Ectopic Pregnancy

Author: Vicken P Sepilian, MD, MSc, Medical Director, Reproductive Endocrinology and Infertility, CHA Fertility Center
Coauthor(s): Ellen Wood, DO, FACOOG, Voluntary Assistant Professor, University of Miami School of Medicine

Introduction

Ectopic pregnancy presents a major health problem for women of childbearing age. It is the result of a flaw in human reproductive physiology that allows the conceptus to implant and mature outside the endometrial cavity, which ultimately ends in death of the fetus. Without timely diagnosis and treatment, ectopic pregnancy can become a life-threatening situation.

Ectopic pregnancy currently is the leading cause of pregnancy-related death during the first trimester in the United States, accounting for 9% of all pregnancy-related deaths. In addition to the immediate morbidity caused by ectopic pregnancy, the woman's future ability to reproduce may be adversely affected as well.

Ectopic pregnancy. Laparoscopic picture of an unr...

Ectopic pregnancy. Laparoscopic picture of an unruptured right ampullary tubal pregnancy with bleeding out of the fimbriated end resulting in hemoperitoneum

History of the Procedure

Ectopic pregnancy was first described in the 11th century, and, until the middle of the 18th century, it was usually fatal. John Bard reported the first successful surgical intervention to treat an ectopic pregnancy in New York City in 1759.

The survival rate in the early 19th century was dismal. One report demonstrated only 5 patients of 30 surviving the abdominal operation. Interestingly, the survival rate in patients who were left untreated was 1 of 3.

In the beginning of the 20th century, great improvements in anesthesia, antibiotics, and blood transfusion contributed to the decrease in the maternal mortality rate. In the early half of the 20th century, 200-400 deaths per 10,000 cases were attributed to ectopic pregnancy. In 1970, the Centers for Disease Control and Prevention (CDC) began to record the statistics regarding ectopic pregnancy, reporting 17,800 cases. By 1992, the number of ectopic pregnancies had increased to 108,800. Concurrently, however, the case-fatality rate decreased from 35.5 deaths per 10,000 cases in 1970 to 2.6 per 10,000 cases in 1992.

Problem

Ectopic pregnancy is derived from the Greek word ektopos, meaning out of place, and it refers to the implantation of a fertilized egg in a location outside of the uterine cavity, including the fallopian tubes, cervix, ovary, cornual region of the uterus, and the abdominal cavity. This abnormally implanted gestation grows and draws its blood supply from the site of abnormal implantation. As the gestation enlarges, it creates the potential for organ rupture because only the uterine cavity is designed to expand and accommodate fetal development. Ectopic pregnancy can lead to massive hemorrhage, infertility, or death.

Frequency

Since 1970, the frequency of ectopic pregnancy has increased 6-fold, and it now occurs in 2% of all pregnancies. An estimated 108,800 ectopic pregnancies in 1992 resulted in 58,200 hospitalizations with an estimated cost of $1.1 billion.

Etiology

Multiple factors contribute to the relative risk of ectopic pregnancy. In theory, anything that hampers the migration of the embryo to the endometrial cavity could predispose women to ectopic gestation. The most logical explanation for the increasing frequency of ectopic pregnancy is previous pelvic infection; however, most patients presenting with an ectopic pregnancy have no identifiable risk factor. The following risk factors have been linked with ectopic pregnancy:

Pelvic inflammatory disease

The most common cause is antecedent infection caused by Chlamydia trachomatis. Patients with chlamydial infection have a range of clinical presentations, from asymptomatic cervicitis to salpingitis and florid pelvic inflammatory disease (PID). More than 50% of women who have been infected are unaware of the exposure. Other organisms causing PID, such as Neisseria gonorrhoeae, increase the risk of ectopic pregnancy. A history of salpingitis increases the risk of ectopic pregnancy 4-fold. The incidence of tubal damage increases after successive episodes of PID (ie, 13% after 1 episode, 35% after 2 episodes, 75% after 3 episodes).

History of prior ectopic pregnancy

After one ectopic pregnancy, a patient incurs a 7- to 13-fold increase in the likelihood of another ectopic pregnancy. Overall, a patient with prior ectopic pregnancy has a 50-80% chance of having a subsequent intrauterine gestation, and a 10-25% chance of a future tubal pregnancy.

History of tubal surgery and conception after tubal ligation

Prior tubal surgery has been demonstrated to increase the risk of developing ectopic pregnancy. The increase depends on the degree of damage and the extent of anatomic alteration. Surgeries carrying higher risk of subsequent ectopic pregnancy include salpingostomy, neosalpingostomy, fimbrioplasty, tubal reanastomosis, and lysis of peritubal or periovarian adhesions.

Conception after previous tubal ligation increases a women's risk of developing ectopic pregnancies. Thirty-five to 50% of patients who conceive after a tubal ligation are reported to experience an ectopic pregnancy. Failure after bipolar tubal cautery is more likely to result in ectopic pregnancy than occlusion using suture, rings, or clips. Failure is attributed to fistula formation that allows sperm passage. Ectopic pregnancies following tubal sterilizations usually occur 2 or more years after sterilization, rather than immediately after. In the first year, only about 6% of sterilization failures result in ectopic pregnancy.

Use of fertility drugs or assisted reproductive technology

Ovulation induction with clomiphene citrate or injectable gonadotropin therapy has been linked with a 4-fold increase in the risk of ectopic pregnancy in a case-control study. This finding suggests that multiple eggs and high hormone levels may be significant factors.

One study has demonstrated that infertility patients with luteal phase defects have a statistically higher ectopic pregnancy rate than patients whose infertility is caused by anovulation. The risk of ectopic pregnancy and heterotopic pregnancy (ie, pregnancies occurring simultaneously in different body sites) dramatically increases when a patient has used assisted reproductive techniques to conceive, such as in vitro fertilization (IVF) or gamete intrafallopian transfer (GIFT). In a study of 3000 clinical pregnancies achieved through in vitro fertilization, the ectopic pregnancy rate was 4.5%, which is more than double the background incidence. Furthermore, studies have demonstrated that up to 1% of pregnancies achieved through IVF or GIFT can result in a heterotopic gestation, compared to an incidence of 1 in 30,000 pregnancies for spontaneous conceptions.

Use of an intrauterine device

The presence of an inert copper-containing or progesterone intrauterine device (IUD) traditionally has been thought to be a risk factor for ectopic pregnancy. However, only the progesterone IUD has a rate of ectopic pregnancy higher than that for women not using any form of contraception . The modern copper IUD does not increase the risk of ectopic pregnancy. Nevertheless, if a woman ultimately conceives with an IUD in place, it is more likely to be an ectopic pregnancy. The actual incidence of ectopic pregnancies with IUD use is 3-4%.

Increasing age

The highest rate of ectopic pregnancy occurs in women aged 35-44 years. A 3- to 4-fold increase in the risk for developing an ectopic pregnancy exists compared to women aged 15-24 years. One proposed explanation involves the myoelectrical activity in the fallopian tube, which is responsible for tubal motility. Aging may result in a progressive loss of myoelectrical activity along the fallopian tube.

Smoking

Cigarette smoking has been shown to be a risk factor for developing an ectopic pregnancy. Studies have demonstrated elevated risk ranging from 1.6-3.5 times that of nonsmokers. A dose-response effect also has been suggested. Based on laboratory studies in humans and animals, researchers have postulated several mechanisms by which cigarette smoking might play a role in ectopic pregnancies. These mechanisms include one or more of the following: delayed ovulation, altered tubal and uterine motility, or altered immunity. To date, no study has supported a specific mechanism by which cigarette smoking affects the occurrence of ectopic pregnancy.

Salpingitis isthmica nodosum

Salpingitis isthmica nodosum is defined as the microscopic presence of tubal epithelium in the myosalpinx or beneath the tubal serosa. These pockets of epithelium protrude through the tube, similar to small diverticula. Studies of serial histopathological sections of the fallopian tube have revealed that approximately 50% of patients treated with salpingectomy for ectopic pregnancy have evidence of salpingitis isthmica nodosum. The etiology of salpingitis isthmica nodosum is unclear, but proposed mechanisms include postinflammatory and congenital as well as acquired tubal changes such as observed with endometriosis.

Other

Other risk factors associated with increased incidence of ectopic pregnancy include previous diethylstilbestrol (DES) exposure, a T-shaped uterus, prior abdominal surgery, failure with progestin-only contraception, and ruptured appendix.

Pathophysiology

Most ectopic pregnancies are located in the fallopian tube.

Sites and frequencies of ectopic pregnancy. By Do...

Sites and frequencies of ectopic pregnancy. By Donna M. Peretin, RN. (A) Ampullary, 80%; (B) Isthmic, 12%; (C) Fimbrial, 5%; (D) Cornual/Interstitial, 2%; (E) Abdominal, 1.4%; (F) Ovarian, 0.2%; (G) Cervical, 0.2%.


The most common site is the ampullary portion of the tube, where over 80% occur. The next most common sites are the isthmic segment of the tube (12%), the fimbria (5%), and the cornual and interstitial region of the tube (2%). Nontubal sites of ectopic pregnancy are a rare occurrence, with abdominal pregnancies accounting for 1.4% of ectopic pregnancies and ovarian and cervical sites accounting for 0.2% each.

Presentation

The classic clinical triad of ectopic pregnancy is pain, amenorrhea, and vaginal bleeding. Unfortunately, only 50% of patients present typically. Patients may present with other symptoms common to early pregnancy, including nausea, breast fullness, fatigue, low abdominal pain, heavy cramping, shoulder pain, and recent dyspareunia. Astute clinicians should have a high index of suspicion for ectopic pregnancy in any woman who presents with these symptoms and who presents with physical findings of pelvic tenderness, enlarged uterus, adnexal mass, or tenderness.

Remember, however, that only 40-50% of patients with an ectopic pregnancy present with vaginal bleeding, 50% have a palpable adnexal mass, and 75% may have abdominal tenderness. Approximately 20% of patients with ectopic pregnancies are hemodynamically compromised at initial presentation, which is highly suggestive of rupture. Fortunately, using modern diagnostic techniques, most ectopic pregnancies may be diagnosed prior to rupturing.

Numerous conditions may have a presentation similar to an extrauterine pregnancy. The most common of these are appendicitis , salpingitis , ruptured corpus luteum cyst or ovarian follicle, spontaneous abortion or threatened abortion , ovarian torsion , and urinary tract disease . Intrauterine pregnancies with other abdominal or pelvic problems such as degenerating fibroids must also be included in the differential diagnosis.

Indications

Medical therapy

Medical therapy involving methotrexate may be indicated in certain patients. A number of factors must be considered. The patient must be hemodynamically stable, with no signs or symptoms of active bleeding or hemoperitoneum. Furthermore, she must be reliable, compliant, and able to return for follow-up. Another factor is size of the gestation, which should not exceed 3.5 cm at its greatest dimension on ultrasound (US) measurement. She should not have any contraindications to the use of methotrexate.

Surgical therapy

Within the last 2 decades, a more conservative surgical approach to unruptured ectopic pregnancy using minimally invasive surgery has been advocated to preserve tubal function (see Surgical Therapy ). Laparoscopy has become the recommended approach in most cases. Laparotomy is usually reserved for patients who are hemodynamically unstable or patients with cornual ectopic pregnancies. It also is a preferred method for surgeons inexperienced in laparoscopy and in patients where laparoscopic approach is difficult (eg, secondary to the presence of multiple dense adhesions, obesity or massive hemoperitoneum). In a patient who has completed childbearing and no longer desires fertility, in a patient with a history of an ectopic pregnancy in the same tube, or in a patient with severely damaged tubes, total salpingectomy is the procedure of choice.

Expectant management

Candidates for successful expectant management are asymptomatic and have no evidence of rupture or hemodynamic instability. Furthermore, they should portray objective evidence of resolution, such as declining bhCG levels. They must be fully compliant and must be willing to accept the potential risks of tubal ruptur

Contraindications

Medical therapy

A bhCG level of greater than 15,000 IU/L, fetal cardiac activity, and free fluid in the cul-de-sac on US (presumably representing tubal rupture) are contraindications to medical therapy with methotrexate. Other contraindications to the use of methotrexate include documented hypersensitivity to methotrexate; breastfeeding; immunodeficiency; alcoholism; alcoholic liver disease or any liver disease; blood dyscrasias; leukopenia; thrombocytopenia; anemia; active pulmonary disease; peptic ulcer disease; and renal, hepatic, or hematologic dysfunction.

Surgical therapy

Surgical treatment in cases in which the pregnancy is located on the cervix, ovary, or in the interstitial or the cornual portion of the tube is often associated with increased risk of hemorrhage, often resulting in hysterectomy or oophorectomy. In these cases, treatment with methotrexate is an especially attractive option.

In cases involving uncontrolled bleeding and hemodynamic instability, conservative treatment methods are avoided in favor of radical surgery.

Workup

Laboratory Studies

  • Patients with early normal intrauterine pregnancies often present with signs and symptoms similar to those encountered in patients with ectopic pregnancies and other gynecological or gastrointestinal conditions. The availability of various biochemical, ultrasonographic, and surgical modalities can aid the health care provider today in establishing a definitive diagnosis and differentiating among various conditions.
  • In order to reduce the morbidity and mortality associated with ectopic pregnancy, a high index of suspicion is necessary to make a prompt and early diagnosis. As mentioned earlier, neither risk factors nor signs and symptoms of ectopic pregnancy are sensitive or specific enough to establish a definitive diagnosis. Hence, screen any female patient in the reproductive years presenting with abdominal pain, cramping, or vaginal bleeding for pregnancy. In recent years, serum and urine assays for the beta subunit of human chorionic gonadotropin (bhCG) have been developed to detect a pregnancy before the first missed period. While some commercial urine test kits are able to detect bhCG in early gestation, they are associated with varying false-negative rates. In addition, the need for a quantitative value makes serum bhCG the criterion standard for biochemical testing.
  • Beta–human chorionic gonadotropin
    • In early healthy intrauterine pregnancies, serum levels of bhCG double approximately every 2 days (1.4-2.1 d). Kadar et al established that the lower limit of the reference range to which serum bhCG should increase during a 2-day period is 66%.1 For example, a pregnant patient with a serum bhCG level of 100 mIU/mL should have a serum bhCG level of at least 166 mIU/mL 2 days later. An increase in bhCG of less than 66% is associated with an abnormal intrauterine pregnancy or an extrauterine pregnancy. Remember that 15% of healthy intrauterine pregnancies do not increase by 66% and that 13% of all ectopic pregnancies have normally rising bhCG levels of at least 66% in 2 days.
    • Shepherd et al demonstrated that 64% of very early ectopic pregnancies initially may have normal doubling bhCG levels.2 Barnhart et al more recently reported that the minimum rise in bhCG for a potentially viable pregnancy in women who present with vaginal bleeding or pain is 53% per 2 days (up to5,000IU/L).3 Hence, intervention when the bhCG level rises less than 66% but more than 53% should be undertaken according to other clinical and biochemical criteria.
    • Furthermore, even though ectopic pregnancies have been established to have lower mean serum bhCG levels than healthy pregnancies, no single serum bhCG level is diagnostic of an ectopic pregnancy. In short, serial serum bhCG levels are necessary to differentiate between normal and abnormal pregnancies and to monitor resolution of ectopic pregnancy once therapy has been initiated.
    • The major disadvantage in relying on serial titers to distinguish between normal and abnormal pregnancies is the potential for delay in reaching the diagnosis. Furthermore, while serial bhCG titers may be used to differentiate between a normal and an abnormal gestation, the test does little to indicate the location of the pregnancy. Hence, additional diagnostic modalities, including US and other biochemical markers, are needed.
  • Progesterone
    • A single serum progesterone level is another tool that is useful in differentiating abnormal gestations from healthy intrauterine pregnancies. Serum progesterone levels are not gestational age–dependent, they remain relatively constant during the first trimester of normal and abnormal pregnancies, they do not return to the reference range if initially abnormal, and they do not correlate with bhCG levels. However, no consensus on a single value that differentiates between a normal and an abnormal pregnancy currently exists. Several authors have proposed different cutoffs with varying sensitivity and specificity. A progesterone value of greater than 25 ng/mL excluded ectopic pregnancy with 97.4% certainty in one large study. Furthermore, levels of less than or equal to 5 ng/mL indicated a nonviable pregnancy, ectopic or intrauterine, and excluded normal pregnancy with 100% sensitivity.
    • Although inexpensive, the usefulness of serum progesterone is limited in that a significant number of results fall in the equivocal range of 5-25 ng/mL. Also, this test is unreliable in differentiating between normal and abnormal pregnancies in patients who conceive after IVF because of excessive progesterone production from multiple corpora lutea, as well as the practice of pharmacologic progesterone supplementation
  • Other markers
    • Several other serum and urine markers are currently under investigation to help distinguish normal and abnormal pregnancies. These include serum estradiol, inhibin, pregnancy-associated plasma protein A, pregnanediol glucuronide, placental proteins, creatinine kinase, and a quadruple screen of serum progesterone, bhCG, estriol, and alfa-fetoprotein.
    • At present, use each of these markers only as a research tool until substantial clinical evidence proves their role in clinical medicine.

Imaging Studies

  • Ultrasonography
    • US probably is the most important tool in diagnosing an extrauterine pregnancy. More frequently, it is used to confirm an intrauterine pregnancy. Visualization of an intrauterine sac, with or without fetal cardiac activity, often is adequate to exclude ectopic pregnancy. The exception to this is in the case of heterotropic pregnancies, which occur from 1 in 4000 to 1 in 30,000 spontaneous pregnancies. Screening the adnexa by US is mandatory despite visualization of an intrauterine pregnancy in patients undergoing ovarian stimulation and assisted reproduction because they have a 10-fold increased risk of heterotropic pregnancy.
    • Transvaginal US, with its greater resolution, can be used to visualize an intrauterine pregnancy by 24 days postovulation, or 38 days after last menstrual period, which is about 1 week earlier than transabdominal US. The gestational sac, which is a sonographic term and not an anatomic term, is the first structure that is recognizable on transvaginal US. It has a thick echogenic rim surrounding a sonolucent center corresponding to the trophoblastic decidual reaction surrounding the chorionic sac. Structures that represent a developing embryo cannot be recognized until a later time.
    • A pseudosac is a collection of fluid within the endometrial cavity created by bleeding from the decidualized endometrium often associated with an extrauterine pregnancy and should not be mistaken for a normal early intrauterine pregnancy. The true gestational sac is located eccentrically within the uterus beneath the endometrial surface, whereas the pseudosac fills the endometrial cavity.
    • The yolk sac is the first visible structure within the gestational sac, and it resembles a distinct circular structure with a bright echogenic rim and a sonolucent center. It can first be recognized 3 weeks postconception, about 5 weeks after last menstrual period. The embryo is recognized first as a thickening along the edge of the yolk sac, and embryonic cardiac motion can be observed 3.5-4 weeks postconception, about 5.5-6 weeks after the last menstrual period.
    • In the absence of reliable menstrual and ovulatory history, a discriminatory zone of bhCG levels validates the US findings. The discriminatory zone is the level of bhCG, using the Third International Standard for quantitative bhCG, at which all intrauterine pregnancies should be visible on US. With abdominal US, that level is 6000-6500 mIU/mL, but high-resolution transvaginal US has reduced this level to 1500-1800 mIU/mL. If transvaginal US does not reveal an intrauterine pregnancy when the discriminatory bhCG levels are reached, the pregnancy generally can be considered extrauterine.
    • An exception to this is multiple gestations. Kadar et al reported that patients with normal multiple gestates were found to have levels of bhCG above the discriminatory zone before any US evidence of the gestation was apparent.1 They showed multiple gestations with bhCG levels of up to 2300 mIU/mL before transvaginal US recognition. Therefore, if a multiple gestation is suspected, as in pregnancies resulting from assisted reproduction, the bhCG discriminatory zone must be used cautiously. Remember that a discriminatory zone is operator and institution dependent, and the clinician must be aware of the zone used by that institution prior to interpreting results.
    • The effectiveness of using US with discriminatory zone of bhCG levels has been well established in the literature.
      • In one large study of more than 1200 patients by Barnhart et al, 78.8% of patients were diagnosed definitively at the initial visit using an algorithm that included the use of US along with serum bhCG levels above the discriminatory zone.4 According to this study, if the patient's serum bhCG level was above the established discriminatory zone at initial presentation and an intrauterine sac was not identified, an operative approach involving curettage and possible operative laparoscopy was used to diagnose ectopic pregnancy.
      • If the patient's serum bhCG levels were below the discriminatory zone, serial bhCG titers were performed every 2 days. Once a patient's levels reached the discriminatory zone, US was performed. If, however, the patient's bhCG levels failed to rise appropriately (ie, at least 66% in 2 d), operative intervention was undertaken with dilatation and curettage or laparoscopy to exclude the diagnosis of ectopic pregnancy. With this protocol, Barnhart et al reported 100% sensitivity and a specificity of 99.9%.4
    • The value of US is highlighted further in its ability to demonstrate free fluid in the cul-de-sac. While free fluid could represent hemoperitoneum, it is not specific for ruptured ectopic pregnancy. Free fluid on US can represent physiological peritoneal fluid or blood from retrograde menstruation and unruptured ectopic pregnancies. Furthermore, US can be used to detect the presence of other pathological conditions that may display the signs and symptoms of ectopic pregnancy.
  • Doppler US
    • Color-flow Doppler US has been demonstrated to improve the diagnostic sensitivity and specificity of transvaginal US, especially in cases where a gestational sac is questionable or absent. A study of 304 patients at high risk for ectopic pregnancy found that the use of color-flow Doppler US, compared with transvaginal US alone, increases the diagnostic sensitivity from 71-87% for ectopic pregnancy, from 24-59% for failed intrauterine pregnancy, and from 90-99% for viable intrauterine pregnancy.
    • The addition of color-flow Doppler US may expedite earlier diagnosis and eliminate delays caused by using levels of bhCG for diagnosis. Furthermore, color-flow Doppler US can potentially be used to identify involuting ectopic pregnancies that may be candidates for expectant management.

Diagnostic Procedures

  • Dilatation and curettage
    • A simple way to rule out an ectopic pregnancy is to establish an intrauterine pregnancy. Dilation and curettage is a rapid cost-effective method to diagnose ectopic pregnancy. Once an abnormal pregnancy is established by bhCG or progesterone levels, curettage can help differentiate between an intrauterine or ectopic pregnancy. If tissue obtained is positive for villi by floating in saline or by histological diagnosis on frozen or permanent section, then a nonviable intrauterine pregnancy has occurred. In the absence of villi, the diagnosis of ectopic pregnancy is made. Laparoscopy can be performed at that time, or the case may be followed by serial serum bhCG levels and treated medically or surgically at a later time, depending on the clinical setting.
    • This method of diagnostic dilatation and curettage may only be used, of course, in cases where continuation of a pregnancy is not desired even if it were an intrauterine gestation.
    • In a patient undergoing a dilatation and curettage for the diagnosis of ectopic pregnancy, obtaining consent for a diagnostic, and possibly operative, laparoscopy is also necessary in case the diagnosis of ectopic pregnancy is made; this spares the patient exposure to an additional operative procedure.
    • While dilatation and curettage is easy and effective, it can provide false reassurance in cases of heterotropic pregnancies where multiple gestations are present, with at least one being intrauterine and one being extrauterine.
  • Culdocentesis
    • Culdocentesis is another rapid and inexpensive method of evaluation for ruptured ectopic pregnancy. It is performed by inserting a needle through the posterior fornix of the vagina into the cul-de-sac and attempting to aspirate blood. When nonclotting blood is found in conjunction with a suspected ectopic pregnancy, operative intervention is indicated because the likelihood of a ruptured ectopic pregnancy is high.
    • Culdocentesis is of historical interest because its use today is rare. It is associated with a high false-negative rate (10-14%) usually reflecting blood from an unruptured ectopic pregnancy, ruptured corpus luteum, incomplete abortion, and retrograde menstruation. Furthermore, the improved technology with US and hormonal assays is far superior in sensitivity and specificity in reaching the correct diagnosis.
  • Laparoscopy
    • Patients in pain and/or those who are hemodynamically unstable should proceed to laparoscopy. Laparoscopy allows assessment of the pelvic structures, size and exact location of ectopic pregnancy, presence of hemoperitoneum (see image below), and presence of other conditions, such as ovarian cysts and endometriosis, which, when present with an intrauterine pregnancy, can mimic an ectopic pregnancy. Furthermore, laparoscopy provides the option to treat once the diagnosis is established.

      Ectopic pregnancy. Laparoscopic picture of an unr...

      Ectopic pregnancy. Laparoscopic picture of an unruptured right ampullary tubal pregnancy with bleeding out of the fimbriated end resulting in hemoperitoneum.

    • Laparoscopy remains the criterion standard for diagnosis; however, its routine use on all patients suspected of ectopic pregnancy may lead to unnecessary risks, morbidity, and costs. Moreover, laparoscopy can miss up to 4% of early ectopic pregnancies, and, as more ectopic pregnancies are diagnosed earlier in gestation, the rate of false-negative results with laparoscopy would be expected to rise.

Treatment

Medical Therapy

Historically, the treatment of ectopic pregnancy was limited to surgery. With evolving experience with methotrexate, the treatment of selected ectopic pregnancies has been revolutionized. Medical therapy of ectopic pregnancy is appealing over surgical options for a number of reasons, including eliminating morbidity from surgery and general anesthesia, potentially less tubal damage, and less cost and need for hospitalization. Measures of current trends in the management of ectopic pregnancy in the United States from 2002-2007 indicate that the percentage of patients treated with methotrexate increased from 11.1% to 35.1%.5

Methotrexate is an antimetabolite chemotherapeutic agent that binds to the enzyme dihydrofolate reductase, which is involved in the synthesis of purine nucleotides. This interferes with DNA synthesis and disrupts cell multiplication. Methotrexate has long been known to be effective in the treatment of leukemias, lymphomas, and carcinomas of the head, neck, breast, ovary, and bladder. It has also been used as an immunosuppressive agent in the prevention of graft versus host disease and in the treatment of severe psoriasis and rheumatoid arthritis. Its effectiveness on trophoblastic tissue has been well established and is derived from experience gained in using methotrexate in the treatment of hydatiform moles and choriocarcinomas. Methotrexate is used in the treatment of ectopic pregnancy as single or multiple intramuscular injections.

Adverse effects associated with the use of methotrexate can be divided into drug adverse effects and treatment effects. Drug adverse effects include nausea, vomiting, stomatitis, diarrhea, gastric distress, and dizziness. Transient elevation in liver enzymes is also known to occur. Serious reactions, such as bone marrow suppression, dermatitis, pleuritis, pneumonitis, and alopecia, can occur with higher doses and are rare with doses used in the treatment of ectopic pregnancy. Treatment effects of methotrexate include an increase in abdominal pain (occurring in up to two thirds of patients), an increase in bhCG levels during first 1-3 days of treatment, and vaginal bleeding or spotting.

In determining whether a patient is a candidate for medical therapy, a number of factors must be considered. She must be hemodynamically stable, with no signs or symptoms of active bleeding or hemoperitoneum. Furthermore, she must be reliable, compliant, and able to return for follow-up. Another factor is size of the gestation, which should not exceed 3.5 cm at its greatest dimension on US measurement. She should not have any contraindications to the use of methotrexate.

A bhCG level of greater than 15,000 IU/L, fetal cardiac activity, and free fluid in the cul-de-sac on US (presumably representing tubal rupture) are contraindications. Although patients with bhCG levels above 15,000 IU/L and fetal cardiac activity have been treated successfully with methotrexate, these patients require much greater surveillance and carry a higher risk of subsequent operative intervention. There is an inverse association between bhCG levels and successful medical management of an ectopic pregnancy. A systematic review by Menon et al, including 503 women, confirmed that there is a substantial increase in failure of medical management of ectopic pregnancy with single dose methotrexate when the initial bhCG is above 5,000 IU/L.6

Contraindications to the use of methotrexate include documented hypersensitivity to methotrexate; breastfeeding; immunodeficiency; alcoholism; alcoholic liver disease or any liver disease; blood dyscrasias; leukopenia; thrombocytopenia; anemia; active pulmonary disease; peptic ulcer disease; and renal, hepatic, or hematologic dysfunction. However, in each case, the risk of surgery must be weighed against any relative contraindication.

A number of accepted protocols with injected methotrexate exist for the treatment of ectopic pregnancy. Initial experience used multiple doses of methotrexate with leucovorin to minimize adverse effects. Leucovorin is folinic acid that is the end product of the reaction catalyzed by dihydrofolate reductase, the same enzyme inhibited by methotrexate. Normal dividing cells preferentially absorb leucovorin; hence, it decreases the action of methotrexate, thereby decreasing its systemic adverse effects. This regimen involves administration of methotrexate as 1 mg/kg IM on days 0, 2, 4, and 6, followed by 4 doses of leucovorin as 0.1 mg/kg on days 1, 3, 5, and 7. Because of higher incidence of adverse effects and the increased need for patient motivation and compliance, the multiple dosage regimen has fallen out of favor in the United States.

The more popular regimen today is the single dose injection. It involves injection of methotrexate as 50 mg/m2 IM in a single injection or as a divided dose injected into each buttock. Studies comparing the multiple methotrexate dosage regimen to the single dosage regimen have demonstrated the 2 methods to be similar in efficacy. With smaller dosing and fewer injections, fewer adverse effects are anticipated and the use of leucovorin can be abandoned.

Prior to injection of methotrexate, the patient must be counseled extensively on the risks, benefits, adverse effects, and the possibility of failure of medical therapy, which would result in tubal rupture necessitating surgery. Patients should be aware of the signs and symptoms associated with tubal rupture and be advised to contact their physician with significantly worsening abdominal pain or tenderness, heavy vaginal bleeding, dizziness, tachycardia, palpitations, or syncope.

Most patients experience at least one episode of increased abdominal pain, which usually occurs 2-3 days after the injection. Increased abdominal pain is believed to be caused by the separation of the pregnancy from the implanted site. It can be differentiated from tubal rupture in that it is milder, of limited duration (lasting 24-48 h), and is not associated with signs of acute abdomen or hemodynamic instability.

Advise patients to avoid alcoholic beverages, vitamins containing folic acid, nonsteroidal anti-inflammatory drugs, and sexual intercourse until advised otherwise. A signed written consent demonstrating the patient's comprehension of the course of treatment must be obtained. Provide an information pamphlet to all patients receiving methotrexate; the pamphlet should include a list of adverse effects, a schedule of follow-up visits, and a method of contacting the physician or the hospital in case of emergency.

Before initiating therapy, draw blood to determine baseline laboratory values for renal, hepatic, and bone marrow function, as well as a baseline bhCG level. Determine blood type, Rhesus (Rh) factor, and the presence of antibodies. Patients who are Rh negative should receive Rh immune globulin. Obtain repeat bhCG levels 4 days and 7 days after the methotrexate injection. An initial increase in bhCG levels often occurs by the third day and is not a cause for alarm. A decline in bhCG levels of at least 15% from days 4-7 postinjection indicates a successful medical response. Other effective monitoring protocols have also been reported.7 The patient's bhCG levels should be measured weekly until they become undetectable.

Failure of medical treatment is defined when bhCG levels increase, plateau, or fail to decrease adequately by 15% from days 4-7 postinjection. At this time, surgical intervention may be warranted. A repeat single dose of methotrexate can also be a viable option after reevaluation of the patients' indications and contraindications (including repeat US) for medical therapy.

Treatment with methotrexate is an especially attractive option when the pregnancy is located on the cervix, ovary, or in the interstitial or the cornual portion of the tube. Surgical treatment in these cases is often associated with increased risk of hemorrhage, often resulting in hysterectomy or oophorectomy.

Ectopic pregnancy. A 12-week interstitial gestati...

Ectopic pregnancy. A 12-week interstitial gestation, which eventually resulted in a hysterectomy. Courtesy of Deidra Gundy, MD, Department of Obstetrics and Gynecology at MCPHU.

 

Ectopic pregnancy. A 12-week interstitial gestati...

Ectopic pregnancy. A 12-week interstitial gestation, which eventually resulted in a hysterectomy. Courtesy of Deidra Gundy, MD, Department of Obstetrics and Gynecology at MCPHU.


Successful medical treatment using methotrexate has been reported in the literature with good subsequent reproductive outcomes. By avoiding surgery, the risk of tubal injury is reduced.

The use of oral methotrexate currently is under investigation, and, while preliminary reports show promising results, efficacy remains to be established. Direct local injection (salpingocentesis) of methotrexate into the ectopic pregnancy under laparoscopic or US guidance has also been reported in the literature; however, reports from these studies have yielded inconsistent results, and its advantage over intramuscular injection remains to be established.

The medical treatment of ectopic pregnancy requires compulsive compliance. The physician must emphasize the importance of patient follow-up and have patient information on hand, including the patient's home address, telephone numbers at home and work, and the means to reach a contact person in case attempts to reach the patient directly are unsuccessful. Proper documentation of attempts to reach the patient, including records of telephone calls and certified mail are important medical-legal considerations.

Surgical Therapy

With advances in the ability to make earlier diagnosis and improvements in microsurgical techniques, conservative surgery has replaced the standard laparotomy with salpingectomy of the past. Within the last 2 decades, a more conservative surgical approach to unruptured ectopic pregnancy using minimally invasive surgery has been advocated to preserve tubal function. The conservative approaches include linear salpingostomy and milking the pregnancy out of the distal ampulla. The more radical approach includes resecting the segment of the fallopian tube that contains the gestation with or without reanastomosis.

Laparoscopy has become the recommended approach in most cases. Laparotomy is usually reserved for patients who are hemodynamically unstable or patients with cornual ectopic pregnancies. It also is a preferred method for surgeons inexperienced in laparoscopy and in patients where laparoscopic approach is difficult (eg, secondary to the presence of multiple dense adhesions, obesity or massive hemoperitoneum). Multiple studies have demonstrated that laparoscopic treatment of ectopic pregnancy results in fewer postoperative adhesions than laparotomy. Furthermore, laparoscopy is associated with significantly less blood loss and a reduced need for analgesia. Finally, laparoscopy reduces cost, hospitalization, and convalescence period.

Linear salpingostomy along the antimesenteric border to remove the products of conception is the procedure of choice for unruptured ectopic pregnancies in the ampullary portion of the tube. Ectopic pregnancies in the ampulla are usually located between the lumen and the serosa and, thus, are ideal candidates for linear salpingostomy. Several studies have demonstrated no benefit of primary closure (salpingotomy) over healing by secondary intention (salpingostomy).

The involved tube is identified and freed from surrounding structures. To minimize bleeding, a dilute solution containing 20 U of vasopressin in 20 mL of isotonic sodium chloride solution may be injected into the mesosalpinx just below the ectopic pregnancy. Make sure that the needle is not in a blood vessel by aspirating before injecting because intravascular injection of vasopressin may precipitate acute arterial hypertension and bradycardia.

Next, using a microelectrode, scissors, harmonic scalpel, or laser, a 1- to 2-cm linear incision is made along the antimesenteric side of the tube along the thinnest segment of the gestation.

Ectopic pregnancy. Linear incision being made at ...

Ectopic pregnancy. Linear incision being made at the antimesenteric side of the ampullary portion of the fallopian tube.


At this time, the pregnancy usually protrudes out of the incision and may slip out of the tube.

Laparoscopic picture of an ampullary ectopic preg...

Laparoscopic picture of an ampullary ectopic pregnancy protruding out after a linear salpingostomy was performed.


Occasionally, it must be teased out using forceps (see image below) or aqua-dissection, which uses pressurized irrigation to help dislodge the pregnancy.

Ectopic pregnancy. Schematic of a tubal gestation...

Ectopic pregnancy. Schematic of a tubal gestation being teased out after linear salpingostomy.


Coagulation of oozing areas may be necessary and can be accomplished using microbipolar forceps.

Some ampullary pregnancies can be teased out and expressed through the fimbrial end (milking of the tube) by using digital expression, suction, or aqua-dissection. However, this approach carries with it a higher rate of bleeding, persistent trophoblastic tissue, tubal damage, and recurrent ectopic pregnancy (33%).

In some cases, resection of the tubal segment containing the gestation or a total salpingectomy is preferred over salpingostomy. This is true for isthmic pregnancies, where the endosalpinx is usually damaged. These patients do poorly with linear salpingostomy, with a high rate of recurrent ectopic pregnancy. Segmental tubal resection is performed by grasping the tube at the proximal and distal borders of the segment of the tube containing the gestation and coagulating thoroughly from the antimesenteric border to the mesosalpinx. This portion of the tube is then excised. The underlying mesosalpinx is also coagulated and excised, with particular attention to minimize the damage to the surrounding vasculature. Delayed microsurgical reanastomosis can be performed to reestablish tubal patency if enough healthy fallopian tube is present. Take care to minimize the thermal injury to the tube during excision, so that an adequate portion of healthy tube remains for the reanastomosis.

Total salpingectomy can be achieved by progressively coagulating and cutting the mesosalpinx, starting from the fimbriated end and advancing toward the proximal isthmic portion of the tube. At this point, the tube is separated from the uterus by coagulating and excising with scissors or laser.

Preoperative Details

The optimal surgical management for a patient with an ectopic pregnancy depends on several factors, including the following:

  • Patient's age, history, and desire for future fertility
  • History of previous ectopic pregnancy or PID
  • Condition of the ipsilateral tube (ie, ruptured or unruptured)
  • Condition of the contralateral tube (eg, adhesions, tubal occlusion)
  • Location of the pregnancy (ie, interstitium, ampulla, isthmus)
  • Size of the pregnancy
  • Presence of confounding complications

In a patient who has completed childbearing and no longer desires fertility, in a patient with a history of an ectopic pregnancy in the same tube, or in a patient with severely damaged tubes, total salpingectomy is the procedure of choice. The presence of uncontrolled bleeding and hemodynamic instability warrants radical surgery over conservative methods. The preferred approach based on the location of the pregnancy varies, as discussed above. In all instances, regardless of desired fertility, fully inform the patient of the possibility of a laparotomy with bilateral salpingectomy.

Intraoperative Details

Throughout the procedure, take care to minimize blood loss and reduce the potential for retained trophoblastic tissue, which can reimplant and persist. Remove large gestations in an endoscopic bag, and perform copious irrigation and suctioning to remove any remaining fragments. Inspect the peritoneal cavity and remove any detected residual trophoblastic tissue.

Note the condition of the contralateral tube, the presence of adhesions, or other pathologic processes because this helps in the postoperative counseling of the patient with regard to future fertility potential.

Postoperative Details

Proper pain control and hemodynamic stability are important postoperative considerations. Most often, patients treated with laparoscopy are discharged on the same day of surgery; however, overnight admission may be necessary for some patients to monitor postoperative bleeding and achieve adequate pain control. Patients treated by laparotomy are usually hospitalized for a few days.

Follow-up

After surgical excision of the ectopic gestation, weekly monitoring of quantitative bhCG levels is necessary until the level is zero to ensure that treatment is complete. This is especially true following treatment with conservative surgery, ie, salpingostomy, which carries a 5-15% rate of persistent trophoblastic tissue. The average time for bhCG to clear the system is 2-3 weeks, but up to 6 weeks can be required.

After tubal-sparing surgical removal of an ectopic pregnancy, a fall in bhCG levels of less than 20% every 72 hours represents incomplete treatment. Although most of these cases are caused by incomplete removal of trophoblastic tissue, some actually may represent multiple ectopic pregnancies in which only one gestation is initially recognized and treated.

The incidence of persistent trophoblastic tissue is greater with higher initial bhCG levels and is relatively rare with titers less than 3000 IU/L. The risk of persistent trophoblastic tissue is very significant with a hematosalpinx greater than 6 cm in diameter, a bhCG titer greater than 20,000 IU/L, and a hemoperitoneum greater than 2 L. While resolution without any further intervention is the general rule, the persistence of trophoblastic tissue has been associated with tubal rupture and hemorrhage even in the presence of declining bhCG levels. Further medical treatment with methotrexate or surgery in symptomatic patients may be necessary if bhCG levels do not decline or persist. Some authors have suggested administration of a prophylactic dose of methotrexate after conservative surgery to reduce the risk of persistent ectopic pregnancy.

Expectant management

The increased incidence of ectopic pregnancy is partially attributed to improved ability in making earlier diagnosis. Ectopic pregnancies that previously would have resulted in tubal abortion or complete spontaneous reabsorption and remained clinically undiagnosed are now detected. Some investigators have questioned the need for unnecessary surgical or medical intervention in very early cases and have advocated expectant management in select cases. Distinguishing patients who are experiencing spontaneous resolution of their ectopic pregnancies from patients who have proliferative ectopic pregnancies could pose a clinical dilemma.

Candidates for successful expectant management are asymptomatic and have no evidence of rupture or hemodynamic instability. Furthermore, they should portray objective evidence of resolution, such as declining bhCG levels. They must be fully compliant and must be willing to accept the potential risks of tubal rupture.

Approximately one fourth of women presenting with ectopic pregnancies have declining bhCG levels, and 70% of this group experience successful outcomes with close observation, as long as the gestation is 4 cm or less in greatest dimension. An initial low bhCG titer also correlates with successful spontaneous resolution. While data are limited on this matter, initial bhCG titers below 1000 mIU/mL have been demonstrated to predict successful outcome in 88% of cases managed expectantly.

Remember that no cutoff value below which expectant management is uniformly safe has been established. Furthermore, rupture despite low and declining serum levels of bhCG has been reported, making close follow-up and patient compliance of paramount importance.

Complications

Complications of ectopic pregnancy can be secondary to misdiagnosis, late diagnosis, or treatment approach. Failure to make the prompt and correct diagnosis of ectopic pregnancy could result in tubal or uterine rupture, depending on the location of the pregnancy, which could lead to massive hemorrhage, shock, disseminated intravascular coagulopathy (DIC), and death. Ectopic pregnancy is the leading cause of maternal death in the first trimester, accounting for 9-13% of all pregnancy-related deaths. In the United States, an estimated 30-40 women die each year from ectopic pregnancy.

Any time a surgical approach is chosen as the treatment of choice, consider the complications attributable to the surgery, whether it is laparotomy or laparoscopy. These include bleeding, infection, and damage to surrounding organs, such as bowel, bladder, ureters, and the major vessels nearby. Consider risks and complications secondary to anesthesia. Make the patient aware of these complications and obtain the appropriate written consents.

Outcome and Prognosis

Treatment success rates and future reproductive outcome

The evidence in the literature reporting on the treatment of ectopic pregnancy with subsequent reproductive outcome is limited mostly to observational data and a few randomized trials comparing the various treatment options. Assessment of successful treatment and future reproductive outcome with various treatment options is often skewed by selection bias. For example, comparing a patient who was managed expectantly to a patient who received methotrexate or to a patient who had a laparoscopic salpingectomy is difficult. A patient with spotting, no abdominal pain, and a low initial bhCG level that is falling may be managed expectantly, while a patient who presents with hemodynamic instability, an acute abdomen, and high initial bhCG levels must be managed surgically. These two patients probably represent different degrees of tubal damage, and comparing the future reproductive outcomes of the two would be flawed.

Data in the literature have failed to demonstrate substantial and consistent benefit of either salpingostomy or salpingectomy in improving future reproductive outcome. Despite the risk of persistent ectopic pregnancy, some studies have shown salpingostomy to improve reproductive outcome in patients with contralateral tubal damage.

In 1997, Yao and Tulandi concluded from a literature review that laparoscopic salpingostomy had equal or slightly better reproductive performance than salpingectomy; however, slightly higher recurrent ectopic pregnancy rates were noted in the salpingostomy group.8

Dubuisson et al, reporting on 10 years of surgical experience in Paris, concluded that, for selected patients who desired future fertility, using salpingectomy, which is simpler and avoids the risk of persistent ectopic pregnancy, is possible and can result in a comparable fertility rate to tubal conservation surgery.9 Future fertility rates were no different with either surgical approach when the contralateral tube was either normal or scarred but patent. In 1996, Clausen reported on a review of the past 40 years and concluded that only a small number of investigators have suggested indirectly that conservative tubal surgery increases the rate of subsequent intrauterine pregnancy, and the more recent studies may reflect an improvement in surgical technique. Maymon et al, after reviewing 20 years of ectopic pregnancy treatment, concluded that conservative tubal surgery provided no greater risk of recurrent ectopic pregnancy than the more radical salpingectomy.10

Parker and Bistis concluded that when the contralateral fallopian tube is normal, the subsequent fertility rate is independent of the type of surgery.11 A prospective study of 88 patients by Ory et al indicated that the surgical method had no effect on subsequent fertility in women with an intact contralateral tube.12 Prior history of infertility was the most significant factor affecting postsurgical fertility. Several other studies have reported that the status of the contralateral tube, the presence of adhesions, and the presence of other risk factors such as endometriosis have a more significant impact on future fertility than choice of surgical procedure. According to Rulin, salpingectomy should be the treatment of choice in women with intact contralateral tubes because conservative treatment provides no additional benefit and incurs the additional costs and morbidity associated with persistent ectopic pregnancy and recurrent ectopic pregnancy in the already damaged tube.13

Future fertility rates are similar in patients who were treated surgically by laparoscopy or laparotomy. Salpingectomy by laparotomy carries a subsequent intrauterine pregnancy rate of 25-70%, compared to laparoscopic salpingectomy with rates of 50-60%. Very similar rates exist for laparoscopic salpingostomy versus laparotomy. The rate of persistent ectopic pregnancy between the two groups is similar, ranging from 5-20%. A slightly higher recurrent ectopic pregnancy rate exists in patients treated by laparotomy (7-28%), regardless of conservative or radical approach, when compared to laparoscopy (6-16%). This surprising finding is believed to be secondary to increased adhesion formation in the group treated by laparotomy. Comparison of medical and surgical treatment of small intact extrauterine pregnancies also revealed similar success and subsequent spontaneous pregnancy rates in a prospective randomized trial.14

The modern pelvic surgeon has been led to believe that the treatment of choice for unruptured ectopic pregnancy is salpingostomy, sparing the affected fallopian tube and thereby improving future reproductive outcome. However, if the treating surgeon has neither the laparoscopic skill nor the instrumentation necessary to atraumatically remove the trophoblastic tissue via linear salpingostomy, then salpingectomy by laparoscopy or laparotomy is not the wrong choice for operation. Leaving a scarred charred fallopian tube behind after removing the ectopic pregnancy but requiring extensive cautery to control bleeding does not preserve reproductive outcome.

The success rates after methotrexate are comparable with laparoscopic salpingostomy, assuming the selection criteria mentioned above are observed. The average success rates using the multiple-dosage regimen are in the range of 91-95%, demonstrated by multiple investigators. One study of 77 patients desiring subsequent pregnancy showed intrauterine pregnancies in 64%, and recurrent ectopic pregnancy occurred in 11%. Other studies have demonstrated similar results, with intrauterine pregnancy rates ranging from 20-80%.

The average success rates for the single-dosage regimen are reported to be from 88-94%. In a study by Stovall and Ling, 113 patients (94%) were treated successfully, 4 (3.3%) of whom needed a second dose.15 No adverse effects were encountered. Furthermore, 87.2% of these patients achieved a subsequent intrauterine pregnancy, whereas 12.8% experienced a subsequent ectopic pregnancy. Other studies have reported similar results with some mild adverse effects and lower reproductive outcomes. A recent meta-analysis including data from 26 trials demonstrated the success with the single-dose regimen to be 88.1%, while the success with the multiple dose regimen was 92.7%.16 A small randomized clinical trial also demonstrated the single-dose regimen to have a slightly higher failure rate.17 A hybrid protocol, involving 2 equal doses of methotrexate (50 mg/m2) given on days 1 and 4 without the use of leucovorin has been shown to be an effective and convenient alternative totheexistingregimens.18

Future and Controversies

As the ability to diagnose ectopic pregnancy improves, physicians will be able to intervene sooner, preventing life-threatening sequelae and extensive tubal damage, which could preserve future fertility. Already, with improving technology, physicians are treating ectopic pregnancies with minimally invasive surgery or no surgery at all. Physicians have been able to reduce the mortality rate secondary to ectopic pregnancy despite its growing incidence. Also, effective vaccination against Chlamydia trachomatis is under investigation. Once clinically available, it should have a dramatic impact on the frequency of ectopic pregnancy, as well as on the overall health of the female reproductive system.

 

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