Gynecology_Novak

Gynecology_Novak. Linear salpingostomy can be considered when the patient has an unruptured ectopic pregnancy, wishes to retain her potential for future fertility, and the affected fallopian tube appears otherwise normal. If the contralateral tube appears damaged, a salpingostomy should be considered.


Gynecology_Novak

Gynecology_Novak. In a salpingostomy, the products of conception are removed through an incision made into the tube on its antimesenteric border. The procedure can be accomplished with needle-tip cautery, laser, scalpel, or scissors. It can be done with operative laparoscopic techniques or via a laparotomy. Contraindications to a salpingostomy include ruptured fallopian tube, use of extensive cautery to obtain hemostasis, severely damaged tube, and a recurrent ectopic pregnancy in the same tube. The main risk factor of salpingostomy is a persistent ectopic pregnancy resulting from failure to remove the entire pregnancy from the fallopian tube. This was reported in 5% to 20% of cases, and the rate appears to be higher in laparoscopic cases as compared to salpingostomies at the time of a laparotomy (181–184). Patients with high starting β-hCG levels, early gestations, and small ectopic pregnancies (<2 cm) are at greater risk of having a persistent pregnancy after a salpingostomy (185). Because of this


Gynecology_Novak

Gynecology_Novak. Patients with high starting β-hCG levels, early gestations, and small ectopic pregnancies (<2 cm) are at greater risk of having a persistent pregnancy after a salpingostomy (185). Because of this risk, it is recommended to follow weekly β-hCG levels to ensure complete resolution of the ectopic pregnancy. β-hCG levels that persist or plateau can usually be treated successfully with a single dose of methotrexate, as described below (26).


Gynecology_Novak

Gynecology_Novak. Milking the tube to effect a tubal abortion was advocated; if the pregnancy is fimbrial, this technique may be effective. When milking was compared with linear salpingostomy for ampullary ectopic pregnancies, milking was associated with a twofold increase in the recurrent ectopic pregnancy rate (186). Reproductive outcome after ectopic pregnancy is evaluated by determining tubal patency by hysterosalpingography, the subsequent intrauterine pregnancy rate, and the recurrent ectopic pregnancy rate. Pregnancy rates are similar in patients treated by either laparoscopy or laparotomy. Tubal patency on the ipsilateral side after conservative laparoscopic management is about 84% (187).


Gynecology_Novak

Gynecology_Novak. In a study of 143 patients followed after undergoing laparoscopic procedures for ectopic pregnancy, the overall intrauterine pregnancy rates for laparoscopic salpingostomy (60%) and laparoscopic salpingectomy (54%) were not significantly different (188). If the patient had evidence of tubal damage, pregnancy rates (42%) were significantly lower than in those women who did not have tubal damage (79%). In another study, the reproductive outcome of 188 patients followed for a mean of 7.2 years (range 3–15 years) was reported after conservation by laparotomy for ectopic pregnancy (189). An intrauterine pregnancy occurred in 83 (70%) patients, with a recurrent ectopic pregnancy rate of 13%, suggesting that reproductive outcome after an ectopic pregnancy treated by laparotomy is similar to that of patients undergoing laparoscopic or medical management. A recent Cochrane review showed no difference in tubal patency rate, future intrauterine pregnancy rates, and recurrent ectopic pregnancy


Gynecology_Novak

Gynecology_Novak. of patients undergoing laparoscopic or medical management. A recent Cochrane review showed no difference in tubal patency rate, future intrauterine pregnancy rates, and recurrent ectopic pregnancy rates in those patients treated with salpingostomy by either laparoscopy or laparotomy approach (177).


Gynecology_Novak

Gynecology_Novak. Medical Treatment The drug most frequently used for medical management of ectopic pregnancy is methotrexate, although other agents were studied, including potassium chloride (KCl), hyperosmolar glucose, prostaglandins, and RU-486. These agents may be given systemically (intravenously, intramuscularly, or orally) or locally (laparoscopic direct injection, transvaginal ultrasonographically directed injection, or retrograde salpingography). Other agents besides methotrexate are not recommended for the treatment of ectopic pregnancy because their safety and efficacy are not well documented. Table 20.2 Contraindications to Medical Therapy Unable to comply with medical management follow-up Alcoholism, alcoholic liver disease or chronic liver disease Known sensitivity to methotrexate Hepatic, renal, or hematologic disorder Gestational sac larger than 3.5 cm Adapted from ACOG Practice Bulletin Medical Management of Ectopic Pregnancy, 2008.


Gynecology_Novak

Gynecology_Novak. Methotrexate is a folic acid analogue that inhibits dehydrofolate reductase and thereby prevents synthesis of DNA. Methotrexate affects actively growing cells including trophoblastic tissues, malignant cells, bone marrow, intestinal mucosa, and respiratory epithelium (190). It is used extensively in the treatment of gestational trophoblastic disease (see Chapter 39). Initially, methotrexate was used for the treatment of trophoblastic tissue left in situ after exploration for an abdominal pregnancy (191). In 1982, Tanaka et al. treated an unruptured interstitial gestation with a 15-day course of intramuscular methotrexate (192). Multiple studies documented the safety and efficacy of methotrexate therapy for the management of ectopic pregnancies, and this is the first-line treatment for many providers. Approximately 35% of patients with ectopic pregnancies are candidates for primary therapy with methotrexate (193). Methotrexate is appropriate for primary treatment and may be given for


Gynecology_Novak

Gynecology_Novak. providers. Approximately 35% of patients with ectopic pregnancies are candidates for primary therapy with methotrexate (193). Methotrexate is appropriate for primary treatment and may be given for the treatment of persistent ectopic pregnancies that failed surgical management.


Gynecology_Novak

Gynecology_Novak. Candidates for Methotrexate Medical management of ectopic pregnancies with methotrexate is safe and effective, however, not all patients are candidates for this medical therapy. According to American College of Obstetricians and Gynecologists (ACOG) guidelines, methotrexate therapy can be considered for those patients with confirmed, or high suspicion for, ectopic pregnancy who are hemodynamically stable with no evidence of rupture. Table 20.2 documents the absolute contraindications to methotrexate therapy including breastfeeding, hepatic, renal, or hematologic disorders and known sensitivity to methotrexate. A patient who is unable to comply with the follow-up protocol should not be offered medical management. Relative contraindications to methotrexate therapy include gestational sac greater than or equal to 3.5 cm and embryonic cardiac motion (Table 20.2). Prior to the administration of methotrexate, a patient should have a complete blood count, blood type, liver function tests,


Gynecology_Novak

Gynecology_Novak. greater than or equal to 3.5 cm and embryonic cardiac motion (Table 20.2). Prior to the administration of methotrexate, a patient should have a complete blood count, blood type, liver function tests, electrolyte panel including creatinine, and a chest x-ray if there is any history of pulmonary disease. These studies are usually repeated 1 week after administration of methotrexate to evaluate for any potential complications from the therapy (190).


Gynecology_Novak

Gynecology_Novak. Methotrexate Dosing Regimens Methotrexate is usually given via intramuscular injection but can be administered orally or by intravenous infusion. Methotrexate traditionally was administered using a multidose regimen, but single dosing protocols were developed that are easier for patient compliance (194). Table 20.3 Methotrexate Treatment Regimens Administer MTX 1 mg/kg IM days 1, 3, 5, 7 Administer leucovorin 0.1 mg/kg days 2, 4, 6, 8 Measure β-hCG levels on days 1, 3, 5, 7 until 15% decrease between two measurements. Once β-hCG levels drop 15%, stop MTX and monitor β-hCG weekly until nonpregnant level If levels drop by 15%, monitor β-hCG weekly until nonpregnant level If levels do not drop by 15%, repeat dose of MTX and measure β-hCG on days 4 and 7 If levels drop by 15%, monitor β-hCG weekly until nonpregnant level


Gynecology_Novak

Gynecology_Novak. If levels do not drop by 15%, repeat dose of MTX and measure β-hCG on days 4 and 7 If levels drop by 15%, monitor β-hCG weekly until nonpregnant level If levels do not drop by 15%, repeat dose of MTX on days 7 and 11 and measure β-hCG on days 7 and 11. If levels drop 15%, monitor β-hCG weekly until nonpregnant level MTX, methotrexate; IM, intramuscular; β-hCG, β-human chorionic gonadotropin; Adapted from ACOG Practice Bulletin Medical Management of Ectopic Pregnancy, 2008.


Gynecology_Novak

Gynecology_Novak. The multidose regimen is outlined in Table 20.3. Patients receive 1 mg/kg of methotrexate intramuscularly on days 1, 3, 5, and 7 with leucovorin 0.1 mg/kg intramuscular administered on days 2, 4, 6, and 8. As a result of the repeat dosing of methotrexate, side effects are more common. The leucovorin helps reduce these side effects and increases patients’ tolerance of the treatment. A patient may not require all four doses of methotrexate and her β-hCG levels should be monitored on days 1, 3, 5, and 7. If the β-hCG level drops 15% between two measurements, the regimen can be stopped and weekly β-hCG monitoring initiated. If the methotrexate is discontinued early, the patient should receive leucovorin after her final dose of methotrexate to help reduce potential side effects. If a patient’s β-hCG level plateaus or increases, a second round of methotrexate and leucovorin can be given 1 week later. Earlier studies indicated approximately 19% will require all four doses, and 17% of women


Gynecology_Novak

Gynecology_Novak. β-hCG level plateaus or increases, a second round of methotrexate and leucovorin can be given 1 week later. Earlier studies indicated approximately 19% will require all four doses, and 17% of women will require only one dose with this regimen (195,196). A more recent meta-analysis showed 10% of women require only one dose, while nearly 54% will require all four doses.


Gynecology_Novak

Gynecology_Novak. Methotrexate Single-Dose Regimens Single-dose regimens were designed to increase patient compliance and simplify the administration of methotrexate. This regimen is well studied and safe and effective in the treatment of ectopic pregnancies. The single-dose regimen is detailed in Table 20.3. Approximately 15% to 20% of patients in the single-dose regimen will require a second dose of methotrexate due to persistent β-hCG levels (194,197). The β-hCG level at the time of treatment appears to predict the subsequent success rate of single-dose therapy. Patients with β-hCG levels greater than 5,000 mIU/mL have a 14.3% chance of treatment failure compared to only 3.7% for women with levels less than 5,000 mIU/mL (198). Compared with the multidose protocol, single-dose methotrexate is less expensive, patient acceptance is greater because less monitoring is required during treatment, and the treatment results and prospects for future fertility are comparable (194).


Gynecology_Novak

Gynecology_Novak. Methotrexate Two-Dose Regimen The two-dose regimen was described as a cross between the single and multidose regimens. Because only 54% require all four doses of the multidose regimen, and 15% to 20% will require a second dose in the single-dose regimen, it is reasonable to consider a two-dose regimen of methotrexate. The protocol is outlined in Table 20.3 and involves Table 20.4 Initiation of Methotrexate: Physician Checklist and Patient Instructions Obtain hCG level. Check CBC, liver function tests, creatinine, and blood type Administer RhoGAM if patient is Rh-negative. Identify unruptured ectopic pregnancy smaller than 3.5 cm (relative contraindication) Prescribe FeSO4 325 mg PO bid if hematocrit is less than 30%. Schedule follow-up appointment on days 4 and 7. Refrain from alcohol use, multivitamins containing folic acid, NSAID use, and sexual intercourse until hCG level is negative. Call your physician if: You experience prolonged or heavy vaginal bleeding.


Gynecology_Novak

Gynecology_Novak. Call your physician if: You experience prolonged or heavy vaginal bleeding. The pain is prolonged or severe (lower abdomen and pelvic pain is normal during the first 10–14 days of treatment). You use oral contraception or barrier contraceptive methods. About 4%–5% of women experience unsuccessful methotrexate treatment and require surgery. hCG, human chorionic gonadotropin; SGOT, serum glutamic-oxaloacetic transaminase; BUN, blood urea nitrogen; CBC, complete blood count; Rho-GAM, Rh0(D) immune globulin; NSAIDs, nonsteroidal anti-inﬂammatory drugs; WBC, white blood cell; PO, by mouth; bid, twice daily. the administration of methotrexate on day 0 and day 4 with monitoring of β-hCG levels on days 4 and 7. If there is less than a 15% drop between the two measures, a repeat administration of methotrexate is given on days 7 and 11 and β-hCG levels drawn accordingly. A single study showed an 87% success rate with low complication rates and high patient satisfaction (199).


Gynecology_Novak

Gynecology_Novak. Effectiveness of Methotrexate The overall effectiveness of methotrexate therapy ranges from 78% to 96% (200). A meta-analysis in 2003 of 26 observational studies including 1,300 women revealed a significantly higher rate (93% versus. 88%) of successful treatment with multidose therapy (194). A meta-analysis comparing two randomized controlled trials showed no difference in success rates between the two regimens; however, the β-hCG levels in both of these studies were less than 3,000 mIU/mL (184,201,202). When comparing methotrexate to laparoscopic salpingostomy, the multidose regimen has similar success rates. The single-dose regimen has lower initial success rates. After women receive additional doses as needed, the success rates are comparable between laparoscopic salpingostomy and single-dose methotrexate protocols (184).


Gynecology_Novak

Gynecology_Novak. Initiating Methotrexate Outlined in Table 20.4 is a checklist that should be followed by the physician before initiating methotrexate. It includes instructions that are helpful to the patient.


Gynecology_Novak

Gynecology_Novak. Patient Follow-Up After intramuscular administration of methotrexate, regardless of the dose regimen used, patients are monitored on an outpatient basis with weekly β-hCG levels. These levels need to be monitored until the β-hCG reaches nonpregnant levels. It is possible that tubal rupture may occur even if β-hCG levels are falling. Signs of a tubal rupture include severe pain, hemodynamic instability, and a drop in hematocrit. Patients who report severe or prolonged pain should be evaluated by measuring hematocrit levels and performing transvaginal ultrasonography. The ultrasonography findings during follow-up, although usually not helpful, can be used to provide reassurance that the tube is not ruptured (203). Cul-de-sac ﬂuid is a common finding, and the amount of ﬂuid may increase if a tubal abortion occurs. It is not necessary to intervene surgically, unless the patient has a precipitous drop in hematocrit levels or she becomes hemodynamically unstable.


Gynecology_Novak

Gynecology_Novak. Side Effects Side effects of methotrexate therapy are dose and frequency dependent. The most commonly reported side effects are the gastrointestinal symptoms of nausea, vomiting, stomatitis, and abdominal pain. Because of these potential effects, women are cautioned against using alcohol and nonsteroidal anti-inﬂammatory medications while being treated with methotrexate (190). Other side effects include bone marrow suppression, hemorrhagic enteritis, alopecia, dermatitis, elevated liver enzyme levels, and pneumonitis (204). These side effects are usually mild and self-limited; few life-threatening side effects are reported with methotrexate treatment for ectopic pregnancy. The risk of these side effects does not appear to differ between single-dose and multidose regimens when adjusting for starting level of β-hCG at initiation of treatment. The frequency of reported side effects ranges from 30% to 40% (194). For those patients on prolonged therapy, leucovorin can reduce the incidence


Gynecology_Novak

Gynecology_Novak. starting level of β-hCG at initiation of treatment. The frequency of reported side effects ranges from 30% to 40% (194). For those patients on prolonged therapy, leucovorin can reduce the incidence of these side effects and is included in the “multidose” regimen. Long-term follow-up of women treated with methotrexate for gestational trophoblastic disease shows no increase in congenital malformations, spontaneous abortions, or tumors recurring after chemotherapy (205). Treatment of ectopic pregnancy differs from that of gestational trophoblastic disease in that a smaller total dose of methotrexate is required and shorter treatment duration is used.


Gynecology_Novak

Gynecology_Novak. Although surgical management of ectopic pregnancy remains the mainstay of treatment worldwide, methotrexate treatment is appropriate in those patients who meet the treatment criteria previously detailed. Reproductive Outcome Reproductive function after methotrexate treatment can be assessed on the basis of repeat ectopic pregnancy rates, tubal patency, and pregnancy outcome. The risk of subsequent ectopic pregnancy is approximately 10% following either methotrexate or salpingostomy (52,53). The tubal patency rates are reported to be higher than 80% in those patients treated with either single-dose or multidose regimens with no difference in rates compared with women treated with salpingostomy (52,53). A randomized trial comparing methotrexate to laparoscopic salpingostomy showed no difference in tubal patency rates among the two groups, although in this trial patency rates were lower than previously reported at 66% in the salpingostomy group (206).


Gynecology_Novak

Gynecology_Novak. Subsequent spontaneous intrauterine pregnancy rates are similar between those women treated with methotrexate versus salpingostomy, with rates ranging from 36% to 64% (207,208). Comparison of laparoscopically treated patients with methotrexate-treated patients indicates that the two methods have similar reproductive outcomes.


Gynecology_Novak

Gynecology_Novak. Salpingocentesis is a technique in which agents such as KCl, methotrexate, prostaglandins, and hyperosmolar glucose are injected into the ectopic pregnancy transvaginally using ultrasonographic guidance, transcervical tubal cannulization, or laparoscopy. Agents injected under ultrasonographic guidance included methotrexate, KCl, combined methotrexate and KCl, and prostaglandin E2 (162,209–215). The potential advantages of salpingocentesis include a onetime injection with the potential avoidance of systemic side effects. Reproductive function after this form of treatment was not reported. Because of the limited experience, this treatment cannot be recommended until there is further study.


Gynecology_Novak

Gynecology_Novak. Agents injected into the amniotic sac at laparoscopy included prostaglandin F2a, hyperosmolar glucose, and methotrexate (216–218). This method has the obvious disadvantage of requiring laparoscopy, but it can be used if laparoscopy is performed for diagnosis. Other agents reported for the treatment of ectopic pregnancy include RU-486 and anti-hCG antibody (219,220). Types of Ectopic Pregnancy


Gynecology_Novak

Gynecology_Novak. Types of Ectopic Pregnancy Spontaneous Resolution Some ectopic pregnancies resolve by resorption or by tubal abortion, obviating the need for medical or surgical therapy (221–225). The proportion of ectopic pregnancies that resolve spontaneously and the reason they do so while others do not are unknown. There are no specific criteria for patient selection that predict successful outcome after spontaneous resolution. A falling hCG level is the most common indicator used, but tubal rupture can occur even with falling hCG levels. Patients with low initial levels of β-hCG are generally the best candidates for expectant management, and there is a reported 88% success rate of spontaneous remission with an initial β-hCG level less than 200 mU/mL (226). These patients should be followed with serial β-hCG levels and active management initiated if these levels plateau or rise or the patient develops abdominal pain or signs of tubal rupture (190).


Gynecology_Novak

Gynecology_Novak. Persistent ectopic pregnancy occurs when a patient underwent conservative surgery (e.g., salpingostomy, fimbrial expression) and viable trophoblastic tissue remains. Histologically, there is no identifiable embryo, the implantation usually is medial to the previous tubal incision, and residual chorionic villi are confined to the tubal muscularis. Peritoneal trophoblastic tissue implants may be responsible for persistence (182,183,227–230).


Gynecology_Novak

Gynecology_Novak. The incidence of persistent ectopic pregnancy increased with the increased use of surgery that conserves the tubes. Persistence is diagnosed when the β-hCG levels plateau after conservative surgery. Risk factors for persistent ectopic pregnancy are based on the type of surgical procedure, the initial β-hCG level, the duration of amenorrhea, and the size of the ectopic pregnancy. Patients treated with laparoscopic salpingostomy have a higher rate of persistent ectopic pregnancies compared to those treated with salpingostomy at the time of a laparotomy, with an incidence of persistence after laparoscopic linear salpingostomy ranging from 4% to 15% (49,177). Other risk factors for persistent ectopic pregnancies include very early gestations (amenorrhea less than 7 weeks’ duration), ectopic pregnancies less than 2 cm, and those with high starting β-hCG levels (183,185,229).


Gynecology_Novak

Gynecology_Novak. Persistent ectopic pregnancy can be treated surgically or medically; surgical therapy consists of either repeat salpingostomy or, more commonly, salpingectomy. Methotrexate offers an alternative to patients who are hemodynamically stable at the time of diagnosis. Methotrexate may be the treatment of choice because the persistent trophoblastic tissue may not be confined to the tube and, therefore, not readily identifiable during repeat surgical exploration (231–233).


Gynecology_Novak

Gynecology_Novak. Chronic ectopic pregnancy is a condition in which the pregnancy does not completely resorb during expectant management. The condition arises when there is persistence of the chorionic villi with bleeding into the tubal wall, which is distended slowly and does not rupture. It may arise from chronic bleeding from the fimbriated end of the fallopian tube with subsequent tamponade. In a series of 50 patients with a chronic ectopic pregnancy, pain was present in 86%, vaginal bleeding was present in 68%, and both symptoms were present in 58% (234). Ninety percent of the patients had amenorrhea ranging from 5 to 16 weeks (mean, 9.6 weeks). Most patients develop a pelvic mass that usually is symptomatic. The β-hCG level usually is low but may be absent; ultrasonography may be helpful in the diagnosis; rarely, bowel involvement or ureteral compression or obstruction exists (234,235).


Gynecology_Novak

Gynecology_Novak. This condition is treated surgically with removal of the affected tube. Often, the ovary must be removed because there is inﬂammation with subsequent adhesion development. A hematoma may be present secondary to chronic bleeding. Cervical Pregnancy The incidence of cervical pregnancy in the United States ranges from Pregnancy 1 in 2,400 to 1 in 50,000 pregnancies and accounts for less than 1% of ectopic pregnancies (236,237). The cause of cervical ectopic pregnancies is unknown and the rare occurrence prevents identification of known risk factors. The incidence does appear to be higher with in vitro fertilization procedures, accounting for 3.7% of IVF-related ectopic pregnancies (238). The clinical criteria for diagnosing a cervical pregnancy include the following findings (239): 1. Uterus is smaller than the surrounding distended cervix; 2. 3. 4. Profuse bleeding on manipulation of cervix.


Gynecology_Novak

Gynecology_Novak. Uterus is smaller than the surrounding distended cervix; 2. 3. 4. Profuse bleeding on manipulation of cervix. Patients classically present with painless vaginal bleeding, but reports of associated cramping and pain are published (240). Table 20.5 Ultrasound Criteria for Cervical Pregnancy 1. Gestational sac or placental tissue visualized within the cervix 2. Cardiac motion noted below the level of the internal os 3. 4. Hourglass uterine shape with ballooned cervical canal 5. No movement of the sac with pressure from transvaginal probe (i.e., no “sliding sign” that is typically seen with incomplete abortions) 6. Adapted from Kung FT, Lin H, Hsu TY, et al. Differential diagnosis of cervical ectopic pregnancy and conservative treatment with the combination of laparoscopy-assisted uterine artery ligation and hysteroscopic endocervical resection. Fertil Steril 2004;81:1642–1649.


Gynecology_Novak

Gynecology_Novak. When a cervical pregnancy is suspected, imaging studies are useful in confirming the diagnosis. Ultrasonographic diagnostic criteria are described that are helpful in differentiating a true cervical pregnancy from an ongoing spontaneous abortion (Table 20.5). MRI of the pelvis is used in this situation (241). Other potential diagnoses that must be differentiated from cervical pregnancy include cervical carcinoma, cervical or prolapsed submucousal leiomyomas, trophoblastic tumor, placenta previa, and low-lying placenta.


Gynecology_Novak

Gynecology_Novak. Management of cervical ectopic pregnancies includes medical treatment with methotrexate and surgical dilation and curettage. The ideal regimen for medical management is unknown and success is reported with both the single-and multidose regimens, as previously described. More advanced gestations, especially with fetal cardiac activity, may require a combination of multidose methotrexate and intra-amniotic/intrafetal injection of PCl. These injections require skill to avoid rupture of membranes during the procedure (240). As with tubal ectopic pregnancies, medical management is appropriate only for those patients who are hemodynamically stable. If the patient and physician elect to proceed with surgical management, the preoperative preparation should include blood typing and cross-matching, establishment of intravenous access, and detailed informed consent. This consent should include the possibility of hemorrhage that may require transfusion or hysterectomy.


Gynecology_Novak

Gynecology_Novak. The diagnosis may not be suspected until the patient is undergoing suction curettage for a presumed incomplete abortion and hemorrhage occurs. In some cases, bleeding is light, whereas in others, there is hemorrhage. Various techniques that can be used to control bleeding include uterine packing, lateral cervical suture placement to ligate the lateral cervical vessels, placement of a cerclage, and insertion of an intracervical 30-mL Foley catheter in an attempt to tamponade the bleeding. Alternatively, angiographic artery embolization can be used. If laparotomy is required, an attempt can be made to ligate the uterine or internal iliac arteries (242–244). When none of these methods is successful, hysterectomy is required.


Gynecology_Novak

Gynecology_Novak. Ovarian Pregnancy A pregnancy confined to the ovary accounts for up to 3% of all ectopic pregnancies and is the most common type of nontubal ectopic pregnancy (1). The incidence ranges from 1 in 40,000 to 1 in 7,000 deliveries (245,246). The diagnostic criteria were described in 1878 by Spiegelberg (Table 20.6) (247). Unlike tubal gestation, ovarian pregnancy is associated with neither PID nor infertility. The risk of ovarian ectopic pregnancies in patients using IUDs is controversial. Patients have symptoms similar to those of ectopic pregnancies in other sites. Misdiagnosis is common because it is confused with a ruptured corpus luteum in up to 75% of cases (245). As with other types of ectopic pregnancy, an ovarian pregnancy was reported after hysterectomy (248). Ultrasonography makes preoperative diagnosis possible in some cases (249).


Gynecology_Novak

Gynecology_Novak. The treatment of ovarian pregnancy has changed. Whereas oophorectomy was advocated in the past, ovarian cystectomy and/or wedge resection is now utilized with success (250–252). Successful treatment with methotrexate is reported (253–255). Table 20.6 Criteria for Ovarian Pregnancy Diagnosis 1. The fallopian tube on the affected side must be intact. 2. The fetal sac must occupy the position of the ovary. 3. The ovary must be connected to the uterus by the ovarian ligament. 4. Ovarian tissue must be located in the sac wall. From Spiegelberg O. Casusistik der ovarialschwangerschaft. Arch Gynaecol 1878;13:73.


Gynecology_Novak

Gynecology_Novak. Abdominal Pregnancy Abdominal pregnancies are classified as primary and secondary. Listed in Table 20.7 are criteria for classifying a primary abdominal pregnancy. Secondary abdominal pregnancies are the most common and result from tubal abortion or rupture or, less often, from subsequent implantation within the abdomen after uterine rupture. The incidence of abdominal pregnancy varies from 1 in 372 to 1 in 9,714 live births and accounts for 1.4% of ectopic pregnancies (1,256). Risk factors for abdominal pregnancy include PID, multiparity, endometriosis, assisted reproductive techniques, and tubal damage (257,258). Abdominal pregnancy is associated with high morbidity and mortality, with the risk for death seven to eight times greater than from tubal ectopic pregnancy and 50 times greater than from intrauterine pregnancy (256). There are scattered reports of term abdominal pregnancies. When this occurs, perinatal morbidity and mortality are high, usually as a result of growth


Gynecology_Novak

Gynecology_Novak. greater than from intrauterine pregnancy (256). There are scattered reports of term abdominal pregnancies. When this occurs, perinatal morbidity and mortality are high, usually as a result of growth restriction and congenital anomalies such as fetal pulmonary hypoplasia, pressure deformities, and facial and limb asymmetry. The incidence of congenital anomalies ranges from 20% to 40% (259,260).


Gynecology_Novak

Gynecology_Novak. The presentation of patients with an abdominal pregnancy varies and depends on the gestational age. In the first and early second trimesters, the symptoms may be the same as with tubal ectopic gestation; in advanced abdominal pregnancy, the clinical presentation is more variable. The patient may report painful fetal movement, fetal movements high in the abdomen, or sudden cessation of movements. Physical examination may disclose persistent abnormal fetal positioning, abdominal tenderness, a displaced uterine cervix, easy palpation of fetal parts, and palpation of the uterus separate from the gestation. The diagnosis may be suspected when there are no uterine contractions after oxytocin infusion. Other diagnostic aids include abdominal radiography, abdominal ultrasonography, CT, and MRI (261–263).


Gynecology_Novak

Gynecology_Novak. Because the pregnancy can continue to term, the potential maternal morbidity and mortality are very high. As a result, surgical intervention is recommended when an abdominal pregnancy is diagnosed. At surgery, the placenta can be removed if its vascular supply can be identified and ligated, but hemorrhage can occur, requiring abdominal packing that is left in place and removed after 24 to 48 hours. Angiographic arterial embolization was described (264). If the vascular supply cannot be identified, the cord is ligated near the placental base, and the placenta is left in place. Placental involution can be monitored using serial ultrasonography and assessment of β-hCG levels. Potential complications of leaving the placenta in place include bowel obstruction, fistula formation, and sepsis as the tissue degenerates. There are concerns regarding the use of methotrexate treatment in abdominal pregnancies. Specifically, there is


Gynecology_Novak

Gynecology_Novak. Table 20.7 Studdiford’s Criteria for Diagnosis of Primary Abdominal Pregnancy 1. Presence of normal tubes and ovaries with no evidence of recent or past pregnancy. 2. No evidence of uteroplacental fistula. 3. The presence of a pregnancy related exclusively to the peritoneal surface and early enough to eliminate the possibility of secondary implantation after primary tubal nidation. Adapted from Anderson PM, Opfer EK, Busch JM, et al. An early abdominal wall ectopic pregancy successfully treated with ultrasound guided intralesional methotrexate: a case report. Obstet Gynecol Int 2009; Article ID 247452 theoretically an increased risk of infection and sepsis resulting from the rapid tissue necrosis that occurs following methotrexate administration (265). There are reports of successful treatment of abdominal pregnancies with methotrexate in patients not considered to be optimal surgical candidates (266).


Gynecology_Novak

Gynecology_Novak. Interstitial Pregnancy Interstitial pregnancies represent about 2.4% of ectopic pregnancies (1). This section of the fallopian tube is relatively thick with an increased capacity to expand prior to rupture. This ability may allow these types of ectopic pregnancies to remain asymptomatic for 7 to 16 weeks of gestation (267). Late presentations are rare and these patients typically present between 6 to 8 weeks of gestation, similar to other types of ectopic pregnancies (268,269). The diagnosis of an interstitial ectopic pregnancy can be difficult, because this area has a relatively high level of vascular supply. Interstitial pregnancies represent a disproportionately large percentage of fatalities from ectopic pregnancy with a 2.5% mortality rate (268,270).


Gynecology_Novak

Gynecology_Novak. Treatment classically was a cornual resection by laparotomy, but early detection allows for a more conservative management approach in hemodynamically stable patients without evidence of rupture. Medical management with methotrexate is well described, with both the single-and multidose regimens. Approximately 10% to 20% of patients treated medically will ultimately require surgery and close follow-up, as is warranted with all medically managed ectopic pregnancies (271). Although cornual wedge resection by laparotomy is an acceptable surgical option, minimally invasive techniques were described, including cornual excision, minicornual excision, and cornuostomy. Laparoscopic approaches are more widely used and are dependent on surgical skill. Transcervical suction evacuation under laparoscopic or ultrasound guidance is reported (271). The appropriate surgical technique and approach depends on the individual patient presentation and the surgeon’s expertise.


Gynecology_Novak

Gynecology_Novak. Interligamentous Pregnancy Interligamentous pregnancy is a rare form of ectopic pregnancy that occurs in about 1 of 300 ectopic pregnancies (272). An interligamentous pregnancy usually results from trophoblastic penetration of a tubal pregnancy through the tubal serosa and into the mesosalpinx, with secondary implantation between the leaves of the broad ligament. It can occur if a uterine fistula develops between the endometrial cavity and the retroperitoneal space. As in abdominal pregnancy, with interligamentous pregnancy the placenta may be adherent to the uterus, bladder, and pelvic side walls. If possible, the placenta should be removed; when this is not possible, it can be left in situ and allowed to resorb. Cases of live birth are reported with this type ectopic gestation (272).


Gynecology_Novak

Gynecology_Novak. Heterotropic Pregnancy Heterotropic pregnancy occurs when intrauterine and ectopic pregnancies coexist. The reported incidence varies widely from 1 in 100 to 1 in 30,000 pregnancies (273). Patients who underwent assisted reproduction have a much higher incidence of heterotropic pregnancy than those who have a spontaneous conception (274,275). An intrauterine pregnancy is seen during ultrasonography examination, and an extrauterine pregnancy may be overlooked, delaying diagnosis. Serial β-hCG levels are not helpful because the intrauterine pregnancy causes the β-hCG level to rise appropriately.


Gynecology_Novak

Gynecology_Novak. The ectopic pregnancy is treated surgically if the intrauterine pregnancy is desired. When the ectopic pregnancy is removed, the intrauterine pregnancy continues in most patients. The rate of spontaneous abortion is higher with approximately one in three ending in miscarriage (276,277). It may be possible to treat the ectopic pregnancy using nonchemotherapeutic medical treatment, such as KCl, by transvaginal or laparoscopically directed injection; however, a reported 55% may require additional surgical treatment (278).


Gynecology_Novak

Gynecology_Novak. Multiple Ectopic Pregnancies Twin or multiple ectopic gestations occur less frequently than heterotropic gestations and may appear in a variety of locations and combinations. Multiple ectopic pregnancies are thought to be rare, but with the advent of assisted reproductive technologies the incidence appears to be rising. A recent review of bilateral tubal pregnancies reported 242 cases between 1918 and 2007, with 42 cases in the past 10 years alone. Fifty percent of these twin tubal pregnancies were associated with assisted reproductive technologies (279). Another review of 163 cases of tubal ectopic pregnancies had a reported rate of twin tubal pregnancies of 2.4% (280). Although most reports are confined to twin tubal gestations, ovarian, interstitial, and abdominal twin pregnancies were reported. Twin and triplet gestations were reported following partial salpingectomy and IVF (281,282). Management is similar to that of other types of ectopic pregnancy and is somewhat dependent on


Gynecology_Novak

Gynecology_Novak. reported. Twin and triplet gestations were reported following partial salpingectomy and IVF (281,282). Management is similar to that of other types of ectopic pregnancy and is somewhat dependent on the location of the pregnancy.


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Gynecology_Novak. Pregnancy after Hysterectomy The most unusual form of ectopic pregnancy is one that occurs after vaginal or abdominal hysterectomy (283,284). Such a pregnancy may occur after supracervical hysterectomy because the patient has a cervical canal that may provide intraperitoneal access. Pregnancy may occur in the perioperative period with implantation of the already fertilized ovum in the fallopian tube. Pregnancy after total hysterectomy probably occurs secondary to a vaginal mucosal defect that allows sperm into the abdominal cavity. 1. Bouyer J, Coste J, Fernandez H, et al. Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases. Hum Reprod 2002;17:3224–3230. 2. Wilcox AJ, Weinberg CR, O’Connor JF, et al. Incidence of early loss of pregnancy. N Engl J Med 1988;319:189–194. 3. Wang X, Chen C, Wang L, et al. Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. Fertil Steril 2003;79:577–584. 4.


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Gynecology_Novak. 3. Wang X, Chen C, Wang L, et al. Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. Fertil Steril 2003;79:577–584. 4. Hill LM, Guzick D, Fries J, et al. Fetal loss rate after ultrasonically documented cardiac activity between 6 and 14 weeks, menstrual age. J Clin Ultrasound 1991;19:221–223. 5. Juliano M, Dabulis S, Heffner A. Characteristics of women with fetal loss in symptomatic first trimester pregnancies with documented fetal cardiac activity. Ann Emerg Med 2008;52:143–147. 6. Wyatt PR, Owolabi T, Meier C, et al. Age-specific risk of fetal loss observed in a second trimester serum screening population. Am J Obstet Gynecol 2005;192:240–246. 7. Stirrat GM. Recurrent miscarriage. Lancet 1990;336:673–675. 8. Deaton JL, Honore GM, Huffman CS, et al. Early transvaginal ultrasound following an accurately dated pregnancy: the importance of finding a yolk sac or fetal heart motion. Hum Reprod 1997;12:2820–2823. 9.


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Gynecology_Novak. 9. Nybo Andersen AM, Wohlfahrt J, Christens P, et al. Maternal age and fetal loss: population based register linkage study. BMJ 2000;320:1708–1712. 10. Kleinhaus K, Perrin M, Friedlander Y, et al. Paternal age and spontaneous abortion. Obstet Gynecol 2006;108:369–377. 11. Buss L, Tolstrup J, Munk C, et al. Spontaneous abortion: a prospective cohort study of younger women from the general population in Denmark. Validation, occurrence and risk determinants. Acta Obstet Gynecol Scand 2006;85:467–475. 12. Chatenoud L, Parazzini F, di Cintio E, et al. Paternal and maternal smoking habits before conception and during the first trimester: relation to spontaneous abortion. Ann Epidemiol 1998;8:520– 526. 13. Nielsen A, Hannibal CG, Lindekilde BE, et al. Maternal smoking predicts the risk of spontaneous abortion. Acta Obstet Gynecol Scand 2006;85:1057–1065. 14.


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Gynecology_Novak. 13. Nielsen A, Hannibal CG, Lindekilde BE, et al. Maternal smoking predicts the risk of spontaneous abortion. Acta Obstet Gynecol Scand 2006;85:1057–1065. 14. Perriera L, Reeves MF. Ultrasound criteria for diagnosis of early pregnancy failure and ectopic pregnancy. Semin Reprod Med 2008;26:373–382. 15. Makrydimas G, Sebire NJ, Lolis D, et al. Fetal loss following ultrasound diagnosis of a live fetus at 6–10 weeks of gestation. Ultrasound Obstet Gynecol 2003;22:368–372. 16. Sotiriadis A, Papatheodorou S, Makrydimas G. Threatened miscarriage: evaluation and management. BMJ 2004;329:152–155. 17. Gerhard I, Gwinner B, Eggert-Kruse W, et al. Double-blind controlled trial of progesterone substitution in threatened abortion. Biol Res Pregnancy Perinatol 1987;8:26–34. 18. Harrison RF. A comparative study of human chorionic gonadotropin, placebo, and bed rest for women with early threatened abortion. Int J Fertil Menopausal Stud 1993;38:160–165. 19.


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Gynecology_Novak. 18. Harrison RF. A comparative study of human chorionic gonadotropin, placebo, and bed rest for women with early threatened abortion. Int J Fertil Menopausal Stud 1993;38:160–165. 19. Lykke JA, Dideriksen KL, Lidegaard O, et al. First-trimester vaginal bleeding and complications later in pregnancy. Obstet Gynecol 2010;115:935–944. 20. Weiss JL, Malone FD, Vidaver J, et al. Threatened abortion: a risk factor for poor pregnancy outcome, a population-based screening study. Am J Obstet Gynecol 2004;190:745–750. 21. Leitich H, Bodner-Adler B, Brunbauer M, et al. Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol 2003;189:139–147. 22. American College of Obstetrics and Gynecology. ACOG Practice Bulletin. Prevention of Rh D alloimmunization. Number 4, May 1999 (replaces educational bulletin Number 147, October 1990). Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet 1999;66:63–70. 23.


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Gynecology_Novak. 23. Ballagh SA, Harris HA, Demasio K. Is curettage needed for uncomplicated incomplete spontaneous abortion? Am J Obstet Gynecol 1998;179:1279–1282. 24. Jurkovic D, Ross JA, Nicolaides KH. Expectant management of missed miscarriage. Br J Obstet Gynaecol 1998;105:670–671. 25. Zhang J, Gilles JM, Barnhart K, et al. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med 2005;353:761–769. 26. Blum J, Winikoff B, Gemzell-Danielsson K, et al. Treatment of incomplete abortion and miscarriage with misoprostol. Int J Gynaecol Obstet 2007;99(Suppl 2):S186–S189. 27. Seeber BE, Barnhart KT. Suspected ectopic pregnancy. Obstet Gynecol 2006;107:399–413. 28. Anonymous. Ectopic pregnancy—United States, 1990–1992. MMWR Morb Mortal Wkly Rep 1995;44:46–48. 29. Anonymous. Ectopic pregnancy—United States, 1988–1989. MMWR Morb Mortal Wkly Rep 1992;41:591–594. 30.


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Gynecology_Novak. 29. Anonymous. Ectopic pregnancy—United States, 1988–1989. MMWR Morb Mortal Wkly Rep 1992;41:591–594. 30. Yao M, Tulandi T. Current status of surgical and nonsurgical management of ectopic pregnancy. Fertil Steril 1997;67:421–433. 31. Murray H, Baakdah H, Bardell T, et al. Diagnosis and treatment of ectopic pregnancy. CMAJ 2005;173:905–912. 32. Ankum WM, Mol BW, Van der Veen F, et al. Risk factors for ectopic pregnancy: a meta-analysis. Fertil Steril 1996;65:1093– 1099. 33. Buckley RG, King KJ, Disney JD, et al. History and physical examination to estimate the risk of ectopic pregnancy: validation of a clinical prediction model. Ann Emerg Med 1999;34:589–594. 34. Dart RG, Kaplan B, Varaklis K. Predictive value of history and physical examination in patients with suspected ectopic pregnancy. Ann Emerg Med 1999;33:283–290. 35. Stovall TG, Kellerman AL, Ling FW, et al. Emergency department diagnosis of ectopic pregnancy. Ann Emerg Med 1990;19:1098– 1103. 36.


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Gynecology_Novak. 40. Mol BW, Ankum WM, Bossuyt PM, et al. Contraception and the risk of ectopic pregnancy: a meta-analysis. Contraception 1995;52:337–341. 41. Peterson HB, Xia Z, Hughes JM, et al. The risk of ectopic pregnancy after tubal sterilization. U.S. Collaborative Review of Sterilization Working Group. N Engl J Med 1997;336:762–767. 42. Rock JA, Guzick DS, Katz E, et al. Tubal anastomosis: pregnancy success following reversal of Falope ring or monopolar cautery sterilization. Fertil Steril 1987;48:13–17. 43. Henderson SR. The reversibility of female sterilization with the use of microsurgery: a report on 102 patients with more than one year of follow-up. Am J Obstet Gynecol 1984;149:57–65. 44. Spivak MM, Librach CL, Rosenthal DM. Microsurgical reversal of sterilization: a six-year study. Am J Obstet Gynecol 1986;154:355– 361. 45.


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Gynecology_Novak. 277. Goldberg JM, Bedaiwy MA. Transvaginal local injection of hyperosmolar glucose for the treatment of heterotopic pregnancies. Obstet Gynecol 2006;107:509–510. 278. Goldstein JS, Ratts VS, Philpott T, et al. Risk of surgery after use of potassium chloride for treatment of tubal heterotopic pregnancy. Obstet Gynecol 2006;107:506–508. 279. De Los Rios JF. Bilateral ectopic pregnancy. J Minim Invasive Gynecol 2007;14:419–427. 280. Svirsky R, Maymon R, Vaknin Z, et al. Twin tubal pregnancy: a rising complication? Fertil Steril 2010;94:1910.e13–e16. 281. Adair CD, Benrubi GI, Sanchez-Ramos L, et al. Bilateral tubal ectopic pregnancies after bilateral partial salpingectomy: a case report. J Reprod Med 1994;39:131–133. 282. Goffner L, Bluth MJ, Fruauff A, et al. Ectopic gestation associated with intrauterine triplet pregnancy after in vitro fertilization. J Ultrasound Med 1993;12:63–64. 283.


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Gynecology_Novak. 282. Goffner L, Bluth MJ, Fruauff A, et al. Ectopic gestation associated with intrauterine triplet pregnancy after in vitro fertilization. J Ultrasound Med 1993;12:63–64. 283. Jackson P, Barrowclough IW, France JT, et al. A successful pregnancy following total hysterectomy. Br J Obstet Gynaecol 1980;87:353–355. 284. Nehra PC, Loginsky SJ. Pregnancy after vaginal hysterectomy. Obstet Gynecol 1984;64:735–737. Camelia A. Lawrence Baiba J. Grube Armando E. Giuliano Early detection of breast cancer is improved by risk assessment, clinical breast examination, screening mammography, and magnetic resonance imaging in selected patients. Triple-test concordance requires agreement between results of clinical breast examination, breast imaging, and tissue diagnosis. In the absence of concordance, further diagnostic intervention is required.


Gynecology_Novak

Gynecology_Novak. The most common benign breast problems include fibrocystic changes and mastalgia. These problems are usually best treated by reassurance. Pharmaceutic agents are available but have side effects that usually are not well tolerated. Histologic differences exist between fibroadenomas and phyllodes tumors; phyllodes tumors require excision, whereas small asymptomatic fibroadenomas can be observed if the diagnosis is confirmed by histologic or cytologic assessment and there is no evidence of growth. Spontaneous, unilateral, bloody discharge requires histologic evaluation to exclude malignancy, but symptoms usually are caused by a benign process such as intraductal papilloma or duct ectasia. Breast abscesses are managed with fine needle aspiration and antibiotics; the use of incision and drainage is reserved for recurrence.


Gynecology_Novak

Gynecology_Novak. Breast abscesses are managed with fine needle aspiration and antibiotics; the use of incision and drainage is reserved for recurrence. Benign breast diseases are among the most common diagnoses that the busy obstetrician-gynecologist will see in practice. An ability to accurately and promptly diagnose both benign and malignant breast diseases is within the purview of the practicing gynecologist (1). Benign breast disease is a complex entity with a range of physiologic changes and clinical manifestations that have an impact on a woman’s health independent of breast cancer risk (2). History Evaluation of a new breast symptom begins with assessment of symptoms based on a thorough clinical history (3). The history should include questions regarding current symptoms, duration of the condition, ﬂuctuation of the signs and symptoms, and factors that aggravate or relieve the symptom. Assessment of breast problems should focus on the following points:


Gynecology_Novak

Gynecology_Novak. Nipple discharge Characteristics of discharge (spontaneous or nonspontaneous, appearance, unilat eral or bilateral, single or multiple duct involvement) Breast mass (size and change in size, density, or texture) Breast pain (cyclic versus continuous) Association of symptoms with menstrual cycle Change in breast shape, size, or texture Previous breast biopsies History of breast trauma The patient should be questioned about the following risk factors for breast cancer (see Chapter 40 for more details):


Gynecology_Novak

Gynecology_Novak. The patient should be questioned about the following risk factors for breast cancer (see Chapter 40 for more details): Increasing age (approximately 50% of breast cancers occur after age 65) Age of menarche less than 12 years Nulliparity or first pregnancy at greater than 30 years of age Late menopause (older than 55 years of age) Family history of breast cancer (especially premenopausal or bilateral disease) Number of first-degree relatives with breast cancer and their ages when diagnosed Family history of male breast cancer Inherited conditions associated with a high risk for breast cancer, including BRCA1 and BRCA2 genes, Li-Fraumeni syndrome, Cowden’s disease, ataxia telangiectasia syndrome, and Peutz-Jeghers syndrome Other malignancies (ovary, colon, and prostate) Pathology of previous breast biopsy showing atypia or lobular or ductal carcinoma Hormone therapy Alcohol consumption Postmenopausal weight gain Personal history of breast cancer


Gynecology_Novak

Gynecology_Novak. Hormone therapy Alcohol consumption Postmenopausal weight gain Personal history of breast cancer Breast cancer risk can be determined by the Gail Risk assessment model, which is available electronically (4). The Gail Risk assessment model calculates risk based on patient race, age, age of menarche, age of first live birth, number of first-degree relatives with breast cancer, number of previous breast biopsies, and presence of atypia on the biopsy.


Gynecology_Novak

Gynecology_Novak. It is important to obtain a current list of medications used, including hormone therapy and herbal medications such as phytoestrogens. The gestational history should take into consideration the possibility that the patient may be pregnant or has a prior history of miscarriage or abortion. A personal history of exposure to radiation, especially in the treatment of childhood malignancies, is associated with a higher incidence of developing breast cancer (5). The goal of breast evaluation is to determine clearly whether the symptom represents a benign breast condition or may be indicative of a neoplastic process.


Gynecology_Novak

Gynecology_Novak. Physical Examination Breast tumors, particularly cancerous ones, usually are asymptomatic and are discovered by the patient or through physical examination or screening mammography. Typically, the breast changes slightly during the menstrual cycle. During the premenstrual phase, most women have increased innocuous nodularity and mild engorgement of the breast. Rarely these characteristics can obscure an underlying lesion and make examination difficult. Findings should be carefully documented in the medical record to serve as a baseline for future reference.


Gynecology_Novak

Gynecology_Novak. Inspection Inspection is performed initially while the patient is seated comfortably with her arms relaxed at her sides. The breasts are compared for symmetry, contour, and skin appearance. Edema or erythema is identified easily, and skin dimpling or nipple retraction is shown by having the patient raise her arms above her head and then press her hands on her hips, thereby contracting the pectoralis muscles (Fig. 21.1). Palpable and even nonpalpable tumors that distort Cooper’s ligaments may lead to skin dimpling with these maneuvers. Figure 21.1 Raising the arm reveals retraction of the skin of the lower outer quadrant caused by a small palpable carcinoma. (From Kruper L, Giuliano AE. Breast disease. In: Berek JS, Hacker NF, eds. Berek & Hacker’s Gynecologic Oncology, 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010:615, with permission.)