Once the decision has been made to treat a pregnancy as an ectopic (or a nonviable intrauterine pregnancy) the physician should attempt to eliminate the potentially dangerous pregnancy to minimize maternal risk. The physician should 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 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 may result 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 surgical 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 postoperatively 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 also 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.
- 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 thin. 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.
- 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 thick. Most often, isthmic ectopic pregnancies grow within the tubal lumen itself (since they can not break through the muscularis layer) 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.
- 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.
- 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.
- 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).
- 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.
- 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%
87% of pregnancies following methotrexate treatment 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
- desired pregnancy (when used in the first trimester, methotrexate has a 30% major malformation rate)
- severe anemia (low red blood cell count), leukopenia (low white blood cell count), or thrombocytopenia (low platelet count)
- marked renal function impairment (the primary route of excretion)
- active infection, due to immunosuppressive effects
- peptic ulcer disease or ulcerative colitis
- 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:
- nonsteroidal antiinflammatory agents (including motrin, alleve, naprosin, indomethacin)
- sulfonamides (including co-trimoxazole)
- aminobenzoic acid
- 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
- a highly compliant and reliable patient, since close followup is required and resolution may take up to 7 weeks (absolute requirement)
- healthy woman, unruptured tubal ectopic pregnancy and hemodynamically stable (absolute requirement)
- ultrasound without evidence of intrauterine pregnancy and ideally a dilatation and curettage failing to find villi (relative contraindication)
- ectopic size less than 4 cm in greatest diameter (relative contraindication)
- hCG titer of less than 10,000 mIU/mL (relative contraindication)
- 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
- decreasing hCG titers on serial determinations,
- tubal location (rather than ovarian, abdominal, cervical),
- no evidence of rupture or significant bleeding,
- ectopic mass with size less than 4 cm, and
- 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).