Adolescent Health Care: A Practical Guide

Chapter 56

Ectopic Pregnancy

Melissa D. Mirosh

Mary AnneJamieson

Ectopic Pregnancy

Ectopic pregnancy in the adolescent population is fortunately uncommon. Teens usually have not had sufficient time to establish enough exposures to infection or other intraabdominal pathologies to acquire tubal damage and then conceive with resultant ectopic pregnancy. However, in managing ectopic pregnancies in teens, one must remember that access to care may be limited before or after the diagnosis, confidentiality must be respected, future fertility should be protected, and reliable and acceptable contraception should be offered and encouraged during and after treatment.

Ectopic pregnancy should be a consideration when any pregnant adolescent presents for an office visit with new onset of abnormal uterine vaginal bleeding or abdominal/pelvic pain.

Incidence and Prevalence

The risk of ectopic pregnancy in United States is approximately 19 per 1,000 pregnancies, which has remained stable for several years (MMWR, 1995). This is only an approximation because there are many miscarriages, abortions, and medically treated ectopic pregnancies that are not reported.

1. Trends: From 1991 to 1999, ectopic pregnancies were responsible for 6% of all pregnancy-related deaths in the United States, of which 93% were due to hemorrhage (Chang et al., 2003). This represents an overall decrease of 13% since 1992, most likely due to increased detection of early pregnancy. The risk of death from ectopic pregnancy in the United Kingdom fell from 16 to 4 per 10,000 ectopic pregnancies during the nearly 30 years spanning 1973 to 2002 (Lewis, 2004), although mortality still remains high in developing countries (Igberase et al., 2005).
2. Ectopic pregnancy occurs throughout the reproductive age spectrum. A review from California found a low rate of 12.5 per 1,000 reported pregnancies in women aged 15 to 19 to a high rate of 42.5 per 1,000 pregnancies in women aged 40 to 49 (Van Den Eeden et al., 2005).
3. Ectopic pregnancies occur more frequently in black women (8%) than in white women (4%). This demographic trend is also seen with respect to overall maternal mortality. This discrepancy is unexplained at present, although it is consistent with the higher sexually transmitted disease (STD) rate and lower socioeconomic status seen in the black population in United States (Anderson et al., 2004; Centers for Disease Control and Prevention, CDC, 2006; MMWR, 1995).
4. Location: Ectopic pregnancies occur almost exclusively in the oviduct (95.5%), while 1.3% are abdominal, and approximately 3% are cervical or ovarian. Within the tube itself, most ectopic pregnancies (70%) are located in the ampullary region, 12% are isthmic, 11% are fimbrial, and 2.4% are interstitial (Bouyer et al., 2002).

Etiology and Risk Factors

There are many factors associated with an increased risk of developing an ectopic pregnancy. (Table 56.1)

1. Tubal abnormalities: The most common predisposing factor for adolescents is a previous episode of pelvic inflammatory disease (PID). This is more likely in females with a previous chlamydial infection because Chlamydia infections tend to be less symptomatic than gonorrhea and therefore may go untreated for longer, causing significant pelvic organ damage. The resulting salpingitis is responsible for approximately 45% of initial ectopic pregnancies (Westrom et al., 1981). Scarring of the tubes impairs the ability of the tube to permit normal motility within its lumen. Histopathological study of excised tubes previously involved with PID has shown multiple pockets and tortuous pathways that may also trap embryos (Green and Kott, 1989). Other tubal pathology associated with ectopic pregnancy includes damage or adhesions from previous pelvic surgery (previous tubal surgery for an ectopic pregnancy, ruptured appendix, trauma, inflammatory bowel disease, endometriosis, tubal ligation, or tubal reanastomosis). Adhesions outside the tube to nearby structures such as bowel or other pelvic organs may also cause distortion of the tube. Diethylstilbestrol (DES) exposure (extremely unlikely in this generation of adolescents) and other reproductive congenital anomalies may contribute to abnormal anatomy as well.
2. Tubal pregnancy with the intrauterine contraceptive device Intrauterine Contraceptive Device (IUD): The IUD has long been erroneously associated with an increased risk of ectopic pregnancy. In fact, the absolute

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risk of ectopic pregnancy is significantly reduced in women with an IUD compared with women who use no method of contraception. The current copper IUDs are no longer considered to increase the absolute risk of ectopic pregnancy (Xiong et al., 1995). However, if a patient becomes pregnant with an IUD in situ, the chance that the fetus will implant outside of the uterus is 15% to 20% (Weir, 2003). Progestin-releasing IUDs are associated with an even lower pregnancy rate than nonhormonal IUDs and thereby further reduce the chance of an ectopic pregnancy when compared with sexually active women who are not using contraception (French et al., 2004).

3. Other factors: Other factors that increase the risk of ectopic pregnancy include smoking, infertility, in vitrofertilization, and prior ectopic pregnancy. In the adolescent population, smoking is the most common risk factor.

TABLE 56.1 Risk Factors for Ectopic Pregnancy

Adjusted OR (95% CI) OR (95% CI) OR, odds ratio; CI, confidence interval. From Farquhar CM. Ectopic pregnancy. Lancet 2005;366(9485):583. Previous tubal surgery 4.0 (2.6–6.1) 4.7–21.0 Infertility (risk increases with length of infertility) 2.1–2.7 2.5–21.0 Previous genital infection confirmed 3.4 (2.4–5.0) 2.5–3.7 Previous miscarriage 3.0 (>2) — Previous induced abortion 2.8 (1.1–7.2) — Past or ever smoker 1.5 (1.1–2.2) 2.5 (1.8–3.4) Current smoker (risk increases with amount smoked per day) 1.7–3.9 2.3–2.5 Age 40 years and older 2.9 (1.4–6.1) — Intrauterine device use (>2 years) 2.9 (1.4–6.3) 4.2–45.0 Previous intrauterine device 2.4 (1.2–4.9) — Sterilizationa — 9.3 (4.9–18.0) Previous ectopic pregnancy — 8.3 (6.0–11.5) Documented tubal pathology 3.7 (1.2–4.8) 2.5–3.5 More than one sexual partner — 2.1–2.5 Diethylstilboestrol exposure — 5.6 (2.4–13.0)

Differential Diagnosis

The differential diagnosis of ectopic pregnancy and those teens presenting with acute abdominal or pelvic pain is best divided into obstetrical, gynecological, and nongynecological categories.

1. Obstetrical
2. Normal intrauterine pregnancy
3. Hemorrhagic corpus luteum
4. Spontaneous or threatened abortion
5. Gynecological
6. Ovarian torsion
7. Hemorrhagic ovarian cyst
8. Symptomatic or ruptured ovarian cyst
9. Pelvic inflammatory disease
10. Nongynecological
11. Appendicitis
12. Renal colic
13. Inflammatory bowel disease
14. Gastroenteritis
15. Severe constipation

Clinical Presentation

The range of symptoms depends on the integrity of the teen's fallopian tube and can range from mild cramping and vaginal spotting to frank hemorrhagic shock. However, the classic triad of vaginal bleeding, delayed menses, and severe lower abdominal pain is associated with tubal rupture and is now a fairly infrequent presentation, because early diagnosis is more routine. In general, there are two distinctly different constellations of signs and symptoms that are expressed by women with ectopic pregnancies, each of which dictates different action plans.

Acute Presentation: Classic, Ruptured Ectopic Pregnancy

1. Symptoms: The patient who presents with an acutely ruptured ectopic pregnancy would typically exhibit the following symptoms:
2. Sudden onset of extreme, sharp, or stabbing unilateral pelvic pain, as well as shoulder pain. The shoulder pain is referred pain resulting from subdiaphragmatic irritation caused by hemoperitoneum.
3. Dizziness, lightheadedness, or loss of consciousness from acute intraperitoneal hemorrhage leading to hypotension.
4. Abnormal menses: The patient may have missed her menses and/or experienced several days of abnormal vaginal spotting or bleeding, as well as vague pelvic pain before the onset of her acute symptoms. Teens often have irregular bleeding, and may not have noticed any difference from their “routine” menstrual pattern.

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1. Pregnancy symptoms: The patient may also have noticed nausea, vomiting, breast tenderness, or other symptoms of early pregnancy.

Statistically, the teen who presents with a ruptured ectopic pregnancy is more likely to have had a previous pregnancy and therefore usually does not suspect a problem (Saxon et al., 1997). Generally, gestational age at the time of active symptom development varies by the implantation site. For example, ampullary implantations are more likely to rupture at 6 to 8 weeks of gestation, but cornual implantations may not rupture until near the end of the first trimester.

2. Classic signs of a ruptured ectopic pregnancy:
3. Vital signs: the patient may be in shock with rapid thready pulse, hypotension, and change in mental status.
4. Abdomen will be tender to palpation, possibly even rigid, with marked rebound tenderness.
5. Bimanual examination: Cervical motion tenderness is apparent with a slightly enlarged and globular uterus. Often a pelvic mass is not palpable, either because of guarding or because the rupture has eliminated the bulging mass in the fallopian tube.
6. Laboratory tests: Laboratory testing requirements are minimal and are necessary only to prepare for surgery and to rule out other pathologies.
7. Pregnancy testing: Sensitive urine pregnancy test results should be positive. A baseline quantitative serum β-human chorionic gonadotropin (β-hCG) will allow monitoring of pregnancy resolution.
8. The “Three C's of hemorrhage:”

• Complete blood cell (CBC) count—including hemoglobin and hematocrit.
• Cross-match—blood group and screen to prepare for possible transfusion as well as Rh typing to determine the need for Rh immunoglobulin.
• Coagulation factors—if the blood loss has been significant, patients may have evidence of disseminated intravascular coagulation (DIC) and consideration should be given to appropriate laboratory testing.

1. Ultrasonography: If the patient is hemodynamically unstable, an ultrasonography is not indicated and should not delay a patient from getting into surgery. If an ultrasonography is performed, however, the most remarkable finding will be free fluid and clots in the pelvis; blood may fill the entire abdominal cavity. If there is a positive pregnancy test result, a corpus luteum cyst may be seen and the endometrium may be thickened with decidual material. In fact, a hemorrhagic corpus luteum cyst is the other main consideration in the differential diagnosis. The presence of an intrauterine pregnancy essentially rules out ectopic pregnancy in an adolescent because heterotopic pregnancy is extremely rare without assisted reproductive technologies. It is not necessary to visualize the pregnancy in the tube, although the absence of a uterine pregnancy seen on ultrasonography is not diagnostic of an ectopic pregnancy. In the context of an acute and unstable presentation, the final diagnosis will usually be confirmed at the time of surgery.
2. Therapy:
3. Fluids: The patient requires intravenous access in the form of at least one (preferably two) large-bore intravenous line(s). Fluid resuscitation should start immediately. Blood transfusion may be started if clinically indicated (and with informed consent whenever possible), but surgery should not be delayed by the need to give the patient a transfusion to some arbitrary hemoglobin level; the patient may be losing blood internally at a rate faster than can be replaced by transfusion.
4. Emergency surgery is required: At surgery, every effort should be made in an adolescent to preserve the fallopian tube if possible, performing a salpingostomy as opposed to salpingectomy. If a hemorrhagic corpus luteum is determined to be the cause of the bleeding then every effort should be made to preserve the ovary. If an oophorectomy is required, progesterone supplementation should be instituted until 10- to 12-weeks gestation if the patient wishes to continue the pregnancy.
5. The patient's Rh status must be confirmed and Rh immunoglobulin given if she is Rh negative.

Subacute Presentations: Probable Ectopic Pregnancy and Possible Ectopic Pregnancy

A woman with a positive pregnancy test result who presents with cramping, abnormal vaginal spotting or bleeding, and lower abdominal/adnexal pain should be suspected of having an ectopic pregnancy, particularly if the diagnosis is supported by physical findings of cervical motion tenderness, a closed cervix, adnexal tenderness, and (possibly) an adnexal mass. Women who present in early pregnancy with complaints of vaginal spotting or bleeding and cramping without those suspicious physical findings must also be evaluated to rule out an ectopic pregnancy, although their diagnosis is more likely to be threatened abortion. The work-up and treatment depend on the woman's risk factors and her pregnancy intentions.

The initial diagnosis of a clinically suspected ectopic pregnancy in the hemodynamically stable patient begins with a complete history and physical examination, lab work, and transvaginal ultrasound imaging. If the patient has a regular menstrual cycle, her last menstrual period may be helpful in establishing correct pregnancy dates. Other history that may assist in establishing gestational age includes the date of the first positive pregnancy test result and findings from any previous ultrasonography. The reason for established gestational age is that some authors have recommended using this as a starting point for the diagnostic work-up. In this approach, the first step in the evaluation is an ultrasonography if the gestational age is at least 6 weeks. However, the last menstrual period is often not a reliable or secure data point, particularly in adolescents who may have irregular cycles or imprecise recollections of their menstrual dates. Mol et al. (1998) reviewed 354 patients evaluated for ectopic pregnancy and found that gestational age did not discriminate between intrauterine and ectopic pregnancy. Quantitative β-hCG levels have more reproducibility and, therefore, are used as the basis of most management protocols. The lab work should include CBC count (for white blood cell [WBC], hemoglobin [Hgb], and hematocrit), blood typing, and screening to determine Rh status, and a serum quantitative β-hCG. The adolescent patient may need an explanation for the role of transvaginal ultrasonography as she may be hesitant to have a probe inserted vaginally.

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Laboratory and Imaging Evaluation

The properties and limitations of each diagnostic test should be recognized to appropriately use each of them in the work-up.

1. β-hCG: Typically, β-hCG levels will double every 2 days in a normal first trimester intrauterine gestation. Only 15% of normal pregnancies will fail to have this appropriate increase in β-hCG levels. The smallest increase over 48 hours that can still be associated with a continuing intrauterine pregnancy is 53% (Barnhart et al., 2004). If β-hCG measurements are unchanged or increasing abnormally, the pregnancy is nonviable; it may be an abnormal intrauterine pregnancy (destined to abort), or it may be an ectopic pregnancy. Pregnancies that have inappropriately low β-hCG levels are more likely to be ectopic. Serial β-hCG measurements can be extremely helpful in determining the fate of these pregnancies.
2. Ultrasonography: Ultrasound studies at appropriate β-hCG levels are usually diagnostic, and often the definitive method of pregnancy dating in adolescents. Although ectopic pregnancies can have characteristic appearances on ultrasonography (Frates and Laing, 1995), ultrasound is not used to visualize the tubal pregnancy, but to identify a pregnancy within the uterine cavity. There is still debate over what β-hCG cutoff should be used as the discriminatory level (the lowest concentration of β-hCG that is associated with a visible normal intrauterine gestation), but this level is generally considered to be above 1,500 to 2,000 IU/L when using a transvaginal ultrasound probe. Above this level of serum β-hCG, a normal intrauterine gestational sac should be seen (Condous et al., 2005; Mehta et al., 1997). Although an intrauterine pregnancy may be detected at lower levels, the possibility that the pregnancy in question is intrauterine cannot be excluded until the β-hCG levels reach the discriminatory range. If no intrauterine gestation is seen, then an ectopic pregnancy should be strongly suspected. One must also keep in mind that multiple gestation pregnancies will not be visible until the β-hCG concentration is above 2,000 IU/L (Mol et al., 1998). If transabdominal scanning is the only method available, the β-hCG cutoff should be 6,500 IU/L (Kadar et al., 1994).

Outpatient Follow-up—Using Serial β-hCG Levels:

1. Declining β-hCG levels: If the β-hCG levels are declining by 50% to 66% every 3 days, it is likely that the patient has experienced a complete resolution of the pregnancy. The β-hCG levels must be followed up until they are undetectable (based on local laboratory values).
2. Increasing β-hCG levels: If the β-hCG levels are increasing by at least 66% every 2 to 3 days, they should be followed up in a mildly symptomatic patient until they reach the discriminatory zone and the diagnosis can be made ultrasonographically. If the patient becomes increasingly symptomatic before reaching the discriminatory zone, laparoscopic investigation may be considered. It is useful to discuss with the patient whether the pregnancy is wanted. A dilation and curettage (D&C) can be performed at the time of laparoscopy if the pregnancy is discovered to be intrauterine. If the pregnancy is wanted, consider delaying insertion of the uterine manipulator until an ectopic gestation is confirmed.
3. Abnormally changing β-hCG levels: If the β-hCG levels are declining or rising at an inappropriate rate, the pregnancy (either intrauterine or ectopic) is likely nonviable.
4. If her β-hCG levels are above the discriminatory level, an ultrasonography should be obtained to localize the pregnancy. If it is not within the endometrial cavity, the pregnancy is presumed to be ectopic.
5. If her β-hCG levels are less than the discriminatory range, it is important to assess the patient's desire for pregnancy. If she does not wish to continue with the pregnancy, the presence of an abnormal uterine pregnancy can be ruled out by performing a D&C. A β-hCG level, obtained 12 to 24 hours after the procedure, should be compared with a preprocedure level (Lipscomb et al., 2000). If levels drop by 50% in that time, an ectopic pregnancy can be ruled out. If time allows, the histopathology from the D&C specimen will usually confirm trophoblastic tissue and villi. Otherwise, the asymptomatic patient who is well-informed and compliant can be followed up expectantly until the β-hCG levels either fall, plateau, or reach the discriminatory zone and the ultrasonography can be performed. At this point, decisions about laparoscopy, D&C, and conservative or medical therapy can be made.
6. Methotrexate may be therapeutic for both abnormal intrauterine pregnancies and ectopic pregnancies. Therefore, some investigators have suggested forgoing the D&C and immediately using the methotrexate therapy (see later discussion) to treat the abnormal pregnancy (Tulandi and Saleh, 1999). Misoprostol can be used orally or intravaginally for treatment of an abnormal intrauterine pregnancy.

Other Diagnostic Modalities

1. Serum progesterone levels: A meta-analysis done by Mol et al., in 1998 looked at the use of a single serum progesterone level for diagnosing ectopic pregnancy. A progesterone level <5 ng/mL is associated with a failing pregnancy (in any location) whereas levels >25 ng/mL are diagnostic of normal intrauterine pregnancies in 98% of cases. Most women presenting with a possible ectopic pregnancy had progesterone levels that fell within this range, therefore it did not appear to be helpful in determining either the potential for viability or the location of the pregnancy (Mol et al., 1998).
2. Culdocentesis to determine if there is blood in the cul-de-sac is rarely used today. It has been replaced by ultrasonic imaging.

Management

Issues Unique to Adolescents

1. Access to care and follow-up: There are several factors in the evaluation and treatment of ectopic pregnancy that are unique to, or should be emphasized in, adolescents. These patients may present later in gestation because of denial of pregnancy or fear of consequences. They may have trouble accessing the medical system, or be unable to seek help due to lack of transportation or money. Once in your office, establishing an accurate history is often difficult as menstrual cycles can be irregular and teens may be poor historians.

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2. Confidentiality and consent for treatment: One must be aware of the local legislation with respect to informed consent for minors. Fortunately, in most states and provinces, health care providers can use clinical judgment and provide medical care to an adolescent who understands the nature of the diagnosis and/or treatment, without necessarily involving a parent or guardian. Teens may have a particular need for confidentiality and this must be respected. On the other hand, health care providers should make every effort to negotiate with the teen to involve a parent or a guardian in such an important issue as the diagnosis and treatment of an ectopic pregnancy.

Approaches to Management

In the adolescent with an ectopic pregnancy, treatment should generally be fertility-sparing and should take into account that adolescents may have difficulty complying with follow-up recommendations.

1. Surgical approach: Most women diagnosed with an ectopic pregnancy will be treated surgically through laparoscopy or laparotomy. Open surgery is the method of choice for hemodynamically unstable patients, surgeons with little laparoscopic experience, or both. Some surgeons may consider laparoscopic treatment of their hemodynamically unstable patients, depending on their surgical experience and available equipment (Sagiv et al., 2001). A recent Cochrane review concluded that although the laparoscopic route was less successful than a laparotomy for complete resolution of trophoblastic tissue, it remains the cornerstone of treatment in hemodynamically stable patients owing to its decreased operative time, hospital stay, and recovery times (Hajenius et al., 2000). Finally, laparoscopy has also been shown to have equivalent success when compared with laparotomy in obese patients (Hsu et al., 2004).

Conservative or radical treatment? The most common surgical procedures are salpingostomy and salpingectomy. Unfortunately, there are no randomized controlled studies that directly compare the two. In theory, the benefit of removing the affected tube is an almost guaranteed resolution of the ectopic pregnancy, while treating conservatively preserves the potential for fertility with that tube (which is crucial in adolescents). Five nonrandomized studies have been published that observed the outcomes of conservative versus radical therapy (Bangsgaard et al., 2003; Bouyer et al., 2000; Job-Spira et al., 1996; Mol et al., 1998; Silva et al., 1993). Three of them showed a significant difference in future fertility, but the two more recent studies have implied that conservative surgery may be advantageous with respect to subsequent fertility (Bangsgaard et al., 2003; Bouyer et al., 2000). A randomized controlled trial will likely be needed to complete the debate. Two studies have confirmed that it is not necessary to close the tubal defect after salpingostomy (Fujishita et al., 2004; Tulandi and Saleh, 1999).

There are some patients in whom salpingectomy is the preferred method of treatment. These would include cases of intractable hemorrhage, three recurrent ectopic pregnancies in the same tube, or in women who have completed childbearing. The latter two scenarios seldom occur in the adolescent. One aspect to consider before removing the affected tube is the state of the contralateral tube. If the patient wishes to conserve her chances for spontaneous conception, the unaffected tube must appear normal. If it is abnormal or damaged, salpingostomy for the ectopic pregnancy would be recommended.

2. Medical therapy: Early diagnosis of ectopic pregnancy using laboratory tests and sensitive imaging techniques has significantly reduced the mortality and morbidity of this condition. It has also enabled the use of outpatient medical therapy in lieu of surgical intervention, which in time has reduced hospitalization costs and surgical complications.

Methotrexate: Methotrexate has become an established method of treatment for patients diagnosed with an unruptured ectopic pregnancy. The main advantage of medical therapy over surgical therapy is that it is less invasive and less expensive.

1. Modality of action: Methotrexate is a folic acid antagonist and therefore exerts its effect on rapidly dividing cells. The medication disrupts cytotrophoblast syncytialization and blunts β-hCG production, thereby decreasing support for progesterone secretion by the corpus luteum (Creinin et al., 1998).
2. Success rate: Meta-analysis of outpatient methotrexate treatment for appropriate candidates demonstrated a cure rate of 92% (Slaughter and Grimes, 1995). At least 85% of those women successfully completed therapy, although 5% to 16% required a second dose of methotrexate (Henry and Gentry, 1994). Only 2.7% required three or more doses. Failure rates are higher with higher initial β-hCG levels. One study found that the failure rate was 32% when the presenting β-hCG levels were more than 15,000, but was 6% when the pretreatment β-hCG level was less than 10,000 (Lipscomb et al., 1999).

There are no randomized controlled trials comparing single dose to multi-dose treatment. However a meta-analysis found that although a multi-dose regimen is more successful (92.7% versus 88.1%), the overall success of medically treating an ectopic pregnancy with any method of methotrexate is 89% (Barnhart et al., 2003). Often one dose is sufficient (Lipscomb et al., 1998). One study reviewed a group of 55 adolescents who had successfully used the single-dose method and were able to follow the strict follow-up protocols. In this group of teens, the success rate of methotrexate for ectopic pregnancy resolution was 85% (McCord et al., 1996).

Efforts to determine factors that argue favorably for methotrexate therapy identified an initial β-hCG level of <4,000 and lack of fetal cardiac activity as strong predictors of success. Indicators predictive of failure included visible extrauterine yolk sac on ultrasonography and previous ectopic pregnancy (Lipscomb et al., 2004). Patients must be counseled about the possibility of treatment failure (and possible tubal rupture) and the signs and symptoms that may indicate complications and necessitate return to hospital. Because it is common for abdominal pain to occur as the ectopic pregnancy resolves 24 to 48 hours after administration of methotrexate, the differentiation of “normal” from “abnormal” pain can be challenging and may result in additional emergency room visits for reassessment and reassurance.

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Gazvani et al., examined the addition of mifepristone to any outpatient regimen of methotrexate and found no benefit (Gazvani et al., 1998).

56. Dose: The dose used for treating ectopic pregnancy, usually 50 mg/m², is much lower than that used for cancer chemotherapy. Many different regimens of methotrexate delivery have been employed for treatment of ectopic pregnancy, including oral, intramuscular, and local injection (under laparoscopic or ultrasound guidance). Tables 56.2 and56.3 list exclusion criteria and logarithm for using methotrexate.

TABLE 56.2 Methotrexate Therapy for Ectopic Pregnancy—Exclusion Criteria

a Relative contraindication. Patient characteristics: Hemodynamically unstable Unable to comply with follow-up visit schedule or to return if complications develop Immunocompromised (white blood cell count <3,000) Anemia (Hemoglobin <8 g/dL) Active pulmonary disease Renal compromise (creatinine clearance >1.3 mg/dL) Hepatic compromise (elevated liver function test results; aspartate aminotransferase >50 IU/L) Hematological dysfunction Thrombocytopenia β-hCG characteristics: Most institutions exclude levels >10,000 mIU/ng Ultrasonography findings: Gestational sac (maximum density of entire mass) >3.5–4.0 cma Fetal cardiac motiona Excessive fluid in cul-de-sac consistent with hemorrhage

TABLE 56.3 Systemic Methotrexate Treatment Algorithm

Treatment Day Investigation/Management hCG, human chorionic gonadotropin; CBC, complete blood cell. 1 Patient eligible for methotrexate therapy Labs: Quantitative β-hCG, renal function tests, liver function tests, CBC count, blood type and screen Methotrexate administered in 50 mg/m2 dose intramuscularly Patient care instructions including anticipated symptoms and analgesia 4 Labs: Quantitative β-hCG 7 Labs: Quantitative β-hCG, renal and liver function tests, CBC count Compare β-hCG levels from day 4 and 7: If the decline in value is ≥15%, continue to monitor β-hCG until they resolve. If the decline is <15%, a second methotrexate dose is needed Consider surgical treatment if the patient becomes hemodynamically unstable, has increasing pain and/or falling hematocrit, or if there is an ineffective response to methotrexate

1. Side effects: Because the doses are so much lower than chemotherapy, the common side effects of methotrexate at higher dosages including nausea, vomiting, stomatitis, and diarrhea are rarely seen with the doses used to treat ectopic pregnancies. Rarely, a reversible leukopenia or transient hair loss may be seen.

Other medical modalities: Other medical interventions have included injecting the embryo with methotrexate, hypertonic saline, or prostaglandins. Although successful, these methods are more cumbersome and invasive compared to oral or intramuscular methotrexate, and therefore are much less frequently used (Hajenius et al., 2000; Yao et al., 1996).

3. Treatment of unusual ectopic pregnancy sites: As mentioned previously, ectopic pregnancies are rarely located outside the fallopian tubes. There are a number of individual case reports documenting surgical and medical management of pregnancies located on ovaries, surgical scars, omentum, and the cervix. The method of treatment for pregnancies in these sites is usually systemic or local methotrexate under ultrasound guidance (Doubilet et al., 2004), as treating them surgically would be technically difficult or dangerous due to uncontrollable bleeding or poor surgical access.

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4. Expectant management: Expectant management is reasonable for a certain subset of women presenting with ectopic pregnancy. These patients are asymptomatic and generally have a β-hCG level below 1,000 IU/L (Trio et al., 1995). They also need to be reliable, as losing a woman to follow-up could be disastrous. Under these circumstances, Pisarska showed that 68% of women had complete resolution of their ectopic pregnancy without intervention (Pisarska et al., 1998). Patients who have spontaneous resolution of their ectopic pregnancies also tend to have a good chance of return to normal fertility. Rantala et al., found that 93% of their study patients had patent tubes on a subsequent hysterosalpingogram and did not have an increased rate of second ectopic pregnancy when compared to the general population (Rantala and Makinen, 1997). Unfortunately, the need to carefully assess these patients over the course of several weeks, especially if they develop pain, may result in the need for repeated clinical visits. Adolescents should be considered on an individual basis as candidates for conservative management because for many teens the follow-up and surveillance requirements will be too compliance demanding.

Follow-up

Surgical

Complete resolution of the ectopic pregnancy must be documented because residual trophoblastic tissue proliferation can cause clinical problems. Overall, with salpingostomy, almost 5% of women undergoing laparotomy and 8% to 15% of women who are treated laparoscopically will develop persistent trophoblastic tissue (Seifer et al., 1993). In this situation, it is prudent to ensure that the β-hCG levels return to normal, and another pregnancy should be prevented until that time. β-hCG levels should be measured 6 days postoperatively. If the sixth day value is greater than 15% of the baseline value obtained at the time of surgery, persistent disease is presumed. Some have suggested that postoperative day 1 determinations replace the more delayed follow-up measurements; if day 1 serum β-hCG levels are decreased by 50%, there is an 85% probability that persistent trophoblastic tissue will not occur, and that the patient has been adequately treated (Spandorfer et al., 1997). Expression of ectopic tissue from the end of the fallopian tube (i.e., milking the tube) has been associated with residual disease in up to 25% of cases. Careful postoperative monitoring in these cases is critical.

Nonsurgical

Obviously, women treated with methotrexate or expectant management will require weekly (or more frequent) quantitative β-hCG determinations until the levels of that hormone become undetectable. Table 56.4 outlines specific guidelines for following up a patient treated with methotrexate.

TABLE 56.4 Systemic Methotrexate Follow-up Instructions

To patients: Avoid sexual intercourse (may rupture ectopic pregnancy) Avoid sun exposure (photosensitivity reaction possible) Avoid consuming gas-producing foods—leeks, beans, corn, cabbage (abdominal bloating may worsen) No alcohol No ibuprofen, naproxen, aspirin, or other nonsteroidal anti-inflammatory agents No penicillin No prenatal vitamins or folate supplements Return to clinic in 4 days for repeat tests of the pregnancy hormone β-human chorionic gonadotropin Be aware that in the next few days, you may experience sharp abdominal pain and some cramping. This discomfort should be self-limited, but if you feel dizzy or weak, or if the pain does not resolve, have someone take you to the emergency room immediately. There is a small chance that the pregnancy could rupture through the tube and you would need immediate surgery Your next period may be particularly heavy To providers: No need for vaginal examination No need for transvaginal ultrasonography unless patient experiences acute clinical deterioration

Persistent Disease

If persistent disease is diagnosed, further treatment is necessary. If surgical treatment was used initially, methotrexate should probably be used as second line as long as the patient is not continuing to bleed from the ectopic pregnancy. If methotrexate was used initially, options include surgical treatment or repeat methotrexate (Graczykowski and Mishell, 1997). Very occasionally, expectant management can be considered but would again require a well-informed, compliant patient.

Contraception

It is important to provide your patient effective contraception during her recovery period, not only to prevent a second pregnancy from complicating the β-hCG results, but also to allow the tubal tissue time to heal, thereby presumably reducing the risk of a second ectopic pregnancy in rapid succession. Waiting until the β-hCG levels “zero out” before starting contraception puts a woman in jeopardy for pregnancy because ovulation often precedes complete β-hCG clearance. Assuming the

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adolescent is not seeking to conceive, every effort should be made to offer and provide reliable and acceptable contraception to the teen who has had a failed pregnancy (intrauterine or ectopic) or any pregnancy for that matter.

Rh Considerations

Unsensitized Rh-negative women should be given an appropriate dose of Rh immunoglobulin (50–120 µg if gestational age <12 weeks; 300 µg if >12 weeks) promptly (ACOG, 1999; Fung Kee Fung et al., 2003). Although very occasionally the blood type of the “father” is used to determine whether an Rh-negative woman receives immunoglobulin, it is always prudent to treat the Rh-negative adolescent anyway, because of the uncertainty that may exist with respect to paternity.

Fertility after Treatment of Ectopic Pregnancy

Several studies have looked at ectopic pregnancy recurrence rates and the rates of subsequent intrauterine gestations. On an average, ectopic pregnancies recur in 10% of patients (Bouyer et al., 2002; Pouly et al., 1991). In women seeking pregnancy, reproductive success varies between 50% and 88% within 2 years of the initial ectopic pregnancy (Bangsgaard et al., 2003; Bouyer et al., 2002; Fernandez et al., 1998).

There is no consensus in the literature about the preferred method of surgical treatment with respect to subsequent fertility (Hajenius et al., 2000). Two recent studies suggest that conservative (tube sparing) surgery may lead to a higher intrauterine conception rate than radical (salpingectomy) surgery (Bangsgaard et al., 2003; Fernandez et al., 1998).

Studies looking at fertility after medical treatment of an ectopic pregnancy are also reassuring. Gervaise et al., showed that 64 of 81 women had spontaneous intrauterine pregnancies after local or systemic methotrexate (Gervaise et al., 2004). Fifty-two of these were intrauterine (with 12 spontaneous abortions), and 12 (18%) were recurrent ectopic pregnancies.

Regardless of the method of treatment, adolescent patients who have had only one ectopic pregnancy can be reassured that their chances of having an intrauterine pregnancy in the future are excellent. The method of treatment can therefore be tailored to the needs of the individual patient.

Web Sites

For Teenagers and Parents

http://www.rxmed.com/b.main/b1.illness/b1.illness.html. RxMed Web site providing basic information on ectopic pregnancy.

For Health Professionals

http://emedicine.com/emerg/topic478.htm. eMedicine Web site on ectopic pregnancy.

http://www.aafp.org/afp/20051101/1719ph.html. American Academy of Family Physicians article on ectopic pregnancy.

http://www2.mc.duke.edu/depts/obgyn/ivf/ectopic.htm. Information on ectopic pregnancy from Duke University.

http://www.cmaj.ca/cgi/content/full/173/8/905. Review article on diagnosis and management of ectopic pregnancy from the Canadian Medical Association Journal.

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