Ectopic pregnancy is gestation located outside the uterine cavity. The fertilized ovum implants outside of the uterus, usually in the fallopian tube. Predisposing factors include adhesions of the tube, salpingitis, congenital and development anomalies of the fallopian tube, previous ectopic pregnancy, use of an intrauterine device for more than 2 years, multiple induced abortions, menstrual reflux, and decreased tubal motility.
Assessment:
1. Abdominal or pelvic pain
2. Amenorrhea in 75% of cases.
3. Vaginal bleeding. usually scarity and dark
4. Uterine size is usually similar to what it would be in a normally implanted pregnancy.
5. Abdominal tenderness on palpation
6. Nausea, vomiting, or faintness may be present.
7. Pelvic examination shows a pelvic mass, posterior or lateral to the uterus, and cervical pain on movement of the cervix.
Treatment:
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%.
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.
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.[9] 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 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 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.
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