Goran Augustin1, 2
(1)
Department of Surgery Division of Gastrointestinal Surgery, University Hospital Center Zagreb, Zagreb, Croatia
(2)
School of Medicine University of Zagreb, Zagreb, Croatia
15.1 Ectopic Pregnancy in General
If one is confronted with a pelvic condition that follows no rules and conforms to no standards, he should think of ectopic pregnancy and pelvic tuberculosis. Howard A. Kelly
15.1.1 Incidence
Although the total number of pregnancies has declined over the past two decades, the rate of ectopic pregnancy has increased dramatically. It is defined as implantation of a fertilized egg outside the uterine endometrium. The Centers for Disease Control and Prevention (CDC) reported that the number of ectopic pregnancies quadrupled from 17,800 in 1970 to 88,000 in 1989 [1]. This is an increase in rate from 4.5 to 16.8/1,000. In 1992, CDC estimated the US ectopic pregnancy rate at 1.97 % of all pregnancies [2] and appears to be rising [3]. Ectopic pregnancy caused an estimated 876 US deaths between 1980 and 2007 [4]. The prevalence of ectopic pregnancy among women who go to an emergency department with first trimester bleeding, pain, or both ranges from 6 to 16 % [5]. Ectopic pregnancy occurs with some seasonal variation and is most common in June and December [6]. The reason is unclear; the authors postulated that reproduction is seasonal, depends on photoperiod and temperature, and varies with different latitudes.
15.1.2 Risk Factors
The overall risk is approximately 1/200 pregnancies but may be increased 20- to 100-fold in certain subsets of women. These risk factors include [3, 7]:
· Previous laparoscopically proven pelvic inflammatory disease (PID)
· Previous tubal (ectopic) pregnancy
· Current intrauterine device use
· Previous tubal surgery, including tubal sterilization
· Previous infertility treatments
As many as 50 % of uterine tubes removed because of an ectopic pregnancy show prior inflammatory disease. The increased incidence of PID is thought to be a major factor in the increased numbers of ectopic pregnancies [8]. Although the risk of pregnancy is very low with a tubal ligation, if a pregnancy does occur, there is a significantly higher risk of the gestation being an ectopic one. Of those pregnancies occurring after tubal ligation, 10–50 % are ectopic, which represents a 20- to 100-fold increased risk [9].
15.1.3 Classification
15.1.3.1 Tubal Pregnancy
The vast majority of ectopic pregnancies implant in the Fallopian tube. Pregnancies can grow in the fimbrial end (11 %), the ampullary section (70 %), the isthmus (12 %), and the cornual and interstitial part of the tube (2 %) [10].
A review published in 2010 supports the hypothesis that tubal ectopic pregnancy is caused by a combination of retention of the embryo within the Fallopian tube due to impaired embryo-tubal transport and alterations in the tubal environment allowing early implantation to occur [11].
15.1.3.2 Non-tubal Ectopic Pregnancy
Two percent of ectopic pregnancies occur in the ovary, cervix, or intra-abdominally [10]. Transvaginal ultrasound examination is usually able to detect a cervical pregnancy. An ovarian pregnancy is differentiated from a tubal pregnancy by the Spiegelberg criteria [12].
· Gestational sac is located in the region of the ovary.
· Ectopic pregnancy is attached to the uterus by the ovarian ligament.
· Ovarian tissue in the wall of the gestational sac is proved histologically.
· Fallopian tube of the involved side is intact.
While a fetus of ectopic pregnancy is typically not viable, very rarely, a live baby has been delivered from an abdominal pregnancy. In such a situation, the placenta sits on the intra-abdominal organs or the peritoneum and has found sufficient blood supply. This is generally bowel or mesentery, but other sites, such as the renal (kidney), liver, or hepatic (liver) artery or even aorta have been described. Support to near viability has occasionally been described, but even in third-world countries, the diagnosis is most commonly made at 16–20 weeks gestation. Such a fetus would have to be delivered by laparotomy.
Maternal morbidity and mortality from extrauterine pregnancy are high as attempts to remove the placenta from the organs to which it is attached usually lead to uncontrollable bleeding from the attachment site. If the organ to which the placenta is attached is removable, such as a section of bowel, then the placenta should be removed together with that organ.
This is such a rare occurrence that true data are unavailable and reliance must be made on anecdotal reports [13]. However, the vast majority of abdominal pregnancies require intervention well before fetal viability because of the risk of hemorrhage.
15.1.3.3 Heterotopic Pregnancy
In rare cases of ectopic pregnancy, there may be two fertilized eggs, one outside the uterus and the other inside. This is called a heterotopic pregnancy. Often the intrauterine pregnancy (IUP) is discovered later than the ectopic, mainly because of the painful emergency nature of ectopic pregnancies. Although rare, heterotopic pregnancies are becoming more common, likely due to increased use of IVF. The survival rate of the uterine fetus of an ectopic pregnancy is around 70 %. Successful pregnancies have been reported from ruptured tubal pregnancy continuing by the placenta implanting on abdominal organs or on the outside of the uterus.
15.1.3.4 Persistent Ectopic Pregnancy
A persistent ectopic pregnancy refers to the continuation of trophoblastic growth after a surgical intervention to remove an ectopic pregnancy. After a conservative procedure that attempts to preserve the affected Fallopian tube such as a salpingotomy, in 15–20 % the major portion of the ectopic growth may have been removed, but some trophoblastic tissue, perhaps deeply embedded, has escaped removal and continues to grow, generating a new rise in βHCG levels [14]. After weeks, this may lead to new clinical symptoms including bleeding. A decline of less than 55 % at day 3 predicts persistent ectopic pregnancy and may select early cases for second-line methotrexate therapy [15]. βHCG dynamics in the week before salpingotomy and bleeding activity at surgery may identify patients who are the most likely candidates for persistent ectopic pregnancy after laparoscopic linear salpingotomy [14].
15.1.4 Clinical Presentation
15.1.4.1 History of Physical Examination
Toward the end of the nineteenth century, the first diagnostic strategies for ectopic pregnancy were reported, occasionally with successful outcome for the women [16]. The diagnosis of ectopic pregnancy based on clinical criteria (of gastric and mammary symptoms of pregnancy, cessation of the menstrual cycle, palpation of a tumor next to an enlarged uterus, ballottement in the tumor, and purple discoloration of the vagina) had false preoperative diagnosis of a ruptured ectopic pregnancy of 20 %, while the diagnosis of an unruptured ectopic pregnancy was virtually impossible [17].
15.1.4.2 Symptoms
Few of the conditions which come under the notice of the gynecologist are of greater interest in diagnosis than extrauterine gestation. Occasionally, cases occur which present features so striking and so characteristic that their nature is readily recognized. But this is not always the case, for the clinical features may be so complex as to puzzle the most experienced observers. And not only are the clinical features complex, they are also subject to extraordinary variation in character and severity, and it may be difficult to believe that the same pathologic condition has given rise to them all. A quote from Howard A. Kelly seems timely, that “if one is confronted with a pelvic condition that follows no rules and conforms to no standards, he should think of ectopic pregnancy and pelvic tuberculosis” [18]. The explanation of these difficulties lies in the fact that the symptoms associated with extrauterine gestation arise, not directly from the presence of the growing ovum in the Fallopian tube, but from certain secondary lesions, either traumatic or inflammatory, which supervene. These secondary lesions may be briefly enumerated as [19]:
· Intraperitoneal flooding from tubal abortion or rupture
· Intratubal bleeding leading to acute distension of the tube, the abdominal ostium being sealed
· Slowly progressive or recurrent hemorrhage leading to the formation of encysted collections of blood (pelvic hematoma, in the broad ligament, pelvic hematocele, in the pouch of Douglas, peritubal hematocele, around the abdominal end of the tube)
· Infection of the gravid tube or of an encysted collection of blood leading to suppuration
Until one or the other of these secondary lesions is produced, extrauterine pregnancy gives raise to no more local or general disturbance than does an early pregnancy in the uterus. An important symptom associated with this phase, a brief period of amenorrhea, is the most useful aid in diagnosis, but it is not always present. When a healthy adult woman, who is usually regular, goes for 2 or 3 weeks over the expected date of her period, there is a “strong presumption of pregnancy,” but at this time, there is nothing to indicate whether pregnancy is uterine or extrauterine. In the latter case, however, amenorrhea is of very brief duration, seldom more than 7 or 8 weeks, and then gives place to hemorrhage. In something like 30 % of the cases, there is no amenorrhea at all. As it is quite unusual, for an extrauterine gestation to continue undisturbed beyond the end of the second month, there is consequently no time for the appearance of other general symptoms of pregnancy. But occasionally, morning sickness and early breast changes may be present. When the course of the gestation becomes interrupted by any of the occurrences mentioned above, the clinical features undergo rapid transformation, and symptoms appear which we are accustomed to regard as those of extrauterine pregnancy – those which result from the interruption of the pregnancy by injury to the developing ovum or to its containing sac.
These symptoms, which are regarded as secondary symptoms, are subject to great variation in their character and intensity in correspondence with the nature of the lesion which has given rise to them. The occurrence which is the simplest and the most easily recognized is intraperitoneal flooding; the symptoms which attend it are uniform and characteristic, and when a clinical history of amenorrhea can be obtained and a careful pelvic examination made, mistakes are hardly possible. Perforation of a hollow viscus, such as the stomach, duodenum, or gall bladder, is the only condition for which it is at all likely to be mistaken, even under circumstances unfavorable for diagnosis.
Hemorrhage from the uterus is a secondary symptom of extrauterine gestation which is constantly present. If no period of amenorrhea has occurred, it forms the initial symptom, and if there has been amenorrhea, it succeeds it. In the great majority of cases, it is the earliest indication of anything wrong, but as the same thing frequently occurs from disturbance of a uterine pregnancy, little importance is usually attached to its appearance by either the patient or her doctor. The hemorrhage is slight or moderate in degree, sometimes continuous, sometimes irregular; it is usually dark, thick, and syrupy in appearance. It may continue for several weeks if the patient is not relieved by operation. The bleeding is no doubt due to separation and discharge of the uterine decidua, sometimes complete, more often in fragments; but in the majority of cases, the pieces of membrane do not attract attention.
This attempt on the part of the uterus to throw off its decidua when the tubal ovum has been damaged is the most interesting phenomenon. Some reflex mechanism is initiated which excites uterine contraction insufficiently powerful to detach portions of the membrane from the uterine wall and so gives rise to hemorrhage, which continues until the whole of the decidua has been expelled. It is possible that at the commencement some of the blood which escapes from the uterus may have made its way there from the gravid tube through the interstitial portion. In cases submitted to operation, the hemorrhage always ceases in a few days after the removal of the tube, and if portions of decidua have been retained, these give rise to persistent bleeding, as is so often the case in uterine abortion.
It is interesting to note that the effects produced by the rapid effusion of a large quantity of blood into the peritoneal cavity are, in the order of their occurrence [19]:
1.
2.
3.
No matter what may be the nature of the secondary lesions occurring in a case of tubal pregnancy, these two symptoms are common to them all – uterine hemorrhage and pain. The pain has certain characteristics. It is almost always sudden in onset, and usually spontaneous, although muscular effort, such as lifting something heavy or the act of defecation, may appear to excite it; it is always severe, and often of the most intense character; it affects at first the whole abdomen, but later may become localized; it is frequently attended with vomiting and other signs of shock, sometimes with faintness or actual syncope; after lasting acutely for several hours, it subsides and thereafter may recur at varying intervals of a few days or a week, until several attacks have been sustained; sometimes continuous pain without exacerbation follows the first attack. The initial attack of pain is almost always due to hemorrhage; the subsequent attacks have a more complex origin. But pain bearing the broad characteristics described above is a constant symptom of extrauterine gestation. In cases not immediately submitted to operation, recurrent attacks of intense pain may occur from repeated intraperitoneal hemorrhages. The classic signs of hemoperitoneum except abdominal pain include shoulder pain caused by irritation of the phrenic nerve which courses along the undersurface of the diaphragm, an urge to defecate, and syncope even in the absence of hypovolemia.
Subjective symptoms of pregnancy may also be present, such as breast tenderness and emesis gravidarum.
15.1.4.3 Signs
Cullen’s Sign
Cullen’s sign (Fig. 15.1) is the bluish-black appearance around the umbilicus, unassociated with any history of injury, together with a definite uterine history usually typical of the slow tubal abortion type of bleeding. Although Cullen first described the sign in 1918 and labeled it a new sign in ruptured extrauterine pregnancy [21], discoloration of the umbilicus due to the presence of peritoneal extravasations had been previously reported by Ransohoff in 1906. This author described jaundice of the umbilicus in a patient with a ruptured common bile duct, and in 1909, Hofstatter observed a blue discoloration of an umbilical hernia (Hofstatter’s sign) in a patient with a ruptured tubal gestation. However, the discoloration in Hofstatter’s case was not due to ecchymosis but rather to transmission of the color of the blood through the thinned-out semitransparent hernia.
Fig. 15.1
Cullen’s sign is a bluish-black appearance around the umbilicus; extension depends on the extension and etiology of the primary process [20]
The notion that the presence of blood in the abdominal wall might be responsible for these signs was first explored by Meyers et al., who used computed tomography [22]. They defined the anatomy of various retroperitoneal spaces and compartments, revealing that there is direct extension of hemorrhagic fluid from the posterior pararenal space to the lateral edge of the quadratus lumborum muscle, where a defect in the transversalis fascia permits access to the abdominal wall musculature. The intramuscular hemorrhagic fluid then presumably reaches the subcutaneous tissues via interruptions in muscular continuity. Cullen’s sign results from the tracking of blood along the round ligament to the umbilicus. The portal of entry to the round ligament complex from the retroperitoneum is via the gastrohepatic ligament to the falciform ligament at the inferior-posterior liver edge [23]. In turn, the falciform ligament contributes to the connective tissue tube covering the round ligament (obliterated left umbilical vein) as it passes to the umbilicus.
The appearance of periumbilical ecchymosis (Fig. 15.1) is a rare observation, and when present, it is a late manifestation of intraperitoneal hemorrhage. In Cullen’s case, the discoloration began 1 week after the onset of pain. Undoubtedly, prompt surgical treatment prevents the development of the sign in a great many cases. It is possible that in some cases the sign appears after operation without being observed. One also wonders how many patients with tubal abortion, who undergo spontaneous resolution without operation, may develop the sign and never come under medical observation. The degree of discoloration, or its presence, does not seem to be related to the amount of bleeding but rather to its duration and to other as yet undetermined factors (Table 15.1).
Table 15.1
Conditions associated with Cullen’s sign
|
Pancreatitis |
|
Ruptured ectopic pregnancy |
|
Ruptured aortic aneurysm |
|
Ruptured spleen |
|
Ruptured common bile duct |
|
Perforated duodenal ulcer |
|
Hepatocellular carcinoma |
|
Hepatic lymphoma |
|
Metastatic thyroid cancer |
Physical examination is variable, and adnexal masses are often not palpable [24, 25]. Tachycardia is not always present. Atypical physical findings include a paradoxical bradycardia [26], fever [27], and uterine enlargement suggestive of an IUP [27].
15.1.5 Diagnosis
15.1.5.1 Laboratory Findings
The urine βHCG assay is sensitive to ≤25 mIU/ml, and more than 95 % of patients with ectopic pregnancies have a positive test result [28]. Transvaginal ultrasound has replaced transabdominal for ectopic pregnancy diagnosis and early screening for an IUP because it can visualize an intrauterine sac at an earlier gestational age. A gestational sac should always be seen in the patient with a viable IUP when the serum βHCG reaches 2,000 mIU/ml. In many cases, the gestational sac can be seen at a level of about 1,000 mIU/ml [29, 30]. Ultrasonography is also very helpful in diagnosing blighted ovum or threatened abortions, which may be part of the differential diagnosis. Following serum βHCG titer (which should double every 48 h in a normal, viable pregnancy) has no role in a patient with a suspected ruptured ectopic pregnancy, as that patient needs immediate surgical attention.
Depending on the severity of hemorrhage, hemoglobin concentration might be lowered or even normal [31]. Misleading and unexpected laboratory values such as hyperglycemia might also be present [32]. Many times diagnosis of an ectopic pregnancy prior to rupture may not be practical because the patient may not even know she is pregnant. These numerous diagnostic pitfalls are the reason for the maxim that any pregnant patient has an ectopic pregnancy until proven otherwise. All women of childbearing age should have a pregnancy test performed regardless of the date of their last menstrual period. Among women with symptoms and inconclusive ultrasound assessments, the progesterone test (five studies with 1998 participants and cutoff values from 3.2 to 6 ng/ml) predicted a nonviable pregnancy with pooled sensitivity of 74.6 %, specificity of 98.4 %, positive likelihood ratio of 45 (7.1–289), and negative likelihood ratio of 0.26. The median prevalence of a nonviable pregnancy was 73.2 %, and the probability of a nonviable pregnancy was raised to 99.2 % if the progesterone was low. For women with symptoms alone, the progesterone test had a higher specificity when a threshold of 10 ng/ml was used and predicted a nonviable pregnancy with pooled sensitivity of 66.5 %, specificity of 96.3 %, positive likelihood ratio of 18 (7.2–45), and negative likelihood ratio of 0.35. The probability of a nonviable pregnancy was raised from 62.9 to 96.8 % [33].
15.1.5.2 Imaging Diagnostic Tests
Positive pregnancy tests in the presence of abdominal pain mandate bedside sonography in the emergency department to locate the position of the fetal sac. The transvaginal technique is preferred because of its increased sensitivity for detecting an IUP and its superior visualization of the adnexa [3]. Most patients with ectopic pregnancies have some abnormality on the sonographic scan [34]. These abnormal findings include a cystic or complex adnexal mass (60–90 %) and free fluid in the peritoneal cavity (25–35 %, higher in a ruptured ectopic pregnancy) and should raise the suspicion of ectopic pregnancy. However, the findings are nonspecific, and not visualizing an ectopic pregnancy on ultrasonography can never definitely exclude it as a possible diagnosis. Location of ectopic fetal heart activity points to a clear diagnosis of ectopic gestation [24]. There are pitfalls involved with overreliance on laboratory values in the evaluation of ectopic pregnancy. Serum βHCG that is above the “discriminatory” level (at which ultrasound should be able to detect an IUP) might lead to a diagnosis of ectopic pregnancy when no IUP is visualized; however, values that fall below this level do not obviate the need for emergent ultrasound. In many cases, ultrasound might nonetheless be diagnostic. Recently, a case was diagnosed with three-dimensional sonography [35].
Since ectopic pregnancies are normally discovered and removed very early in the pregnancy, an ultrasound may not find the additional pregnancy inside the uterus. When βHCG levels continue to rise after the removal of the ectopic pregnancy, there is the chance that a pregnancy inside the uterus is still viable. This is normally discovered through an ultrasound. Ectopic pregnancy commonly occurs in the Fallopian tube and presents as a ring-enhancing adnexal cystic mass surrounded by hemoperitoneum on abdominal CT [36, 37] (Fig. 15.2).
Fig. 15.2
A 42-year-old woman with increasing pelvic pain and negative urine pregnancy test. Axial contrast-enhanced CT section shows pelvic hematoma (black arrows) around ring-enhancing left adnexal mass (white arrow) and adjacent high-attenuation foci indicative of active bleeding (curved arrow). Rupture of ectopic pregnancy in the left Fallopian tube was confirmed at surgery. Serum βHCG test confirmed elevated levels after completion of CT scan [37]
15.1.5.3 Culdocentesis
Culdocentesis may be performed to gain additional information. A needle is inserted through the vaginal wall into the posterior cul-de-sac. These findings are possible:
· A dry tap is inconclusive.
· A few cubic centimeters of clear fluid (peritoneal fluid) rules out a ruptured ectopic, but neither rules out an unruptured ectopic.
· A lightly bloody fluid (hematocrit <15) is inconclusive. This could be from a traumatic tap, or early, mild bleeding from an ectopic.
· Moderately bloody fluid (hematocrit >15) indicates hemoperitoneum consistent with ruptured ectopic, but is nonspecific, and any internal bleeding (hemorrhagic ovarian cyst) can give this result.
· Bright red, clotting blood usually indicates a traumatic tap or aspiration of blood from a vessel.
Today, it is rarely done because it is not specific and is invasive, and with the use of abdominal CT scan, its lost it significance. Only about 50 % of patients with a positive culdocentesis have a ruptured Fallopian tube [38].
15.1.5.4 Diagnostic Laparoscopy/Laparotomy
Ectopic pregnancy is commonly diagnosed during exploration (Fig. 15.3); primary ovarian pregnancy is usually diagnosed only at operation, although it may resemble a hemorrhagic corpus luteum (Fig. 15.4). The use of a laparoscope in the diagnosis of ectopic pregnancy was suggested in 1937 by Hope in the United States [41]. For example, a correct diagnosis at the time of surgery could be made in only 28 % in a series of 25 cases, because it was difficult to distinguish an ovarian pregnancy from a hemorrhagic corpus luteal cyst intraoperatively [42].
Fig. 15.3
The left Fallopian tube has been cleansed with an irrigator aspirator so that it is free of blood. The distal portion of the Fallopian tube can clearly be seen to be distended and blue [39]
Fig. 15.4
Intraoperative view of right ovarian pregnancy. Note the yellowish-red corpus luteum on the left side of the congested ovarian pregnancy [40]
Figure 15.5 shows one of the recommended approaches to investigating first trimester pain or bleeding in the hemodynamically stable patient in the emergency department.
Fig. 15.5
Recommended approach to investigating first trimester pain or bleeding in the hemodynamically stable patient in the emergency department (ED). βHCG β-human chorionic gonadotropin, USultrasonography, IUP intrauterine pregnancy, EP ectopic pregnancy [5]
15.1.6 Treatment
When the diagnosis of ectopic pregnancy can be neither established nor excluded by ultrasound and laboratory evaluation, management depends upon many factors. The overall condition and stability of the patient, the availability of close follow-up care with an obstetrician/gynecologist, and the proximity of the patient to the hospital are important considerations if discharge is being contemplated. Decisions regarding disposition of such patients should be made with a consulting obstetrician/gynecologist, and in some cases, admission to the hospital or surgical exploration might be preferred options.
15.1.6.1 Laparotomy
In 1849, Harbert of Louisville was the first to perform surgery early enough to stop fatal bleeding [43]. Robert Lawson Tait in London, after having performed autopsies on several women, recognized that appropriate dissection and ligation of bleeding vessels would be effective in the treatment of ectopic pregnancy. He successfully performed a laparotomy to ligate the broad ligament and removed a ruptured tube. By 1885, Tait had accumulated a relatively large number of successful cases of laparotomic salpingectomies [44, 45]. The diagnosis of an ectopic pregnancy was difficult, but if recognized, the procedure of choice was a laparotomy before rupture. In 1913, it is stated in Hartmann’s textbook that: “every ectopic when diagnosed should be operated upon.” Expectant management led in 86 % of women to death, but surgery saved 85 % of women [46].
In the first decades of the twentieth century, the introduction of asepsis, anesthesia, antibiotics, and blood transfusions saved the lives of many women with ectopic pregnancy. Still, the maternal mortality rate in the United States ranged from 200 to 400/10,000 cases of ectopic pregnancies [47].
Fallopian Tube-Sparing Surgery
Tube-sparing surgery is accomplished by removal of the ectopic pregnancy from the Fallopian tube via linear salpingostomy by making an incision on the antimesenteric portion of the tube over the bulge of the ectopic pregnancy, removing the pregnancy, achieving hemostasis, and allowing the tube to heal by secondary intention. There are no differences in subsequent pregnancy rates, adhesion formations, or fistula formation with or without closure of the incision site [48, 49]. Complications of salpingostomy include hemorrhage and persistent trophoblastic tissue. Trophoblastic tissue persists in approximately 5 % of patients [50]. Therefore, all patients must undergo follow-up βHCG levels. Fimbrial expression consists of “milking” the pregnancy out of the tube. This technique has been associated with complications such as persistent trophoblastic tissue and postoperative bleeding and probably should be reserved for ectopic pregnancies located at or very near the fimbria itself.
Salpingectomy
Salpingectomy is the procedure of choice if the woman has no desire for further pregnancies. It also may be necessary for hemostatic control of an attempted conservative approach with salpingostomy or with a tube that appears unable to be salvaged. Salpingectomy is the standard procedure in a patient who is hemodynamically unstable. It has also been suggested that women with a history of infertility may be better served with salpingectomy; as it has been shown in that subset of patients, treatment with salpingectomy resulted in equivalent pregnancy rates and a decrease in recurrent ectopic pregnancy [51].
Hemodynamically Unstable Patient
A patient who is hemodynamically unstable requires emergency laparotomy for surgical treatment, and laparoscopy and medical therapy (i.e., methotrexate) have no role. Patients who have a diagnosis or suspected diagnosis of ruptured ectopic pregnancy might require vigorous and immediate resuscitation with fluids and blood products before surgical intervention. Oxygen should be applied and an emergent obstetric consultation should be obtained. In a stable patient who does not have suspected rupture, nonoperative management with methotrexate therapy and close follow-up care might be considered in consultation with the obstetrician/gynecologist [3].
15.1.6.2 Laparoscopy
During the 1970s and 1980s, laparotomy was gradually replaced by operative laparoscopic options. Shapiro and Adler [52] reported laparoscopic salpingectomy using electrocoagulation followed by excision for an ectopic pregnancy in 1973. Salpingotomy by laparoscopy was first reported using multiple punctures in 1980 [53]. Linear salpingotomy with a cutting current was described by DeCherney et al. in 1981 [54]. If clinically possible, the patient is better served with a laparoscopic approach with reduced morbidity, recovery time, costs, and equivalent future fertility rates compared with laparotomy [55–57]. Whether laparoscopic treatment should be performed conservatively (salpingotomy) or radically (salpingectomy) in women wishing to preserve their reproductive capacity has long been subject of debate. The result of a randomized controlled trial on salpingotomy versus salpingectomy in 454 women with a tubal pregnancy without contralateral tubal pathology showed that salpingotomy does not improve time to spontaneous ongoing pregnancy and leads more often to persistent trophoblast [58]. In women with desire for future pregnancy and with a tubal ectopic pregnancy in a solitary tube or in the presence of contralateral tubal pathology, salpingotomy is the treatment of choice [59, 60]. In case salpingectomy is performed due to a failed salpingotomy or other surgical difficulties, IVF is the appropriate treatment option for the loss of fertility. It should be remembered that approximately 3 % of ectopic pregnancies are not visualized by laparoscopy. Typically, these are very early gestations.
If a pregnancy has been previously determined to be nonviable by serum βHCG or if it is an undesired pregnancy, endometrial sampling by suction curettage may be performed to determine whether an IUP is present. If chorionic villi are obtained from the uterine cavity, the presence of a concurrent ectopic pregnancy along with the intrauterine one is highly unlikely. The reported incidence of coexistent pregnancies in the general population (i.e., intrauterine and extrauterine) is between 1/4,000 and 1/30,000 [55, 61]. Sampling the endometrium with biopsy instruments does not obtain an adequate sample for diagnosis and should not be used.
15.1.7 Prognosis
While the number of ectopic pregnancies has increased, the death rate from this disorder has steadily declined. It is an assumption that the decreased mortality rate is secondary to the effects of early detection and intervention. Despite this improvement, approximately 34 women die yearly of the complications of ectopic pregnancy. This accounts for 13 % of all pregnancy-related deaths [62]. With the advent of conservative surgery, the emphasis on early diagnosis and increased awareness of this condition may be an important factor in reducing the morbidity and mortality of ectopic pregnancy.
Mortality of a tubal pregnancy at the isthmus or within the uterus (interstitial pregnancy) is higher as there is increased vascularity that may result more likely in sudden major internal hemorrhage.
15.2 Ruptured Cornual Pregnancy
15.2.1 Definition
Rudimentary horn of a unicornuate uterus arises as a result of a partial development of one uterine horn and incomplete fusion of the two Müllerian ducts. In more than 75 % of cases of unicornuate uterus, a contralateral rudimentary horn is present. The majority of rudimentary horns contains functional endometrium and do not communicate with the unicornuate uterus [63–65].
15.2.2 Incidence and Pathophysiology
Pregnancy in a noncommunicating rudimentary horn has a reported incidence of 1/76,000–1/150,000 [63, 66], with less than 600 cases published. The first case was described by Mauriceau in 1669 [67], and the first case of cornual pregnancy diagnosed on ultrasound was reported in 1983 [68]. It occurs following transperitoneal migration of sperm or of fertilized ovum (zygote) [65]. Pregnancy in a rudimentary horn can result in rupture between 10 and 20 weeks of gestation with associated life-threatening hemorrhage [69] due to poorly developed musculature that cannot stretch. It is extremely uncommon for such cases to result in a viable fetus as they often result in rupture of the horn before the third trimester [70]. Only 10 % cases reach term, and the fetal salvage rate is only 2 % [71, 72]. Rupture occurs commonly because of underdevelopment, variable thickness, and poor distensibility of myometrium and dysfunctional endometrium. Rudimentary horn pregnancy can be further complicated by placenta percreta due to the poorly developed musculature, scant decidualization, and small size of the horn, the reported incidence being 11.9 % [73].
15.2.3 Clinical Examination
As rudimentary horn pregnancies are always associated with catastrophic outcome, every effort should be made to diagnose them at an early gestation. A detailed history should be taken in every patient on her first visit including any complaints of severe dysmenorrhea. However, the rudimentary horn may be underdeveloped and its endometrium nonfunctional and dysmenorrhea may be absent [70]. A careful pelvic examination in the first trimester showing deviated uterus with a palpable adnexal mass should arouse suspicion of a Müllerian anomaly.
The unicornuate uterus with a rudimentary horn may be associated with complications such as hematometra, endometriosis, infertility, urinary tract anomalies, recurrent miscarriages, preterm labor, malpresentation, and placenta accreta [74].
15.2.4 Diagnosis
Diagnostic criteria for pregnancy in a rudimentary horn have subsequently been described such as [75]:
· Detection of a single interstitial tube in an empty uterus adjacent to the pregnancy
· Free mobility and the presence of a vascular pedicle adjoining the gestational sac and the lateral aspect of the empty uterus
Despite this, the sensitivity of ultrasound diagnosis of pregnancy in rudimentary horn is around 30 % [76, 77]. These criteria can be used with relative ease in the first trimester as pregnancy progresses it becomes more difficult to diagnose pregnancy in the rudimentary horn [78]. Furthermore, it is difficult to demonstrate the subtle anomalies that may be associated with this condition. Three-dimensional ultrasound may also play a useful role in evaluating uterine anomalies [75, 76, 78]. A high level of agreement between 3D ultrasound, hysterosalpingography, and laparoscopy in the classification of uterine morphology has been reported previously [79, 80].
The enlarging horn with thinned myometrium can obscure the adjacent anatomic structures, and the sensitivity further decreases as the gestation increases. If abdominal and/or vaginal ultrasound are equivocal and the patient stable, abdominal CT or MRI is indicated. MRI has proven to be a very useful tool for the diagnosis of pregnancy with a Müllerian anomaly and to confirm the presence of placenta percreta [81]. MRI can define a didelphys uterus with a fetus in one of the uterine bodies (Fig. 15.6).
Fig. 15.6
MRI picture showing right uterine horn (arrow) and rudimentary horn above with fetus in situ. The placenta was left lateral, and there was no free fluid in abdomen [70]
Even with abdominal MRI, the placental invasion could remain elusive and is diagnosed only at laparotomy (Figs. 15.7 and 15.8) [70].
Fig. 15.7
(a) Placental blood vessels seen on the fundus of rudimentary horn. (b) Gravid left rudimentary horn seen attached to the unicornuate uterus by a fibrous band [70]
Fig. 15.8
Ruptured cornual area (0.5 cm) of the uterus with exposure of underlying intact amnion membrane [82]
15.2.5 Treatment
15.2.5.1 Laparotomy/Laparoscopy
Traditionally laparotomy has been the preferred approach of choice, but with increasing expertise in laparoscopic surgery, there have been several reports of laparoscopic management of the pregnant rudimentary horn [83–87]. Laparoscopy, though the gold standard for surgical management of hemodynamically stable women with ectopic pregnancy, had long been considered a contraindication in women with hypovolemic shock. This is because of the effect of pneumoperitoneum, positioning of the patient, and the duration of surgery. There is always special concern of pressure on the diaphragm and stomach posing significant threat of resuscitation and aspiration and pressure on the blood vessels which results in reduced cardiac output [88, 89]. Second trimester rudimentary horn pregnancies have all been managed by laparotomy [63, 65, 69, 90–92] with the exception of one 19-week unruptured rudimentary horn pregnancy which was managed by hand-assisted laparoscopy and one case of laparoscopic management in 16-week pregnancy [93].
15.2.5.2 Procedures
When diagnosed early, excision of rudimentary horn with ipsilateral salpingectomy is the recommended surgical treatment and provides the best prognosis. This has been recommended in the literature due to a remote possibility of ectopic pregnancy as a result of transperitoneal migration of embryo [85].
Microsurgical Fallopian tube transposition of the ipsilateral tube is recommended in the presence of a damaged contralateral tube [94]. Even a case of spontaneous cornual rupture of a primigravidauterus occurring at 21 weeks’ gestation was described, who underwent a direct repair followed by a continuing pregnancy until 33 weeks gestation, and finally delivered a normal fetus successfully via Cesarean section [82]. It is vital to evaluate the type of rudimentary horn and possible presence of urological anomalies before embarking on the surgical excision, in order to avoid associated complications [85]; hence, the interval excision of the rudimentary horn after complete preoperative evaluation is recommended [93, 95].
15.2.5.3 Perioperative Considerations
The use of calf length sequential pneumatic compression stockings in this group of patients not only increases venous return but also prevents the risk of venous thromboembolism [96].
15.2.6 Prognosis
The mortality rate has reduced from 23 % at the turn of the twentieth century to 0.5 % today probably due to earlier intervention. Despite this reduction in mortality, prompt intervention is necessary to remove the horn [97] and the ipsilateral Fallopian tube [83] if a diagnosis of pregnancy in rudimentary horn is made.
15.3 Abdominal Pregnancy
15.3.1 Classification
Abdominal pregnancies can be classified as primary when fertilization takes place outside the uterine adnexa or as secondary (thought to be more common) believed to result from undetected rupture of a tubal pregnancy. Primary peritoneal pregnancy can be clinically distinguished from secondary peritoneal pregnancy by Studdiford’s criteria [98]:
· Normal tubes and ovaries with no evidence of recent or remote injury
· Absence of any evidence of a utero-peritoneal fistula
· Presence of pregnancy related exclusively to the peritoneal surface and early enough to eliminate the possibility of secondary implantation following a primary nidation in the tube
Implantation can occur anywhere in the abdomen including ligaments, liver, and spleen. Abdominal pregnancy is not strictly defined as early before which includes 12–28 weeks of gestation and advancedafter that period.
15.3.2 Incidence
The incidence varies widely with geographical location, degree of antenatal attendance, level of medical care, and socioeconomic status [99]. It is believed that abdominal pregnancy is more common in developing countries probably because of the high frequency of pelvic inflammatory disease in these areas with suboptimal treatment [100, 101]. Heterotopic pregnancy is the coexistence of intrauterine and extrauterine pregnancies. Abdominal pregnancies make up a small percentage of ectopic pregnancies which are a common occurrence [102]. Moreover, 98 % of all extrauterine pregnancies are intratubal, 1 % is ovarian, and the rest are primary or secondary peritoneal implantations. Atrash et al. estimated in 1987 the incidence of abdominal pregnancy at 10.9/100,000 live births and 9.2/1,000 ectopic pregnancies in the United States [99] or between 1/3,000 and 1/8,000 deliveries in other studies [103, 104]. Ombelet et al. found an incidence of 1/402 pregnancies in developing countries and 1/10,000 pregnancies in developed countries [105]. Advanced abdominal pregnancy is rare and accounts for 1/25,000 pregnancies [106]. Recent estimated rate of occurrence of heterotopic pregnancy is 1/15,000 live births, and the ectopic component is commonly tubal. Its incidence is increased in women undergoing assisted conception with superovulation, IVF-ET, and gamete intrafallopian transfer [107]. Incidence of heterotopic pregnancy has been reported as 1/8,000–1/30,000 in natural conception [108]. It may increase as high as 1 % with assisted reproductive techniques.
15.3.3 Risk Factors
Risk factors include a history of tubal pregnancies, pelvic inflammatory disease, tubal sterilization, and tubal infertility or tubal reconstructive surgery. Other women at risk include those who conceive despite the use of an intrauterine contraceptive device (IUCD) or progestagen-only contraceptive pills [109]. If none of the above risk factors is present, the undetected rupture of a tubal pregnancy is considered as case of heterotopic pregnancy. Cocaine abuse has been identified as a risk factor specific for abdominal pregnancy; the associated increase in risk may be up to 20-fold [110]. The first case of abdominal pregnancy after IVF was described in 1988 [111]. Mechanisms discussed for abdominal pregnancy during IVF are [112]:
· Uterine perforation during the transfer
· Spontaneous intra-abdominal fertilization
· Microfistula at the interstitial portion of the uterus
15.3.4 Clinical Presentation
Diagnosis of heterotopic pregnancy is a challenge not only for the obstetricians but also for other physicians who are following or treating the patient. Clinical findings are extremely variable, and the preoperative diagnosis is unsuspected in up to 60 % of cases [113]. Spontaneous progression of undetected IUP from the time of surgical management of acute or subacute ruptured ectopic pregnancy on postoperative follow-up is rare. On the contrary, spontaneous abortion of an IUP has followed ectopic rupture [114]. Early diagnosis depends on the clinician having a high index of suspicion. Reece et al. defined four common symptoms and findings [114]:
· Abdominal pain
· Adnexal mass
· Peritoneal irritation
· Increase in the size of the uterus
Frequent signs and symptoms include crampy abdominal pain, vaginal spotting or hemorrhage, nausea, vomiting, malaise, and painful fetal movement [103, 104, 113, 115]. The most common physical findings are abdominal tenderness, an abnormal fetal position, and displacement of the cervix. Tal et al. reported abdominal pain in 83 % and abdominal tenderness with hypovolemic shock in 13 % of the heterotopic pregnancy cases and vaginal bleeding in half of the patients. Finding of vaginal bleeding that can be concurrent in ectopic pregnancies is rarely seen in heterotopic pregnancies on account of intact endometrium of IUP [116].
15.3.5 Diagnosis
15.3.5.1 Laboratory Findings
Laboratory tests such as abnormally increasing βHCG are not sufficiently reliable on their own to make a diagnosis, as are signs and symptoms such as abdominal pain and tenderness, persistent transverse or oblique lie, and palpable fetal parts [102]. Quantitative measurements of serum βHCG levels are of no use, because the IUP will be producing normal and increasing levels of serum βHCG [117]. The absence of uterine contractions during oxytocin challenge testing is highly suggestive of abdominal pregnancy [115].
15.3.5.2 Ultrasound
Transabdominal ultrasound (Figs. 15.9 and 15.10), when coupled with clinical evaluation, has approximately 50–75 % success rate [102]. Guidelines have been provided for the use of ultrasound to diagnose abdominal pregnancy (Figs. 15.9 and 15.10) [119, 120]:
Fig 15.9
Abdominal ultrasound: pregnancy developing outside of the uterus [118]
Fig. 15.10
Abdominal pregnancy: live fetus at 17 weeks with normal amniotic fluid [118]
· Demonstration of a fetus in a gestational sac outside the uterus or the depiction of an abdominal or pelvic mass identifiable as the uterus separate from the fetus
· Failure to see a uterine wall between the fetus and urinary bladder
· Recognition of a close approximation of the fetus to the material abdominal wall
· Localization of the placenta outside the confines of the uterine cavity
The most frequent and reliable finding was separation of the uterus from the fetus (90 %). Extrauterine placenta (75 %) and oligohydramnios (45 %) were the next in frequency. Other features such as fetal parts close to the maternal abdominal wall (25 %), failure to visualize myometrium between the fetus or placenta and maternal bladder (15 %), abnormal fetal lie (25 %), poor visualization of the placenta (25 %), and maternal bowel gas impeding fetal visualization (25 %) were noted [120]. To establish the diagnosis, clear identification of the empty uterus as a separate structure is important. This can be accomplished by giving close attention to the lower pelvis to ensure that there is continuity between normally appearing vaginal and endometrial echoes. Also, false-positive diagnoses must be avoided. Findings that mimic abdominal pregnancy include pregnancy in a bicornuate uterus, pedunculated uterine fibroids associated with a gravid uterus, and even an early normal pregnancy in a sharply retroflexed or anteflexed uterus.
15.3.5.3 Magnetic Resonance Imaging
An MRI scan can also be used to confirm the diagnosis of abdominal pregnancy showing the same characteristics as abdominal ultrasound (Fig. 15.11).
Fig. 15.11
MRI showing abdominal pregnancy: placenta is inserted on the posterior wall of the uterus [118]
15.3.6 Treatment
For the management of abdominal pregnancy, factors such as maternal hemodynamic status, fetal congenital abnormality, fetal viability, gestational age at presentation, and the availability of neonatal facilities should be considered. If the fetus is dead, surgical intervention is generally indicated owing to the risk of infection and disseminated intravascular coagulation. Various clinicians, however, recommend a period of observation of 3–8 weeks to allow atrophy of placental vessels [121]. If the diagnosis is uncertain and ectopic/abdominal pregnancy suspected, laparoscopy can be both diagnostic and therapeutic (Fig. 15.12).
Fig. 15.12
Laparoscopic findings of a reddish and edematous mass on the left infundibulopelvic ligament of early abdominal pregnancy [122]
15.3.6.1 Conservative Therapy
In the management of abdominal pregnancy with an embryo, treatment with methotrexate does not seem to be effective [123], but it could be added to surgical treatment [124]. Preoperative methotrexate treatment to minimize blood loss during surgery can facilitate maximal placental removal and has been described for abdominal pregnancy by Worley et al. [125]. Because of the risks of placental separation, most advise surgical intervention as soon as the diagnosis of abdominal pregnancy is confirmed, regardless of the fetal condition [99]. However, in some circumstances, it could be possible to await fetal maturity.
>20 Weeks’ Gestation
If a conservative approach is to be considered with a diagnosis of abdominal pregnancy at >20 weeks’ gestation, the following prerequisites have been proposed [126, 127]:
· Absence of fetal malformation
· Absence of maternal or fetal decompensation
· Continued surveillance of fetal well-being
· Placental implantation low in the abdomen, far away from the liver or spleen
· Adequate amniotic fluid
· Continuous hospitalization in an appropriate facility
· Informed consent from the patient
Maternal surveillance comprises physical examinations, serial ultrasound assessments, measurement of fetal growth, and daily fetal heart rate monitoring. Laparotomy can be planned for 34 weeks’ gestation in the absence of complication.
<20 Weeks’ Gestation
When the diagnosis is established before 20 weeks, continuing the pregnancy should be exceptional. The importance of informed consent is paramount [124].
15.3.6.2 Surgical Therapy
If the fetus is alive, laparotomy should be performed (Fig. 15.13), regardless of gestational age or fetal condition [100]. The reason is mainly based on the unpredictability of placental separation and consequential massive hemorrhage.
Fig. 15.13
Delivery of the fetus during abdominal pregnancy with the placenta was meticulously separated (which separation during pregnancy caused hemoperitoneum) [109]
Perioperative Embolization
Nevertheless, removal of an abdominal pregnancy by laparoscopy after embolization has been described [128]. Embolization of the placental vascular supply can be performed before surgery to minimize blood loss, during surgery to facilitate maximal placental removal [128–130], and after surgery in case of postoperative hemorrhage [131]. Although no consensus regarding the treatment of the placenta in abdominal pregnancy has been established, most authors advocate leaving the placenta in situ unless the surgeon can be confidently assured that the entire blood supply to the placental bed can be surgically ligated without loss of excessive amounts of blood and the need for extensive blood replacement therapy. Preoperatively, the primary task of the angiographer is to identify all sources of blood supply to the placenta (Fig. 15.14) and to embolize vessels that could be difficult to ligate, such as the hypogastric artery.
Fig. 15.14
Catheterization of the right ovarian artery, which was supplying the placenta in abdominal pregnancy [118]
Routine angiographic evaluation should include abdominal aortography with renal evaluation, selective celiac and superior mesenteric arteriography, and selective internal iliac arteriography. If embolization is not performed preoperatively, it can be performed postoperatively with the same technique in the presence of persistent bleeding.
Surgical Procedure
Laparotomy should be performed through a midline incision [102]. It is advisable to make the incision in the amniotic sac as far as possible from the placental attachment and large enough to extricate the fetus without trauma and to permit the subsequent drainage of amniotic fluid [127]. Because of the high risk of hemorrhage, it is preferable to leave the placenta in place by ligating the umbilical cord at its base. There is no effective method of controlling bleeding in the placental bed by clamping or cautery. Prolonged pressure, hot packs, and topical thrombin-containing compresses have been used with variable success. Use of temporary aortic compression or an abdominal balloon pressure pack in the pelvis can be lifesaving [127]. All efforts should be made to avoid leaving a drainage tube in place, as this increases the risk of abscess formation and septicemia [132]. Nevertheless, it may be advisable to remove the placenta if its blood supply can be secured, if the diagnosis is made early in pregnancy, or in cases with fetal demise of more than 4 weeks’ duration [133]. In these circumstances, removing the placenta has been followed by fewer complications, less need for repeat surgery, and fewer repeat hospitalizations [134, 135]. In fact, placental removal has been associated with low morbidity but high mortality [136]. In cases where placental implantation has occurred in vascular areas such as the mesentery and vital organs, it has been recommended that the placenta should be left in situ, because surgical excision can result in uncontrollable and life-threatening hemorrhage [137]. If discovery is not made until attempted Cesarean delivery, even then a safer alternative would be to defer delivery if possible, close the abdominal incision, and transfer the woman to an appropriate hospital. This could be done even after the delivery of the fetus or neonate with the placenta left in situ if there was no bleeding [125].
Postoperative Management
Patients should remain in intensive care for 24–72 h postoperatively. Complications may continue to occur for several weeks. A retained placenta can persist in situ for a number of weeks and has remained detectable for as long as 5 years [127].
Methotrexate can be used in the postoperative period to expedite absorption of the placenta. However, its use is controversial. It might increase infectious complications because of rapid tissue necrosis, but some authors argue for complete regression of the placenta. Methotrexate as a folate antagonist causes acute intracellular deficiency of these folate coenzymes, thus affecting synthesis of DNA especially in rapidly multiplying cells. Methotrexate acts on rapidly dividing cells, and it is likely to have limited effects on the mature placenta with its limited proliferative activity. With or without its utilization, the retained placenta will frequently undergo suppuration and require surgical removal [128, 138]. Risks of secondary hemorrhage could be diminished while keeping the infection risk low. A case of placental infusion with methotrexate via the umbilical arteries has also been described [139]. Its use preoperatively, or alternatively the use of actinomycin D, has been proposed to destroy trophoblastic activity in cases with an established fetal death [140].
15.3.7 Prognosis
15.3.7.1 Maternal Outcome
Abdominal pregnancy poses a serious threat to the survival of equally the mother and the fetus. Hence, it is vital that the diagnosis is made early in the pregnancy. Maternal mortality ranges 6–30 % [103, 104, 127]. This is principally because of the risk of massive hemorrhage from incomplete or entire placental separation. The placenta can be attached to the uterine wall, bowel, mesentery, liver, spleen, bladder, and ligaments, which can separate at anytime during pregnancy leading to heavy blood loss.
15.3.7.2 Fetal Outcome
The fetal outcome tends to be poorer than the mother’s with perinatal mortality in range 40–95 % [126, 141]. Fetal abnormalities (congenital malformations) range 20–40 %, mostly because of associated oligohydramnios [142]. However, with advanced pregnancy and if the fetus is surrounded by a normal volume of amniotic fluid, fetal outcome tends to be better [127].
References
1.
Centers for Disease Control. Ectopic pregnancy surveillance in the United States, 1970–1987. Morb Mortal Wkly Rep. 1990;39:9–17.
2.
Centers for Disease Control and Prevention (CDC). Ectopic pregnancy – United States, 1990–1992. Morb Mortal Wkly Rep. 1995;44:46–8.
3.
Luciano A, Roy G, Solima E. Ectopic pregnancy: from surgical to medical management. Ann N Y Acad Sci. 2001;943:235–54.PubMed
4.
Creanga AA, Shapiro-Mendoza CK, Bish CL, et al. Trends in ectopic pregnancy mortality in the United States: 1980–2007. Obstet Gynecol. 2011;117:837–43.PubMed
5.
Murray H, Baakdah H, Bardell T, Tulandi T. Diagnosis and treatment of ectopic pregnancy. CMAJ. 2005;173:905–12.PubMedCentralPubMed
6.
Cagnacci A, Landi S, Volpe A. Rhythmic variation in the rate of ectopic pregnancy throughout the year. Am J Obstet Gynecol. 1999;180:1067–71.PubMed
7.
Ling FW, Stovall TG. Update on the diagnosis and management of ectopic pregnancy. In: Advances in obstetrics and gynecology. Chicago: Mosby Year Book Inc; 1994. p. 55–83.
8.
DeCherney AH. Ectopic pregnancy. Rockford: Aspen Publishers; 1986. p. 1–81. 89, 103.
9.
Weinstein L, Morris MB, Dotters D, Christian CD. Ectopic pregnancy, a new surgical epidemic. Obstet Gynecol. 1983;61:698–701.PubMed
10.
Bouyer J, Coste J, Fernandez H, et al. Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases. Hum Reprod. 2002;17:3224–30.PubMed
11.
Shaw JL, Dey SK, Critchley HO, Horne AW. Current knowledge of the aetiology of human tubal ectopic pregnancy. Hum Reprod Update. 2010;16:432–44.PubMedCentralPubMed
12.
Spiegelberg O. Zur Casuistik den Ovarial-Schwangenschaft. Arch Gynaekol. 1878;13:73.
13.
Zhang J, Li F, Sheng Q. Full-term abdominal pregnancy: a case report and review of the literature. Gynecol Obstet Invest. 2008;65:139–41.PubMed
14.
Kemmann E, Trout S, Garcia A. Can we predict patients at risk for persistent ectopic pregnancy after laparoscopic salpingotomy? J Am Assoc Gynecol Laparosc. 1994;1:122–6.PubMed
15.
Poppe WA, Vandenbussche N. Postoperative day 3 serum human chorionic gonadotropin decline as a predictor of persistent ectopic pregnancy after linear salpingotomy. Eur J Obstet Gynecol Reprod Biol. 2001;99:249–52.PubMed
16.
Lurie S. The history of the diagnosis and treatment of ectopic pregnancy: a medical adventure. Eur J Obstet Gynecol Reprod Biol. 1992;43:1–7.PubMed
17.
Eastman NJ. Williams obstetrics. 10th ed. New York: Appleton, Century, Crofts; 1950.
18.
Beacham WD. Progress in gynecology. New York: Grune & Stratton; 1950. p. 370–1.
19.
Eden TW. On the importance of pain and haemorrhage as symptoms of extrauterine gestation. Br Med J. 1909;1:940–3.PubMedCentralPubMed
20.
Harris S, Naina HV. Cullen’s sign revisited. Am J Med. 2008;121:682–3.PubMed
21.
Cullen TS. A new sign in ruptured extrauterine pregnancy. Am J Obstet. 1918;78:457.
22.
Meyers MA, Feldberg MA, Oliphant M. Grey Turner’s sign and Cullen’s sign in acute pancreatitis. Gastrointest Radiol. 1989;14:31–7.PubMed
23.
Mabin TA, Gelfand M. Cullen’s sign, a feature of liver disease. Br Med J. 1974;1:493–4.PubMedCentralPubMed
24.
Dart RG, Kaplan B, Varaklis K. Predictive value of history and physical examination in patients with suspected ectopic pregnancy. Ann Emerg Med. 1999;33:283–90.PubMed
25.
Tilden F, Powers R. Ectopic pregnancy: avoiding missed diagnosis and reducing morbidity. Emerg Med Rep. 1996;17:199–206.
26.
Bailey LE, Finley RK, Miller SF, Jones LM. Acute appendicitis during pregnancy. Am Surgeon. 1986;52:218–21.PubMed
27.
Weckstein L. Current perspective on ectopic pregnancy. Obstet Gynecol Surv. 1985;40:259–72.PubMed
28.
Cartwright PS. Diagnosis of ectopic pregnancy. Obstet Gynecol Clin North Am. 1991;18:19–37.PubMed
29.
Stovall TG. Diagnosis and surgery for ectopic pregnancy. In: Mann WI, Stovall TG, editors. Gynecologic surgery. New York: Churchill Livingstone; 1996. p. 592.
30.
Bree RL, Edwards M, Bohm VM, et al. Transvaginal sonography in the evaluation of normal early pregnancy with hCG level. Am J Roentgenol. 1989;53:75–9.
31.
Snyder HS. Lack of tachycardic response to hypotension with ruptured ectopic pregnancy. Ann J Emerg Med. 1990;8:23–6.
32.
Aaryya B, Tymms DJ. Ruptured ectopic pregnancy presenting as hyperglycemia. Int J Clin Pract. 2000;54:409–10.
33.
Verhaegen J, Gallos ID, van Mello NM, et al. Accuracy of single progesterone test to predict early pregnancy outcome in women with pain or bleeding: meta-analysis of cohort studies. Br Med J. 2012;345:e6077.
34.
Romero R, Kadar N, Castro D, et al. The value of adnexal sonographic findings in the diagnosis of ectopic pregnancy. Am J Obstet Gynecol. 1988;158:52–5.PubMed
35.
Ghi T, Banfi A, Marconi R, et al. Three-dimensional sonographic diagnosis of ovarian pregnancy. Ultrasound Obstet Gynecol. 2005;26:102–4.PubMed
36.
Pham H, Lin EC. Adnexal ring of ectopic pregnancy detected by contrast-enhanced CT. Abdom Imaging. 2007;32:56–8.PubMed
37.
Furlan A, Fakhran S, Federle MP. Spontaneous abdominal hemorrhage: causes, CT findings, and clinical implications. Am J Roentgenol. 2009;193:1077–87.
38.
Vermesh M, Graczykowski JW, Sauer MV. Reevaluation of the role of culdocentesis in the management of ectopic pregnancy. Am J Obstet Gynecol. 1990;162:411–3.PubMed
39.
www.thenewjerseyectopicpregnancycenter.com/p_ruptured_ampullary_0202.php
40.
Bagga R, Suri V, Verma P, et al. Failed medical management in ovarian pregnancy despite favorable prognostic factors – a case report. Med Gen Med. 2006;8:35.
41.
Hope R. The differential diagnosis of ectopic pregnancy by peritoneoscopy. Surg Gynecol Obstet. 1937;64:229–34.
42.
Hallatt JG. Primary ovarian pregnancy: a report of twenty-five cases. Am J Obstet Gynecol. 1982;143:55–60.PubMed
43.
Harbert WW. A case of extra uterine pregnancy. West J Med Surg. 1849;3:110.
44.
Tait RL. Five cases of extrauterine pregnancy operated upon at the time of rupture. Br Med J. 1884;1:1250–5.PubMedCentralPubMed
45.
Tait RL. Lectures on ectopic pregnancy and pelvic haematocele. Birmingham: Engl J Printing Works; 1888. p. 23–5.
46.
Hartman H. Gynecological operation including non-operative treatment and minor gynecology. Philadelphia: P. Blakiston’s Son & Co; 1913. p. 460–4.
47.
Speroff L, Glass RH, Kase NG. Ectopic pregnancy. Clinical gynecologic endocrinology and infertility. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 1999.
48.
DeCherney AH, Jones EE. Ectopic pregnancy. Clin Obstet Gynecol. 1985;28:365–74.PubMed
49.
Nelson LM, Margara RA, Winston RML. Primary and secondary closure of ampullary salpingostomy compared in the rabbit. Fertil Steril. 1986;45:292–5.PubMed
50.
Vancaillie TG. Salpingectomy. Obstet Gynecol Clin North Am. 1991;18:111–22.PubMed
51.
Ory SJ, Nnadi E, Herrmann R, et al. Fertility after ectopic pregnancy. Fertil Steril. 1993;60:231–5.PubMed
52.
Shapiro HI, Adler DH. Excision of an ectopic pregnancy through the laparoscope. Am J Obstet Gynecol. 1973;117:290–1.PubMed
53.
Bruhat MA, Manhes H, Mage G, Pouly JL. Treatment of ectopic pregnancy by means of laparoscopy. Fertil Steril. 1980;33:411–4.PubMed
54.
DeCherney AH, Maheaux R, Naftolin F. Salpingostomy for ectopic pregnancy in the sole patent oviduct: reproductive outcome. Fertil Steril. 1982;37:619–22.PubMed
55.
Ling FW, Stovall TG. Update on the management of ectopic pregnancy. Adv Obstet Gynecol. 1994;1:57.
56.
Thorburn J, Philipson M, Lindblom B. Fertility after ectopic pregnancy in relation to background factors and surgical treatment. Fertil Steril. 1988;49:595–601.PubMed
57.
Hajenius PJ, Mol F, Mol BW et al. Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev. 2007;(1):CD000324
58.
Mol F, van Mello NM. Salpingotomy versus salpingectomy in women with tubal ectopic pregnancy, a randomised controlled trial. Hum Reprod. 2012;27 Suppl 2:ii73–4.
59.
Mol BW, Matthijsse HC, Tinga DJ, et al. Fertility after conservative and radical surgery for tubal pregnancy. Hum Reprod. 1998;13:1804–9.PubMed
60.
Bouyer J, Job-Spira N, Pouly JL, et al. Fertility following radical, conservative-surgical or medical treatment for tubal pregnancy: a population-based study. Br J Obstet Gynecol. 2000;107:714–21.
61.
Bello GV, Schonholz D, Moshirpur J, et al. Combined pregnancy: the Mount Sinai experience. Obstet Gynecol Surv. 1986;41:603–13.PubMed
62.
Centers for Disease Control. Ectopic pregnancy in the United States 1988–89. Morb Mortal Wkly Rep. 1992;41.
63.
Nahum GG. Rudimentary uterine horn pregnancy. The 20th-century worldwide experience of 588 cases. J Reprod Med. 2002;47:151–63.PubMed
64.
Jayasinghe Y, Rane A, Stalewski H, Grover S. The presentation and early diagnosis of the rudimentary uterine horn. Obstet Gynecol. 2005;105:1456–7.PubMed
65.
O’Leary JL, O’Leary JA. Rudimentary horn pregnancy. Obstet Gynecol. 1963;22:371–5.PubMed
66.
Johansen K. Pregnancy in a rudimentary horn. Obstet Gynecol. 1983;61:565–7.
67.
Gagnon AL, Galerneau F, Williams K. Twin pregnancy with one fetus in a rudimentary horn: a case report of a surviving twin. Br J Obstet Gynaecol. 1998;105:1326–8.PubMed
68.
Holden R, Hart P. First-trimester rudimentary horn pregnancy: prerupture ultrasound diagnosis. Obstet Gynecol. 1983;61:56S–8.PubMed
69.
Heinonen PK, Aro P. Rupture of pregnant noncommunicating uterine horn with fetal salvage. Eur J Obstet Gynecol Reprod Biol. 1988;27:261–5.PubMed
70.
Jain R, Gami N, Puri M, Trivedi S. A rare case of intact rudimentary horn pregnancy presenting as hemoperitoneum. J Hum Reprod Sci. 2010;3:113–5.PubMedCentralPubMed
71.
Rolen AC, Choquette AJ, Aemmens JP. Rudimentary uterine horn: obstetric and gynecologic complications. Obstet Gynecol. 1966;68:224–30.
72.
Pal K, Majumdar S, Mukhopadhyay S. Rupture of rudimentary uterine horn pregnancy at 37 weeks gestation with fetal survival. Arch Gynecol Obstet. 2006;274:325–6.PubMed
73.
Oral B, Güney M, Özsoy M, Sönal S. Placenta accreta associated with a ruptured pregnant rudimentary uterine horn: case report and review of the literature. Arch Gynecol Obstet. 2001;265:100–2.PubMed
74.
Fedele L, Bianchi S, Tozzi L, et al. Fertility in women with unicornuate uterus. Br J Obstet Gynaecol. 1995;102:1007–9.PubMed
75.
Mavrelos D, Sawyer E, Helmy S, et al. Ultrasound diagnosis of ectopic pregnancy in the non-communicating horn of a unicornuate uterus (cornual pregnancy). Ultrasound Obstet Gynecol. 2007;30:765–70.PubMed
76.
Jurkovic D, Gruboeck K, Tailor A, Nicolaides KH. Ultrasound screening for congenital uterine anomalies. Br J Obstet Gynaecol. 1997;104:1320–1.PubMed
77.
Nishi H, Funayama H, Fukumine N. Rupture of pregnant noncommunicating rudimentary uterine horn with fetal salvage: a case report. Arch Gynecol Obstet. 2003;268:224–6.PubMed
78.
Salim R, Woelfer B, Backos M, et al. Reproducibility of three-dimensional ultrasound diagnosis of congenital uterine anomalies. Ultrasound Obstet Gynecol. 2003;21:578–82.PubMed
79.
Raga F, Bonilla-Musoles F, Blanes J, Osborne NG. Congenital Müllerian anomalies: diagnostic accuracy of three-dimensional ultrasound. Fertil Steril. 1996;65:523–8.PubMed
80.
Jurkovic D, Geipel A, Gruboeck K, et al. Three-dimensional ultrasound for the assessment of uterine anatomy and detection of congenital anomalies: comparison with hysterosalpingography and two-dimensional ultrasonography. Ultrasound Obstet Gynecol. 1995;5:233–7.PubMed
81.
Leyendecker JR, Gorengaut V, Brown JJ. MR imaging of maternal diseases of the abdomen and pelvis during pregnancy and the immediate postpartum period. Radiographics. 2004;24:1301–16.PubMed
82.
Wang PH, Chao HT, Too LL, Yuan CC. Primary repair of cornual rupture occurring at 21 weeks gestation and successful pregnancy outcome. Hum Reprod. 1999;14:1894–5.PubMed
83.
Dicker D, Nitke S, Shoenfeld A, et al. Laparoscopic management of rudimentary horn pregnancy. Hum Reprod. 1998;13:2643–4.PubMed
84.
Dulemba J, Midgett W, Freeman M. Laparoscopic management of a rudimentary horn pregnancy. J Am Assoc Gynecol Laparosc. 1996;3:627–30.PubMed
85.
Falcone T, Gidwani G, Paraiso M, et al. Anatomical variation in the rudimentary horns of a unicornuate uterus: implications for laparoscopic surgery. Hum Reprod. 1997;12:263–5.PubMed
86.
Park JK, Dominguez CE. Combined medical and surgical management of rudimentary uterine horn pregnancy. JSLS. 2007;11:119–22.PubMedCentralPubMed
87.
Sonmezer M, Taskin S, Atabekoglu C, et al. Laparoscopic management of rudimentary uterine horn pregnancy: case report and literature review. JSLS. 2006;10:396–9.PubMedCentralPubMed
88.
Carson SA, Buster JE. Ectopic pregnancy. N Engl J Med. 1993;329:1174–81.PubMed
89.
Maruri F, Azziz R. Laparoscopic surgery for ectopic pregnancies: technology assessment and public health implications. Fertil Steril. 1993;59:487–98.PubMed
90.
Lazenby GB, Huang C, Rahall AM, Fogelson NS. Pregnancy termination via laparotomy in a woman with bicornuate uterus. Contraception. 2007;75:241–3.PubMed
91.
Panayotidis C, Abdel-Fattah M, Leggott M. Rupture of rudimentary uterine horn of a unicornuate uterus at 15 weeks’ gestation. J Obstet Gynaecol. 2004;24:323–4.PubMed
92.
Samuels TA, Awonuga A. Second-trimester rudimentary uterine horn pregnancy: rupture after labor induction with misoprostol. Obstet Gynecol. 2005;106:1160–2.PubMed
93.
Shahid A, Olowu O, Kandasamy G, et al. Laparoscopic management of a 16-week ruptured rudimentary horn pregnancy: a case and literature review. Arch Gynecol Obstet. 2010;282:121–5.PubMed
94.
Goldberg JM, Friedman CI. Microsurgical fallopian tube transposition with subsequent term pregnancy. Fertil Steril. 1988;50:660–1.PubMed
95.
Cutner A, Saridogan E, Hart R, et al. Laparoscopic management of pregnancies occurring in non-communicating accessory uterine horns. Eur J Obstet Gynecol Reprod Biol. 2004;113:106–9.PubMed
96.
Soriano D, Yefet Y, Oelsner G, et al. Operative laparoscopy for management of ectopic pregnancy in patients with hypovolemic shock. J Am Assoc Gynecol Laparosc. 1997;4:363–7.PubMed
97.
Heinonen PK. Unicornuate uterus and rudimentary horn. Fertil Steril. 1997;68:224–30.PubMed
98.
Studdiford WE. Primary peritoneal pregnancy. Am J Obstet Gynecol. 1942;44:487–91.
99.
Atrash HK, Friede A, Hogue CJ. Abdominal pregnancy in the United States: frequency and maternal mortality. Obstet Gynecol. 1987;69:333–7.PubMed
100.
Maas DA, Slabber CF. Diagnosis and treatment of advanced extra-uterine pregnancy. S Afr Med J. 1975;49:2007–10.PubMed
101.
Riethmuller D, Courtois L, Maillet R, Schaal JP. Ectopic pregnancy management: cervical and abdominal pregnancies. J Gynecol Obstet Biol Reprod (Paris). 2003;32(7 Suppl):S101–8.
102.
Costa SD, Presley J, Bastert G. Advanced abdominal pregnancy. Obstet Gynecol Surv. 1991;46:515–25.PubMed
103.
Beacham WD, Hernquist WC, Beacham DW, et al. Abdominal pregnancy at Charity Hospital in New Orleans. Am J Obstet Gynecol. 1962;84:1257–70.PubMed
104.
Stratford JC, Ragan WD. Abdominal pregnancy: review of current management. Obstet Gynecol. 1977;50:548–52.
105.
Ombelet W, Vendermerve JV, Van Assche FA. Advanced extrauterine pregnancy: description of 38 cases with literature survey. Obstet Gynecol Surv. 1988;43:386–97.PubMed
106.
Lastra A, Ruiz Bedoya JA, Jiménez Balderas EA. Abdominal pregnancy with fetal survival. A report of 2 cases. Ginecol Obstet Mex. 1993;61:348–50.
107.
Selo-Ojeme DO, GoodFellow CF. Simultaneous intrauterine and ovarian pregnancy following treatment with clomiphene citrate. Arch Gynecol Obstet. 2002;266:232–4.PubMed
108.
Ceci O, Caradonna F, Loizzi P, et al. Ultrasound diagnosis of heterotopic pregnancy with viable fetuses. Eur J Obstet Gynecol Reprod Biol. 1993;52:229–31.PubMed
109.
Tutuncu L, Mungen E, Muhcu M, et al. Does previous Cesarean delivery increase the risk of ectopic pregnancy? Perinatal J. 2005;13:105–9.
110.
Audain L, Brown WE, Smith DM, Clark JF. Cocaine use as a risk factor for abdominal pregnancy. J Natl Med Assoc. 1998;90:277–83.PubMedCentralPubMed
111.
Oehninger S, Kreiner D, Bass MJ, Rosenwaks Z. Abdominal pregnancy after in vitro fertilization and embryo transfer. Obstet Gynecol. 1988;72:499–502.PubMed
112.
Kalchman GG, Meltzer RM. Interstitial pregnancy following homolateral salpingectomy: report of 2 cases and review of the literature. Am J Obstet Gynecol. 1966;96:1139–43.PubMed
113.
Aahman MS, Al-Suleiman SA, Aahman J, Al-Sibai MH. Advanced abdominal pregnancy: observations in 10 cases. Obstet Gynecol. 1981;59:366–72.
114.
Storeide O, Veholmen M, Eide M, et al. The incidence of ectopic pregnancy in Hordaland County, Norway 1976-1993. Acta Obstet Gynecol Scand. 1997;76:345–9.PubMed
115.
Delke I, Vendiano WP, Tawcer ML. Abdominal pregnancy: review of current management and addition of 10 cases. Obstet Gynecol. 1982;60:200–3.PubMed
116.
Jacobson A, Galen D. Heterotopic pregnancies and IVF. Fertil Steril. 1990;54:179–80.PubMed
117.
Dündar O, Tütüncü L, Müngen E, et al. Heterotopic pregnancy: tubal ectopic pregnancy and monochorionic monoamniotic twin pregnancy: a case report. Perinatal J. 2006;14:96–100.
118.
Bertrand G, Le Ray C, Simard-Emond L, et al. Imaging in the management of abdominal pregnancy: a case report and review of the literature. J Obstet Gynaecol Can. 2009;31:57–62.PubMed
119.
Allibone GW, Fagan CJ, Porter SC. The sonographic features of intra-abdominal pregnancy. J Clin Ultrasound. 1981;9:383–7.PubMed
120.
Stanley JH, Horger 3rd EO, et al. Sonographic findings in abdominal pregnancy. Am J Roentgenol. 1986;147:1043–6.
121.
Meinert J. Advanced ectopic pregnancy including combined ectopic and intrauterine pregnancy. Geburtshilfe Frauenheikd. 1981;41:490–5.
122.
Koo HS, Bae JY, Kang IS, et al. Laparoscopic management of early primary peritoneal pregnancy: a case report. Clin Exp Reprod Med. 2011;38:109–14.PubMedCentralPubMed
123.
Zinger M, Rosenfeld D. Failed treatment of abdominal pregnancy with methotrexate. A case report. J Reprod Med. 2001;46:392–4.PubMed
124.
Beddock R, Naepels P, Gondry C, et al. Diagnosis and current concepts of management of advanced abdominal pregnancy. Gynecol Obstet Fertil. 2004;32:55–61.PubMed
125.
Worley KC, Hnat MD, Cunningham FG. Advanced extra uterine pregnancy: diagnostic and therapeutic challenges. Am J Obstet Gynecol. 2008;198:297.e1–7.
126.
Ang LP, Tan AC, Yeo SH. Abdominal pregnancy: a case report and literature review. Singapore Med J. 2000;41:454–7.PubMed
127.
Martin Jr JN, McCaul IVJF. Emergent management of abdominal pregnancy. Clin Obstet Gynecol. 1990;33:438–47.PubMed
128.
Rahaman J, Berkowitz R, Mitty H, et al. Minimally invasive management of an advanced abdominal pregnancy. Obstet Gynecol. 2004;103(5 Pt 2):1064–8.PubMed
129.
Cardosi RJ, Nackley AC, Londono J, Hoffman MS. Embolization for advanced abdominal pregnancy with a retained placenta. A case report. J Reprod Med. 2002;47:861–3.PubMed
130.
Kerr A, Trambert J, Mikhail M, et al. Preoperative transcatheter embolization of abdominal pregnancy: report of three cases. J Vasc Interv Radiol. 1993;4:733–5.PubMed
131.
Kivikoski AI, Martin C, Weyman P, et al. Angiographic arterial embolization to control hemorrhage in abdominal pregnancy: a case report. Obstet Gynecol. 1988;71(3 Pt 2):456–9.PubMed
132.
Ludwig M, Kaisi M, Bauer O, Diedrich K. The forgotten child-a case of heterotopic, intra-abdominal and intrauterine pregnancy carried to term. Hum Reprod. 1999;14:1372–4.PubMed
133.
Martin Jr JN, Sessums JK, Martin RW, et al. Abdominal pregnancy: current concepts of management. Obstet Gynecol. 1988;71:549–57.PubMed
134.
Hreshchyshyn MM, Bogen B, Loughran CH. What is the actual present-day management of the placenta in late abdominal pregnancy? Analysis of 101 cases. Am J Obstet Gynecol. 1961;81:302–17.PubMed
135.
Ayinde OA, Aimakhu CO, Adeyanju OA, Omigbodun AO. Abdominal pregnancy at the University College Hospital, Ibadan: a ten-year review. Afr J Reprod Health. 2005;9:123–7.PubMed
136.
Clark JF, Jones SA. Advanced ectopic pregnancy. J Reprod Med. 1975;14:30–3.PubMed
137.
Hallatt JG, Grove JA. Abdominal pregnancy: a study of twenty-one consecutive cases. Am J Obstet Gynecol. 1985;152:444–8.PubMed
138.
Rahman MS, Al-Suleiman SA, Rahman J, Al-Sibai MH. Advanced abdominal pregnancy. Observations in 10 cases. Obstet Gynecol. 1982;59:366–72.PubMed
139.
St Clair JT, DA Jr W, Fish SA. Methotrexate in abdominal pregnancy. J Am Med Assoc. 1969;208:529–31.
140.
Lathrop JC, Bowles GE. Methotrexate in abdominal pregnancy. Report of a case. Obstet Gynecol. 1968;32:81–5.PubMed
141.
Tan KL, Goon SM, Wee JH. The pediatric aspect of advanced abdominal pregnancy. J Obstet Gynaecol Br Commonw. 1969;76:1021–8.PubMed
142.
Tan KL, Goon SM, Wee JH. The pediatric aspects of advanced abdominal pregnancy. J Obstet Gynecol Br Commonw. 1971;78:1444–6.