Ectopic Pregnancy: Diagnosis, Treatment, and Risk Factors

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2. Ectopic Pregnancy • implantation of a fertilized ovum outside of the endometrial cavity, is a condition that is unique to primates. • Although ectopic pregnancy remains a leading cause of life-threatening first-trimester morbidity, informed clinical suspicion and modern diagnostic procedures now routinely lead to diagnosis and treatment at the early signs of symptoms.

3. Management of ectopic pregnancy has changed dramatically over the years. Medical therapy with systemic methotrexate, an intervention targeted specifically toward proliferating trophoblasts, is now often preferred to surgery as standard first-line treatment. However, surgery remains the first choice when rupture causes intraperitoneal hemorrhage, medical failures, neglected cases, and cases where medical therapy is contraindicated.

4. Incidence • Several recent epidemiologic trends make it likely that the current incidence of ectopic pregnancy is even higher. • First, there is a continued increase in the risk factors associated with ectopic pregnancy (Table 5.1). • Second, there is increased ascertainment of ectopics from use of more sensitive and specific diagnostic methods that detect many cases that in the past may have resolved spontaneously without diagnosis or treatment (increase in prevalence due to lead-time bias). • Third, with the increasing use of assisted reproductive technology (ART) for treatment of infertility, there is increased risk of ectopics, which comprise up to 5% of pregnancies achieved by using ART

5. High risk • Tubal ligation • Previous ectopic pregnancy • In utero exposure to DES • Use of IUD • Tubal pathology • Assisted reproduction

6. Moderate risk • Infertility • Previous genital infections • Multiple sexual partners • Salpingitisisthmicanodosa

7. Low risk • Previous pelvic infection • Cigarette smoking • Vaginal douching • First intercourse <18 y

8. In most tubal implantations, the proliferating trophoblast invades the tubal wall. • Ectopic pregnancies in the ampullary portion of the tube are often within the tubal lumen and have not caused tubal rupture, while those in the isthmic portion are more likely to be found outside the lumen, having caused tubal rupture. • The degree of trophoblastic invasion of maternal tissues, the age and viability of the pregnancy, and the site of implantation determine the sequence of clinical events.

9. As the trophoblasts proliferate, the growth may extend from the luminal mucosa, into the muscularis and lamina propria, through to the serosa and, ultimately, full thickness even into large blood vessels in the broad ligament. • With vascular disruption, bleeding takes place that distorts the tube, stretches the serosa, and causes pain. • The embryo is abnormal and degenerates in about 80% of cases.

10. If left untreated, spontaneous tubal abortion occurs in about 50% of tubal ectopic pregnancies and may often be clinically silent. • Likewise, spontaneous tubal abortion with hemorrhage can occur with bleeding that is self-limited. • However, the remaining cases of ectopic pregnancy will eventually cause tubal rupture and are associated with significant and possibly life-threatening hemorrhage • As noted previously, this complication is most likely to occur in the isthmic part of the tube, which has limited distensibility. • Chronic tubal rupture with extension into the broad ligament can produce a pelvic hematoma that can last for several weeks.

12. Tubal Damage and Infection • Patients with a previous ectopic pregnancy are six to eight times more likely to experience another ectopic pregnancy, and 8% to 14% of patients experience more than one ectopic pregnancy. • The approximate recurrent ectopic pregnancy rate is 13% after a history of one ectopic and 28% after two previous ectopics. • Patients with a history of tubal surgery have a 21-fold common adjusted odds ratio of ectopic pregnancy, but it is not clear if it is the tubal disease itself or the surgery required for the disease.

13. SalpingitisIsthmicaNodosa • Salpingitisisthmicanodosa is a disease defined by an anatomic thickening of the proximal portion of the fallopian tubes at the junction with the uterus and is histologically characterized by multiple luminal diverticula. • The etiology of this disease is not known; however, this pattern of tubal pathology increases the incidence of ectopic pregnancy by 52% in age- and race-matched controls

14. Cigarette Smoking • Patients who smoke cigarettes are at a slightly increased risk for ectopic pregnancy. • It is difficult to conceptualize the link between ectopic pregnancy and cigarettes. • Theories include impaired immunity in smokers predisposing them to pelvic infections, alterations in tubal motility, or a representation of a lifestyle associated with an increased risk of tubal infection

15. Contraception • Intrauterine devices (IUDs) have been associated with ectopic pregnancy. • A multicenter case-controlled study conducted by the World Health Organization in ten countries found an odds ratio of 6.4 for ectopic pregnancy in current IUD users compared with pregnant controls, whereas the odds ratio was only 0.5 when the comparison was made with nonpregnant controls. • Tubal ligation carries a similar risk for ectopic pregnancy to what is observed with current IUD use

16. Contraception • Oral contraceptives are associated with a reduced risk of ectopic pregnancy when compared with nonpregnant controls but with elevated risk when compared with pregnant controls. • This protection is presumably due to the suppression of ovulation by oral contraceptives. • It is therefore not surprising that patients who take emergency contraception, such as oral contraceptives after fertilization, are at substantial risk for an ectopic pregnancy. This has been attributed to altered tubal motility, but this etiology remains controversial. • Barrier contraception (condoms, spermicides, and diaphragms) also reduces the odds ratio of ectopic pregnancy. • An additional advantage may be attributed to the decreased risk of sexually transmitted diseases in women using barrier methods.

17. Signs and Symptoms • The classic symptoms of an ectopic pregnancy are abdominal or pelvic pain and vaginal bleeding or spotting in the context of a positive pregnancy test. • However, these symptoms may be variable, range from mild to severe, and are neither sensitive nor specific for the diagnosis of ectopic pregnancy. • The most common signs are detected on abdominal examination. • Abdominal tenderness is present in 90% of patients and rebound tenderness in 70%. • The pelvic examination is usually nonspecific; cervical motion tenderness is present in up to two thirds of patients, while a tender adnexal mass is present in 10% to 50%. • Pain radiating to the shoulder, syncope, and shock, as a result of hemoperitoneum, occur in up to 20% of patients and are indications for immediate surgical intervention

18. Diagnosis The diagnosis of ectopic pregnancy begins by excluding a normal intrauterine pregnancy. Transvaginal ultrasound examination should identify an intrauterine pregnancy with nearly 100% accuracy for gestations greater that 5آ½ weeks by identifying structures such as a gestational sac, a yolk sac, and fetal pole with later cardiac motion (usually seen around 6 weeks).

19. The hCG, produced by trophoblastic cells in normal pregnancy, has long been accepted to rise at least 66% and up to twofold every 2 days. • Recent data has shown that the minimum rise for a potentially viable pregnancy that presents with pain and/or vaginal bleeding may be as low as 53% in 2 days, based on the 99th percentile confidence interval (CI) around the mean of the curve of normal hCGrise. • This generally applies to hCGvalues below 10,000 mIU/mL.

20. Eight-five percent of abnormal pregnancies, whether intrauterine or ectopic, have impaired hCGproduction with an abnormal rate of hCGrise. • hCGlevels that plateau or fail to rise normally along with a low serum progesterone value should be considered nonviable. • Rapidly declining hCGvalues (at least 21% to 35% in 2 days) are likely consistent with a miscarriage that may resolve spontaneously but could still represent a spontaneously resolving ectopic gestation. • In such situations hCGlevels should be followed serially until no longer detectable, indicating complete resolution of the pregnancy, regardless of the implantation site.

21. If a viable intrauterine gestation is not visible by transvaginal ultrasonography when the hCGis above the discriminatory cutoff,‌ and no fetal heartbeat can be visualized in the adnexa, uterine curettage or manual vacuum extraction can be performed. • This intervention is necessary to accurately differentiate between an abnormal intrauterine gestation (spontaneous abortion) and an ectopic pregnancy. • Either treatment of a nonviable intrauterine pregnancy is performed or ectopic pregnancy is diagnosed when the uterine contents fail to demonstrate presence of chorionic villi on histologic examination or the hCGlevels do not fall appropriately postuterine evacuation..

22. Progesterone • progesterone levels are higher in intrauterine pregnancies than in ectopic pregnancies, there is no established cutoff to use to discriminate between these two entities. • A meta-analysis has shown that although low progesterone levels can identify patients at risk for ectopic pregnancy, this test alone is insufficient to diagnose ectopic pregnancy with certainty. • In addition, a low progesterone level of less than 5 ng/mL can rule out a normal pregnancy with almost 100% accuracy but does not differentiate whether that pregnancy is an abnormal one in the uterus or at an ectopic site

23. Ultrasonography • transvaginal ultrasonography reliably detects intrauterine gestations when the hCGlevels are between 1,500 and 2,500 mIU/mL (third IRP), or as early as 1 week after missed menses. • An intrauterine gestation should almost always be visualized when the hCGlevel is greater than 2,000 mIU/mL.

24. Diagnosis of an ectopic pregnancy can be made with 100% sensitivity but with low specificity (15% to 20%) if an extrauterine gestational sac containing a yolk sac or embryo is identified. • A complex adnexal mass without an intrauterine pregnancy improves specificity to 21% to 84% at the expense of lower sensitivity (93.0% to 99.5%). • In reviewing the literature, the presence of any noncystic, extraovarian adnexal mass in the absence of an intrauterine gestation was diagnostic of an ectopic pregnancy with 98.9% sensitivity, 96.3% positive predictive value, 84.4% specificity, and a 94.8% negative predictive value):1393-8

25. serial hCGand ultrasonography alone cannot diagnose all ectopic pregnancies. • In order to make the definitive diagnosis and differentiate an abnormal intrauterine from an ectopic pregnancy, uterine evacuation for tissue diagnosis is necessary. • In order to minimize the inadvertent interruption of a desired intrauterine pregnancy, a high (not low) discriminatory zone should be used before uterine evacuation is considered

26. Treatment for Ectopic Pregnancy • Medical Management • Hemodynamically stable patients with unruptured ectopic pregnancy measuring less than or equal to 4 cm by ultrasonography are eligible for methotrexate therapy. • Patients with larger masses or evidence of acute intra-abdominal bleeding should undergo immediate surgical treatment. • Methotrexate treatment regimens are shown in include the multiple dose, single dose, and the newly introduced two-dose protocol.

27. Prior to instituting methotrexate therapy, physicians should evaluate baseline laboratory values. • The patient should be screened with a complete blood count, liver function tests, and serum creatinine. • A chest x-ray should be considered in women reporting a history of prior pulmonary disease due to their risk of developing methotrexate-related interstitial pneumonitis

28. Transient pelvic pain from tubal bleeding or hematoma formation at the ectopic site frequently occurs 3 to 7 days after the start of therapy, lasts 4 to 12 hours, and is presumably due to tubal abortion. • Perhaps the most difficult aspect of methotrexate therapy is learning to distinguish the transient abdominal pain of successful therapy from that of a rupturing ectopic pregnancy. • Physicians must therefore carefully observe for clinical indications that an operation is necessary • Thus, surgical intervention is required when pain is worsening and persistent beyond 12 hours. • Orthostatic hypotension or a falling hematocrit should lead to immediate surgery. Sometimes, it is necessary to hospitalize thepatient with pain for observation (usually about 24 hours) to insure a correct diagnosis

29. Side Effects • High doses of methotrexate can cause bone marrow suppression, hepatotoxicity, stomatitis, pulmonary fibrosis, alopecia, and photosensitivity. • These side effects are infrequent in the short treatment schedules used in ectopic pregnancy and can be attenuated by the administration of leucovorin (citrovorum factor). • The side effects of methotrexate resolve within 3 to 4 days after the therapy is discontinued. • Impaired liver function is the most common side effect. • Other side effects include stomatitis, gastritis and enteritis, and bone marrow suppression. • Local therapy by direct injection of methotrexate into the ectopic gestation resulted in fewer side effects, likely because of less systemic absorption. • Even with local injection, impaired liver function tests, gastritis and enteritis, and bone marrow suppression can occur.

30. Multiple-dose systemic methotrexate is the first-line medical treatment for ectopic pregnancy. Nearly half of patients under a multidose protocol will require fewer doses for ectopic pregnancy resolution. (Strength of recommendation: A.)

31. Surgical Treatment • The laparoscopic approach is associated with less blood loss, less analgesia requirement, and a shorter duration of hospital stay. • In addition, cost analysis has demonstrated significant savings in randomized trials. • When evaluating subsequent fertility, intrauterine pregnancy rates are comparable for laparoscopy and laparotomy, as are rates of recurrent ectopic pregnancy.

32. linear salpingostomy • salpingectomy

33. Persistent Ectopic Pregnancy Following Salpingostomy • Risk factors for persistent ectopic: include • a very early gestation, • a small ectopic of <2 cm, or • high starting concentrations of hCG preoperatively • treated successfully by using single-dose systemic methotrexate

34. Heterotopic Pregnancy • Heterotopic pregnancies occur in 1% to 3% of pregnancies following ART procedures and are usually diagnosed incidentally on routine follow-up ultrasonographic studies. • This increased prevalence of heterotopic pregnancies following ART may be related to ovarian hyperstimulation and multiple ovum development. • Of 111 reported heterotopic pregnancies following ART, 88.3% were tubal, 6.3% cornual, 2.7% abdominal, 1.8% cervical, and 0.9% ovarian

35. Abdominal Pregnancy • The incidence of abdominal pregnancy is estimated at 1 in 8,000 births and represents 1.4% of all ectopic pregnancies. • The prognosis is poor, with an estimated maternal mortality rate of 5.1 per 1,000 cases. • The risk of dying from an abdominal pregnancy is 7.7 times higher than from other forms of ectopic pregnancy. • The high rate of morbidity and mortality from abdominal pregnancy often results from a delay in diagnosis. • Abdominal pregnancies can be categorized as primary or secondary. • These ectopic pregnancies may become apparent anywhere throughout gestation, from the first trimester to fetal viability. • Symptoms may vary from those considered normal for pregnancy to severe abdominal pain, intra-abdominal hemorrhage, and hemodynamic instability..

36. Primary abdominal pregnancies are rare and are thought to occur as a result of primary peritoneal implantation. • They usually abort early in the first trimester due to hemorrhagic disruption of the implantation site and hemoperitoneum. • Secondary abdominal pregnancies occur with reimplantation after a partial tubal abortion or intraligamentary extension following tubal rupture. • Historical criteria to distinguish between primary and secondary abdominal pregnancies are moot, because treatment is guided by the clinical picture

37. TUBAL REANASTOMOSIS hospitalization is recommended. If time permits, bowel preparation, administration of prophylactic antibiotics, and adequate blood replacement should be made available prior to an operative delivery. Unless the placenta is implanted on major vessels or vital structures, it should be removed

38. Sterilization reversal, although not always successful, is the most successful surgical reconstructive procedure for improving fertility. Factors that may influence the success rate of tubal reanastomosis include the age of the patient, time from sterilization, and sterilization technique.

39. Ovarian Pregnancy • Ovarian pregnancy, the most common form of abdominal pregnancy, is rare, accounting for less than 3% of all ectopic gestations. • Clinical findings are similar to those of tubal ectopic gestations: abdominal pain, amenorrhea, and abnormal vaginal bleeding. • In addition, hemodynamic instability as a result of rupture occurs in 30% of patients. • Women with ovarian pregnancies are usually young and multiparous, but the factors leading to ovarian pregnancies are not clear. • The diagnosis usually is made by the pathologist because many ovarian pregnancies are mistaken for a ruptured corpus luteum or other ovarian tumors. • Only 28% of cases were diagnosed correctly at time of laparotomy. The recommended treatment is cystectomy, wedge resection, or oophorectomy during laparotomy, although laparoscopic removal has been successful

40. Cornual Pregnancy • Cornual or interstitial pregnancy accounts for 4.7% of ectopic gestations and carries a 2.2% maternal mortality. • Clinically, a pregnancy implanted at this site where the fallopian tube is traversing the muscular wall of the uterus is seen as a swelling lateral to the round ligament. • Almost all cases are diagnosed after the patient is symptomatic. The most frequent symptoms are menstrual aberration, abdominal pain, abnormal vaginal bleeding, and shock, resulting from the brisk hemorrhage associated with uterine rupture. • Due to myometrial distensibility, rupture is usually delayed, occurring at 9 to 12 weeks gestation. • A unique risk factor for interstitial pregnancy is previous salpingectomy, present in about 25% of patients. • Only a high index of suspicion and repeated ultrasonographic examination with Doppler flow studies allows early diagnosis. • With a timely early diagnosis, alternatives to the traditional cornual resection during laparotomy have been performed successfully.

41. These include laparoscopic cornual resection, systemic methotrexate administration, local injection of methotrexate, potassium chloride injection, and removal by hysteroscopy. • Regardless of the initial treatment attempted, if uncontrolled hemorrhage occurs, immediate laparotomy with uterine repair or hysterectomy is warranted to stop the blood loss • .

42. Cervical Pregnancy • The incidence of cervical pregnancy ranges from 1 in 2,500 to 1 in 12,422 pregnancies. • The most common predisposing factor is a prior D&C, present in 68.6% of patients. • Interestingly, 31% of these were performed for termination of pregnancy. • Other predisposing factors implicated in cervical pregnancies are previous cesarean delivery and IVF • The cervix is usually enlarged, globular, or distended.

43. When the patient is hemodynamically stable, conservative therapy commonly is employed. • There are no large studies—only several case series for clinical guidance. These have shown that use of methotrexate, local prostaglanding or hyperosmolar glucose injection, curettage, or a combination of these methods have been successful. • Prior to curettage, uterine artery embolization minimizes the substantial risk of postevacuation hemorrhage. • Systemic and local treatment with various agents carries an overall success rate of 81.3%. • Unfortunately, massive hemorrhage may occur despite conservative measures, and hysterectomy may be the only lifesaving option