Mousa Shamonki, Anita L. Nelson, Joseph C. Gambone
An ectopic pregnancy is a gestation that implants outside the endometrial cavity. Despite recent advances in earlier detection, it continues to represent a serious hazard to women’s health and their future reproductive potential. An ectopic pregnancy is estimated to occur in 1 of every 80 spontaneously conceived pregnancies. More than 95% of ectopic pregnancies implant in various anatomic segments of the fallopian tube, including the ampullary (75% to 80%), isthmic (12%), infundibular and fimbrial (6% to 11%), and interstitial (2%). Other, less common sites of ectopic implantation are the ovary, uterine cervix, and a rudimentary uterine horn. Rarely, an ectopic pregnancy may be intraligamentous or in the peritoneal cavity (abdominal pregnancy). With in vitro fertilization (IVF) and other assisted reproductive technologies (ARTs), the risk for ectopic pregnancy increases substantially, and the location of those ectopic implantations changes (Figure 24-1). Importantly, the risk for heterotropic implantations (one intrauterine and one ectopic) may rise to 1 in 100 with IVF. Other risk factors for an ectopic pregnancy include a history of a previous ectopic pregnancy, a pregnancy after tubal ligation or with an intrauterine device (IUD) in place, and a history of pelvic inflammatory disease (PID).
FIGURE 24-1 Possible locations of ectopic pregnancy with spontaneous conception vs pregnancies that result from assisted reproductive technologies (ART) such as in vitro fertilization (IVF).
(Modified from Pisarska MD and Carson SA: Incidence and risk factors for ectopic pregnancy. Clin Obstet Gynecol 42:2-8,1999.)
Epidemiology and Etiology
Even though the mortality rates for ectopic pregnancy have dropped as a result of early diagnosis, this condition still causes 4% to 6% of maternal deaths in the United States and is the most common cause of maternal mortality in the first trimester.
In the past two decades, there was a significant increase in diagnosed ectopic pregnancy rates because of the following:
1. Improved technology, which has allowed for earlier and more complete recognition of early ectopic pregnancies, including ectopic pregnancies that would previously have gone undetected
2. Rising incidence of acute and chronic salpingitis, especially related to Chlamydia trachomatis
3. Increasing number of tubal surgeries, such as tubal ligation and tubal reconstruction
4. Increase in ARTs, especially IVF
The key to the successful management of ectopic pregnancy is early diagnosis. A high index of suspicion and vigorous efforts at early diagnosis are needed, so “think ectopic!” is a sign that should be in every emergency room.
The etiology of ectopic pregnancy is not always clear but often is associated with known risk factors (Box 24-1). As many as half of cases result from an alteration of tubal transport mechanisms because of damage to the ciliated surface of the endosalpinx caused by infections, such as chlamydia and gonorrhea. Other etiologies include delayed fertilization, possible transmigration of the oocyte to the contralateral tube, and slowed tubal transport, which delays passage of the morula to the endometrial cavity. Chromosomal abnormalities of the fetus are not a cause of ectopic pregnancy.
BOX 24-1 Risk Factors for Ectopic Pregnancy
• History of tubal infection
• Cigarette smoking (increased relative risk, 1.26)
• Prior ectopic pregnancy
• History of tubal sterilization within the past 1 to 2 years (higher incidence if cauterization was used)
• History of tubal reconstructive surgery
• Pregnancy with current intrauterine device, depot medroxyprogesterone acetate, or emergency contraceptive pill use
• Infertility due to tubal factors
• Use of assisted reproductive technology
Natural History of Untreated Tubal Ectopic Pregnancy
Tubal pregnancies rapidly invade the tubal mucosa, eroding into the tubal vessels, which are enlarged and engorged. The segment of the affected tube distends as the pregnancy grows and as blood from the eroded vessels dissects along the tubal wall. Women may have vaginal bleeding or spotting because the pregnancy hormones do not adequately support the endometrial lining and because bleeding from the tube may spill into the uterus as well as into the abdominal cavity. The most common outcomes of established tubal pregnancies include the following:
1. Tubal rupture, with resulting intraperitoneal hemorrhage
2. Pregnancy resorption, as a result of the restricted blood supply
3. Tubal abortion into the peritoneal cavity
Symptoms and Clinical Diagnosis of Ectopic Tubal Pregnancy
The classic triad of symptoms of ectopic pregnancy consists of prior missed menses, vaginal bleeding, and lower abdominal pain. Clinical presentations represent a continuum: (1) acutely ruptured ectopic pregnancy, (2) probable ectopic pregnancy in a symptomatic woman, and (3) possible ectopic pregnancy. Each of these is discussed separately.
ACUTELY RUPTURED ECTOPIC PREGNANCY
The patient who has experienced rupture of her ectopic pregnancy most likely has intraperitoneal hemorrhage and presents with severe abdominal pain and dizziness. She may also complain of ipsilateral shoulder pain from phrenic nerve irritation caused by the blood in her upper abdomen. There may be signs of hemodynamic instability with tachycardia, diaphoresis, hypotension, and even loss of consciousness. Her abdomen may be distended and acutely tender, with guarding and rebound tenderness. The patient usually has cervical motion tenderness and a slightly enlarged, globular uterus. However, she may not have a palpable adnexal mass. The diagnosis is facilitated by a positive urine pregnancy test.
This clinical scenario represents a surgical emergency. Although other tests are often not necessary, an ultrasound would reveal an empty uterus and significant amounts of free fluid in the cul-de-sac. It is critical to establish large-bore intravenous lines and to start fluid resuscitation. Transfusion is important but should not delay emergency surgical intervention (usually by laparotomy, although laparoscopy may be appropriate when a patient is hemodynamically stable).
PROBABLE ECTOPIC PREGNANCY
Women who present with lower pelvic pain and vaginal spotting or bleeding, with or without amenorrhea, can be rapidly tested for pregnancy. The differential diagnosis includes threatened abortion or ectopic pregnancy. The patient generally has other clinical signs, such as tenderness of the abdomen with adnexal or cervical motion tenderness. The diagnosis of ectopic pregnancy may be confirmed by the absence of intrauterine pregnancy (IUP) on ultrasound in a woman with a level of human chorionic gonadotropin (hCG) that is sufficiently high to guarantee visualization of a normal IUP(see “Diagnostic Tests” later). There may be a variable amount of free fluid in the cul-de-sac detected by ultrasound. Only occasionally will the ectopic pregnancy be seen on ultrasound as a “double-ring sign” in the adnexa, but a corpus luteum cyst is often present. In such symptomatic women, even though they have stable vital signs, surgical exploration is generally recommended. Conservative surgical procedures, which preserve the fallopian tube, are generally indicated in women desiring future fertility (see “Management” later).
POSSIBLE ECTOPIC PREGNANCY
The most common clinical presentation is that of a possible ectopic pregnancy. Because her symptoms are so mild and nonspecific, a patient with an ectopic pregnancy may be seen at more than one visit before the diagnosis is confirmed.
Lower abdominal pain is present in most cases, although it may be mild. Amenorrhea or a history of an abnormal last menstrual period is obtained in 75% to 90% of ectopic pregnancies. Abnormal vaginal bleeding is seen in more than half of patients and ranges from spotting to the equivalent of a normal menstrual period. This spotting or bleeding results from an abnormally low production of hCG by the ectopic trophoblastic tissue. Distinguishing patients with ectopic pregnancy from those with an early threatened abortion or a spontaneous abortion can be challenging.
On physical examination, most patients are afebrile, and less than half have a discernable adnexal mass on pelvic examination. Often, the mass is palpated on the side opposite to the ectopic pregnancy and represents a corpus luteum in the contralateral ovary. The uterus is soft and is either of normal size or slightly enlarged. On ultrasound, there is a thickened endometrial stripe representing the visible sign of an Arias-Stella reaction, the histologic changes in the endometrial epithelium due to hCG stimulation. There may be a small amount of fluid seen in the cul-de-sac representing some slight intraperitoneal hemorrhage. Rarely is the ectopic pregnancy actually visualized.
Many gynecologic and nongynecologic disorders have symptoms in common with ectopic pregnancy and are listed in Box 24-2. A diagnostic algorithm for ectopic pregnancy is illustrated in Figure 24-2.
BOX 24-2 Differential Diagnosis for Ectopic Pregnancy
Threatened or incomplete abortion
Ruptured corpus luteum cyst
Acute pelvic inflammatory disease
Degenerating leiomyoma (especially in pregnancy)
FIGURE 24-2 Diagnostic algorithm for ectopic pregnancy. β-hCG, β-subunit human chorionic gonadotropin; D&C, dilation and curettage; Dx, diagnosis.
(Seeber BE, Barnhart KT: Suspected ectopic pregnancy. Obstet Gynecol 107[2 Part 1]:399-413, 2006.)
The diagnosis of early ectopic pregnancy is facilitated by quantitative hCG testing and transvaginal ultrasonography. Office curettage can also be used.
The rapidly dividing fertilized egg begins to produce hCG even before pregnancy occurs, but communication with the maternal circulation to allow detection in maternal serum starts with implantation. The sensitivity of the current methods for detection of hCG in the maternal serum may allow for the confirmation of pregnancy before a missed period.
An accurate diagnosis of ectopic pregnancy requires knowledge of the dynamics of hCG. In the first trimester of normal pregnancies, serum titers of hCG increase exponentially following a nonlinear model. The doubling time of hCG in the serum varies from 1.2 days shortly after implantation to 3.5 days at 2 months after the last menstrual period. Healthy, normally developing pregnancies generally can be detected by a normal rate of increase of maternal serum hCG levels. More than 66% of normal pregnancies show doubling of hCG levels every 48 hours in the first few weeks of pregnancy. However, a normal range exists, and the slowest rise for a normal pregnancy in 2 days is 53%. If the hCG levels rise by less than 53%, the differential diagnosis includes an abnormal IUP or an ectopic pregnancy. After a spontaneous pregnancy loss, the minimal decline in hCG is 21% to 35% in 2 days. Therefore, if the hCG levels are declining more slowly than 20%, an ectopic pregnancy is likely. Lower levels of hCG (<500) clear from the circulation more slowly than do higher levels.
There are a number of different assays available today, most of which use at least two separate antibody binding sites to detect the presence or measure the concentration of hCG. Until there is greater standardization of laboratory testing, it is important to compare over time only titers that are obtained from the same laboratory. Technically, the correct test to order today is “hCG,” but many institutions use the designation “β-hCG” to determine serial titers of the pregnancy hormone even when the entire molecule is being measured.
Additional tests are often needed to assist in the diagnosis if the patterns in serial hCGs do not give complete results. Transvaginal ultrasound is helpful in diagnosing an ectopic pregnancy by failure to identify an IUP after the hCG levels are adequately high. Although some IUPs may be seen at lower hCG levels, every IUP should be visualized by the time the hCG levels reach the so-called discriminatory zone. The discriminatory zone, or DZ, is defined as the titer of hCG at which an intrauterine sac should reliably be seen with transvaginal ultrasonography in a normal pregnancy. DZ titers differ among institutions, but on average are equal to 1500 to 2000 mIU/mL of hCG for a singleton pregnancy and 3000 mIU/mL for a twin gestation (Figure 24-3).
FIGURE 24-3 Distribution curve of human chorionic gonadotropin (hCG) in normal pregnancies with an example of a discriminatory zone (DZ) in shaded area. The range of hCG levels (usually 1500 to 2000 mIU/mL per gestation, using the Third International Standard) represents the possible range of the DZ. Every institution should establish a DZ level based on variation in laboratory measurement and the interpretive skill of their ultrasonographer. This DZ level then is recognized as the hCG level above which ultrasound evidence of an intrauterine pregnancy should be seen. LMP, last menstrual period.
(Modified from Pittaway DE, Reisch RL, Wentz AC: Doubling times of human chorionic gonadotropin increase in early variable intrauterine pregnancies. Am J Obstet Gynecol 152:299, 1985.)
An abnormally rising hCG level above 2000 with no gestational sac seen on ultrasound is diagnostic of ectopic pregnancy. However, if the hCG level is below the DZ, an endometrial aspiration with a manual vacuum extractor can be performed. If the hCG levels are not changing appropriately and no products of conception are found on “stat” (immediate) histologic study of the aspirate, the diagnosis of ectopic pregnancy is secure.
Serum progesterone levels greater than 25 ng/mL can reliably indicate a normal IUP, and levels less than 5 ng/mL are consistent with an abnormal pregnancy. However, the value of progesterone testing for ectopic pregnancy is limited by the fact that it requires almost 24 hours to obtain a result and most of the progesterone levels that would be obtained in this situation fall into the gray zone between 5 and 25 ng/mL.
The management of ectopic pregnancy depends on the stability of the patient, the availability of resources, and the desire for future fertility.
Laparotomy is the preferred surgical approach for women who are hemodynamically unstable because rapid access to the bleeding site is critical. Laparotomy is also appropriate whenever it is anticipated that laparoscopy would not be successful, such as when the patient has significant intraperitoneal adhesions from prior surgeries, infection, or endometriosis. For hemodynamically stable patients, laparoscopy (when available) is the preferred surgical approach because after laparoscopic surgery, patients require fewer days of postoperative hospitalization, suffer less postoperative pain, and recover more quickly. Laparoscopy also offers the potential to reduce overall treatment costs. If it is determined intraoperatively that laparoscopy is not possible, the surgery can always be converted to laparotomy. Laparoscopy is discussed further in Chapter 30.Figure 24-4 shows a tubal ectopic pregnancy viewed through the laparoscope.
FIGURE 24-4 A tubal ectopic pregnancy as seen through the laparoscope.
(Courtesy of B. Beller, MD, Eugene, Oregon.)
Regardless of the surgical approach, the surgery performed on the fallopian tube itself depends on the amount of tubal damage and the patient’s wishes for future fertility. The options include salpingectomy, partial salpingectomy, salpingotomy, and salpingostomy.
Salpingectomy (removal of the entire fallopian tube) is recommended when there has been significant damage to the tube, when removal of the damaged elements would leave in place less than 6 cm of functional tube, or when a patient who previously has been sterilized verifies that she still does not desire future fertility. Figure 24-5A illustrates a laparoscopic salpingectomy. Partial salpingectomy(removal of a portion of the fallopian tube) is generally performed only if the ectopic pregnancy is implanted in the mid-ampullary portion. The remnants of the tube may be reapproximated in the future. Figure 24-5B illustrates a laparoscopic Endoloop partial salpingectomy. Salpingotomy and salpingostomy are both procedures in which the ectopic pregnancy site is identified and vasoconstrictive agents are injected beneath the implantation site prior to an incision. With salpingotomy, the incision is closed, whereas it is left open in salpingostomy. An incision is made parallel to the axis of the tube along its antimesenteric border over the site of implantation. The products of conception are removed by gentle dissection or hydrodissection (the use of injected fluid to separate tissues). Bleeding is controlled by judicious use of electrocoagulation. The tube and pelvis are copiously irrigated. Figure 24-5C illustrates a laparoscopic linear salpingostomy. Most studies have shown that salpingostomy (incision left open), compared with salpingotomy, results in better long-term tubal function.
FIGURE 24-5 Methods of laparoscopic management of tubal pregnancy. A: Salpingectomy using Endoloop and cautery scissors for isthmic tubal pregnancy. B: Partial salpingectomy with Endoloop. C:Linear salpingostomy for an ampullary ectopic pregnancy.
There is a 10% to 20% risk for residual trophoblastic tissue whenever the products of conception are dissected from the tube (i.e., when salpingostomy or salpingotomy are performed). Women who do not have resection of the affected tubal areas should have repeat hCG titers 3 to 7 days postoperatively to confirm that no hormone-producing cells remain behind to reinvade the tube. If repeat hCG titers fail to decline appropriately, methotrexate (MTX) therapy can be started (see later). The risk for incomplete trophoblastic tissue removal is greatest when the ectopic is “milked” through the tube to extrude through the fimbria. This technique should never be used, even when it appears that the pregnancy is spontaneously aborting through the fimbria. If there is any concern about significant tubal damage or a high likelihood of retained products of conception, salpingectomy should be performed.
MEDICAL MANAGEMENT WITH METHOTREXATE
Ambulatory diagnosis and management of women with early, unruptured ectopic pregnancies has replaced surgical diagnosis and treatment in most cases. The most commonly used agent is MTX, which is a folic acid antagonist that inhibits DNA synthesis and cell reproduction. Because of the side effects of MTX and the potential for tubal rupture, careful guidelines for patient selection are required, as shown in Box 24-3.
BOX 24-3 Criteria for Medical Management of Ectopic Pregnancy with Methotrexate
Data from American College of Obstetricians and Gynecologists (ACOG): Medical management of tubal pregnancy. Practice Bulletin No. 3. Washington, DC, ACOG, December 1998.
Hemodynamically stable without active
bleeding or signs of hemoperitoneum
Patient desires future fertility
General anesthesia poses a significant risk
Patient is able to return for follow-up care
No contraindications to methotrexate
Unruptured mass ≤ 3.5 cm at its greatest dimension
No fetal cardiac motion detected
Patients whose human chorionic gonadotropin level does not exceed a predetermined value (6000-15,000 mIU/mL)
Overt or laboratory evidence of immunodeficiency
Alcoholism, alcoholic liver disease, or other chronic liver disease
Preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia
Known sensitivity to methotrexate
Active pulmonary disease
Peptic ulcer disease
Hepatic, renal, or hematologic dysfunction
Gestational sac ≥ 3.5 cm
Embryonic cardiac motion
A suitable patient may be administered MTX in divided doses of 50 mg/m2 intramuscularly (half of the dose into each buttock). She should return on days 4 and 7 for repeat hCG determinations. If the hCG titers fall at least 15% between those days, the patient can be followed at weekly intervals to verify at least a 15% decline every 7 days until the titers are undetectable (usually <5 mIU/mL). If the titers plateau or fall too slowly, another divided dose of MTX may be given if all the other criteria continue to be met. If the patient becomes more symptomatic or if hCG titers increase during therapy, surgical intervention is required. Some centers routinely recommend multiple doses of MTX to reduce treatment failures. Similar outcomes have been shown between single and multidose regimens, and multidose regimens have the disadvantage of needing leucovorin rescue to avoid the significant side effects of relative folate deficiency.
After injection and throughout treatment, patients should be instructed to avoid folate-containing vitamins, nonsteroidal antiinflammatory agents, and alcoholic beverages. Pelvic rest is required. Effective contraception should be initiated and continued for at least 3 months after the decrease in hCG titers is observed.
OTHER THERAPEUTIC INTERVENTIONS
When ectopic pregnancy is diagnosed at the time of laparoscopy, MTX, prostaglandins, or hyperosmolar glucose may be injected into the amniotic sac by a technique called salpingocentesis. The intention is to destroy the ectopic pregnancy without the need for any other procedure. This technique can also be performed transvaginally using ultrasonographic guidance in patients who have not had laparoscopy. The potential advantage of this technique is that it is a one-time injection that reduces systemic side effects. Because information about long-term reproductive function after this technique has not yet been reported, its use is still considered experimental.
Selected patients may qualify for expectant management if they are stable and the diagnosis of ectopic pregnancy is not yet certain or if their symptoms are spontaneously resolving. They must be carefully followed with serial hCG testing and monitoring. As many as 80% of ectopic pregnancies with hCG levels of 1000 mIU/mL or less will not rupture spontaneously or bleed profusely but will undergo spontaneous resolution. Unfortunately, the 20% who experience severe sequelae are not identifiable in advance. Expectant management is generally reserved for reliable, relatively asymptomatic patients in whom the hCG titers are low enough to make rupture very unlikely (<200 mIU/mL and declining).
IMPORTANT THERAPEUTIC CONSIDERATIONS
All Rh-negative, unsensitized women who have ectopic pregnancies should receive anti-Rh immunoglobulin (RhO-GAM). After an ectopic gestation, pregnancy should be avoided for at least 3 months to permit the architecture of the fallopian tube to normalize and to allow complete elimination of MTX, if that agent has been given. Highly effective contraception should be provided as soon as the ectopic pregnancy starts to resolve.
Treatment of Uncommon Types of Ectopic Pregnancies
An ovarian ectopic pregnancy produces the same symptoms as a tubal pregnancy. The treatment is aimed at removing the pregnancy and preserving as much normal ovarian tissue as possible. When ovarian preservation is not possible, usually because of profuse bleeding, oophorectomy is indicated. If identified early enough, ovarian ectopic pregnancies may be successfully treated with MTX.
Cervical pregnancy usually presents with profuse vaginal bleeding, and attempts at removal of the pregnancy are often unsuccessful. MTX and arterial embolization are used to manage cervical pregnancy if the patient is not actively bleeding. An alternative is to aspirate the cervical ectopic using an oocyte aspiration needle traversing the cervical stroma. Hysterectomy is reserved for large cervical ectopic pregnancies not amenable to nonsurgical intervention and for actively bleeding cervical pregnancies that cannot be controlled conservatively. All patients with cervical ectopic pregnancies should be typed and crossmatched for blood products before surgical intervention is undertaken.
Pregnancies rarely implant in the abdominal cavity (e.g., on the omentum, bowel, or parietal or visceral peritoneum), but if they do so, they may proceed to full term. At the time of laparotomy in advanced gestations, the placenta presents a major technical difficulty. Vital organs may be entirely or partially covered by the firmly attached placenta, and any attempt at removal may cause massive bleeding. Partial bowel resection may be required if the bowel is involved. In most cases, it is best to leave the placenta attached, especially if the pregnancy is in the second or third trimester, anticipating eventual spontaneous reabsorption. MTX treatment may also be useful to accelerate and enhance placental resorption.
Implications for Future Fertility
Patients who have experienced an ectopic pregnancy are at increased risk for subsequent ectopic pregnancies and problems with infertility. One study demonstrated that the pregnancy rate is just over 80% after either medical or surgical treatment for ectopic pregnancy, with a mean time to conception of 9 to 12 months. Fertility rates are similar after expectant management or surgical intervention. Having one ectopic pregnancy increases the risk for a future ectopic pregnancy by 7- to 13-fold. There is about a 50% to 80% chance that the next pregnancy will be intrauterine and a 10% to 25% chance that it will be ectopic. All patients with recent ectopic pregnancies should receive counseling about this increased risk before attempting another pregnancy.
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