;17:10–14.

63. Chow JM, Yonekura ML, Richwald GA, et al. The association between Chlamydia trachomatis and ectopic pregnancy. A matched-pair, case-control study. JAMA 1990;263:3164–3167.

64. Hillis SD, Owens LM, Marchbanks PA, et al. Recurrent chlamydial infections increase the risks of hospitalization for ectopic pregnancy and pelvic inflammatory disease. Am J Obstet Gynecol 1997;176:103–107.

65. Goldberg JM, Falcone T. Effect of diethylstilbestrol on reproductive function. Fertil Steril 1999;72:1–7.

66. DeCherney AH, Cholst I, Naftolin F. Structure and function of the fallopian tubes following exposure to diethylstilbestrol (DES) during gestation. Fertil Steril 1981;36:741–745.

67. Barnes AB, Colton T, Gundersen J, et al. Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol. N Engl J Med 1980;302:609–613.

68. Borgatta L, Murthy A, Chuang C, et al. Pregnancies diagnosed during Depo-Provera use. Contraception 2002;66:169–172.

69. Trussell J, Hedley A, Raymond E. Ectopic pregnancy following use of progestin-only ECPs. J Fam Plann Reprod Health Care 2003;29:249.

70. Sivin I. Risks and benefits, advantages and disadvantages of levonorgestrel-releasing contraceptive implants. Drug Saf 2003;26:303–335.

71. Furlong LA. Ectopic pregnancy risk when contraception fails. A review. J Reprod Med 2002;47:881–885.

72. Anonymous. A multinational case-control study of ectopic pregnancy. The World Health Organization’s Special Programme of Research, Development and Research Training in Human Reproduction: Task Force on Intrauterine Devices for Fertility Regulation. Clin Reprod Fertil 1985;3:131–143.

73. Xiong X, Buekens P, Wollast E. IUD use and the risk of ectopic pregnancy: a meta-analysis of case-control studies. Contraception 1995;52:23–34.

74. Farley TM, Rosenberg MJ, Rowe PJ, et al. Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet 1992;339:785–788.

75. Ni HY, Daling JR, Chu J, et al. Previous abdominal surgery and tubal pregnancy. Obstet Gynecol 1990;75:919–922.

76. Trimbos-Kemper T, Trimbos B, van Hall E. Etiological factors in tubal infertility. Fertil Steril 1982;37:384–388.

77. Weinstein D, Polishuk WZ. The role of wedge resection of the ovary as a cause for mechanical sterility. Surg Gynecol Obstet 1975;141:417–418.

78. Marchbanks PA, Coulam CB, Annegers JF. An association between clomiphene citrate and ectopic pregnancy: a preliminary report. Fertil Steril 1985;44:268–270.

79. Chow WH, Daling JR, Cates W Jr, et al. Epidemiology of ectopic pregnancy. Epidemiol Rev 1987;9:70–94.

80. Cohen J, Mayaux MJ, Guihard-Moscato ML, et al. In-vitro fertilization and embryo transfer: a collaborative study of 1163 pregnancies on the incidence and risk factors of ectopic pregnancies. Hum Reprod 1986;1:255–258.

81. McBain JC, Evans JH, Pepperell RJ, et al. An unexpectedly high rate of ectopic pregnancy following the induction of ovulation with human pituitary and chorionic gonadotrophin. Br J Obstet Gynaecol 1980;87:5–9.

82. Gemzell C, Guillome J, Wang CF. Ectopic pregnancy following treatment with human gonadotropins. Am J Obstet Gynecol 1982;143:761–765.

83. Oelsner G, Menashe Y, Tur-Kaspa I, et al. The role of gonadotropins in the etiology of ectopic pregnancy. Fertil Steril 1989;52:514–516.

84. Steptoe PC, Edwards RG. Reimplantation of a human embryo with subsequent tubal pregnancy. Lancet 1976;1:880–882.

85. Corson SL, Dickey RP, Gocial B, et al. Outcome in 242 in vitro fertilization-embryo replacement or gamete intrafallopian transfer-induced pregnancies. Fertil Steril 1989;51:644–650.

86. Herman A, Ron-El R, Golan A, et al. The role of tubal pathology and other parameters in ectopic pregnancies occurring in in vitro fertilization and embryo transfer. Fertil Steril 1990;54:864–868.

87. Dor J, Seidman DS, Levran D, et al. The incidence of combined intrauterine and extrauterine pregnancy after in vitro fertilization and embryo transfer. Fertil Steril 1991;55:833–834.

88. Strandell A, Thorburn J, Hamberger L. Risk factors for ectopic pregnancy in assisted reproduction. Fertil Steril 1999;71:282–286.

89. Saraiya M, Berg CJ, Kendrick JS, et al. Cigarette smoking as a risk factor for ectopic pregnancy. Am J Obstet Gynecol 1998;178:493–498.

90. Bouyer J, Coste J, Shojaei T, et al. Risk factors for ectopic pregnancy: a comprehensive analysis based on a large case-control, population-based study in France. Am J Epidemiol 2003;157:185–194.

91. Honore LH. A significant association between spontaneous abortion and tubal ectopic pregnancy. Fertil Steril 1979;32:401–402.

92. Fedele L, Acaia B, Parazzini F, et al. Ectopic pregnancy and recurrent spontaneous abortion: two associated reproductive failures. Obstet Gynecol 1989;73:206–208.

93. Thorp JM Jr, Hartmann KE, Shadigian E. Long-term physical and psychological health consequences of induced abortion: review of the evidence. Obstet Gynecol Surv 2003;58:67–79.

94. Atrash HK, Strauss LT, Kendrick JS, et al. The relation between induced abortion and ectopic pregnancy. Obstet Gynecol 1997;89:512–518.

95. Skjeldestad FE, Atrash HK. Evaluation of induced abortion as a risk factor for ectopic pregnancy. A case-control study. Acta Obstet Gynecol Scand 1997;76:151–158.

96. Tharaux-Deneux C, Bouyer J, Job-Spira N, et al. Risk of ectopic pregnancy and previous induced abortion. Am J Public Health 1998;88:401–405.

97. Jenkins CS, Williams SR, Schmidt GE. Salpingitis isthmica nodosa: a review of the literature, discussion of clinical significance, and consideration of patient management. Fertil Steril 1993;60:599–607.

98. Homm RJ, Holtz G, Garvin AJ. Isthmic ectopic pregnancy and salpingitis isthmica nodosa. Fertil Steril 1987;48:756–760.

99. Niles, Clark JF. Pathogenesis of tubal pregnancy. Am J Obstet Gynecol 1969;105:1230–1234.

100. Benjamin CL, Beaver DC. Pathogenesis of salpingitis isthmica nodosa. Am J Clin Pathol 1951;21:212–222.

101. Persaud V. Etiology of tubal ectopic pregnancy. Radiologic and pathologic studies. Obstet Gynecol 1970;36:257–263.

102. Arias-Stella J. The Arias-Stella reaction: facts and fancies four decades after. Adv Anat Pathol 2002;9:12–23.

103. Stabile I, Grudzinskas JG. Ectopic pregnancy: a review of incidence, etiology, and diagnostic aspects. Obstet Gynecol Surv 1990;45:335–347.

104. Seeber B. Endometrial stripe thickness and pregnancy outcome in first trimester pregnancies with pain bleeding or both. J Reprod Med Sep 2007;52:757.

105. Tuomivaara L, Kauppila A, Puolakka J. Ectopic pregnancy—an analysis of the etiology, diagnosis and treatment in 552 cases. Arch Gynecol 1986;237:135–147.

106. Storring PL, Gaines-Das RE, Bangham DR. International reference preparation of human chorionic gonadotrophin for immunoassay; potency estimates in various bioassays and protein binding assay systems; and international reference preparations of the alpha and beta subunits of human chorionic gonadotrophin for immunoassay. J Endocrinol 1980;84:295–310.

107. Cole LA. Phantom hCG and phantom choriocarcinoma. Gynecol Oncol 1998;71:325–329.

108. Rotmensch S, Cole LA. False diagnosis and needless therapy of presumed malignant disease in women with false-positive human chorionic gonadotropic concentration. Lancet 2000;35:712–715.

109. Marshall JR, Hammond CB, Ross GT, et al. Plasma and urinary chorionic gonadotropin during early human pregnancy. Obstet Gynecol 1968;32:760–764.

110. Daus K, Mundy D, Graves W, et al. Ectopic pregnancy: what to do during the 20-day window. J Reprod Med 1989;34:162–166.

111. Kadar N, Caldwell BV, Romero R. A method of screening for ectopic pregnancy and its indications. Obstet Gynecol 1981;58:162–165.

112. Cartwright PS, Moore RA, Dao AH, et al. Serum beta-human chorionic gonadotropin levels relate poorly with the size of a tubal pregnancy. Fertil Steril 1987;48:679–680.

113. Pearlstone AC, Oei ML, Wu TCJ. The predictive value of a single, early human chorionic gonadotropin measurement and the influence of maternal age on pregnancy outcome in an infertile population. Fertil Steril 1992;57:302–304.

114. Milwidsky A, Adoni A, Segal S, et al. Chorionic gonadotropin and progesterone levels in ectopic pregnancy. Obstet Gynecol 1977;50:145–147.

115. Radwanska E, Frankenberg J, Allen EI. Plasma progesterone levels in normal and abnormal early human pregnancy. Fertil Steril 1978;30:398–402.

116. Stovall TG, Ling FW, Andersen RN, et al. Improved sensitivity and specificity of a single measurement of serum progesterone over serial quantitative beta-human chorionic gonadotrophin in screening for ectopic pregnancy. Hum Reprod 1992;7:723–725.

117. 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.

118. Cowan BD, Vandermolen DT, Long CA, et al. Receiver operator characteristics, efficiency analysis, and predictive value of serum progesterone concentration as a test for abnormal gestations. Am J Obstet Gynecol 1992;166:1729–1734.

119. Barnes ER, Oelsner G, Benveniste R, et al. Progesterone, estradiol, and alpha-human chorionic gonadotropin secretion in patients with ectopic pregnancy. J Clin Endocrinol Metab 1986;62:529–531.

120. Witt BR, Wolf GC, Wainwright CJ, et al. Relaxin, CA125, progesterone, estradiol, Schwangerschaft protein, and human chorionic gonadotropin as predictors of outcome in threatened and non-threatened pregnancies. Fertil Steril 1990;53:1029–1036.

121. Guillaume J, Benjamin F, Sicuranza BJ, et al. Serum estradiol as an aid in the diagnosis of ectopic pregnancy. Obstet Gynecol 1990;76:1126–1129.

122. Lavie O, Beller U, Neuman M, et al. Maternal serum creatine kinase: a possible predictor of tubal pregnancy. Am J Obstet Gynecol 1993;169:1149–1150.

123. Ho PC, Chan SYW, Tang GWK. Diagnosis of early pregnancy by enzyme immunoassay of Schwangerschafts-protein 1. Fertil Steril 1988;49:76–80.

124. Bell RJ, Eddie LW, Lester AR, et al. Relaxin in human pregnancy serum measured with an homologous radioimmunoassay. Obstet Gynecol 1987;69:585–589.

125. Meunier K, Mignot TM, Maria B, et al. Predictive value of the active renin assay for the diagnosis of ectopic pregnancy. Fertil Steril 1991;55:432–435.

126. Niloff JM, Knapp RC, Schaetzl E, et al. CA125 antigen levels in obstetric and gynecologic patients. Obstet Gynecol 1984;64:703–707.

127. Kobayashi F, Sagawa N, Nakamura K, et al. Mechanism and clinical significance of elevated CA125 levels in the sera of pregnant women. Am J Obstet Gynecol 1989;160:563–566.

128. Check JH, Nowroozi K, Winkel CA, et al. Serum CA125 levels in early pregnancy and subsequent spontaneous abortion. Obstet Gynecol 1990;75:742–744.

129. Brumsted JR, Nakajima ST, Badger G, et al. Serum concentration of CA125 during the first trimester of normal and abnormal pregnancies. J Reprod Med 1990;35:499–502.

130. Sadovsky Y, Pineda J, Collins JL. Serum CA125 levels in women with ectopic and intrauterine pregnancies. J Reprod Med 1991;36:875–878.

131. Cederqvist LL, Killackey MA, Abdel-Latif N, et al. Alpha-fetoprotein and ectopic pregnancy. BMJ 1983;286:1247–1248.

132. Grosskinsky CM, Hage ML, Tyrey L, et al. hCG, progesterone, alpha-fetoprotein, and estradiol in the identification of ectopic pregnancy. Obstet Gynecol 1993;81:705–709.

133. Horne A, Shaw JL, Murdoch A, et al. Placental growth factor: a promising diagnostic biomarker for tubal ectopic pregnancy. J Clin Endocrinol Metab 2010;96:E104–108.

134. Cartwright J, Duncan WC, Critchley HO, et al. Serum biomarkers of tubal ectopic pregnancy: current candidates and future possibilities. Reproduction 2009;138:9–22.

135. Theron GB, Shepherd EGS, Strachan AF. C-reactive protein levels in ectopic pregnancy, pelvic infection and carcinoma of the cervix. S Afr Med J 1986;69:681–682.

136. Cacciatore B. Can the status of tubal pregnancy be predicted with transvaginal sonography? A prospective comparison of sonographic, surgical, and serum hCG findings. Radiology 1990;177:481–484.

137. Thorsen MK, Lawson TL, Aiman EJ, et al. Diagnosis of ectopic pregnancy: endovaginal vs transabdominal sonography. Am J Roentgenol 1990;155:307–310.

138. Bateman BG, Nunley WC Jr, Kolp LA, et al. Vaginal sonography findings and hCG dynamics of early intrauterine and tubal pregnancies. Obstet Gynecol 1990;75:421–427.

139. Cacciatore B, Stenman UH, Ylostalo P. Comparison of abdominal and vaginal sonography in suspected ectopic pregnancy. Obstet Gynecol 1989;73:770–774.

140. Condous G. The accuracy of transvaginal ultrasonography for the diagnosis of ectopic pregnancy prior to surgery. Hum Reprod 2005;20:1404–1409.

141. Fleischer AC, Pennell RG, McKee MS, et al. Ectopic pregnancy: features at transvaginal sonography. Radiology 1990;174:375–378.

142. Timor-Tritsch IE, Yeh MN, Peisner DB, et al. The use of transvaginal ultrasonography in the diagnosis of ectopic pregnancy. Am J Obstet Gynecol 1989;161:157–161.

143. Bree RL, Marn CS. Transvaginal sonography in the first trimester: embryology, anatomy, and hCG correlation. Semin Ultrasound CT MR 1990;11:12–21.

144. Bottomley C. The optimal timing of an ultrasound scan to assess the location and viability of an early pregnancy. Hum Reprod 2009;24:1811–1817.

145. Cacciatore B, Ylostalo P, Stenman UH, et al. Suspected ectopic pregnancy: ultrasound findings and hCG levels assessed by an immunofluorometric assay. BJOG 1988;95:497–502.

146. Abramovici H, Auslender R, Lewin A, et al. Gestational-pseudogestational sac: a new ultrasonic criterion for differential diagnosis. Am J Obstet Gynecol 1983;145:377–379.

147. Nyberg DA, Filly RA, Laing FC, et al. Ectopic pregnancy, diagnosis by sonography correlated with quantitative hCG levels. J Ultrasound Med 1987;6:145–150.

148. Bradley WG, Fiske CE, Filly RA. The double sac sign of early intrauterine pregnancy: use in exclusion of ectopic pregnancy. Radiology 1982;143:223–226.

149. Nyberg DA, Mack LA, Harvey D, et al. Value of the yolk sac in evaluating early pregnancies. J Ultrasound Med 1988;7:129–135.

150. Jain KA, Hamper UM, Sanders RC. Comparison of transvaginal and transabdominal sonography in the detection of early pregnancy and its complications. AJR Am J Roentgenol 1988;151:1139–1143.

151. Bree RL, Edwards M, Bohm VM, et al. Transvaginal sonography in the evaluation of normal early pregnancy: correlation with hCG level. AJR Am J Roentgenol 1989;53:75–79.

152. Nyberg DA, Hughes MP, Mack LA, et al. Extrauterine findings of ectopic pregnancy at transvaginal US: importance of echogenic fluid. Radiology 1991;178:823–826.

153. Rottem S, Thaler I, Levron J, et al. Criteria for transvaginal sonographic diagnosis of ectopic pregnancy. J Clin Ultrasound 1990;18:274–279.

154. Nyberg DA, Mack LA, Laing FC, et al. Early pregnancy complications: endovaginal sonographic findings correlated with human chorionic gonadotropin levels. Radiology 1988;167:619–622.

155. Goldstein SR. Embryonic death in early pregnancy: a new look at the first trimester. Obstet Gynecol 1994;84:294–297.

156. Westrom L, Bengtsson LPH, Mardh P-A. Incidence, trends, and risks of ectopic pregnancy in a population of women. BMJ 1981;282:15–18.

157. Brown DL. Transvaginal sonography for diagnosing ectopic pregnancy: positivity criteria and performance characteristics. J Ultrasound Med 1994;13:259–266.

158. Emerson DS, Cartier MS, Altieri LA, et al. Diagnostic efficacy of endovaginal color Doppler flow imaging in an ectopic pregnancy screening program. Radiology 1992;183:413–420.

159. Dart R. Isolated fluid in the cul-de-sac how well does it predict ectopic pregnancy? Am J Emerg Med 2002;20:1–4.

160. Bernaschek G, Rudelstorfer R, Csaicsich P. Vaginal sonography versus serum human chorionic gonadotropin in early detection of pregnancy. Am J Obstet Gynecol 1988;158:608–612.

161. Diamond MP, DeCherney AH. Ectopic pregnancy. Philadelphia, PA: WB Saunders, 1991:163.[MB4]

162. Menard A, Crequat J, Mandelbrot L, et al. Treatment of unruptured tubal pregnancy by local injection of methotrexate under transvaginal sonographic control. Fertil Steril 1990;54:47–50.

163. Campbell S, Pearce JM, Hackett G, et al. Qualitative assessment of uteroplacental blood flow: early screening test for high-risk pregnancies. Obstet Gynecol 1986;68:649–653.

164. McCowan LM, Ritchie K, Mo LY, et al. Uterine artery flow velocity waveforms in normal and growth-retarded pregnancies. Am J Obstet Gynecol 1988;158:499–504.

165. Taylor KJ, Ramos IM, Feyock AL, et al. Ectopic pregnancy: duplex Doppler evaluation. Radiology 1989;173:93–97.

166. Dillon EH, Feyock AL, Taylor KJW. Pseudogestational sacs: Doppler US differentiation from normal or abnormal intrauterine pregnancies. Radiology 1990;176:359–364.

167. Chew S. The role of TVUS and colour Doppler imaging in the detection of ectopic pregnancy. J Obstetrics Gynaecol Res 1996;22:455–460.

168. Condous G. The conservative management of early pregnancy complication: a review of the literature. Ultrasound Obstet Gynecol 2003;22:420–430.

169. Kurman RJ, Main CS, Chen HC. Intermediate trophoblast: a distinctive form of trophoblast with specific morphological, biochemical, and functional features. Placenta 1984;5:349–369.

170. Vermesh M, Graczykowski JW, Sauer MV. Reevaluation of the role of culdocentesis in the management of ectopic pregnancy. Am J Obstet Gynecol 1990;162:411–413.

171. Glezerman M, Press F, Carpman M. Culdocentesis is an obsolete diagnostic tool in suspected ectopic pregnancy. Arch Obst Gynecol 1992;252:5–9.

172. Stovall TG, Ling FW, Carson SA, et al. Serum progesterone and uterine curettage in the differential diagnosis of ectopic pregnancy. Fertil Steril 1992;57:456–458.

173. Stovall TG, Ling FW. Ectopic pregnancy: diagnostic and therapeutic algorithms minimizing surgical intervention. J Reprod Med 1993;38:807–812.

174. Hill GA, Segars JH Jr, Herbert CM III. Laparoscopic management of interstitial pregnancy. J Gynecol Surg 1989;5:209–212.

175. 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.

176. Lundorff P, Hahlin M, Kallfelt B, et al. Adhesion formation after laparoscopic surgery in tubal pregnancy: a randomized trial versus laparotomy. Fertil Steril 1991;55:911–915.

177. Hajenius PJ, Mol F, Mol BW, et al. Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev 2007;1:CD000324.

178. Sharma JB, Gupta S, Malhotra M, et al. A randomized controlled comparison of minilaparotomy and laparotomy in ectopic pregnancy cases. Indian J Med Sci 2003;57:493–500.

179. Jeffcoate TN. Salpingectomy or salpingo-oophorectomy. J Obstet Gynaecol Br Emp 1955;62:214–215.

180. Schenker JG, Eyal F, Polishuk WZ. Fertility after tubal surgery. Surg Gynecol Obstet 1972;135:74–76.

181. Dimarchi JM, Kosasa TS, Kobara TY, et al. Persistent ectopic pregnancy. Obstet Gynecol 1987;70:555–560.

182. Vermesh M, Silva PD, Sauer MV, et al. Persistent tubal ectopic gestation: patterns of circulating beta-human chorionic gonadotropin and progesterone, and management options. Fertil Steril 1988;50:584–588.

183. Seifer DB, Gutmann JN, Grant WD, et al. Comparison of persistent ectopic pregnancy after laparoscopic salpingostomy versus salpingectomy at laparotomy for ectopic pregnancy. Obstet Gynecol 1993;81:378–382.

184. Mol F, Mol BW, Ankum WM. Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis. Hum Reprod Update 2008;14:309–319.

185. Gracia CR, Brown HA, Barnhart KT. Prophylactic methotrexate after linear salpingostomy: a decision analysis. Fertil Steril 2001;76:1191–1195.

186. Smith HO, Toledo AA, Thompson JD. Conservative surgical management of isthmic ectopic pregnancies. Am J Obstet Gynecol 1987;157:604–610.

187. 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.

188. Silva PD, Schaper AM, Rooney B. Reproductive outcome after 143 laparoscopic procedures for ectopic pregnancy. Obstet Gynecol 1993;81:710–715.

189. Langer R, Raziel A, Ron-El R, et al. Reproductive outcome after conservative surgery for unruptured tubal pregnancies—a 15-year experience. Fertil Steril 1990;53:227–231.

190. American College of Obstetricians and Gynecologists. Medical management of ectopic pregnancy. ACOG Practice Bulletin No. 94. Obstet Gynecol 2008;111:479–485.

191. St. Clair JT, Whealer DA, Fish SA. Methotrexate in abdominal pregnancy. JAMA 1969;208:529–531.

192. Tanaka T, Hayashi H, Kutsuzawa T, et al. Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case. Fertil Steril 1982;37:851–852.

193. Van Den, Eeden SK, Shan J, et al. Ectopic pregnancy rate and treatment utilization in a large managed care organization. Obstet Gynecol 2005;105:1052.

194. Barnhart KT, Gosman G, Asnby R, et al. The medical management of ectopic pregnancy: a meta-analysis comparing “single dose” and multidose regimens. Obstet Gynecol 2003;101:778–784.

195. Stovall TG, Ling FW, Buster JE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril 1989;51:435–438.

196. Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of ectopic pregnancy. Obstet Gynecol 1991;77:754–757.

197. Lipscomb GH, Bran D, McCord ML, et al. Analysis of three hundred fifteen women with tubal ectopic pregnancies treated with single-dose methotrexate. Am J Obstet Gynecol 1998;178:1354–1358.

198. Menon S, Colins J, Barnhart KT. Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review. Fertil Steril 2007;87:481–484.

199. Barnhart KT, Hummel AC, Sammel MD, et al. Use of “2-dose” regimen of methotrexate to treat ectopic pregnancy. Fertil Steril 2007;87:250–256.

200. Pisarka MD, Carson SA, Buster JE. Ectopic pregnancy. Lancet 1998;351:1115–1120.

201. Klauser CK, May WL, Johnson VK, et al. Methotrexate for ectopic pregnancy: a randomized single dose compared with multiple dose. Obstet Gynecol 2005;105:64S.

202. Alleyassin A, Khademi A, Aghahosseini M, et al. Comparison of success rates in the medical management of ectopic pregnancy with single-dose and multiple dose administration of methotrexate: a prospective, randomized clinical trial. Fertil Steril 2006;85:1661–1666.

203. Brown DL, Felker RE, Stovall TG, et al. Serial endovaginal sonography of ectopic pregnancies treated with methotrexate. Obstet Gynecol 1991;77:406–409.

204. Berkowitz RS, Goldstein DP, Jones MA, et al. Methotrexate with citrovorum factor rescue: reduced chemotherapy toxicity in the management of gestational trophoblastic neoplasms. Cancer 1980;45:423–426.

205. Rustin GJS, Rustin F, Dent J, et al. No increase in second tumors after cytotoxic chemotherapy for gestational trophoblastic tumors. N Engl J Med 1983;308:473–476.

206. Hajenius PJ, Engelsbel S, Mol BW, et al. Randomized trial of systemic methotrexate versus laparoscopic salpingostomy in tubal pregnancy. Lancet 1997;350:774–779.

207. Olofsson JI, Poromaa IS, Ottander U, et al. Clinical and pregnancy outcome following ectopic pregnancy; a prospective study comparing expectancy, surgery and systemic methotrexate treatment. Acta Obstet Gynecol Scand 2001;80:744–749.

208. Dias Pereira G, Hajenius PJ, Mol BW, et al. Fertility outcome after systemic methotrexate and laparoscopic salpingostomy for tubal pregnancy. Lancet 1999;353:724–745.

209. Shalev E, Peleg D, Bustan M, et al. Limited role for intratubal methotrexate treatment of ectopic pregnancy. Fertil Steril 1995;63:20–24.

210. Tulandi T, Atri M, Bret P, et al. Transvaginal intratubal methotrexate treatment of ectopic pregnancy. Fertil Steril 1992;58:98–100.

211. Fernandez H, Benifla JL, Lelaidier C, et al. Methotrexate treatment of ectopic pregnancy: 100 cases treated by primary transvaginal injection under sonographic control. Fertil Steril 1993;59:773–777.

212. Fernandez H, Pauthier S, Daimerc S, et al. Ultrasound-guided injection of methotrexate versus laparoscopic salpingotomy in ectopic pregnancy. Fertil Steril 1995;63:25–29.

213. Oelsner G, Admon D, Shalev E, et al. A new approach for the treatment of interstitial pregnancy. Fertil Steril 1993;59:924–925.

214. Aboulghar MA, Mansour RT, Serour GI. Transvaginal injection of potassium chloride and methotrexate for the treatment of tubal pregnancy with a live fetus. Hum Reprod 1990;5:887–888.

215. Feichtinger W, Kemeter P. Treatment of unruptured ectopic pregnancy by needling of sac and injection of methotrexate or PGE₂ under transvaginal sonography control. Arch Gynecol Obstet 1989;246:85–89.

216. Hagstrom HG, Hahlin M, Sjöblom P, et al. Prediction of persistent trophoblastic activity after local prostaglandin F_2a injection for ectopic pregnancy. Hum Reprod 1994;9:1170–1174.

217. Laatikainen T, Tuomivaara L, Kauppila K. Comparison of a local injection of hyperosmolar glucose solution with salpingostomy for the conservative treatment of tubal pregnancy. Fertil Steril 1993;60:80–84.

218. Kojima E, Abe Y, Morita M, et al. The treatment of unruptured tubal pregnancy with intratubal methotrexate injection under laparoscopic control. Obstet Gynecol 1990;75:723–725.

219. Kenigsberg D, Porte J, Hull M, et al. Medical treatment of residual ectopic pregnancy: RU 486 and methotrexate. Fertil Steril 1987;47:702–703.

220. Frydman R, Fernandez H, Troalen F, et al. Phase I clinical trial of monoclonal anti-human chorionic gonadotropin antibody in women with an ectopic pregnancy. Fertil Steril 1989;52:734–738.

221. Garcia AJ, Aubert JM, Sama J, et al. Expectant management of presumed ectopic pregnancies. Fertil Steril 1987;48:395–400.

222. Carson SA, Stovall TG, Ling FW, et al. Low human chorionic somatomammotropin fails to predict spontaneous resolution of unruptured ectopic pregnancies. Fertil Steril 1991;55:629–630.

223. Fernandez H, Rainhorn JD, Papiernik E, et al. Spontaneous resolution of ectopic pregnancy. Obstet Gynecol 1988;71:171–174.

224. Gretz E, Quagliarello J. Declining serum concentrations of the beta-subunit of human chorionic gonadotropin and ruptured ectopic pregnancy. Am J Obstet Gynecol 1987;156:940–941.

225. Makinen JI, Kivijarvi AK, Irjala KMA. Success of non-surgical management of ectopic pregnancy. Lancet 1990;335:1099.

226. Korhonen J, Stenman UH, Ylotalo P. Serum human chorionic gonadotropin dynamics during spontaneous resolution of ectopic pregnancy. Fertil Steril 1994;61:632–636.

227. Seifer DB, Gutmann JN, Doyle MB, et al. Persistent ectopic pregnancy following laparoscopic linear salpingostomy. Obstet Gynecol 1990;76:1121–1125.

228. Pouly JL, Mahnes H, Mage G, et al. Conservative laparoscopic treatment of 321 ectopic pregnancies. Fertil Steril 1986;46:1093–1097.

229. Lundorff P, Hahlin M, Sjoblom P, et al. Persistent trophoblast after conservative treatment of tubal pregnancy: prediction and detection. Obstet Gynecol 1991;77:129–133.

230. Cartwright PS. Peritoneal trophoblastic implants after surgical management of tubal pregnancy. J Reprod Med 1991;36:523–524.

231. Higgins KA, Schwartz MB. Treatment of persistent trophoblastic tissue after salpingostomy with methotrexate. Fertil Steril 1986;45:427–428.

232. Rose PG, Cohen SM. Methotrexate therapy for persistent ectopic pregnancy after conservative laparoscopic management. Obstet Gynecol 1990;76:947–949.

233. Bengtsson G, Bryman I, Thorburn J, et al. Low-dose oral methotrexate as second-line therapy for persistent trophoblast after conservative treatment of ectopic pregnancy. Obstet Gynecol 1992;79:589–591.

234. Cole T, Corlett RC Jr. Chronic ectopic pregnancy. Obstet Gynecol 1982;59:63–68.

235. Rogers WF, Shaub M, Wilson R. Chronic ectopic pregnancy: ultrasonic diagnosis. J Clin Ultrasound 1977;5:257–260.

236. Parente JT, Ou CS, Levy J, et al. Cervical pregnancy analysis: a review and report of five cases. Obstet Gynecol 1983;62:79–82.

237. Marcovici I, Rosenzweig BA, Brill AI, et al. Cervical pregnancy. Obstet Gynecol Surv 1994;49:49–55.

238. Karande VC, Flood JT, Heard N, et al. Analysis of ectopic pregnancies resulting from in-vitro fertilization and embryo transfer. Hum Reprod 1991;6:446.

239. Hofmann HMH, Urdl W, Hofler H, et al. Cervical pregnancy: case reports and current concepts in diagnosis and treatment. Arch Gynecol Obstet 1987;241:63–69.

240. Leeman LM, Wendland CL. Cervical ectopic pregnancy: diagnosis with endovaginal ultrasound examination and successful treatment with methotrexate. Arch Fam Med 2000;9:72–77.

241. Bader-Armstrong B, Shah Y, Rubens D. Use of ultrasound and magnetic resonance imaging in the diagnosis of cervical pregnancy. J Clin Ultrasound 1989;17:283–286.

242. Bernstein D, Holzinger M, Ovadia J, et al. Conservative treatment of cervical pregnancy. Obstet Gynecol 1981;58:741–742.

243. Wharton KR, Gore B. Cervical pregnancy managed by placement of a Shirodkar cerclage before evacuation: a case report. J Reprod Med 1988;33:227–229.

244. Nolan TE, Chandler PE, Hess LW, et al. Cervical pregnancy managed without hysterectomy: a case report. J Reprod Med 1989;34:241–243.

245. Hallatt JG. Primary ovarian pregnancy: a report of twenty-five cases. Am J Obstet Gynecol 1982;143:55–60.

246. Grimes HG, Nosal RA, Gallagher JC. Ovarian pregnancy: a series of 24 cases. Obstet Gynecol 1983;61:174–180.

247. Spiegelberg O. Casusistik der ovarialschwangerschaft. Arch Gynaecol 1878;13:73.

248. Malinger G, Achiron R, Treschan O, et al. Case report: ovarian pregnancy-ultrasonographic diagnosis. Acta Obstet Gynecol Scand 1988;67:561–563.

249. DeVries K, Atad J, Arodi J, et al. Primary ovarian pregnancy: a conservative surgical approach by wedge resection. Int J Fertil 1981;26:293–294.

250. Van Coevering RJ, Fisher JE. Laparoscopic management of ovarian pregnancy: a case report. J Reprod Med 1988;33:774–776.

251. Russell JB, Cutler LR. Transvaginal ultrasonographic detection of primary ovarian pregnancy with laparoscopic removal: a case report. Fertil Steril 1989;51:1055–1056.

252. Tinelli A, Hudelist G, Malvasi A, et al. Laparoscopic management of ovarian pregnancy. J Soc Laparosc Surg 2008;12:169–172.

253. Habbu J, Read MD. Ovarian pregnancy successfully treated with methotrexate. J Obstet Gynaecol 2006; 26:587–588.

254. Raziel A, Golan A. Primary ovarian pregnancy successfully treated with methotrexate. Am J Obstet Gynecol 1993;169:1362–1363.

255. Shamma FN, Schwartz LB. Primary ovarian pregnancy successfully treated with methotrexate. Am J Obstet Gynecol 1992;167:1307–1308.

256. Atrash HK, Friede A, Hogue CJR. Abdominal pregnancy in the United States: frequency and maternal mortality. Obstet Gynecol 1987;69:333–337.

257. Ludwig M, Kaisi M, Bauer O, et al. The forgotten chid—a case of heterotopic, intraabdominal and intrauterine pregnancy carried to term. Hum Reprod 1999;14:1372–1374.

258. Tsudo T, Harada T, Yoshioka H, et al. Laparoscopic management of early primary abdominal pregnancy. Obstet Gynecol 1997;90:687–688.

259. Rahman MS, Al-Suleiman SA, Rahman J, et al. Advanced abdominal pregnancy—observations in 10 cases. Obstet Gynecol 1982;59:366–372.

260. Stevens CA. Malformations and deformations in abdominal pregnancy. Am J Med Genetics 1993;47:1189–1195.

261. Stanley JH, Horger EO III, Fagan CJ, et al. Sonographic findings in abdominal pregnancy. AJR Am J Roentgenol 1986;147:1043–1046.

262. Harris MB, Angtuaco T, Frazer CN, et al. Diagnosis of a viable abdominal pregnancy by magnetic resonance imaging. Am J Obstet Gynecol 1988;159:150–151.

263. Lockhat F, Corr P, Ramphal S, et al. The value of magnetic resonance imaging in the diagnosis and management of extra-uterine abdominal pregnancy. Clin Radiol 2006;61:264–269.

264. Martin JN Jr, Ridgway LE III, Connors JJ, et al. Angiographic arterial embolization and computed tomography-directed drainage for the management of hemorrhage and infection with abdominal pregnancy. Obstet Gynecol 1990;76:941–945.

265. Martin JN Jr, Sessums JK, Martin RW, et al. Abdominal pregnancy: current concepts of management. Obstet Gynecol 1988;71:549–557.

266. Moores KL, Keriakos RH, Anumba DO, et al. Management challenges of a live 12-week sub-hepatic intra-abdominal pregnancy. BJOG 2010;117:365–368.

267. Lau S, Tulandi T. Conservative medical and surgical management of interstitial ectopic pregnancy. Fertil Steril 1999;72:207–215.

268. MaCrae R, Olowu O, Rizzuto MI, et al. Diagnosis and laparoscopic management of 11 consecutive cases of cornual ectopic pregnancy. Arch Gynecol Obstet 2009;280:59–64.

269. Elito J, Camano L. Unruptured tubal pregnancy: different treatments for early and late diagnosis. Sao Paulo Med J 2006;124:321–324.

270. Walker JJ. Ectopic pregnancy. Clin Obstet Gynecol 2007;50:89–99.

271. Moawad NS, Mahajan ST, Moniz MH et al. Current diagnosis and treatment of interstitial pregnancy. Am J Obstet Gynecol 2010;202:15–29.

272. Vierhout ME, Wallenburg HCS. Intraligamentary pregnancy resulting in a live infant. Am J Obstet Gynecol 1985;152:878–879.

273. Reece EA, Petrie RH, Sirmans MF, et al. Combined intrauterine and extrauterine gestations: a review. Am J Obstet Gynecol 1983;146:323–330.

274. Tal J, Haddad S, Gordon N, et al. Heterotopic pregnancy after ovulation induction and assisted reproductive technologies: a literature review from 1971 to 1993. Fertil Steril 1996;66:1–12.

275. Cheng PJ, Chueh HY, Qiu JT. Heterotopic pregnancy in a natural conception cycle presenting as hematometra. Obstet Gynecol 2004;104:1195–1198.

276. Clayton HB, Schieve LA, Peterson HB, et al. A comparison of heterotopic and intrauterine-only pregnancy outcomes after assisted reproductive technologies in the United States from 1999 to 2002. Fertil Steril 2007;87:303–309.

277. Goldberg JM, Bedaiwy MA. Transvaginal local injection of hyperosmolar glucose for the treatment of heterotopic pregnancies. Obstet Gynecol 2006;107:509–510.

278. Goldstein JS, Ratts VS, Philpott T, et al. Risk of surgery after use of potassium chloride for treatment of tubal heterotopic pregnancy. Obstet Gynecol 2006;107:506–508.

279. De Los Rios JF. Bilateral ectopic pregnancy. J Minim Invasive Gynecol 2007;14:419–427.

280. Svirsky R, Maymon R, Vaknin Z, et al. Twin tubal pregnancy: a rising complication? Fertil Steril 2010;94:1910.e13–e16.

281. Adair CD, Benrubi GI, Sanchez-Ramos L, et al. Bilateral tubal ectopic pregnancies after bilateral partial salpingectomy: a case report. J Reprod Med 1994;39:131–133.

282. Goffner L, Bluth MJ, Fruauff A, et al. Ectopic gestation associated with intrauterine triplet pregnancy after in vitro fertilization. J Ultrasound Med 1993;12:63–64.

283. Jackson P, Barrowclough IW, France JT, et al. A successful pregnancy following total hysterectomy. Br J Obstet Gynaecol 1980;87:353–355.

284. Nehra PC, Loginsky SJ. Pregnancy after vaginal hysterectomy. Obstet Gynecol 1984;64:735–737.