In ectopic pregnancy, a fertilized ovum implants outside the endometrial cavity (Fig. 13–7). Nearly all ectopic pregnancies (>95%) occur in the fallopian tube (tubal pregnancy); however, an ectopic pregnancy may also be found implanted within the endocervical canal (cervical pregnancy), on or in the ovary (ovarian pregnancy), within a scar from a prior caesarean delivery (caesarean scar pregnancy), or within the peritoneal cavity (abdominal pregnancy).
Locations of ectopic pregnancies. (Reproduced, with permission, from: Benson RC. Handbook of Obstetrics & Gynecology. 8th ed. Los Altos, CA: Lange; 1983.)
Ectopic pregnancy occurs in approximately 1.5–2.0% of all pregnancies. The incidence has increased from 4.5 per 1000 in 1970 to 19.7 per 1000 in 1992, the last time data were reported by the US Centers for Disease Control and Prevention. This may be due, at least in part, to a higher incidence of pelvic inflammatory disease, use of assisted reproductive technology, and higher rates of tubal sterilization.
The morbidity and mortality associated with ectopic pregnancy has decreased dramatically, mainly because of earlier diagnosis with ultrasound and hCG levels and subsequent treatment before rupture. Nevertheless, ectopic pregnancy is the leading cause of pregnancy-related death in the first trimester and accounts for 4–10% of all pregnancy-related deaths.
Classification & Incidence
Ectopic pregnancy can be classified as follows (Fig. 13–7).
Includes ampullary (70%), isthmic (12%), fimbrial (11%), and interstitial (2%).
Includes cervical, ovarian, caesarean scar, and abdominal. Primary abdominal pregnancies have been reported, but most abdominal pregnancies result from tubal abortion or rupture with subsequent implantation in the bowel, omentum, or mesentery. Caesarean scar pregnancy is becoming an increasingly recognized clinical entity, with its incidence presumably paralleling the rise in caesarean section rates.
An ectopic pregnancy that occurs in combination with an intrauterine pregnancy. The risk of a heterotopic pregnancy is <1 in 30,000 of spontaneous pregnancies. The incidence ranges from 1 in 100 to 1 in 500 with assisted reproductive technologies.
There are many known risk factors for ectopic pregnancy, such as previous pelvic inflammatory disease, current and past smoking, and the presence of an intrauterine device (IUD). Despite our knowledge of these predisposing factors, up to one-third of ectopic pregnancies occur in women without any apparent risk factors.
Damage to the fallopian tube from a number of factors increases the risk of ectopic pregnancy. In pelvic inflammatory disease (PID), microorganisms ascend from the lower genital tract, infecting and causing inflammation of the uterus, fallopian tubes, and ovaries. Salpingitis can result in damage to fallopian tube cilia and blockage or closure of the tube. PID can also lead to adhesion formation among pelvic organs.
Other causes of distorted tubal anatomy leading to an increased risk of ectopic pregnancy include previous tubal surgery, endometriosis, uterine leiomyomas, and developmental abnormalities of the tube or abnormal tubal anatomy from in utero DES exposure. Up to one-third of pregnancies after tubal ligation and approximately 7% of pregnancies after sterilization reversal are ectopic. Additionally, one-third of pregnancies after an ectopic pregnancy are also ectopic implantations.
Assisted Reproductive Technology (ART)
The rate of ectopic pregnancy with ART ranges from 2.1% to as high as 8.6% of all clinical pregnancies. The etiology of ectopic pregnancy in patients undergoing ART and in vitro fertilization (IVF) is not completely understood, but several theories are currently under investigation.
Medications used to increase ovarian follicle production result in high levels of progesterone and estradiol that may affect tubal peristalsis and uterine relaxation. Women with tubal factor infertility undergoing IVF have even higher rates of ectopic pregnancy, and most physicians will recommend removal of diseased tubes before IVF. Ectopic pregnancy rates are associated with the number of transferred embryos as well as placement of the embryos.
Pregnancy is uncommon in women who use an IUD for contraception. However, approximately 5% of pregnancies that do occur in women using an IUD are ectopic pregnancies. Nevertheless, women with an IUD are overall less likely to develop an ectopic pregnancy than women who do not use contraception. Smoking also significantly increases the risk of ectopic pregnancy, likely because cigarette smoke affects cilia and smooth muscle function in the fallopian tube.
Rupture of an ectopic pregnancy is usually spontaneous. Isthmic pregnancies tend to rupture earliest, at 6–8 weeks' gestation, because of the small diameter of this portion of the tube. Ampullary pregnancies rupture later, generally at 8–12 weeks. Interstitial pregnancies are the last to rupture, usually at 12–16 weeks, as the myometrium allows more room for the ectopic to grow. Interstitial rupture is quite dangerous because its proximity to uterine and ovarian vessels can result in massive hemorrhage.
Prevention and early treatment of sexually transmitted diseases is important to prevent tubal damage and subsequent ectopic pregnancy. Smoking cessation can also help reduce the risk of ectopic pregnancy. Smoking decreases the motility of the fallopian tube cilia and makes a fertilized egg less likely to traverse the tube normally. Unfortunately, other known risk factors are more difficult to control, and up to one-third of ectopic pregnancies occur without any associated risk factors.
No specific symptoms or signs are pathognomonic for ectopic pregnancy, and many disorders can present similarly. Normal pregnancy, threatened or incomplete abortion, ovarian cyst rupture, ovarian torsion, gastroenteritis, and appendicitis can all be confused with ectopic pregnancy. Because early diagnosis is crucial, a high index of suspicion should be maintained when any pregnant woman in the first trimester presents with bleeding and/or abdominal pain.
The following symptoms may assist in the diagnosis of ectopic pregnancy.
Pelvic or abdominal pain is present in almost 100% of cases. Pain can be unilateral or bilateral, localized or generalized. The presence of subdiaphragmatic or shoulder pain is suggestive of intra-abdominal bleeding. In tubal ectopic pregnancy, implantation typically occurs in the wall of the tube, in the connective tissue beneath the serosa. There may be little or no decidual reaction within the tube and minimal defense against the permeating trophoblast. The trophoblast invades blood vessels, causing local hemorrhage. A hematoma in the subserosal space enlarges as the pregnancy grows, and progressive distention of the tube eventually leads to pain and rupture.
Abnormal uterine bleeding occurs in roughly 75% of cases and represents decidual sloughing. Bleeding usually presents as intermittent, light spotting; however, bleeding may be heavier. A decidua cast is passed in 5–10% of ectopic pregnancies and may be mistaken for products of conception. Vaginal bleeding is of endometrial origin and results when the decidua breaks down from lack of progesterone support, a hallmark of an abnormal pregnancy. Occasionally the entire decidua may be shed in one or more large pieces as a decidual cast of the endometrial cavity. On pathologic examination, only decidua is seen, whereas chorionic villi are notably absent.
Secondary amenorrhea is variable. Approximately half of women with ectopic pregnancies have some bleeding at the time of their expected menses and may not realize they are pregnant.
Dizziness, lightheadedness, and/or syncope may be part of the initial presentation and should raise suspicion for intra-abdominal bleeding from a ruptured ectopic pregnancy.
On examination, the following signs are important in the diagnosis of ectopic gestation.
Diffuse or localized abdominal tenderness is present in the majority of patients with ectopic pregnancies. Adnexal and/or cervical motion tenderness is also a common finding.
A unilateral adnexal mass is palpated in one-third to one-half of patients. More often, unilateral adnexal fullness rather than a discrete mass is appreciated. Occasionally, a cul-de-sac mass is noted.
The uterus may undergo the typical changes of pregnancy, including softening and a slight increase in size.
Vital signs will reflect the hemodynamic status of patients with tubal rupture and intra-abdominal bleeding.
The hematocrit is an important initial test that indirectly assesses the hemodynamic status of the patient and reflects the amount of intra-abdominal bleeding.
The qualitative serum or urine hCG assay is positive in virtually 100% of ectopic pregnancies. A positive result, however, does not help distinguish an intrauterine from ectopic pregnancy. More helpful is a quantitative hCG value that, in conjunction with transvaginal ultrasound, can often make the diagnosis. If ultrasound is nondiagnostic (eg, in an early ectopic, early normal pregnancy, or early failed pregnancy), serial hCG values can be followed. The hCG level should rise at a minimum of 53% over 48 hours in a normal pregnancy. An inappropriate rise in hCG has a sensitivity of 99% for an abnormal gestation. Of note, two-thirds of ectopic pregnancies have abnormally rising values, whereas the remaining third show a normal progression.
Serum progesterone levels may help confirm an ectopic pregnancy diagnosis. Serum progesterone values are independent of hCG levels. A serum progesterone level less than 5 ng/mL has a 100% specificity for identifying an abnormal pregnancy, but does not identify the location of the pregnancy. Progesterone levels greater than 20 ng/mL are associated with normal intrauterine pregnancies. All values in between 5 and 20 ng/mL are equivocal.
Ultrasound is an essential part of the evaluation for an ectopic pregnancy. An initial transvaginal ultrasound can be used to visualize an intrauterine pregnancy or a definite ectopic gestation. If neither diagnosis is made, the patient is considered to have a “pregnancy of unknown location.” Approximately 25–50% of women with an ectopic pregnancy initially present in this manner. An intrauterine pregnancy may not be visualized because the gestational sac has not yet developed or has collapsed. Likewise, an early ectopic pregnancy may be too small to be detected by ultrasound. When a diagnosis cannot be made, the patient is then followed with serial hCG levels and ultrasound until either an ectopic pregnancy, intrauterine gestation, or early pregnancy failure is confirmed.
In general, ultrasound should detect an intrauterine gestation when the hCG value falls within or surpasses the “discriminatory zone,” defined as an hCG value between 1500 and 2000 mIU/mL. If the hCG level is higher than the discriminatory zone, and the transvaginal ultrasound is nondiagnostic, ectopic pregnancy or early abnormal pregnancy is likely. Caution should be used when interpreting hCG values because they may be falsely elevated in a pregnancy with multiple gestations.
A normal intrauterine sac appears regular and well defined on ultrasound. It has been described as an echolucent area having a “double ring” or “double decidual” sign, which represents the decidual lining and the chorion around the early gestational sac. In ectopic pregnancy, ultrasound may reveal only a thickened, decidualized endometrium. Decidual sloughing results in intracavitary fluid or blood and creates the so-called pseudogestational sac, a small and irregular structure that may be confused with an intrauterine gestational sac.
The presence of an adnexal mass with an empty uterus raises the suspicion for an ectopic pregnancy, especially if the hCG titers are above the discriminatory zone. Visualization of a gestational sac with a yolk sac or embryo within the adnexa confirms the diagnosis; however, it is more common to find a hyperechoic “tubal ring” or complex mass within the adnexae (Fig. 13–8). If rupture has occurred, anechoic or echogenic free fluid in the cul-de-sac may be visualized.
Empty uterus (U) with an adnexal mass (A) suspicious for an ectopic pregnancy.
Ultrasound is increasingly being relied on to differentiate several less common types of ectopic pregnancies. Both interstitial tubal and caesarean section scar pregnancies can be difficult to distinguish from intrauterine gestations because of their proximity to the intrauterine cavity.
The most likely alternative diagnosis of an adnexal mass in early pregnancy is a corpus luteum cyst, which can also rupture and bleed, thus making its distinction from an ectopic pregnancy challenging.
In the past, laparoscopy was often used to diagnosis ectopic pregnancy. In current practice, however, transvaginal ultrasound has replaced laparoscopy as the preferred diagnostic tool. Compared with laparoscopy, ultrasound is equally effective in confirming the presence or absence of ectopic pregnancy. Ultrasound also has the advantages of being both cost-effective and noninvasive. In terms of surgical treatment for ectopic pregnancy, laparoscopy is the standard method, assuming the patient is hemodynamically stable.
D&C can be performed to confirm or exclude intrauterine pregnancy. D&C is usually performed when an early ectopic or abnormal intrauterine gestation is suspected based on hCG levels and ultrasound. D&C should not be performed if a pregnancy is desired because it may remove a normal, early intrauterine gestation. If chorionic villi are seen on pathology examination of the D&C specimen, an intrauterine pregnancy is confirmed. On the other hand, if only decidua is obtained on D&C, ectopic pregnancy is highly likely.
Immediate surgery is indicated in the hemodynamically unstable patient with a presumed ectopic pregnancy. Laparoscopy is generally the preferred surgical method for evaluation of suspected ectopic pregnancy in the stable patient; however, exploratory laparotomy can provide rapid access to control intra-abdominal hemorrhage. Laparotomy also may be performed if the laparoscopic approach does not allow adequate visualization or if scar tissue from previous surgeries makes the laparoscopic approach too difficult.
Culdocentesis, the vaginal passage of a needle into the posterior cul-de-sac, was once used to confirm the presence of hemoperitoneum. This technique has now been replaced by transvaginal ultrasound and is rarely performed in modern medicine.
Magnetic Resonance Imaging
Magnetic resonance imaging is a useful adjunct to ultrasound in cases in which an unusual ectopic location is suspected. The location of the ectopic pregnancy and recognition of cervical, caesarean scar, or interstitial pregnancy determines the options for treatment and management. In these types of ectopic pregnancy, conservative treatment with methotrexate is often preferred and usually attempted before surgery to avoid the potential catastrophic hemorrhage associated with surgical management in these cases.
Expectant management is appropriate and can be successful in a select population of patients. In general, these women should be asymptomatic, with lower starting hCG levels and evidence that the ectopic pregnancy is spontaneously resolving (eg, decreasing hCG levels). If the initial hCG level is less than 200 mU/mL, 88% of patients experience resolution with expectant management. These women should be educated about the potential risks of tubal rupture, intra-abdominal bleeding, and the need for emergent surgery.
Methotrexate (MTX) is a drug that inhibits the action of dihydrofolate reductase, thereby inhibiting DNA synthesis. MTX affects actively proliferating tissues such as bone marrow, intestinal mucosa, malignant cells, and trophoblastic tissue. This antimetabolite can be considered for women who are hemodynamically stable with a confirmed ectopic pregnancy or if clinical suspicion is high for an ectopic pregnancy. Although treatment of early ectopic pregnancy with MTX has significantly decreased the number of women who need surgery, there are several contraindications to its use.
Embryonic cardiac motion or the presence of a gestational sac larger than 3.5 cm are relative contraindications to MTX due to the higher rate of treatment failure in patients with either one of these findings. The level of hCG is also predictive of MTX success. With hCG values greater than 5000 mIU/mL, the failure rate is 14% with a single dose of MTX compared with 3.7% with a multiple-dose regimen. Because MTX affects rapidly dividing tissues within the body, it should not be given to women with blood dyscrasias or active gastrointestinal or respiratory disease. MTX is toxic to hepatocytes and is cleared by the kidneys; thus serum creatinine level and liver transaminases should be normal before administration. Patients must also be considered reliable for follow-up (Table 13–2).
Table 13–2. Contraindications to Methotrexate in Treatment of Ectopic Pregnancy. ||Download (.pdf)
Table 13–2. Contraindications to Methotrexate in Treatment of Ectopic Pregnancy.
|Overt or laboratory evidence of immunodeficiency|
|Alcoholism, alcoholic liver disease, or other chronic liver disease|
|Pre-existing 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 larger than 3.5 cm|
|Embryonic cardiac motion|
There are three different regimens for giving MTX: single dose, two-dose, and a fixed multidose protocol. The single 50 mg/m2 dose of MTX is most commonly used, given as an intramuscular injection. hCG levels are measured at 4 and 7 days posttreatment with an expected 15% decrease from day 4 to day 7. Weekly hCG levels are then checked until zero. If hCG levels do not drop appropriately, a second MTX dose or surgical intervention is advised. Overall, the fixed multidose regimen has been shown to be the most effective regimen, especially in treating more advanced gestations and those with embryonic cardiac activity. However, these patients may experience more side effects, and adherence to the treatment plan may be more difficult.
It is not unusual for women given MTX to have an increase in abdominal pain 2–3 days after administration, likely from the effect of the drug on trophoblast tissue and tubal distention or tubal abortion. Despite this common finding, monitoring for tubal rupture during MTX therapy is extremely important, and worsening pain should prompt immediate evaluation.
Once the mainstay of therapy for ectopic pregnancy, surgical treatment is now mainly reserved for patients with contraindications to medical management and for those with evidence of tubal rupture. Despite declining rates of surgical management, surgery remains the most definitive treatment for ectopic pregnancies.
In a hemodynamically stable patient, laparoscopy is the standard approach for surgical management of a known or suspected ectopic pregnancy that is not amenable to medical treatment. In some instances, previous surgeries with subsequent intra-abdominal adhesions makes laparotomy the preferred approach. Tubal pregnancies can be treated with either linear salpingostomy or salpingectomy. The decision to perform either procedure depends on the patient's desire for future fertility as well as the appearance of the contralateral tube. If the contralateral tube appears abnormal and fertility is desired, a linear salpingostomy can be performed, and future fertility seems to be improved. In this technique, an incision is made along the fallopian tube, proximal to the ectopic pregnancy. The gestational tissue is gently removed from the tube with an effort to remove the ectopic in one piece. Patients who undergo linear salpingostomy are at risk for having persistent trophoblastic tissue and must be evaluated with weekly hCG levels until undetectable. hCG levels may remain elevated in up to 20% of patients who have undergone salpingostomy. In these cases, MTX is given, with high rates of resolution. Linear salpingostomy also increases the risk of a second ectopic pregnancy occurring in this tube, with rates up to 15%. In general, if the contralateral tube is normal, salpingectomy should be performed to reduce the risk of subsequent ectopic pregnancy.
Salpingectomy (removal of the fallopian tube) is preferred if the patient has completed child bearing, if the affected tube appears damaged, or if salpingostomy has already been performed on that tube. Salpingectomy is a simpler technique and carries minimal risk of retained trophoblastic tissue and postoperative tubal bleeding.
Interstitial pregnancies are uncommon, accounting for only 2–4% of all ectopic pregnancies. MTX and surgery can be offered to these patients. Expectant management is currently not recommended because it has not been well studied in these patients and the risks are considered greater than for tubal ectopics. Interstitial pregnancies implant into the vascular uterine cornua, and subsequent rupture can cause significant bleeding. MTX is a reasonable first-line therapy for the treatment of asymptomatic patients with an unruptured interstitial pregnancy, with reported success rates of >80%. Similar to MTX treatment of tubal pregnancies, close follow-up and patient education are necessary. Surgery is an option for patients who desire definitive management. Laparotomy was once the standard surgical approach; however, several laparoscopic techniques have now been described. Earlier diagnosis has allowed for management of interstitial pregnancies with less invasive surgical procedures.
Immediate surgery is indicated when the diagnosis of a ruptured ectopic pregnancy is made. Blood products should be requested immediately because transfusion is often necessary. There is no place for conservative management in a patient with a ruptured ectopic. Even patients who initially present with normal vital signs can quickly become hemodynamically unstable. Rho (D) immunoglobulin should be given to any Rh-negative mother with the diagnosis of ectopic pregnancy because sensitization may occur.
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