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The word "ectopic" means "out of place." An ectopic pregnancy is a pregnancy that is not growing in the usual location (the uterine cavity). Ectopic pregnancies can occur in a number of abnormal locations, each with different characteristic growth patterns and treatment options.
The word "ectopic" means "out of place." An ectopic pregnancy is a pregnancy that is not growing in the usual location (the uterine cavity). Ectopic pregnancies can occur in a number of abnormal locations, each with different characteristic growth patterns and treatment options. The most common sites for an ectopic pregnancy are the
Ectopic pregnancies are dangerous. Any growing pregnancy requires a large nutrient source (blood supply) and develops many communications with the mother's (pregnant woman's) vascular system (blood vessels). The uterus is uniquely designed to accommodate this development, so that when a pregnancy begins to grow in other surrounding structures the vascular communication may be inadequate.
Furthermore, as the pregnancy grows in size the uterus dramatically changes shape and size. Surrounding structures are usually not able to change as readily so they are often damaged or "ruptured" by a contained growing ectopic pregnancy. When the ectopic pregnancy outgrows the limits of the space enclosing it, there can be life threatening bleeding.
Ectopic pregnancies were initially described in the 11th century and for a long time were universally fatal events for the mother. Initial treatments (in the old days) were desperate primitive attempts designed to destroy the growing pregnancy without sacrificing the mother's life. These included
Surgery attempted in the 1800s resulted in a high maternal mortality rate (greater than 80% of women died from the surgery alone) so it was rarely performed.
Since these times, several developments in the management of ectopic pregnancies have led to remarkable success in "saving the mother's life." Further developments recently have resulted in a shift in focus (concern) from saving the mother's life to additionally "saving the woman's fertility." The decrease in maternal morbidity (death) from ectopic pregnancy has been largely due to development and refinement of
At this point in time, gynecologists appropriately attempt to diagnose ectopic pregnancy early (since greater treatment options are available) and treat the ectopic pregnancy in such a way as to maximize fertility and minimize the risk for a future ectopic.
Ectopic Pregnancy: Incidence Rates & Rick Factors
In the USA, ectopic pregnancies are reported. This allows some tabulation of incidence rates and outcomers.
The Centers for Disease Control (CDC) examined ectopic pregnancies occurring during the 17 year period between 1970 and 1987 and noted that the
During this same time period, the
Despite the sharp improvement in the fatality rate by the end of this period of time, ectopics were still the second leading cause of maternal mortality in the USA (accounting for 12% of all maternal deaths in 1987).
The reason for the increase in ectopic pregnancy during this time period is not entirely clear. Of the known risk factors, it is believed that an increased number of cases of sexually transmitted disease (which damage fallopian tube transport of embryos into the uterus) is responsible for a significant portion of the increased number of cases of ectopic pregnancy.
Risk factors for ectopic pregnancy that should be recognized include:
Ectopic Pregnancy: Diagnosis
Early diagnosis of an ectopic pregnancy is critically important in terms of outcome. When an ectopic pregnancy is detected early in development, especially prior to rupture or damage to surrounding tissue, major morbidity is decreased and the treatment options are enhanced.
There is no uniformly accepted diagnostic protocol for the determination of an ectopic pregnancy. Different gynecologists seem to have protocols that "work for them." These are often modifications of the published flow diagrams found in the major text books. Some of the common themes are discussed here.
A universal characteristic of a good "early diagnosis" protocol is a "high index of suspicion." Even in the absence of known risk factors, ectopic pregnancy may occur as often as 1-2% of pregnancies. If there are multiple risk factors, the risk may be 25% of pregnancies.
Sensitive blood hCG assays allow very early diagnosis of pregnancy. Typically these assays have a sensitivity of 1-5 mIU/mL so they can detect the occurrence of pregnancy (not location) about 7-8 days after fertilization (a few days prior to a missed menstrual flow). If the hCG assay is negative (generally less than 5 mIU/mL) then complications from an ectopic pregnancy are generally thought to be ruled out. Exceptions may occur in unusual circumstances, such as when one of my patients was treated for an ectopic pregnancy with medication (methotrexate) and she ruptured a blood vessel from the ectopic pregnancy site after her hCG dropped from a few thousand mIU/mL to negative (less than 5 mIU/mL). Caution should always prevail.
Other blood concentrations of pregnancy related polypeptides or steroid hormones have been used for the early detection of ectopic pregnancy. Included are progesterone, early pregnancy factor (EPF), pregnancy specific beta-1 glycoprotein (SP1), and placental protein 5 (PP 5). These other factors have not been adequately characterized to allow widespread routine use in ectopic pregnancy detection.
The second most common hormone (hCG is the most common) followed in pregnancy is progesterone. Unfortunately, there is a wide overlap between circulating progesterone concentrations in normal intrauterine pregnancy and ectopic pregnancy. Generally, a progesterone concentration of greater than 25 ng/mL is highly correlated (greater than 95%) with a normal intrauterine pregnancy while a concentration of less than 5 ng/mL is highly correlated (almost 100%) with an abnormal and nonviable pregnancy. Concentrations between 10 and 20 ng/mL (the most common concentrations) are of little differential value. Of concern for those who use 5 ng/mL as an indicator of fetal nonviability are the reports of several women with documented very low progesterone concentrations (typically thought to be inconsistent with a viable intrauterine pregnancy) who have gone on to deliver babies at term. These reports force one to reconsider the value of the progesterone concentrations, and include:
Serial circulating hCG concentrations are often used to gain insight into the normalcy of an existing pregnancy. A period of intense research characterized the rate of rise of hCG in normal pregnancy as at least 66% and more often 100% in a 2 day period during the first 6 weeks of pregnancy. If there is a rate of rise of less than 66% in hCG over a 2 day period of time (in early pregnancy) then this suggests an abnormally growing intrauterine pregnancy or an ectopic pregnancy. Again, there are several reports of women (up to 10%) who have abnormal rates of rise in hCG and who go on to deliver babies at term.
It would be ideal to have an "ectopic pregnancy hormone" to check whenever the concern for an ectopic arose. There is active research is this field, but thus far there are no clinically useful direct tests for ectopic pregnancy. If such a test becomes available, this would revolutionize the diagnosis of these potentially fatal complications of pregnancy.
If the concern for an ectopic pregnancy is raised by either the woman's history of risk factors, pelvic or adnexal pain in early pregnancy, or an abnormal doubling of the hCG titers then additional diagnostic intervention is appropriate.
Transvaginal ultrasonography is a sensitive radiologic test and should be able to detect an intrauterine gestational sac at an hCG concentration of about 1500 mIU/mL (using the 1st International Reference Preparation) which normally occurs at about 5 weeks "estimated gestational age" (EGA). The absence of a gestational sac with an hCG concentration of greater than 1500 mIU/mL suggests either an abnormally developing intrauterine pregnancy or an ectopic pregnancy. Exceptions do occur. Multiple gestations have two placentae each producing its own hCG so the concentration of 1500 mIU/mL will occur several days prior to a singleton gestation at the same EGA. Also, pregnancies with large placentae may produce hCG concentrations that are greater than expected for their EGA.
In the absence of pain, evidence of hemoperitoneum (rupture) or cardiovascular instability a conservative approach is most appropriate if the status and location of the pregnancy is unclear and the pregnancy is desired by the couple. When it becomes clear that there is an abnormal or ectopic pregnancy or if the woman becomes less stable then active treatment must be quickly reevaluated and selected.
If the woman is stable hemodynamically and an abnormal or ectopic pregnancy is diagnosed then one can consider a dilatation and curettage (D+C) to evacuate the uterine cavity in hope of finding or eliminating the abnormal pregnancy. If a D+C is performed and products of conception (placental villi) are identified or the hCG titers start to fall, then an incomplete or missed abortion is diagnosed. If no villi are identified, then an ectopic pregnancy is very likely (occasionally one will not be able to disrupt an early small intrauterine pregnancy even with a thorough D+C). One can consider checking an hCG concentration to confirm that the level is not decreasing after the D+C and then consider active management of the likely ectopic pregnancy.
Ectopic Pregnancy: Treatment Options
Once the decision has been made to treat a pregnancy as an ectopic (or a nonviable intrauterine pregnancy) the physician will attempt to eliminate the potentially dangerous pregnancy to minimize maternal risk. The physician will also try to preserve as much future fertility as possible.
Three primary types of treatment are available for an ectopic pregnancy. These include surgical management, medical management, and expectant management. The most common treatment is surgical.
Surgery allows a rapid and usually definite resolution of the pregnancy, however the woman does assume the usual surgical risks. Medical management primarily involves the use of methotrexate, which has gained popularity as a way of avoiding surgical risk. Methotrexate management results in destruction of the growing pregnancy but is comparatively slow-- often taking 4-6 weeks for complete resolution of the ectopic pregnancy. Medical management risks rupture of the ectopic over this relatively long course of management. Expectant management is essentially observation and monitoring without active treatment, understanding that up to 25% of ectopic pregnancies will resolve on their own. The risk of expectant management is rupture of the ectopic pregnancy during the observation period.
(1) Surgery is the most common management of an ectopic pregnancy.
Treatment for all ruptured ectopic pregnancies is surgery.
If the woman has a ruptured ectopic pregnancy and she is hemodynamically unstable then surgery is required and laparoscopy is contraindicated. In this situation, a laparotomy (larger incision with open surgery) should be performed and usually a (partial) salpingectomy (removal of the tube) is performed regardless of whether significant damage to the tubal lumen is suspected. The removal of the damaged tube allows rapid control of bleeding and the best chance for continued hemostasis throughout the postoperative period.
If the woman has a ruptured ectopic pregnancy and is hemodynamically stable, then surgery is required and laparoscopy is not absolutely contraindicated. The decision on whether a laparoscopy or laparotomy is to be performed depends on the specific clinical details, the couple's desires, the surgeon's laparoscopic expertise, and the operating room's equipment. The advantage of laparoscopy is in terms of postoperative recovery for the woman having surgery. The same type of surgery would be done regardless of the size of the incisions made to perform the surgery.
If the woman has a non ruptured ectopic pregnancy, then the treatment options are broadened to include nonsurgical management. If surgery is decided upon, then the decision must be made in terms of laparoscopy or laparotomy. This decision depends primarily on the surgeon's expertise with laparoscopy and the operating room's laparoscopic equipment. Generally, women prefer the shorter recovery period, reduction in postoperative pain, and smaller incisions in the abdomen associated with laparoscopy.
It should be emphasized that either approach (laparoscopy or laparotomy) is (medically) acceptable and capable of achieving the goals of decreasing morbidity and increasing future fertility. If the surgeon identifies an ectopic by laparoscopy yet is not comfortable in performing the necessary surgery on the ectopic pregnancy site through the laparoscope (and cannot call for an intraoperative consult with someone able to do the surgery via laparoscopy), then the appropriate decision is to perform the surgery by laparotomy. Occasionally one hears about a patient taken for diagnostic laparoscopy to evaluate an ectopic pregnancy, an ectopic pregnancy is identified, the surgeon is not comfortable with removing the ectopic pregnancy via laparoscopy, the surgeon desires that the woman's pregnancy be treated laparoscopically, and so the case is concluded so that the patient can be transferred postop to a surgeon who will remove the ectopic pregnancy laparoscopically. This should be discouraged since there is a chance for significant morbidity if the ectopic ruptures and the woman requires a second surgery. The surgeon in this situation would hopefully have counseled the patient preoperatively that if an ectopic is identified then the decision will be to proceed to definitive management by laparotomy.
Surgical treatment options for removal of an ectopic pregnancy partially depend on the location of the ectopic pregnancy.
Surgical treatment options for the removal of an ectopic pregnancy also partially depend on the prior history of tubal disease, infertility, ectopic pregnancy and the couple's desires. Although a bit controversial (due to the lack of strong factual data), consideration should include:
(2) Methotrexate has become popular in selected cases of ectopic pregnancy.
Unruptured tubal ectopic pregnancies in women who elect conservative (saving the tube) management may be able to be treated with methotrexate. The current (somewhat limited) factual data suggests that methotrexate management and conservative surgical management have similar success in terms of subsequent tubal patency, fertility, ectopic pregnancy and intrauterine pregnancy. One classic article on these rates when using the single IM dosing protocol is a prospective clinical trial of 120 women (published in 1993) where Drs. Stovall and Ling report
The first experience with methotrexate was in Japan (Dr. Tanaka) in 1982 and the first use of methotrexate in the USA (with Dr. Steven Ory) was in 1986. Ectopic pregnancy is not an approved FDA indication for methotrexate. FDA approved uses of methotrexate include cancer treatment (including trophoblast disease, breast cancers and leukemia), psoriasis, and rheumatoid arthritis.
Methotrexate is a mixture containing at least 85% of "4-amino-10-methylfolic acid," is a folic acid antagonist (reversibly inhibiting dihydrofolate reductase which normally reduces folic acid to tetrahydrofolic acid), and consequently interferes with DNA synthesis and cell reproduction. Leucovorum calcium is a derivative of tetrahydrofolic acid which replaces the missing active form of folic acid to block the effects of methotrexate (the so called "rescue").
Methotrexate crosses the placenta and is found in breast milk. The medication is absolutely contraindicated in pregnant women intending to carry the pregnancy to term. Therefore, many treatment protocols require pregnant women with either an abnormally growing intrauterine pregnancy or an ectopic pregnancy to have a pretreatment dilatation and curettage (D+C). Others simply include in the consent form for methotrexate that it is agreed to undergo definitive surgical management of the pregnancy if the methotrexate fails to resolve it.
Peak serum concentrations of methotrexate occur 2 hours after an IM dose, and have a serum half life of about 2-4 hours. Methotrexate does not seem to be appreciably metabolized with up to about 90% of an IV dose excreted via the kidneys within 24 hours.
The single IM injection of 50 mg per meters squared (body surface area) for the treatment of ectopic pregnancy is associated with (uncommon) transient side effects but persistent complications are virtually absent. Major complications of methotrexate at doses used for the FDA indications include
Contraindications to the use of methotrexate generally include
Drug interactions with methotrexate can occur and may enhance toxicity. This usually occurs with high doses of methotrexate but should be avoided whenever able. The drugs known to interact with methotrexate include:
The initial protocols utilized a multiple dose regimen with methotrexate (typically 1 mg/kg IM) and leukovorum (citrovorum, 0.1 mg/kg IM) on alternate days for up to 4 doses of methotrexate. Side effects were seen in about 5% of women and typically included gastrointestinal upset (stomatitis [oral ulcers], gastritis, diarrhea, transient elevation in liver enzymes). Significant side effects involving bone marrow suppression, dermatitis and pleuritis have been very uncommon. Failure to adequately treat the ectopic pregnancy has been about 3-5%. Tubal rupture of the ectopic pregnancy occurs in less than 5%.
Currently the most popular protocol uses far less methotrexate and does not require citrovorum as a rescue. A single IM dose of methotrexate (50 mg per meters squared [surface area]) is administered with few side effects (occasional stomatitis, gastritis and diarrhea) and virtually no serious side effects (bone marrow suppression, dermatitis, pleuritis).
Additional criteria in selecting appropriate candidates for methotrexate management of an ectopic pregnancy might include
Once a candidate has been selected, the following protocol should be adhered to
Then the medication should be given as 50 mg per meters squared (surface area) IM (divided dosed if desired)-- this will be considered DAY 1.
On DAY 4, an hCG titer should be obtained (the hCG concentration will continue to increase for a few days following methotrexate administration)
On DAY 7, an hCG titer should be obtained
If the DAY 7 hCG concentration reflects a drop from the maximal hCG concentration (at DAY 4) of at least 15% then weekly hCG titers should be obtained until negative. If the DAY 7 hCG concentration did not drop from the maximal hCG concentration (at DAY 4) by 15% or if the hCG titer begins to rise on subsequent weeks then consideration of another dose of 50 mg per meters squared is considered.
DAY 7 blood work does not need to include a CBC and chemistry profile, but many physicians (including myself) like to confirm that the RBCs, WBCs, platelets and liver function tests have not changed. Using this dose of methotrexate, I have never seen a significant change in any of these parameters.
Important Note #1: Many women will have adnexal discomfort or pain about 3 or 4 days following administration of methotrexate. Several physicians refer to this as "methotrexate pain" but rupture of the existing ectopic pregnancy must be considered and ruled out.
Important Note #2:Non tubal ectopic pregnancies are often managed with methotrexate. Cervical, abdominal and cornual pregnancies are very dangerous and require careful consideration of existing treatment options. Severe bleeding can be associated with methotrexate or surgical treatments and very close observation until the pregnancy is resolved is absolutely necessary.
(3) Expectant management of an ectopic pregnancy is generally discouraged.
Expectant management of ectopic pregnancy may be appropriate in selected situations. The risk of rupture for an ampullary ectopic pregnancy is thought to be roughly 10% for circulating hCG concentrations less than 1000 mIU/mL. The risk of rupture for an isthmic ectopic pregnancy is thought to be about 10% for a circulating hCG concentration less than 100 mIU/mL (since the space in which isthmic pregnancies must grow is far smaller than for ampullary pregnancies). Therefore, consideration of expectant management for an ectopic pregnancy when hCG concentrations are low is possible. There is always a risk of rupture until the pregnancy has been completely resolved.
Criteria that are occasionally used in deciding on expectant management include
I have generally discouraged the use of expectant management of ectopic pregnancy unless the hCG titer is spontaneously declining since the risk of serious morbidity with rupture appears to be increased (even if only slightly).
Dr. Daiter's Background
Dr. Eric Daiter graduated from the University of Pennsylvania, where he was awarded an academic scholarship and was enlisted into the University Scholar's Program and the Benjamin Franklin Scholar's Program.
Dr. Daiter graduated medical school at Temple University Medical School in Philadelphia and completed the Obstetrics and Gynecology residency program at Albert Einstein College of Medicine in New York. He completed his Reproductive Endocrinology and Infertility fellowship at the Hospital of the University of Pennsylvania. He has considered a career as a physician scientist in research medicine and has published several articles on molecular events that occur during the human embryo's implantation into the uterus.
Dr. Daiter entered private practice in 1994, where he joined a successful referral based infertility practice and further developed his clinical skills. Dr. Daiter emphasizes the basic principles of infertility patient care, including the importance of highly personalized, cost considerate, state of the art, one on one care for his patients. He specializes in all aspects of In Vitro Fertilization, with a patient success rate among the highest in the state. He has performed several hundred advanced operative laparoscopic and hysteroscopic surgeries, utilizing the most modern laser techniques.
Dr. Daiter opened his Edison, NJ office in 1997. The office continues to support the highest level of professional care for infertile couples. Extended office hours are available for patient convenience.