Ectopic Pregnancy

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Chapter 48 Ectopic Pregnancy

INTRODUCTION

Ectopic pregnancy, the implantation of a fertilized ovum outside the endometrial cavity, is a curious phenomenon unique to primates. It does not occur in laboratory animals and has likewise not been reported in domestic or farm animals. In addition, no animal model of the disease exists.

If undiagnosed or untreated, ectopic pregnancy may result in rupture of the fallopian tube and massive intraperitoneal hemorrhage. In the past decade, this phenomenon accounted for approximately 9% of maternal pregnancy-related deaths in the United States.1 Because ectopic pregnancy diagnosis and treatment has moved from an inpatient to an outpatient setting, there are no clear reporting standards, and the most up-to-date incidence rates and morbidity and mortality statistics date back to the mid-1990s.1

Fortunately, due to increased awareness of this problem by clinicians and the public, coupled with improved methods of diagnosis and treatment, the outcomes for women with ectopic pregnancy appear to be improving. Today, complications of ectopic pregnancy stem from misdiagnosis or delay in seeking medical care. It is no longer the case that the disease entity is missed due to a deficit in clinical knowledge or lack of means to diagnosis. Despite this, however, the condition continues to be a major cause of morbidity and mortality in reproductive-age women.

This chapter reviews the epidemiology and pathophysiology of ectopic pregnancy, the clinical presentation and diagnosis of the disease, surgical and medical treatments, and reproductive outcomes.

EPIDEMIOLOGY

It is estimated that about 2% of pregnancies in the United States are ectopic pregnancies. The number of ectopic pregnancies diagnosed in the United States continues to rise, with a sixfold increase documented between 1970 and 1992.24 In Europe, the prevalence of ectopic pregnancy appears stable in France, Sweden, and the Netherlands, but has continued to increase in Norway.4 U.S. healthcare statistics demonstrate that of the 108,800 patients diagnosed with ectopic pregnancy in 1992, 58,000 needed hospitalization, at a cost of $1.1 billion.5 Recent trends of outpatient treatment and decreased need for hospitalization have likely led to an underreporting of the condition and a consequent underestimation in U.S. government figures.

The etiology of the observed increase in ectopic pregnancy prevalence appears to be multifaceted. An important factor appears to be the recent rise in sexually transmitted diseases, leading to an increased incidence of clinical and subclinical tubal infections. Another contributing factor may be our improved ability to diagnose ectopic pregnancies earlier and more accurately. Finally, the increased utilization of assisted reproductive technologies is believed to play a role in this increased prevalence.

The vast majority of ectopic pregnancies (more than 90%) occur in the tube, with 80% to 90% of these occurring in the ampullary region, 5% to 10% in the isthmic region, 5% in the fimbrial region, and about 2.4% located in the cornual (interstitial) region. The other sites include 3.2% in the ovary, 1.3% elsewhere in the abdomen, and less than 0.15% in the cervix.68

Risk Factors

Multiple risk factors have been consistently shown to be associated with ectopic pregnancies (Table 48-1).12 The strongest association has been found with prior pelvic inflammatory disease (PID), a prior history of ectopic pregnancy, and previous tubal surgery (including previous tubal ligation). These conditions are believed to alter tubal integrity and thus impede the migration of the fertilized ovum to the uterus.

Table 48-1 Risk Factors for Ectopic Pregnancy

Weaker associations have been made between ectopic pregnancy and infertility (a possible marker in some patients for subclinical tubal infection), cigarette smoking (thought to affect tubal motility), increasing age, having more than one lifetime sexual partner, any pelvic or abdominal surgery (other than cesarean delivery), and a history of having a sexually transmitted disease. Although use of an intrauterine device (IUD) does not increase the risk of ectopic pregnancy compared to controls, women using an IUD found to have a positive pregnancy test are more likely to have an ectopic than an intrauterine pregnancy, in a manner similar to women who have had a tubal ligation.13 Unfortunately, the sensitivity of these risk factors is low, and as many as 50% of patients with proven ectopic pregnancies will have none.13

No clear association has been documented between ectopic pregnancy and oral contraceptive use, previous elective pregnancy termination or spontaneous miscarriage, or cesarean section.9,10

Heterotopic Pregnancy

IVF also appears to increase the incidence of simultaneous intrauterine and ectopic pregnancy, termed heterotopic pregnancy.16 In the late 1940s, the prevalence of heterotopic pregnancy was estimated to be 1:30,000 pregnancies.17 The prevalence is now estimated to be 1:4000 pregnancies in the general population, and as high as 1:100 pregnancies resulting from IVF.15,18,19 This dramatic increase is believed to be the result of the increased risk of multiple pregnancies and the unknown effects on tubal motility, in combination with the invasive nature of ART. The clinician must be aware that although ultrasound verification of intrauterine pregnancy dramatically decreases the chance of an ectopic pregnancy, it does not completely rule it out, especially in patients whose pregnancy has resulted from ART.

PRESENTATION

Symptoms

The most common symptoms of ectopic pregnancy are abdominal or pelvic pain and vaginal bleeding or spotting in a patient with a positive pregnancy test. However, both the sensitivity and specificity of these symptoms for ectopic pregnancy are low. In some cases, these symptoms can be intermittent or even absent. Depending on their degree, these can sometimes be mistaken for a normal menstrual period or early pregnancy loss; thus some women may not initially report them to their physicians. Even though these symptoms may be due to other conditions, pain and bleeding during early pregnancy are always an indication to exclude ectopic pregnancy.

DIAGNOSIS

Early in pregnancy, it is often impossible to differentiate a viable pregnancy from an impending spontaneous abortion or an ectopic pregnancy. The diagnosis of an ectopic pregnancy is therefore a diagnosis of exclusion, utilizing modern noninvasive diagnostic approaches.

Ultrasonography

The first step in evaluating a pregnancy is to determine viability. If the pregnancy is determined to be nonviable, the second step is to differentiate between an abnormal intrauterine pregnancy (spontaneous abortion) and an ectopic pregnancy. Therefore, the first step in a diagnostic workup for ectopic pregnancy is to verify or exclude an intrauterine pregnancy (normal as well as abnormal), because the odds of heterotopic pregnancies are extremely low even after IVF.

Human Chorionic Gonadotropin

Quantitative measurement of serum β-hCG is a very accurate method for determining gestational age in the first trimester of a normal pregnancy.26 This is extremely important in the diagnosis of ectopic pregnancy, because at the time of initial evaluation, many women will be unsure of their menstrual or conception dates; thus the exact gestational age is not known. The use of radioimmunoassay to measure serum β-hCG has greatly improved the time to obtain results as well as their accuracy.

Discriminatory Zone

An important factor when determining the viability and location of a pregnancy by vaginal ultrasound is the discriminatory zone. The discriminatory zone is defined as that level of β-hCG at which a normal singleton intrauterine pregnancy can be visualized on transvaginal ultrasonography.28 At most institutions, the discriminatory zone for a singleton pregnancy when using transvaginal ultrasonography is between 1500 and 2500mIU/mL (using the WHO Third International Standard, or International Reference Preparation).2

Each clinician will have to determine the discriminatory zone in their practice. Important variables include the type of β-hCG test used, the expertise of the ultrasonographer, and the quality of the ultrasound equipment. If the discriminatory zone is set too high, diagnosis of ectopic pregnancies will be delayed. If the discriminatory zone is set too low, the risk of intervening in a normal intrauterine pregnancy increases. This is especially important in patients who have become pregnant after ART, because multiple gestations can present with a β-hCG level well above the discriminatory zone long before an intrauterine pregnancy is visible by vaginal ultrasound.

In practice, the discriminatory zone should be used as a guide rather than an absolute. In a symptomatic patient whose β-hCG is above the discriminatory zone but has no evidence of an intrauterine pregnancy, intervention is often warranted. In contrast, in an asymptomatic patient with this same scenario, repeat measurements will often demonstrate viability of normal, and sometimes multiple, gestations. Like all gray areas of medical diagnosis, patient education should be aimed at minimizing both anxiety and risk to the patient while waiting to make a definitive diagnosis.

Serial β-hCG Determination

To distinguish a normal intrauterine pregnancy from a nonviable intrauterine or ectopic gestation, serial β-hCG determinations are performed. It is now well-established that the beta-hCG concentration rises almost linearly in the early weeks of a normally growing gestation, doubling every 1.4 to 2.1 days.2729 Many clinicians rely on the rule of at least a 66% rise in β-hCG over 2 days based on earlier studies.27,3033 More recent evidence suggests that the rise of β-hCG may be slower than previously reported, with 99% of all normal viable intrauterine pregnancies having an increase in β-hCG of at least 24% in 1 day and 53% in 2 days.34 Intervening when the 2-day rise in β-hCG is between 53% and 66% may result in the interruption of a viable pregnancy.

Uterine Cavity Sampling

If the β-hCG level is not rising normally and is above the discriminatory zone, and an intrauterine pregnancy is not visualized by ultrasound, the diagnosis of an abnormal, nonviable gestation can be made with relative certainty. To differentiate between a spontaneous miscarriage and an ectopic pregnancy, the uterine cavity should be sampled to determine the presence or absence of chorionic villi. This is most commonly done by performing a dilation and curettage (D&C) in the operating room. Failure to accurately detect the presence of chorionic villi can lead to unnecessary surgical and medical interventions in women without an ectopic pregnancy.

In cases where gross products of conception (gestational sac or fetal parts) are not visible, verification of the presence of chorionic villi can be a problem, because final diagnosis with a permanent pathologic specimen takes up to 24 hours. One solution is to obtain a frozen section at the time of D&C, which has been shown to be very accurate in identifying products of conception, with almost no risk of false-positive results.35

Other techniques used to identify chorionic villi have not been found to be as sensitive. Floating the tissue obtained in saline solution will allow the trained gynecologist to identify villi in only 60% of cases where they can be identified histologically.36 The use of a stereomicroscope significantly improves the ability to identify chorionic villi, but is rarely available in common practice.37 Sampling of the uterine cavity with a pipelle biopsy instrument in an outpatient setting has been found to have relatively poor sensitivity of 30% to 63%.38,39 In the future, perhaps other forms of less invasive endometrial sampling, such as the handheld manual vacuum aspirator, will prove to have the necessary sensitivity for confirming products of conception.

Other Diagnostic Tests

Other techniques have been used to diagnose ectopic pregnancy. Prior to accurate ultrasound, culdocentesis was used to diagnose acute intra-abdominal bleeding. For this often painful transvaginal technique, a spinal needle is placed though the posterior cul-de-sac to aspirate peritoneal fluid. The presence of clotting blood indicates hemoperitoneum secondary to acute bleeding, because blood that had been present for any period of time will have already lysed, and thus not clot. Today, the presumptive diagnosis of hemoperitoneum is made by transvaginal ultrasound whenever a hemodynamically compromised patient with a positive pregnancy test is found to have free intra-abdominal fluid.

Serum progesterone levels have also been used to aid in the diagnosis of ectopic pregnancy. Overall, serum progesterone levels are lower in ectopic pregnancies than in intrauterine pregnancies.40 Levels less than 5ng/mL are almost always (99.8%) associated with nonviable pregnancies, but these can be either abnormal intrauterine pregnancies (impending spontaneous abortion) or ectopic pregnancies.41 Conversely, progesterone levels of greater than 17.5ng/mL are rarely associated with ectopic pregnancies, with only 8% of ectopic pregnancies falling into this category.

Despite these strong correlations at either end of the concentration spectrum, serum progesterone levels have limited value in diagnosing ectopic pregnancies, because many patients’ values will fall between these extremes of values, where there is too much overlap to be discriminatory.42 In addition, serum progesterone levels are not readily available in many hospital laboratories on a “stat” basis, making the use of this test impractical in emergency situations.

Other laboratory tests evaluated for usefulness in the diagnosis of ectopic pregnancy include vascular endothelial growth factor (VEGF), CA-125, fetal fibronectin, and creatine kinase.4349 Like serum progesterone, overlapping ranges of values for normal and abnormal pregnancies have prevented any of these markers from being useful in distinguishing ectopic and nonectopic gestations. Using genomics approaches, other promising serum protein markers have been identified that may ultimately prove to be discriminatory between intrauterine and ectopic pregnancies.50

Algorithm for Diagnosis

A simple diagnostic algorithm using ultrasound and serum β-hCG determinations can be helpful (Fig. 48-1).51 When a patient presents in early pregnancy with pain or uterine bleeding, the first step is transvaginal ultrasound. If a nonviable intrauterine pregnancy (e.g., impending spontaneous abortion) is visualized, standard management options are indicated based on symptomatology. Likewise, if an ectopic pregnancy is seen in the adnexa, treatment options are clear.

image

Figure 48-1 Diagnostic algorithm flow chart

(adapted from Gracia CR, Barnhart KT: Diagnosing ectopic pregnancy: A decision analysis comparing six strategies. Obstet Gynecol 97:464-470, 2001.)

If the ultrasound is nondiagnostic, revealing neither an intrauterine or ectopic pregnancy, and the β-hCG is below the discriminatory zone, the most likely diagnosis remains an intrauterine pregnancy, and viability needs to be determined. To distinguish between a growing intrauterine pregnancy and a nonviable gestation, serial β-hCG determinations are performed. As long as serial β-hCG levels rise appropriately, treatment remains expectant. If serial β-hCG levels rise at an abnormal rate, plateau, or drop, a nonviable pregnancy is diagnosed and a D&C is needed to differentiate between an abnormal intrauterine pregnancy and an ectopic pregnancy. Likewise, when vaginal ultrasound is nondiagnostic and the initial or subsequent β-hCG level is found to be well above the discriminatory zone, the next step for diagnosis and treatment of the symptomatic patient is D&C. Caution should be used in the asymptomatic patient with a β-hCG level at or slightly above the discriminatory zone, because viable multiple gestations can have β-hCG levels above the discriminatory zone before the time that an intrauterine pregnancy can be seen with vaginal ultrasound.

Identification of chorionic villi in the D&C specimen verifies the diagnosis of spontaneous abortion, and further treatment is rarely needed. Alternatively, inability to identify chorionic villi makes an ectopic pregnancy the most likely diagnosis. At this point, a decision must be made between either surgical or medical treatment.

In some cases where no chorionic villi are found on D&C, the clinical history is suggestive of a complete spontaneous abortion before evacuation, with heavy vaginal bleeding with passage of tissue and an open cervix. In these cases, it is appropriate to manage the patient expectantly with re-evaluation of serum β-hCG levels 12 to 24 hours after evacuation. If the β-hCG level drops sharply from preoperative levels, a complete spontaneous abortion is the most likely diagnosis, although a resolving ectopic pregnancy (sometimes referred to as a tubal abortion) is also possible. Keep in mind that 35% of women with an ectopic pregnancy are diagnosed when the β-hCG level is falling.28 If the β-hCG level plateaus or continues to rise, an ectopic pregnancy is highly likely, and immediate treatment should be instituted. This approach can also be used when the clinical suspicion of ectopic pregnancy is low, but no pathologist is available for intraoperative examination of the D&C specimen.

All patients for whom ectopic pregnancy was among the differential diagnoses should be followed with at least weekly β-hCG levels until β-hCG is no longer detectable in the serum. This may take up to several weeks, because a minimum decline in serial β-hCG concentration for a completed abortion ranges from 21% to 35% in 48 hours.52 A negative β-hCG value is the only sure way to confirm complete resolution of the ectopic pregnancy. There have been reports of tubal rupture with β-hCG levels as low as 5mIU/mL.53

Of all women with ectopic pregnancies who present with symptoms, about 50% will have β-hCG levels above the discriminatory zone and are therefore diagnosed within a single evaluation.3 The remaining 50% of women with ectopic pregnancies who seek medical attention will be found to have β-hCG levels below the discriminatory zone, and ultrasound is usually nondiagnostic. At this point in time, the sensitivity of transvaginal ultrasound for the diagnosis of intrauterine pregnancy, spontaneous miscarriage, and ectopic pregnancy has been shown to be only 25% to 33% and the predictive value is low.54

Screening Asymptomatic Patients

There may be some advantage to screening patients at high risk for ectopic pregnancy before the development of symptoms.55 Risk factors include previous history of ectopic pregnancy, tubal surgery, PID, sterilization, current IUD, and known tubal disease seen by hysterosalpingography or laparoscopy. In a study of 143 symptom-free women with these risk factors, screening was started before 7 weeks’ gestation with serial β-hCG measurements and ultrasound studies. In this particular study, 5.6% of the women were diagnosed with ectopic pregnancies. It is yet to be established that the potential benefits of this approach, including decreasing the risk of complications and patient reassurance, outweighed the drawbacks of false-positive diagnoses, increased costs, and increased emotional stress.56 For this reason, universal screening of women at increased risk for ectopic pregnancy cannot be recommended at this time.

TREATMENT

Before the twentieth century, ectopic pregnancy was nearly always fatal, due to late diagnosis and absence of effective treatment options. Today, the primary goal of accurate and expeditious diagnosis is to limit morbidity and eliminate mortality associated with this condition. Early diagnosis of ectopic pregnancy makes a greater number of treatment options available to the physician and patient. Instead of the traditional treatment with laparotomy and fallopian tube resection (salpingectomy), clinically stable patients can often be treated with minimally invasive surgery (i.e., laparoscopy) and tubal conservation (salpingostomy). Alternatively, these patients may be candidates for medical therapy with methotrexate. In experienced hands, these modern treatment modalities appear to have comparable success rates, while maintaining the potential for future fertility.

Laparotomy versus Laparoscopy

Laparoscopy has become the most common surgical approach to ectopic pregnancy, primarily due to the increased comfort level most gynecologic surgeons have gained with the laparoscopic approach. However, laparotomy remains the treatment of choice for the hemodynamically unstable patient with a ruptured ectopic pregnancy.

Laparotomy versus laparoscopy for the treatment of ectopic pregnancy has been compared in three prospective, randomized trials.5759 Each concluded that the laparoscopic approach is superior to laparotomy. Laparoscopy resulted in less blood loss, less analgesia requirement, and a shorter duration of hospital stay compared to laparotomy. Laparoscopy was also found to be less costly in all three trials. Not surprisingly, a Cochrane review of the surgical treatment of ectopic pregnancy likewise concluded that laparoscopy is the treatment of choice for eligible patients.60

Exploratory Laparotomy: The Unstable Patient

Exploratory laparotomy is still indicated for the treatment of the hemodynamically unstable patient in whom a ruptured fallopian tube has caused extensive intraperitoneal bleeding, leading to intravascular volume depletion. These patients present to the emergency room in distress, with hypotension and tachycardia; if intervention is not immediate, they may develop hypovolemic shock. Prompt evaluation and stabilization should be followed by expeditious surgery under general anesthesia. Although laparotomy is usually the most expedient approach, if hemodynamic stability can be reestablished with intravenous therapy, some experienced gynecologists find the laparoscopic approach satisfactory even with a ruptured ectopic pregnancy and associated hemoperitoneum as long as a large-bore (10-mm) suction– irrigator is available to allow adequate visualization of the pelvis.

Regardless of approach, fluid and blood product replacement is the first priority in any patient exhibiting early signs of hemorrhagic shock. Large-bore IV lines should be placed, and the patient’s volume loss should be aggressively replaced. The patient should be cross-matched for at least 4 units of packed red blood cells before initiation of surgery, because additional volume losses may be expected once the abdomen is open and there is no pressure tamponade. Packed red blood cell transfusion should be initiated at the discretion of the anesthesiologist based on the patient’s physiologic condition and need for colloid fluid repletion, keeping in mind that young, healthy patients can usually tolerate anemia well. With every 4 units of packed red blood cells, 2 units of fresh frozen plasma are often transfused to replace clotting factors. The patient’s blood count and coagulation profile should be monitored closely throughout the case.

Laparotomy via a pfannensteil incision will usually allow expeditious entry into the peritoneal cavity. On visualization of the pelvic structures, the site of implantation of the ectopic pregnancy should be immediately identified. A Kelly forceps (“clamp”) is then placed at the proximal portion of the fallopian tube, at the uterine cornu. This should virtually eliminate further blood loss, because most of the blood supply to the fallopian tube comes from branches of the uterine artery. A second Kelly clamp can then be placed along the mesosalpinx, meeting the end of the first clamp, so that all vessels within the mesosalpinx are occluded. Alternatively, a succession of Kelly clamps can be used to clamp the mesosalpinx as close to the tube as possible, as described by Damario and Rock.61 The entire tube and the ectopic gestation are then excised as one specimen. The pedicles are suture ligated with 2-0 or 3-0 vicryl or other synthetic absorbable suture. After assuring hemostasis, the pelvis should be evacuated of blood and clots, which can total up to several liters of blood loss (Table 48-2).

Table 48-2 Salpingectomy via Laparotomy or Laparoscopy — Surgical Steps

Suprapubic Pfannensteil incision made for laparotomy
Fallopian tube elevated using Allis or Babcock clamp
Mesosalpinx clamped with succession of Kelly clamps or hemostats, just below the fallopian tube
Tube removed at site of uterine attachment close to cornua
Interrupted 2-0 or 3-0 delayed-absorbable suture (e.g., Vicryl) used for closure of pedicles
Inspection for hemostasis
or
Laparoscopic trocar ports placed (umbilical and at least 2 additional) for laparoscopic approach
Fallopian tube grasped and elevated distally with endo-grasper
Tube cauterized and then transected at cornual end, close to uterus

Specimen placed in endoscopic bag and removed via large port site

Laparotomy can be the preferred approach for reasons other than hemodynamic instability. Other clinical indications include (1) multiple previous pelvic surgeries with documented or highly suspected extensive pelvic adhesions; (2) an underlying medical condition precluding laparoscopy; (3) an ectopic pregnancy that is outside the fallopian tube, in which case resection via laparoscopy is technically difficult; and (4) inadequate equipment or experience to safely remove the ectopic pregnancy laparoscopically.