Ectopic Pregnancy Treatment & Management
- Author: Vicken P Sepilian, MD, MSc; Chief Editor: Michel E Rivlin, MD more...
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%.[8]
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.[9]
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.[10] 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.
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 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 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 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.[11]
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.[12] 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.[13]
Parker and Bistis concluded that when the contralateral fallopian tube is normal, the subsequent fertility rate is independent of the type of surgery.[14] 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.[15] 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.[16]
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.[17]
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.[18] 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%.[19] A small randomized clinical trial also demonstrated the single-dose regimen to have a slightly higher failure rate.[20] 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.[21]
Patient education
For excellent patient education resources, visit eMedicine's Pregnancy and Reproduction Center. Also, see eMedicine's patient education articles Ectopic Pregnancy; Pregnancy, Bleeding; Vaginal Bleeding, Birth Control Overview; and Birth Control FAQs.
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.
Ectopic pregnancy mortality - Florida, 2009-2010. MMWR Morb Mortal Wkly Rep. Feb 17 2012;61:106-9. [Medline].
Mol F, van den Boogaard E, van Mello NM, et al. Guideline adherence in ectopic pregnancy management. Hum Reprod. Feb 2011;26(2):307-15. [Medline].
Kadar N, Bohrer M, Kemmann E, Shelden R. The discriminatory human chorionic gonadotropin zone for endovaginal sonography: a prospective, randomized study. Fertil Steril. Jun 1994;61(6):1016-20. [Medline].
Shepherd RW, Patton PE, Novy MJ. Serial beta-hCG measurements in the early detection of ectopic pregnancy. Obstet Gynecol. Mar 1990;75(3 Pt 1):417-20. [Medline].
Barnhart KT, Sammel MD, Rinaudo PF, Zhou L, Hummel AC, Guo W. Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined. Obstet Gynecol. Jul 2004;104(1):50-5. [Medline].
Stein JC, Wang R, Adler N, Boscardin J, Jacoby VL, Won G, et al. Emergency physician ultrasonography for evaluating patients at risk for ectopic pregnancy: a meta-analysis. Ann Emerg Med. Dec 2010;56(6):674-83. [Medline].
Barnhart K, Mennuti MT, Benjamin I. Prompt diagnosis of ectopic pregnancy in an emergency department setting. Obstet Gynecol. Dec 1994;84(6):1010-5. [Medline].
Hoover KW, Tao G, Kent CK. Trends in the diagnosis and treatment of ectopic pregnancy in the United States. Obstet Gynecol. Mar 2010;115(3):495-502. [Medline].
Menon S, Colins J, Barnhart KT. Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review. Fertil Steril. Mar 2007;87(3):481-4. [Medline].
[Best Evidence] Thurman AR, Cornelius M, Korte JE, Fylstra DL. An alternative monitoring protocol for single-dose methotrexate therapy in ectopic pregnancy. Am J Obstet Gynecol. Feb 2010;202(2):139.e1-6. [Medline].
Yao M, Tulandi T. Current status of surgical and nonsurgical management of ectopic pregnancy. Fertil Steril. Mar 1997;67(3):421-33. [Medline].
Dubuisson JB, Morice P, Chapron C, et al. Salpingectomy - the laparoscopic surgical choice for ectopic pregnancy. Hum Reprod. Jun 1996;11(6):1199-203. [Medline].
Maymon R, Shulman A, Halperin R, et al. Ectopic pregnancy and laparoscopy: review of 1197 patients treated by salpingectomy or salpingotomy. Eur J Obstet Gynecol Reprod Biol. Sep 1995;62(1):61-7. [Medline].
Parker J, Bisits A. Laparoscopic surgical treatment of ectopic pregnancy: salpingectomy or salpingostomy?. Aust N Z J Obstet Gynaecol. Feb 1997;37(1):115-7. [Medline].
Ory SJ, Nnadi E, Herrmann R. Fertility after ectopic pregnancy. Fertil Steril. Aug 1993;60(2):231-5. [Medline].
Rulin MC. Is salpingostomy the surgical treatment of choice for unruptured tubal pregnancy?. Obstet Gynecol. Dec 1995;86(6):1010-3. [Medline].
Moeller LB, Moeller C, Thomsen SG, Andersen LF, Lundvall L, Lidegaard O. Success and spontaneous pregnancy rates following systemic methotrexate versus laparoscopic surgery for tubal pregnancies: A randomized trial. Acta Obstet Gynecol Scand. Sep 11 2009;1-7. [Medline].
Stovall TG, Ling FW, Carson SA, Buster JE. Serum progesterone and uterine curettage in differential diagnosis of ectopic pregnancy. Fertil Steril. Feb 1992;57(2):456-7. [Medline].
[Best Evidence] Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing "single and multidose" regimens. Obstetrics and Gynecology. 2003;101:778-84.
Alleyassin A, Khademi A, Aghahosseini M, Safdarian L, Badenoosh B, Hamed EA. Comparison of success rates in the medical management of ectopic pregnancy with single-dose and multiple-dose administration of methotrexate: a prospective, randomized clinical trial. Fertil Steril. Jun 2006;85(6):1661-6. [Medline].
Barnhart KT, Sammel MD, Hummel A, Jain J, Chakhtoura N, Strauss J. A novel "two dose" regimen of methotrexate to treat ectopic pregnancy. Fertil Steril. 2005;84(Suppl):S130.
Ankum WM, Mol BW, Van der Veen F, Bossuyt PM. Risk factors for ectopic pregnancy: a meta-analysis. Fertil Steril. Jun 1996;65(6):1093-9. [Medline].
Bengtsson G, Bryman I, Thorburn J, Lindblom B. Low-dose oral methotrexate as second-line therapy for persistent trophoblast after conservative treatment of ectopic pregnancy. Obstet Gynecol. Apr 1992;79(4):589-91. [Medline].
Breen JL. A 21 year survey of 654 ectopic pregnancies. Am J Obstet Gynecol. Apr 1 1970;106(7):1004-19. [Medline].
Bruhat MA, Manhes H, Mage G, Pouly JL. Treatment of ectopic pregnancy by means of laparoscopy. Fertil Steril. Apr 1980;33(4):411-4. [Medline].
Centers for Disease Control and Prevention. Ectopic pregnancy--United States, 1990-1992. JAMA. Feb 15 1995;273(7):533. [Medline].
Chi IC, Potts M, Wilkens L. Rare events associated with tubal sterilizations: an international experience. Obstet Gynecol Surv. Jan 1986;41(1):7-19. [Medline].
Chow WH, Daling JR, Cates W Jr, Greenberg RS. Epidemiology of ectopic pregnancy. Epidemiol Rev. 1987;9:70-94. [Medline].
Clausen I. Conservative versus radical surgery for tubal pregnancy. A review. Acta Obstet Gynecol Scand. Jan 1996;75(1):8-12. [Medline].
DeStefano F, Peterson HB, Layde PM, Rubin GL. Risk of ectopic pregnancy following tubal sterilization. Obstet Gynecol. Sep 1982;60(3):326-30. [Medline].
Diquelou JY, Pia P, Tesquier L, et al. [The role of Chlamydia trachomatis in the infectious etiology of extra- uterine pregnancy]. J Gynecol Obstet Biol Reprod (Paris). 1988;17(3):325-32. [Medline].
Dor J, Seidman DS, Levran D, et al. The incidence of combined intrauterine and extrauterine pregnancy after in vitro fertilization and embryo transfer. Fertil Steril. Apr 1991;55(4):833-4. [Medline].
Doubilet PM, Benson CB, Frates MC. Sonographically guided minimally invasive treatment of unusual ectopic pregnancies. J Ultrasound Med. Mar 2004;23(3):359-70. [Medline].
Emerson DS, Cartier MS, Altieri LA, et al. Diagnostic efficacy of endovaginal color Doppler flow imaging in an ectopic pregnancy screening program. Radiology. May 1992;183(2):413-20. [Medline].
Fernandez H, Coste J, Job-Spira N. Controlled ovarian hyperstimulation as a risk factor for ectopic pregnancy. Obstet Gynecol. Oct 1991;78(4):656-9. [Medline].
Fylstra DL. Tubal pregnancy: a review of current diagnosis and treatment. Obstet Gynecol Surv. May 1998;53(5):320-8. [Medline].
Goldner TE, Lawson HW, Xia Z, Atrash HK. Surveillance for ectopic pregnancy--United States, 1970-1989. MMWR CDC Surveill Summ. Dec 17 1993;42(6):73-85. [Medline].
Gracia CR, Brown HA, Barnhart KT. Prophylactic methotrexate after linear salpingostomy: a decision analysis. Fertil Steril. Dec 2001;76(6):1191-5. [Medline].
Graczykowski JW, Mishell DR Jr. Methotrexate prophylaxis for persistent ectopic pregnancy after conservative treatment by salpingostomy. Obstet Gynecol. Jan 1997;89(1):118-22. [Medline].
Langer R, Raziel A, Ron-El R, et al. Reproductive outcome after conservative surgery for unruptured tubal pregnancy--a 15-year experience. Fertil Steril. Feb 1990;53(2):227-31. [Medline].
Levin AA, Schoenbaum SC, Stubblefield PG, et al. Ectopic pregnancy and prior induced abortion. Am J Public Health. Mar 1982;72(3):253-6. [Medline].
Lipscomb GH, Bran D, McCord ML, et al. Analysis of three hundred fifteen ectopic pregnancies treated with single-dose methotrexate. Am J Obstet Gynecol. Jun 1998;178(6):1354-8. [Medline].
Lipscomb GH, Givens VM, Meyer NL, Bran D. Comparison of multidose and single-dose methotrexate protocols for the treatment of ectopic pregnancy. American Journal of Obstetrics & Gynecology. 2005;192(6):1844-7. [Medline].
Lundorff P, Hahlin M, Sjoblom P, Lindblom B. Persistent trophoblast after conservative treatment of tubal pregnancy: prediction and detection. Obstet Gynecol. Jan 1991;77(1):129-33. [Medline].
Lundorff P, Thorburn J, Lindblom B. Fertility outcome after conservative surgical treatment of ectopic pregnancy evaluated in a randomized trial. Fertil Steril. May 1992;57(5):998-1002. [Medline].
Majmudar B, Henderson PH 3d, Semple E. Salpingitis isthmica nodosa: a high-risk factor for tubal pregnancy. Obstet Gynecol. Jul 1983;62(1):73-8. [Medline].
Marchbanks PA, Annegers JF, Coulam CB, et al. Risk factors for ectopic pregnancy. A population-based study. JAMA. Mar 25 1988;259(12):1823-7. [Medline].
McCausland A. High rate of ectopic pregnancy following laparoscopic tubal coagulation failures. Incidence and etiology. Am J Obstet Gynecol. Jan 1 1980;136(1):97-101. [Medline].
Nieuwkerk PT, Hajenius PJ, Van der Veen F, et al. Systemic methotrexate therapy versus laparoscopic salpingostomy in tubal pregnancy. Part II. Patient preferences for systemic methotrexate. Fertil Steril. Sep 1998;70(3):518-22. [Medline].
Perkins JD, Mitchell MR. Heterotopic pregnancy in a large inner-city hospital: a report of two cases. J Natl Med Assoc. Mar 2004;96(3):363-6. [Medline].
Pouly JL, Chapron C, Manhes H, et al. Multifactorial analysis of fertility after conservative laparoscopic treatment of ectopic pregnancy in a series of 223 patients. Fertil Steril. Sep 1991;56(3):453-60. [Medline].
Pulkkinen MO, Talo A. Tubal physiologic consideration in ectopic pregnancy. Clin Obstet Gynecol. Mar 1987;DA - 19870626(1):164-72. [Medline].
Ransom MX, Garcia AJ, Bohrer M, et al. Serum progesterone as a predictor of methotrexate success in the treatment of ectopic pregnancy. Obstet Gynecol. Jun 1994;83(6):1033-7. [Medline].
Robertson JN, Hogston P, Ward ME. Gonococcal and chlamydial antibodies in ectopic and intrauterine pregnancy. Br J Obstet Gynaecol. Jul 1988;95(7):711-6. [Medline].
Saraiya M, Berg CJ, Kendrick JS. Cigarette smoking as a risk factor for ectopic pregnancy. Am J Obstet Gynecol. Mar 1998;178(3):493-8. [Medline].
Savare J. Heterotopic pregnancies after in-vitro fertilization and embryo transfer - A Danish survey. Human Reproduction. 1993;8:116. [Medline].
Shalev E, Peleg D, Tsabari A, et al. Spontaneous resolution of ectopic tubal pregnancy: natural history. Fertil Steril. Jan 1995;63(1):15-9. [Medline].
Sivin I. Dose- and age-dependent ectopic pregnancy risks with intrauterine contraception. Obstet Gynecol. Aug 1991;78(2):291-8. [Medline].
Stock RJ. Persistent tubal pregnancy. Obstet Gynecol. Feb 1991;77(2):267-70. [Medline].
Stovall TG, Ling FW. Single-dose methotrexate: an expanded clinical trial. Am J Obstet Gynecol. Jun 1993;168(6 Pt 1):1759-62; discussion 1762-5. [Medline].
Stovall TG, Ling FW, Buster JE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril. Mar 1989;51(3):435-8. [Medline].
Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of ectopic pregnancy. Obstet Gynecol. May 1991;77(5):754-7. [Medline].
Trio D, Strobelt N, Picciolo C, et al. Prognostic factors for successful expectant management of ectopic pregnancy. Fertil Steril. Mar 1995;63(3):469-72. [Medline].
Tuomivaara L, Kauppila A. Radical or conservative surgery for ectopic pregnancy? A follow-up study of fertility of 323 patients. Fertil Steril. Oct 1988;50(4):580-3. [Medline].
US Department of Health and Human Services, Public Health Services. National Center for Health Statistics: Advanced report of final mortality statistics, 1992. Washington, DC. 1994.
Van Den Eeden SK, Shan J, Bruce C, Glasser M. Ectopic pregnancy rate and treatment utilization in a large managed care organization. Obstetrics & Gynecology. 2005;105:1052-7. [Medline].
Vermesh M, Silva PD, Rosen GF, et al. Management of unruptured ectopic gestation by linear salpingostomy: a prospective, randomized clinical trial of laparoscopy versus laparotomy. Obstet Gynecol. Mar 1989;73(3 Pt 1):400-4. [Medline].
Vermesh M, Silva PD, Sauer MV. Persistent tubal ectopic gestation: patterns of circulating beta-human chorionic gonadotropin and progesterone, and management options. Fertil Steril. Oct 1988;50(4):584-8. [Medline].
Westrom L, Bengtsson LP, Mardh PA. Incidence, trends, and risks of ectopic pregnancy in a population of women. Br Med J (Clin Res Ed). Jan 3 1981;282(6257):15-8. [Medline].
Ylostalo P, Cacciatore B, Sjoberg J, et al. Expectant management of ectopic pregnancy. Obstet Gynecol. Sep 1992;80(3 Pt 1):345-8. [Medline].
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