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

1. ampullary (mid) portion of the fallopian tube (80-90%),
2. isthmic (area closer to the uterus) portion of the fallopian tube (5-10%),
3. fimbrial (distal end away from the uterus) portion of the fallopian tube (about 5%),
4. cornual (within the uterine muscle) portion of the fallopian tube (1-2%),
5. abdomen (1-2%),
6. ovary (less than 1%), or
7. cervix (less than 1%).

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

• starvation (hoping that the fetus would starve before the mother),
• bleeding (intentional exsanguination of the mother in the hope that the fetus would die and the mother could be spared),
• administration of strychnine (to preferentially destroy the fetus), and
• administration of electricity into the growing gestational (pregnancy) sac.

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

1. early detection of pregnancy, primarily with the development of sensitive pregnancy tests (hCG assays) and characterization of the normal rate of rise in the circulating human chorionic gonadotropin (hCG) concentrations during early pregnancy
2. aseptic (sterile) technique, where surgeries are now performed in operating rooms with protocols for cleansing, scrubbing and gowning that inhibit transmission of infection
3. antibiotics to fight infections, with tremendous advances in infectious disease and antibiotic research during the past few decades
4. anesthetic agents, with new agents allowing increasingly safe administration and a greater understanding of intraoperative patient monitoring
5. availability of blood or blood products for perioperative transfusions, including advances in terms of blood collection, storage and determination of compatibility with the recipient
6. surgical techniques to identify and remove the ectopic pregnancy, such as salpingectomy and salpingostomy (when appropriate)

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.

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

• ectopic pregnancy rate increased almost 4 fold (from 4.5 per 1000 pregnancies to 16.8 per 1000 pregnancies).

During this same time period, the

• fatality rate from ectopic pregnancies dropped almost 90% (from 35.5 per 1000 ectopics to 3.8 per 1000 ectopics).

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:

1. a prior history of ectopic pregnancy. When an ectopic pregnancy in the fallopian tube is treated conservatively (by preserving the tube), there is a roughly 10 fold increase in ectopic pregnancy.
2. a history of surgery on the fallopian tubes or within the pelvis. When a bilateral tubal ligation (tubes tied) is followed by either an unexpected pregnancy (failed tubal ligation) or is "reversed" with a tubal reanastomosis (tubal reconstruction) there is an increased risk of a tubal ectopic pregnancy. When a woman has a history of pelvic surgery that is associated with significant adhesion formation (such as myomectomy) there is an increased risk of an ectopic pregnancy.
3. a history of pelvic infection. Salpingooophoritis, or Pelvic Inflammatory Disease (PID), is particularly destructive to the fallopian tubes. Chlamydia (a common sexually transmitted disease) and Gonorrhea are both able to grow within the fallopian tubes and cause tremendous damage to the endosalpinx (lining of the inner tubal lumen), agglutination (sticking together) of the mucosal folds in the tube, and peritubal adhesions (scar tissue). The increased risk of an ectopic pregnancy is greater with an increased number of pelvic infections. It also appears that the risk of an ectopic pregnancy is greater when the woman with the infection is younger (possibly related to avoiding or otherwise delaying appropriate medical care). Other pelvic or lower abdominal infections can also result in pelvic adhesions and an increase in the ectopic pregnancy rate (such as appendicitis).
4. use of assisted reproductive technology (such as IVF and GIFT). When multiple embryos or gametes are replaced into the uterus or the fallopian tubes, the risk for multiple pregnancy rises significantly. The risk of a heterotopic pregnancy (twins with one pregnancy in the uterus and one in the fallopian tube) is generally thought to be about 1 in 30,000 pregnancies in an unselected population. This incidence rate was determined in 1948 by using the rates of dizygotic twins and ectopic pregnancy at that time. At this time, the rates of both ectopics and dizygotic twins have increased and the rate of heterotopic pregnancy is more likely about 1 in 10,000 to 1 in 15,000 pregnancies. In women conceiving with one of the assisted reproductive technologies the incidence of heterotopic pregnancy may increase to as frequently as 1 in 100 pregnancies since multiple gestation is much more common and the hormone concentrations achieved may enhance tubal implantation.
5. a history of IUD use. The use of an IUD is a classic "risk factor" for ectopic pregnancy. Actually, all but the progesterone containing IUDs are relatively protective against ectopic pregnancy while the IUD is in place. That is, the number of ectopic pregnancies in women using an IUD for contraception is about one half that of women using no contraception. However, of IUD pregnancies there is a greater chance of an ectopic location (3-4%) since the number of intrauterine pregnancies with an IUD in place is markedly reduced. Additionally, IUDs can be associated with infections of the uterine cavity and fallopian tubes (especially just after insertion) which can independently increase the chance for an ectopic pregnancy. The Population Council's Center for Biomedical Research reviewed the association between IUDs and ectopic pregnancy and found that progestin only IUDs are the only nonprotective IUDs (in terms of ectopic pregnancy) when compared to women without contraception. The Progestasert IUD releases about 65 mcg of progesterone per day and large studies report a greater than 2 fold increase in ectopic pregnancy rates over women not using contraception. The reason for this increase is not clear. A theory is that somehow the progesterone enhances tubal implantation.
6. a history of destruction of the uterine cavity or lining. If the woman has a history of uterine synechiae (scar tissue) from previous surgery (say, endometrial ablation for dysfunctional bleeding in a woman with no fertility interest) or if implantation is limited due to the presence of multiple submucosal fibroid tumors then a larger percentage of the pregnancies that are achieved will occur in a space other than the uterine cavity. Similar to the situation with IUDs, the total ectopic pregnancy rate may not be increased but when a pregnancy does occur the reduced likelihood of an intrauterine pregnancy increases the relative percentage of ectopic pregnancies.
7. a history of DES exposure in utero. The mechanism for this association is not clear. There often are uterine cavity defects that may limit intrauterine implantation. Also, tubal defects exist that may increase the chance for a tubal ectopic pregnancy.
8. a history of non-infectious pelvic inflammation (endometriosis, foreign body). Inflammation of the delicate tubal structures can result in adhesion formation (scar tissue) which will then increase the risk of an ectopic pregnancy. This inflammation may be due to endometriosis or the presence of a foreign body, either of which are strongly associated with scar tissue formation.
9. Salpingitis Isthmica Nodosa These uncommon diverticulae in the proximal (isthmic) portion of the fallopian tube may enhance tubal implantation. The cause of SIN is not known but most think it is related to chronic inflammation or infection.

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:

• women with the congenital abnormality known as "abetalipoproteinemia" have cells that are unable to take up and use VLDL-cholesterol. VLDL-cholesterol is a primary source for cellular cholesterol. Since cholesterol is required for the synthesis of progesterone these women have very low circulating progesterone concentrations. There are reports of women with abetalipoproteinemia who have documented low progesterone concentrations throughout pregnancy and have carried their pregnancy to term
• fetuses with a rare deficiency in one of the enzymes required for progesterone production, such as "3-beta hydroxysteroid dehydrogenase" or the "cholesterol side chain cleavage complex," may be delivered at term despite the inability of these fetuses (and presumably also their placentas) to produce adequate progesterone. Prenatal diagnosis of these conditions has never been early enough to actually document low progesterone throughout pregnancy (at least from the time of placental takeover of progesterone production)
• an In Vitro Fertilization patient from a well known NYC program with a diagnosis of unexplained infertility discontinued her prescribed progesterone when she noted vaginal bleeding at 4-5 weeks gestation (and assumed that she was not pregnant). Bloodwork documented a progesterone concentration of less than 2.0 ng/mL at 5-6 weeks gestation, she did not return to progesterone supplementation and she delivered a normal fetus at term. It is generally accepted that a progesterone concentration of less than 7 ng/ml at the time of hCG rescue (the usual nadir in progesterone concentration which occurs at about 4 weeks gestation) is ominous and predicts spontaneous abortion.

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.

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.

1. the ampullary portion of the fallopian tube is the most common site for ectopic pregnancy (80-90%). In the tubal ampulla, the muscular area (muscularis) between the outer tubal serosa and inner tubal lumen is relatively thick. Often, ectopic pregnancies in the ampullary portion of the tube grow in the muscularis (outside the tubal lumen) so that despite the ectopic site achieving a large size the tubal lumen is spared from damage. In the cases where the tubal lumen is not damaged, simply opening the fallopian tube's outer serosa (along the less vascular antimesenteric border) and removing the bulk of the products of conception is possible. Care should be exercised to avoid excessive removal of tissue since the lumen will be adjacent to the growing placental (trophoblast) cells and can easily be damaged.
2. the isthmic portion of the fallopian tube is the second most common site for ectopic pregnancy (5-15%). In the tubal isthmus (close to the uterus) the muscular area (muscularis) between the outer tubal serosa and inner tubal lumen is very thin. Most often, isthmic ectopic pregnancies grow within the tubal lumen itself and therefore the lumen is often destroyed as the pregnancy becomes larger in size. These isthmic ectopic pregnancies are classically thought to be best treated by segmental resection (removal) of the involved portion of the tube. If simple opening of the outer serosa and removal of the ectopic is performed, a tubal fistula tract (hole) through the inner tubal lumen to the outer pelvis can result.
3. the distal fimbrial (infundibular) portion of the fallopian tube is the third most common site for an ectopic pregnancy (about 5%). Many of these represent "tubal abortions" in which the products of conception (POCs) are already being exuded from the tube into the abdomen. In some cases simple removal of the POCs at the end of the tube is all that is required. More often the POCs are within the muscular area (muscularis) outside the tubal lumen, so that the outer serosa can be opened and the POCs removed without damage to the lumen. The literature will occasionally recommend or report on "milking" the pregnancy manually from the end of the tube, which is a procedure that can damage the tubal lumen and cause unnecessary bleeding. Milking the tube is discouraged.
4. the cornual (interstitial) portion of the fallopian tube is an uncommon site for ectopic pregnancy (about 1-2%). In these cases, the pregnancy is growing within the muscular wall of the uterus as the tube enters the uterine cavity. The abundant potential blood supply to this area will occasionally allow the pregnancy to grow to a very large size (for an ectopic pregnancy) and also makes the removal of the pregnancy difficult. Removal of the POCs from this highly vascular area will often require a hemi (partial) or occasionally a complete hysterectomy. Removal of these ectopic pregnancies is usually not attempted via laparoscopy and immediate laparotomy should be available if a laparoscopic approach is attempted.
5. the abdominal pregnancy is one in which the pregnancy has been expelled from the fallopian tube and implants into a highly vascular region of the abdomen. Most often the blood supply comes from mesenteric vessels of the bowel. The abundant blood supply to these pregnancies may allow the ectopic pregnancy to grow to term. Removal of the placental bed of these pregnancies is often impossible without causing tremendous bleeding, so that the placental site of usually left in situ. The maternal morbidity and mortality is quite high (maternal mortality is about 20 fold higher than with a tubal ectopic pregnancy) with these very dangerous ectopic sites. Nonsurgical approaches can be considered either as primary treatment or adjuvant therapy (treating residual placental tissue).
6. the ovarian pregnancy is relatively rare (less than 1% of ectopics) and can also be quite vascular. Partial resection of the involved ovary is occasionally possible, but if significant bleeding cannot be readily controlled then an oophorectomy (removal of the ovary) may be required. Control of bleeding is usually possible with removal of the ovary since the vascular pedicles to the ovary (the uteroovarian and the infundibulopelvic ligaments) are generally clearly visible and can be transected and tied.
7. the cervical pregnancy is relatively rare (less than 1%) and is often difficult to distinguish from an incomplete abortion since both can be located within the cervix. The uterine artery and vein approach the uterus at the level of the cervix, so these ectopic pregnancies often have an abundant blood supply. Tremendous bleeding can be encountered if removal of these ectopic pregnancies is attempted, often requiring a hysterectomy. These ectopic pregnancies are very dangerous and the risk of maternal mortality and morbidity is high. Nonsurgical approaches should be considered.

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:

• When there is significant damage to the inner lumen of the tube (poor prognosis for repair regardless of surgical technique used), or if the health of the mother is significantly improved by less conservative and more definitive management (possibly after a significant volume of blood has been lost regardless of pregnancy location or when the tubal site continues to bleed following directed coagulation of apparent bleeding sites) then a salpingectomy (removal of the fallopian tube) is appropriate. Removal of the tube is also appropriate when the woman's intended childbearing is complete or when there was a prior ectopic in the same fallopian tube.
• women with decreased fertility and their first ectopic pregnancy have a greater subsequent intrauterine pregnancy rate when the tube containing an ampullary ectopic is preserved, even if the opposite tube looks totally normal
• recurrent ectopic pregnancy after conservative surgery (saving the tube) for an ectopic pregnancy has an equal risk of affecting either fallopian tube (recurrence on the previously damaged tube is not greater)
• salpingotomy (when the serosal defect in the fallopian tube is closed with fine, nonreactive, interrupted sutures) and salpingostomy (when the serosal defect in the fallopian tube is left open so that it can close by secondary intention- "on its own") have roughly equivalent success in terms of future fertility
• conservative surgery (saving the tube) in a woman with her second ectopic on the same side has a reasonable subsequent intrauterine pregnancy rate. Ballpark rates of ectopic pregnancy after 1 ectopic pregnancy on the side is 15-20% and after 2 ectopic pregnancies on the side is about 25%. If the only tube remaining has a second ectopic and IVF is not a realistic option, then a highly motivated fertility patient might elect to save that tube (after discussing the risks and benefits).
• persistent trophoblast (placental) tissue can grow at the ectopic site and require further active management if the fallopian tube is saved. This occurs about 5-10% of the time. Methotrexate medical management appears to be ideal for these cases.

(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

• mean time to resolution (negative pregnancy test) was 36 days, and as high as 7 weeks
• post treatment hysterosalpingograms demonstrated tubal patency on the side of the ectopic in 83% of those treated with methotrexate
• subsequent fertility in the methotrexate group of women was 80%
• of those achieving pregnancy following methotrexate treatment, 87% were intrauterine and 13% were ectopic

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

• bone marrow suppression. The nadir in hemoglobin concentration occurs after about 6-13 days, leukocytes (white blood cells) after about 4-7 days and again after about 12-21 days (second depression), and platelets after about 5-12 days. These complications are very rare with the single IM dose used for ectopic pregnancy.
• both acute and chronic hepatotoxicity with occasional transient elevations in serum liver transaminases within a week of administration. These acute elevations do not seem to predict subsequent liver damage. These complications are very rare with the single IM dose used for ectopic pregnancy.
• rapidly progressive pulmonary toxicity, including pneumonitis and pulmonary fibrosis. The minimum dosage required to precipitate these complications is not clear. These complications are very rare with the single IM dose used for ectopic pregnancy.
• dermatologic effects including rashes, itch, hives, folliculitis, photosensitivity, pigment changes, and (rarely) alopecia (hair loss). These complications are very rare with the single IM dose used for ectopic pregnancy.

Contraindications to the use of methotrexate generally include

1. desired pregnancy (when used in the first trimester, methotrexate has a 30% major malformation rate)
2. severe anemia (low red blood cell count), leukopenia (low white blood cell count), or thrombocytopenia (low platelet count)
3. marked renal function impairment (the primary route of excretion)
4. active infection, due to immunosuppressive effects
5. peptic ulcer disease or ulcerative colitis
6. AIDS, due to additive immunosuppressive effects

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:

1. aspirin
2. nonsteroidal antiinflammatory agents (including motrin, alleve, naprosin, indomethacin)
3. sulfonamides (including co-trimoxazole)
4. phenytoin
5. phenylbutazone
6. tetracycline
7. chloramphenicol
8. aminobenzoic acid
9. vaccination with live attenuate viruses (including mumps, measles, rubella, varicella, smallpox)

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

1. a highly compliant and reliable patient, since close followup is required and resolution may take up to 7 weeks (absolute requirement)
2. healthy woman, unruptured tubal ectopic pregnancy and hemodynamically stable (absolute requirement)
3. ultrasound without evidence of intrauterine pregnancy and ideally a dilatation and curettage failing to find villi (relative contraindication)
4. ectopic size less than 4 cm in greatest diameter (relative contraindication)
5. hCG titer of less than 10,000 mIU/mL (relative contraindication)
6. absence of fetal heart tones (relative contraindication)

Once a candidate has been selected, the following protocol should be adhered to

• obtain a pre treatment hCG titer, type and Rh, CBC and chemistry profile (with at least liver enzymes and renal function tests)
• consider dilatation and curettage or entry into the informed consent that definitive treatment of the pregnancy will be agreed to if the methotrexate fails
• sign the consent form after discussing the risks and benefits as well as the alternatives
• give Rhogam if Rh negative and greater than 7-8 weeks gestation (mini-Rhogam is adequate)
• instruct the woman to refrain from alcohol use, folic acid containing vitamins and sexual relations during treatment
• review the medications that may interact and disallow their use

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

1. decreasing hCG titers on serial determinations
2. tubal location (rather than ovarian, abdominal, cervical)
3. no evidence of rupture or significant bleeding
4. ectopic mass with size less than 4 cm
5. highly motivated patient with strong desire to avoid both surgery and medical management

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. 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.