Ectopic pregnancy is a potentially fatal condition. It occurs in approximately 2% of all pregnancies and is a leading cause of first trimester maternal death (8). There has seen a sixfold increase in the prevalence of ectopic pregnancy in the last 30 years(3) and it is believed to be caused by an increased prevalence of sexually transmitted diseases, increased frequency of sterilization procedures, and delay in child-bearing until later in life (23). Some of the increase is artificial, however, because of more sophisticated diagnostic techniques that allow physicians to detect early ectopic pregnancies that might previously have resolved spontaneously and remained undiagnosed.

Causes and risk factors

More than 97% of ectopic pregnancies are located within the fallopian tube, with the remainder in the interstitial part of tube, abdomen, cervix, or ovaries (7). Most ectopic pregnancies develop from a delay in ovum transport caused by an abnormality of the fallopian tube. A much smaller percentage of ectopic pregnancies are caused by an abnormality of the fertilized egg or its hormonal environment.

Multiple risk factors for ectopic pregnancy have been identified in two meta-analyses (1,13). More than 50% of women with ectopic pregnancies, however, give no history of any of these factors (1).Factors associated with a high risk for ectopic pregnancy include fallopian tube surgery, tubal sterilization, previous ectopic pregnancy, diethylstilbestrol exposure in utero, intrauterine device (IUD) use, and documented tubal damage. Although tubal sterilization decreases the rate of pregnancy overall, at least one third that do occur are ectopic. The risk for ectopic pregnancy in IUD users is not increased compared with the general population of women of child-bearing age, but if pregnancy does occur, it is significantly more likely to be ectopic (19). Factors associated with a moderately increased risk include technology-assisted pregnancies, previous genital infections, and multiple sexual partners. Prior abdominal or pelvic surgery, cigarette smoking, vaginal douching, and early age at first intercourse may also be associated with a slight increase in risk. Likewise, prior elective abortions and previous cesarean deliveries have not been shown to be associated with an increased risk(6).

Clinical presentation

The symptoms of ectopic pregnancy are often non-specific, and as many as 50% of women with ectopic pregnancies are misdiagnosed on their initial visit (2). Abdominal pain with amenorrhea is the most common presenting complaint (17), and clinicians should have a high index of suspicion for ectopic pregnancy in every woman of reproductive age who presents with these symptoms. Vaginal bleeding is present in only 40% to 50% of patients and may often be mistaken for a normal menstrual period (6).

Clinical signs are also non-specific. Abdominal tenderness occurs in approximately 75% of women with ectopic pregnancies and may or may not be accompanied by rebound tenderness. Cervical motion tenderness is present in approximately two thirds of patients, and adnexal mass is palpable in only approximately 50%. Hemodynamic compromise, manifested by orthostatic hypotension, and shock is seen at initial presentation in approximately 20% of patients (16).Today, with modern diagnostic techniques, more than 80% can be diagnosed before rupture, thereby greatly reducing the morbidity and mortality rates.

Diagnosis

Because the presenting signs and symptoms of ectopic pregnancy are neither sensitive nor specific, a high index of suspicion is necessary to make the diagnosis. A pregnancy test for beta-hCG should be included in the early evaluation of any woman of reproductive age that presents with abdominal pain and irregular vaginal bleeding or amenorrhea. Urinary assays for beta-hCG have become so sensitive and specific that they are nearly always positive by the time an ectopic pregnancy becomes symptomatic. None of our patients whose pregnancy test was negative had a live ectopic pregnancy. A dead ectopic pregnancy with a negative pregnancy test can be left alone without treatment. Thus, in nearly all cases, a negative pregnancy test rules out the diagnosis of ectopic pregnancy.

When a positive pregnancy test has been established, it is important to differentiate an ectopic pregnancy from an intrauterine pregnancy. A combination of hormonal testing, sonography evaluation, and other diagnostic procedures is helpful in distinguishing among these entities.

Hormonal testing

In patients with normal intrauterine pregnancies, the beta-hCG doubling time ranges from 1.5 days in early pregnancy to 3.5 days at 7 weeks' gestation. Ectopic pregnancies and abnormal intrauterine pregnancies have impaired hCG production with prolonged doubling times. The clinical utility of serial beta-hCG measurement is limited because of the inherent delay in determining the pattern of increase or decrease of the hormone. It is also not possible to distinguish an ectopic pregnancy from an abnormal IUP. Finally, approximately 17% of patients with ectopic pregnancies have normal beta-hCG doubling times, whereas 15% of patients with normal intrauterine pregnancies have serial increase rates of less than 66% (11)

Progesterone is produced by the corpus luteum when stimulated by a viable pregnancy. Its level is, therefore, significantly decreased in patients with extrauterine gestations and nonviable intrauterine pregnancies compared with that of patients with normal intrauterine pregnancies. A serum progesterone level of more than 25 ng/mL rules out an ectopic pregnancy with nearly 98% sensitivity and strongly favours a viable IUP. Conversely, a progesterone level of less than 5 ng/mL is not compatible with a normal gestation and identifies a nonviable pregnancy with nearly 100% sensitivity (7). Progesterone values between 5 and 25 ng/mL are less sensitive and specific and require additional confirmatory testing to establish a diagnosis.

Sonography

The use of sonography has revolutionized the diagnosis of ectopic pregnancy. Transvaginal sonography is capable of reliably detecting IUP when beta-hCG levels range from 1000 to 2000 mIU/mL (approximately 5 weeks' gestation and within 1 week of missed menses) (23).

If an intrauterine pregnancy can be demonstrated, ectopic pregnancy can be virtually excluded, as heterotopic pregnancy is rare in spontaneous conception. But it is important to examine the adnexal region for an abnormality. There are three sonographic features of tubal pregnancy. First is the demonstration of a live embryo with in a gestational sac in the adnexa. It typically appears as an intact, well defined tubal ring in which the yolk sacs and/or the embryonic pole with or without cardiac action are seen with in a completely sonolucent sac. An ectopic embryo/foetus is seen in 20% of cases(4).

The second sonographic feature is that of a poorly defined tubal ring, possibly containing echogenic structures. Typically, pouch of Douglas contains fluid. These features are consistent with a tubal pregnancy, which is aborting.

The third picture is the presence of varying amounts of fluid in POD representing rupture of the tubal pregnancy. In one study, echogenic fluid alone was seen in 15% of patients with ectopic pregnancy (18). A pseudosac may be present, which can be distinguished sonographically from IUP. A true gestational sac will be eccentrically placed in the endometrial cavity.The use of transvaginal colour Doppler sonography can detect the increased blood flow in the tubal artery caused by the implanted trophoblast and allow a rapid diagnosis.

The use of uterine curettage and culdocentesis are obsolete with the availability of transvaginal sonography.

MANAGEMENT

Until recently, surgery was the only feasible option for the management of most patients with ectopic pregnancies. A laparotomy or laparoscopy was needed to visualize the fallopian tube, followed by either a salpingectomy or salpingostomy to remove the ectopic pregnancy. In the past decade, however, medical therapy with methotrexate has gained broad acceptance as an additional first-line treatment option in many patients with ectopic pregnancies.

Surgical treatment

Surgery remains the treatment of choice for majority of patients with ectopic pregnancy. Laparoscopic approach is usually preferred because of its lower cost, less blood loss, decreased analgesia requirements, and shorter postoperative recovery time. Three prospective, randomised trials involving a total of 231 patients have shown definitely that laparoscopic surgery is superior to laparotomy (15). Laparotomy is indicated in patients who are haemodynamically unstable.

Salpingectomy is the best option in cases of uncontrollable haemorrhage, significant anatomic distortion, recurrent ectopic pregnancy in the same tube, or when future fertility is not desired (17)

Salpingostomy removes the ectopic pregnancy while preserving the fallopian tube. It may be offered to women with unruptured ectopic pregnancies who wish to improve their chances for future fertility.

The risk for persistent ectopic pregnancy (i.e., the persistence of viable ectopic tissue postoperatively) is significantly increased with salpingostomy compared with salpingectomy, so salpingostomy should be reserved for situations in which future fertility is desired and in which fertility is most likely to be improved by sparing the tube. If a patient has only one remaining tube and is interested in future fertility, salpingostomy is the best option. Under these circumstances, the patient should be counselled that, although preserving the remaining fallopian tube offers her some hope for a future pregnancy, the subsequent rate of IUP is low and the risk for a future ectopic pregnancy is high (9).

Persistent ectopic pregnancy occurs in approximately 8% of patients who are treated with salpingostomy (12). Factors that increase the likelihood of persistent tissue include small ectopic pregnancies (< 2 cm in diameter), early therapy (< 42 days from the last menstrual period), and a high beta-hCG level preoperatively (> 3000 IU/L) (22).A single dose of methotrexate is sometimes used prophylactically in these higher-risk patients when salpingostomy has been performed (10). We perform urine pregnancy test after one week and if positive beta hCG level is estimated. If raised, test is repeated after one week to see whether it is regressing. Single dose of prophylactic methotrexate is given if the beta hCG level is not regressing..

Medical treatment

Methotrexate is a folic-acid antagonist that interferes with DNA synthesis and cell multiplication. It has been used for many years as a chemotherapeutic agent for inhibiting highly proliferative tumor cells but inhibits the rapidly growing trophoblastic cells in patients with ectopic pregnancies.

Candidates for medical management with methotrexate must be hemodynamically stable and have no active bleeding or evidence of hemoperitoneum. They should also have gestational sacs of less than 3.5 cm in diameter, a quantitative beta-hCG level of less than 10,000 mIU/mL, and no fetal cardiac motion on transvaginal sonography (14).Absolute contraindications to treatment with methotrexate include breast-feeding, immunodeficiency, liver disease, blood dyscrasias, active pulmonary disease, peptic ulcer disease, renal dysfunction, or known sensitivity to methotrexate.

Two common regimens have been described: (1) a variable-dose approach and (2) a single-dose approach. Before initiating either regimen, a complete blood count, liver and renal function tests should be done.

The single-dose approach involves a one-time intramuscular dose of 50 mg/m2 . This regimen has a slightly lower success rate (87%) but has the advantage of being much simpler to administer (17).] The levels of beta-hCG may initially increase after treatment with a single dose of methotrexate, (24) so the first quantitative beta-hCG should not be checked until post-treatment day 4. The level is then rechecked on day 7 and should demonstrate a decrease of at least 15%. If it does not decrease, the patient is given another injection (13). The beta-hCG should then be checked weekly and additional injections given if the weekly beta-hCG values do not decrease appropriately.

Side effects of systemic methotrexate include nausea, diarrhoea, oral irritation, and transient transaminase elevations . The individualized, multidose regimen has a side-effect rate of 5%, and the single dose regimen 1% (24).High-dose methotrexate can cause bone-marrow suppression, hepatotoxicity, pulmonary fibrosis, and reversible alopecia, but these side effects are unlikely with the lower doses used for ectopic pregnancy.

Most patients have a transient increase in abdominal pain after treatment with methotrexate. Whether this is caused by trophoblastic degeneration and subsequent peritoneal irritation or is a side effect of the methotrexate is not clear. Because it is found in as many as 60% of patients, distinguishing patients with this pain from patients with increased abdominal pain from a ruptured tubal pregnancy (which can occur in approximately 5% of medically treated patients with ectopic pregnancies) is sometimes difficult (11). Physicians may counsel these patients about the likelihood of increased abdominal pain after treatment and suggest using a nonsteroidal anti-inflammatory drug for pain management. If increased abdominal pain persists, the patient is evaluated and a hemoglobin level is obtained. If the hemoglobin level is stable, and TVS doesn’t show increased fluid in POD, the patient can be managed noninvasively and observed. Otherwise, the possibility of a ruptured ectopic pregnancy should be considered.

In an attempt to increase the success rates of systemic methotrexate treatment, investigators have examined the effects of adding mifeprostone to the treatment protocol. As a single agent, it has not been found to be an effective therapy for ectopic pregnancy. When added to a regimen of methotrexate, however, it resulted in a higher success rate and less need for a second injection or laporotomy. One non-randomised trial involving 30 patients found a decrease in treatment failures from 26% to 3% when patients treated with the combination therapy were compared with patients previously treated with methotrexate alone (16).

Successful treatment rates are nearly identical among the two options, (21) as are rates of subsequent fertility (26) and requirements for postoperative follow-up. In these cases, individual patient preferences often help to guide this decision

Expectant Management

Expectant managemet has poor efficacy and unproven benefit in subsequent reproductive outcome; therefore its use should be limited to situations in which the EP is suspected but cannot be excluded by transvaginal US. Other conditions for use of expectant management occur when surgery and methotrexate carry higher risk, such as in presence of heterotopic pregnancy or ovarian hyperstimulation syndrome (15).

A metaanalysis of 9 studies involving 2,635 patients compared the reproductive outcome of salpingostomy versus salpingectomy(15 ). This included 528 patients in the conservative group and 1246 patients in radical group desiring fertility. The rate of subsequent intrauterine pregnancy was 53%in conservative group and 49.3% in the salpingectomy group. The recurrent EP rates were 14.8 % and 9.9%, respectively. Another metanalysis reported reproductive outcome after conservative surgery in women with solitary patent tube. Among the 176 women attempting to conceive, there were 54.5% IUPs and 20.5% recurrent ectopic(15).

Many other factors influence the subsequent fertility rate, than the type of surgical approach alone. A history of infertility was found to be associated with a decreased fertility rate(27). Others have found that the status of the contralateral tube at the time of surgery is related directly to the subsequent fertility, regardless the surgical modality used (20). Silva etal (25) found prior tubal damage to be associated significantly with decreased pregnancy rate: 79% pregnancy rate in group without prior damage versus 42% in the group with prior tubal damage.

Majority of spontaneous pregnancies after surgical treatment of ectopic pregnancy occur in the first 18 months(5).

Ectopic pregnancy is a common clinical condition with high risks for morbidity and mortality. Although its prevalence seems to be increasing, the ability to diagnose and manage this problem continues to improve. Physicians should identify and screen high-risk patients early in their pregnancies and should have a high index of suspicion for ectopic pregnancy in women who present with abdominal pain, amenorrhea, or vaginal bleeding. The diagnosis is commonly made through a combination of hormonal testing and transvaginal sonography. Management options include the traditional surgical salpingectomy or salpingostomy, as well as nonsurgical management with methotrexate in selected patients.

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