Abstract
Ectopic pregnancy remains to be an important cause of maternal morbidity and mortality worldwide, although the incidence has remained unchanged especially in developed countries over the last decade. Several factors are responsible for this, including misdiagnosis and failure to institute timely appropriate treatment aimed at preserving fertility and minimizing the associated morbidity. Recent advances in imaging and biomonitoring have reduced the number of women presenting with ruptured ectopic pregnancy. Any attempt to reduce the consequences of ectopic pregnancies must, therefore, focus on improving the diagnosis of the unruptured type and evidenced-based treatment, which is cost effective. In this review, the authors discuss the diagnosis and treatment of this complication in the light of the recent evidence highlighting how improvements can be made to reduce the consequences.
Keywords
Ectopic pregnancy, an important cause of maternal morbidity and mortality, is estimated to occur in approximately 1–2% of pregnancies worldwide [1,2]. Although the incidence increased by a factor of three to six between 1970 and 1996, it has since remained stable, especially in developed countries [3,4]. In the UK, nearly 12,000 cases are diagnosed each year giving a prevalence of1.1%. While this incidence has remained unchanged, the case fatality rate has almost halved from 31.2 to 16.9 per 1000 maternities [5]. This drop is most likely attributable to early diagnosis and management before rupture. Nevertheless, ruptured cases remain an important cause of maternal morbidity and mortality, mostly owing to either misdiagnosis or late presentation [6,7]. Atypical ectopic pregnancies, such as those in the cervix, ovary, abdomen, cesarean section scar and the interstitial portion of the fallopian tube, are rare and make up less than 10% of all ectopic pregnancies [8]. Such ectopic pregnancies are not only difficult to diagnose, but also to manage and are, therefore, not surprisingly associated with a high morbidity.
Pathogenesis
A common factor in the etiopathogenesis of most cases is tubal damage, which results in the impairment of oviductal transport of the embryo and its resultant implantation into the tube. This may occur in a variety of ways, including the progressive loss of myoelectrical activity, which occurs with aging and is a possible explanation of an increased incidence in perimenopausal women; salpingitis, which damages oviductal ciliated epithelium leading to delayed propulsion of the embryo; and deciliation of the tube and atrophy of the endometrial cavity owing to an increase in the levels of progesterone [9,10]. Furthermore, factors endogenous to the embryo, which may also increase the chances of tubal implantation, include an embryo reaching the implantation state while still in the oviduct, for example, because growth and proliferation of the trophoblast is too advanced; and a delay in the transportation of the embryo, such that it becomes too large to pass through the isthmic–utero tubal junction.
Risk factors
Although several factors have been identified as increasing the risk of ectopic pregnancy, approximately half of the patients with this diagnosis do not have any known risk factor [11,12]. In a meta-analysis that included 36 studies, Ankum et al. summarized known risk factors, some of which are discussed below [13].
Pelvic inflammatory disease
Tubal infection by pathogens, such as chlamydia trachomatis, damages ciliated epithelium leading to the formation of intraluminal adhesions that predispose to entrapment of the zygote and the resultant ectopic implantation of the blastocyst. Westrom et al. studied 450 women with laparoscopically proven pelvic inflammatory disease (case–control study) and reported that the incidence of tubal obstruction increased with successive episodes: 13% after one, 35% after two and 79% after three episodes [14]. Following one episode of laparoscopically verified acute salpingitis, the ratio of ectopic to intrauterine pregnancy was 1:24, a sixfold increase compared with women with laparoscopically negative results. Only 50% of fallopian tubes removed for an ectopic pregnancy have histological evidence of salpingitis.
Previous tubal surgery
Under this category are those with a previous ectopic pregnancy and those who have had tubal surgery, including sterilization and/or reversal and tubal reconstructive surgery [13].
The recurrence risk following one previous ectopic pregnancy is approximately 10%, and this increases to 25–30% after two or more ectopic pregnancies [15–17]. An accurate assessment of the recurrence risk is difficult as this is partly dependent upon the size and location of previous ectopic pregnancy, status of the contralateral adenexa, treatment method and a history of subfertility.
Although the absolute risk of ectopic pregnancy is reduced following sterilization, the ratio of ectopic to intrauterine pregnancy is higher. This risk, and that of pregnancy, is greatest in the first 2 years after sterilization. The cumulative probability of ectopic pregnancy for all methods of tubal sterilization is 7.3 per 1000 procedures. The technique of sterilization and the woman's age at the time of the procedure influence this risk. For example, women sterilized before the age of 30 years by bipolar tubal coagulation have a 27-times higher probability of ectopic pregnancy compared with postpartum partial salpingectomy (31.9 vs 1.2 ectopic pregnancies per 1000 procedures, respectively) [18]. Tubal coagulation, on the other hand, has a lower risk of pregnancy compared with spring-loaded clips but the risk of ectopic pregnancy is ten-times higher when a pregnancy does occur [19].
Assisted reproduction techniques
Subfertile women are at an increased risk of ectopic pregnancy, partly because of altered tubal integrity (or function) and the procedures used to treat the subfertility [20]. The first pregnancy after IVF and embryo transfer (IVF–ET) was an ectopic pregnancy [21]. Approximately 1–4% of pregnancies following induction of ovulation are ectopic pregnancies, while the incidence of ectopic pregnancy following IVF–ET is approximately 4.5% [10,22]. The increase following IVF–ET is partly explained by the increase in the heterotopic pregnancy ratio from 1:4000 to 1:100 [23].
Demographic attributes
Smoking is considered a risk factor for ectopic pregnancy [24]. A case–control study in France revealed that smoking was associated with a significantly higher risk [25]. There was a direct relationship between the number of cigarettes smoked and the risk of having an ectopic pregnancy, for example, the risk was 1.3 for those who smoked one to nine cigarettes per day compared with 2 for those smoking ten to 20 per day, and was even higher at 2.5 for those smoking more than 20 cigarettes per day [26]. This increased risk is thought to be secondary to the effect of nicotine, which inhibits oocyte cumulus complex pickup by the fimbrial end of the tube and also decreases ciliary-beat frequency [27].
Women aged 35–44 years have a three- to four-fold increased risk of ectopic pregnancy compared with 15–24 year olds [28]. As discussed above, this is partly linked to the progressive loss of myoelectrical activity that occurs with age.
Although the intrauterine contraceptive device (IUCD; medicated or unmedicated) reduces the overall pregnancy rate, if it fails, the woman is seven-times more likely to have an ectopic pregnancy compared with conception without an IUCD in situ [10]. Indeed, 4 and 17% of all accidental pregnancies are tubal in those with a copper- and progesterone-coated IUCDs, respectively. Women who had used the IUCD for more than 24 months were 2.6-times more likely to have an ectopic pregnancy compared with short-term users (<24 months). The ‘lasting effect’ of the IUCD may be related to the loss of the cilia from the tubal epithelium, especially if the IUCD had been <i>in situ for 3 years or more [29].
Evaluation
Clinical evaluation
Clinical evaluation is based on a combination of clinical features, findings at imaging and, where appropriate, biochemical markers. The clinical presentation depends on the site and whether it is ruptured or not. A high index of suspicion is vital to making a diagnosis, especially where the presentation is atypical. The main symptoms include abdominal or pelvic pain, amenorrhea or missed period and vaginal bleeding with or without clots. Others include GI tract (GIT) symptoms, dizziness, fainting or syncope, shoulder-tip pain, urinary symptoms and rectal pressure or pain on defecation [30].
Symptoms and signs in 300 consecutive cases of ectopic pregnancy at admission.
Adapted with permission from [10].
Abdominal pain
Abdominal pain is the most common symptom; it may be sudden in onset, progressive, continuous or intermittent. The pain may be generalized pelvic or abdomino–pelvic or localized pelvic (unilateral or bilateral) and/or radiating to the shoulder. Generalized abdominal pain is usually due to rupture of the ectopic pregnancy and intraperitoneal hemorrhage. Shoulder pain is an indirect indication of intraperitoneal hemorrhage and is secondary to accumulation of blood in the subdiaphragmatic region, which stimulates the phrenic nerve. Localized pain in the pelvis may be due to distension of the fallopian tube. It is important to note that, as most women with a threatened miscarriage also present with lower abdominal pain, distinguishing this from the pain of an ectopic pregnancy may be difficult. While the pain of miscarriage invariably settles, that of ectopic pregnancy persists even with the alleged passage of tissue [32]. An estimated 10–20% of women with ectopic pregnancy, however, do not report any pain at all [33].
Amenorrhea & abnormal uterine bleeding
Most cases present with an amenorrhea of at least 2 weeks duration; however, absence does not exclude the diagnosis as some of the patients will present with irregular/abnormal vaginal bleeding (which may be mistaken for a period) [10]. This abnormal bleeding, which is a presenting feature in approximately 75% of women, may be light, recurrent or even heavy [34]. Where the bleeding is disproportionate to the pain, for example, little bleeding and severe pain, then an ectopic pregnancy is likely, and similarly, where bleeding is more severe than the pain an intrauterine pregnancy is most likely [34].
Atypical features
GIT symptoms, such as nausea, vomiting and diarrhea in women, in the reproductive age group and, especially, if accompanied with syncopate, are highly suspicious of an ectopic pregnancy. This may be a presentation of a ruptured tubal ectopic pregnancy complicated by severe intraabdominal hemorrhage. These gastrointestinal symptoms may lead to a diagnosis or suspicion of a GIT disorder, thus leading to a delay in the diagnosis of an ectopic pregnancy. In just over a-third of the women who died from an ectopic pregnancy in the UK since 1977, there was an initial misdiagnosis of a GIT problem. The confidential enquiries into maternal mortality in the UK strongly recommend considering a diagnosis of ectopic pregnancy in women of reproductive age with sudden onset of severe GIT problems. Since most of these cases present to either general practitioners or the accident and emergency department, a pregnancy test should at least be carried out [6,35]. Thus, all healthcare professionals involved in the care of women of reproductive age should have access to pregnancy tests [6,31].
Clinical presentation
Although approximately 10–30% of all women with an ectopic pregnancy present after rupture, acute presentation is becoming less common [36]. This is due primarily to increased patient awareness and early referral to the hospital for evaluation of ‘suspected ectopic’ pregnancies. Furthermore, the availability of more sensitive and rapid biochemical tests for β-human chorionic gonadotrophin (βhCG) quantification and the wider availability of transvaginal ultrasonography and laparoscopy have significantly reduced the interval between presentation and treatment. Subacute presentation occurs in 80–90% of ectopic pregnancies. In cases with such a presentation, the establishment of an accurate diagnosis becomes more difficult, hence the need for further investigations [35].
Those with a ruptured ectopic pregnancy (~10–30%) may present with features of shock (e.g., hypotension and tachycardia), abdominal pain and rebound tenderness. Subacute cases, on the other hand, may present with nonspecific manifestations simulating the clinical features of either complicated viable intrauterine pregnancies or miscarriage (threatened, incomplete or complete), for example, intermittent, light and either bright or dark red first-trimester bleeding, unilateral or diffuse ‘crampy’ abdominal or pelvic pain (ranging from mild to debilitating), or both.
While the diagnosis of ruptured ectopic pregnancies is clinical, the use of transvaginal imaging combined with sensitive quantification of serum βhCG often leads to a rapid and accurate diagnosis in unruptured cases. When a patient presents with the subacute symptoms outlined above, an essential step in her evaluation is the determination of whether the pregnancy is potentially viable and, if not, its location. Ultimately, management will be determined based on whether it is a growing intrauterine pregnancy, a nonviable intrauterine pregnancy (miscarriage) or an ectopic pregnancy [8].
Physical examination
The findings on clinical examination are determined by the severity and type of ectopic pregnancy. These will vary from typical features of shock to nonspecific findings. Abdominal examination may demonstrate features of significant intraperitoneal hemorrhage, including fullness in the flanks and generalized or localized mild tenderness. Where the hemoperitoneum is considerable, the Cullen's sign (bluish discoloration of the skin around the umbilicus) will be positive. Typical findings on pelvic examination vary from vague nonspecific findings to the presence of a large, fixed, soft and tender mass. An adnexal mass may be palpable in up to 55% of cases [10]. In many cases, this mass is ill-defined and may consist not only of the tubal pregnancy, but also of adherent omentum, and the small and large bowel. Often, the uterus is slightly enlarged; however, its size does not normally correspond to the gestational age. Cervical motion tenderness may or may not be present. A tender boggy mass in the pouch of Douglas, when present, represents either a collection of blood or a dilated tube adherent to the posterior uterine wall.
Biochemical evaluation
Serum βhCG subunit quantification
Serum βhCG is considered to be the most valid biomarker of ectopic pregnancy. Despite this, it will neither identify the absence or presence of an intrauterine or ectopic pregnancy nor predict rupture; however, it may serve as a surrogate marker for gestational age. With a single discriminatory value, it is possible to determine the serum βhCG levels for the detection of an intrauterine pregnancy by ultrasonography, with a sensitivity approaching 100% and at which the absence of an intrauterine pregnancy suggest ectopic or abnormal gestation [8]. Furthermore, an understanding of the physiological changes in these levels over time allows for the possibility to distinguish between a resolving spontaneous miscarriage, a potentially viable intrauterine pregnancy and an ectopic pregnancy. Although it was previously shown that in a normal intrauterine pregnancy, βhCG levels double over 2.2 days with 85% of cases showing a 66% rise, more recent data have shown that in approximately 99% of viable intrauterine pregnancies, there is an increase in βhCG levels of at least 53% in 2 days – a rate of rise significantly slower than the previously reported 66% [37,38]. Barnhart et al., in a prospective study, showed that in women with a continuing viable intrauterine pregnancy, βhCG levels rose by 124% after 48 h in 50% of cases, by 63% in 85% of cases and by 53% in 99% of cases [37]. In those who spontaneously miscarried, the rate of fall depended on the initial baseline value, with the fall slower for lower values and vice versa for higher values.
Where the measurement is a single reading, a discriminatory value for βhCG of between 1500 and 3000 IU/l above which an intrauterine gestational sac should be visualized on ultrasound is generally recommended [39–41]. Using values at the lower end of this discriminatory zone will increase the sensitivity for the diagnosis of an ectopic pregnancy, but this is unfortunately also associated with an increase in the false-positive rate and, therefore, the attendant risk of interrupting a normal intrauterine pregnancy by instituting interventions. It therefore follows that using a higher discriminatory value will increase specificity.
An alternative to using the discriminatory measurement is serial quantification to determine the rate of change in measured βhCG. The rate of increase in singleton and multiple pregnancies is similar; however, the absolute values are higher at a given gestational age in multiple pregnancies [42]. Unfortunately, the rate of change in some ectopic pregnancies may sometimes be similar to that of normal and abnormal intrauterine pregnancies, thus reducing its reliability as a discriminatory test [43,44]. In fact, the doubling time and discriminatory zone may be normal in as many as 15–20% of ectopic pregnancies [45]. A declining β hCG or a single initial low reading may suggest a pregnancy undergoing spontaneous resolution regardless of location. If the decline is rapid then the need for any form of intervention diminishes significantly [44,46]. In approximately 50% of women with an ectopic pregnancy, serial βhCG values fall, while in another 50%, these rise [47]; however, in approximately 70% of cases, the rise or fall is slower than would be expected for a viable intrauterine pregnancy or a miscarriage [39,43].
Serum progesterone assay
A progesterone value lower than 20 nmol/l is highly suggestive of a nonviable pregnancy, while values above 60 nmol/l suggest an intrauterine pregnancy. Values between 20 and 60 nmol/l can be either. This gray area significantly limits the clinical usefulness of measuring progesterone [48,49]. Although serum progesterone is not discriminatory enough to be diagnostic, algorithms have been constructed for its use in the diagnosis of ectopic pregnancy, and studies have shown that its inclusion improves diagnostic accuracy and reduces the number of unnecessary surgeries for misdiagnosis [36,50–53].
Progesterone concentrations have been widely used for the diagnosis and management of pregnancies of unknown location (PUL), for example, where ultrasound is inconclusive. In failing pregnancies, whether ectopic or miscarriage, progesterone concentrations are expected to be low compared with values in healthy ongoing pregnancies [54]. Most studies report cutoff concentrations of <16 nmol/l for failing pregnancies and >80 nmol/l for healthy ongoing pregnancies [55–57]. Progesterone levels of >25 nmol/l are ‘likely to indicate’ and > 60 nmol/l are ‘strongly associated with’ pregnancies subsequently shown to be normal. A progesterone concentration of <25 nmol/l in an embryonic pregnancy has been shown to be diagnostic of nonviability [58]. Concentrations of <20 nmol/l have a sensitivity of 93% and a specificity of 94% for the prediction of spontaneous resolution of PULs [59]. A meta-analysis has demonstrated that a single serum progesterone measurement is good at predicting a viable intrauterine or failed pregnancy, but it is not useful for locating the site of pregnancy [53]. When interpreting progesterone measurements, variations in concentrations should be taken into account because of the assay methods and departmental protocol should state the normal range for that unit.
Radiological
Ultrasonography
Transvaginal ultrasound is the gold standard approach to assessment and diagnosis of suspected ectopic pregnancies. An understanding of ultrasound findings in normal and complicated early pregnancies is vital to its utilization in the diagnosis of ectopic pregnancies [60–63]. Various ultrasound features have been described for the identification of early intrauterine pregnancies.
The identification of an intrauterine pregnancy by transvaginal ultrasound is possible from as early as 4 weeks. At this stage, there may be an eccentrically placed small gestational sac (2–5 mm in diameter) between the endometrial layers, followed by a double decidual sac sign characterized by two echogenic rings surrounded by intrauterine fluid collection, and then the visualization of the yolk sac, the most reliable sign to differentiate between a pseudosac and a true sac [60,61]. The double ring comprises of chorionic villi, intervillous lakes, the extravillous trophoblast and the maternal decidua [64]. This decidual sac sign can also be seen in a third of ectopic pregnancies. The yolk sac, which is identified when the mean gestational sac diameter is greater than 8 mm (i.e., at 5.5 weeks), is considered to be a definitive confirmation of an intrauterine pregnancy even before a live embryo is detected [65]. At this gestation, a transvaginal ultrasound should identify an intrauterine pregnancy with an accuracy of almost 100% [66–68]. Transabdominally, the embryonic pole should be visualized at 6 weeks followed by fetal cardiac activity at 6.5 weeks [62]. Where the assessment is made transvaginally, these should be visualized 1-week earlier (i.e., at 5 and 5.5 weeks, respectively). The presence of an intrauterine pregnancy does not conclusively exclude an ectopic pregnancy; however, the occurrence of a heterotopic pregnancy is rare. Features of a nonviable intrauterine pregnancy include a gestational sac of mean diameter 20–25 mm with no fetal pole or an embryo of more than 6 mm without fetal cardiac activity [30,65,69,70]. In 20% of patients with an ectopic pregnancy, fluid collection within the uterine cavity results in the formation of a pseudogestational sac, which mimics a true intrauterine sac [10].
While the sensitivity of a transvaginal ultrasound scan is almost 100% for the identification of an intrauterine pregnancy from 5.5 weeks gestation, it ranges from 73 to 93% for the diagnosis of an ectopic pregnancy and this is dependent on the expertise of the clinician or ultrasonographer [66–68]. Various criteria have been described for the diagnosis of an ectopic pregnancy by ultrasound with varying degrees of sensitivity and specificity. These include an extrauterine gestational sac with a fetal pole and cardiac activity, the viable extrauterine pregnancy; an extrauterine gestational sac with a fetal pole, but no cardiac activity, the nonviable extrauterine pregnancy seen in approximately 13% of cases; the presence of an adnexal mass with a hyperechoic ring around a gestational sac, the ring sign seen in approximately 20% of cases of ectopic pregnancies diagnosed by ultrasound; and an adnexal mass separate from the ovary, the nonhomogenous mass seen in approximately 60% of ectopic pregnancies diagnosed by ultrasound [70–72]. While the viable extrauterine pregnancy sign is 100% accurate in diagnosing an ectopic pregnancy, the nonhomogenous mass has a positive predictive value that has been shown to vary from 80 to 90% [8]. These so called hyperechogenic tubal rings or ‘doughnut’ or ‘bagel’ signs are the most common finding on ultrasound scan. It has been reported that 74% of ectopic pregnancies can be visualized on the initial transvaginal ultrasound scan and more than 90% can be visualized prior to treatment [71]. Ultrasound findings, however, are not diagnostic in the 15–20% of women with a clinical suspicion of an early pregnancy failure.
In a review of the various features identified on ultrasound in ectopic pregnancies, Brown and Doubilet found an empty uterus in 28% of cases, an empty uterus and an adnexal mass in 35%, an intrauterine sac or pseudogestational sac in 25%, an empty uterus and an ectopic gestational sac in 12% with or without a yolk sac and cardiac activity and varying amount of fluid in the pouch of Douglas in 25% of cases [70].
The initial ultrasound scan examination will fail to demonstrate either an intrauterine or an extrauterine pregnancy in approximately 8–31% of women in whom an ectopic pregnancy is suspected [66,68,71,72]. These cases are currently labeled PUL. Various reasons have been advanced to explain the failure of distinguishing these cases, including an intrauterine pregnancy that is too early. For example, the gestational sac has collapsed or has not yet developed; an early ectopic pregnancy with no obvious evidence of hemorrhage, probably because it is too small to be detected by ultrasound scan; inadequate operator expertise or ultrasound equipment; and the associated uterine abnormalities, such as fibroids and hydrosalpinx, which may mask the diagnosis of the location of the pregnancy. In fact, it has been estimated that up to 50% of patients with an ectopic pregnancy present with PUL and approximately 10–20% of these PULs will ultimately be diagnosed as ectopic pregnancies [66,68,71,72].
Combining ultrasound & biochemistry in diagnosis
The measurement of serum βhCG levels is essential for the accurate interpretation of ultrasonographic findings. As stated above, a single measurement has to be interpreted based on a discriminatory level to help with the diagnosis of ectopic pregnancy. The absence of an intrauterine gestational sac, for example, with serum βhCG levels of ≥6500 IU/l, has an 86% positive predictive value and a 100% negative predictive value for the presence of an ectopic pregnancy [40]. As transvaginal ultrasound scan has continued to improve the sensitivity in diagnosing ectopic pregnancies, different discriminatory levels of serum βhCG (e.g., 1000, 1500 and 2000 IU/l) have been used but with no significant difference in the detection rates [8,72]. Failure to visualize an intrauterine gestational sac by transvaginal ultrasound at βhCG concentrations of ≥1000–2000 IU/l is highly suggestive of an abnormal intrauterine pregnancy, a recent miscarriage or an ectopic pregnancy. Although the discriminatory zone for an intrauterine pregnancy is well established, there is no such discriminatory zone (i.e., a level at which a diagnosis can either be confirmed or excluded by ultrasound scan) for ectopic pregnancies.
When an ultrasound scan is combined with biochemistry in making a diagnosis of an ectopic pregnancy, the accuracy of findings varies with the serum βhCG levels; when the value is less than 1500 IU/l, for example, the positive predictive value of ultrasound scanning for the diagnosis of an intrauterine pregnancy has been shown to be only between 60 and 80% for the diagnosis of an ectopic pregnancy [8,71]. When the βhCG levels are above the discriminatory level, all attempts must be made to localize the pregnancy that has been deemed as nonviable from failure to visualize an intrauterine pregnancy on ultrasonography [39,72]. Where serum quantification is being used as an adjunct to monitoring, a fall in levels 12–24 h after uterine evacuation of 20% or more is suggestive of trophoblast having been removed from the uterus, while a plateauing or an increase is strongly suggestive of an ectopic pregnancy [8]. While women with falling βhCG levels should be monitored until the levels are undetectable, those with rising or plateauing levels should have an ultrasound examination and then surgery/intervention.
Other imaging
Although various studies have reported on the use of Doppler ultrasonography and 3D ultrasonography, there are no current clear criteria for their application in clinical practice, hence, their sensitivity and specificity has not been demonstrated to improve the accuracy of conventional B-mode ultrasound [73–75]. It may be that refinement of 3D scanning may result in improved sensitivity and eventual clinical application to aid in diagnosis.
Diagnostic laparoscopy
With advancing technology, the availability of sensitive quantitative serum βhCG assays and high-resolution transvaginal ultrasound, diagnostic laparoscopy is seldom used as a primary diagnostic tool, but may be required in certain cases where the clinical diagnosis is based on symptoms and these highly sensitive tests and skills are unavailable. In some units, it is used to diagnose ectopic pregnancy in the presence of an empty uterus with serum βhCG levels above the discriminatory level. A major disadvantage of laparoscopy is that a small ectopic pregnancy may not be visualized and in 3–4% of cases the diagnosis will be missed [10].
Culdocentesis
With the availability of modern equipment and biochemical tests, culdocentesis is rarely used for the diagnosis of ectopic pregnancy. However, in parts of the world where these facilities are lacking, aspirating blood from the pouch of Douglas that does not clot on standing is most likely suggestive of an ectopic pregnancy.
Management
The aim of treatment is to minimize disease- and treatment-related morbidity while maximizing reproductive potential. This can be achieved through expectant, medical or surgical management.
Expectant
Expectant management is based on the presumption that a significant proportion of all tubal ectopic pregnancies will be resolved through regression or a tubal abortion without any treatment. There is no marker that can identify women in whom ectopic pregnancies will spontaneously resolve. However, expectant management can be tried in clinically stable asymptomatic women with an ultrasound diagnosis of ectopic pregnancy, no evidence or less than 100 ml of fluid in the pouch of Douglas and a decreasing serum βhCG, initially less than 1000 IU/l [76]. In a large prospective study of expectant treatment, Korhonen et al. reported an overall success rate of 65% [77]. A higher rate of 70–89% has been reported in those with an initial βhCG concentration of less than 1000 IU/l [78]. Twice-weekly serial βhCG measurements and weekly ultrasound scans are vital in the monitoring of these women to ensure that βhCG levels are declining and the gestational sac is reducing in size. The ultimate aim of treatment is to reduce βhCG levels to less than 20 IU/l [30]. Only one randomized trial published to date compared expectant management with oral methotrexate [79]. Where the woman has been offered the option of expectant management she must be informed of the potential risk of tubal rupture even though βhCG values may be decreasing. Furthermore, they should be informed that complete resolution takes between 2 and 3 weeks but may be as long as 6–8 weeks, especially with a high pretreatment βhCG level [80–82].
Surgical
Surgical management options include salpingectomy (removal of the affected fallopian tube), salpingostomy (dissecting out the ectopic with conservation of the tube) or milking of the pregnancy out of the tube (a procedure considered almost obsolete in developed countries but one that may still have a role in less developed countries). The decision to perform either a salpinectomy or salpingostomy should be discussed preoperatively based on the patient's history, desire for future fertility and availability, including affordability of assisted reproductive techniques and the skill of the surgeon. Ultimately, however, the procedure performed is influenced by intraoperative findings including the extent of damage to the affected tube and the state of the contralateral tube. Postoperative follow-up with serial βhCG monitoring is vital following conservative surgical management because in 5–20% of cases, trophoblastic cells remain in the tubes. Such persistence is best managed either medically or surgically [8].
A laparoscopic approach is the most cost-effective and preferred approach to surgery [83,84]. While this is considered to be the gold standard, with evidence showing it can be achieved in almost 100% of cases, including those who are hemodynamically unstable [85–87], considerable obstacles to this remain especially in unstable cases, and attempts ought to be made to resist them using the supportive evidence above. The alternate approach, laparotomy, which ought to be extremely rare should, therefore, be reserved for cases where the expertise is unavailable or there is poor visualization of the pelvis at the time of laparoscopy [8]. Subsequent intrauterine pregnancy rates have been shown in observational studies to be higher following salpingostomy (73%) than after salpingectomy (57%); however, the rates of ectopic pregnancy are higher with the former than the later (15 vs 10%) [39,83,84]. In general, tubal preservation surgery should be the preferred approach if fertility preservation is important to the patient; however, where there is significant tubal damage or the contralateral tube is visualized to appear structurally normal then a salpingectomy would be the preferred treatment.
Medical
Medical management is commonly achieved with the folic acid antagonist, methotrexate, administered systemically. Various regimens have been used including a single dose, two doses and multiple doses [8]. While the single dose is the most popular regimen as it requires fewer visits to the hospital, it is associated with a higher failure rate (88%; 95% CI: 86–90% for a single dose vs 93%; 95% CI: 89–96% for multiple doses) [81]. Factors that increase or are associated with a higher failure rate include the presence of moderate-to-large amounts of free fluid in the peritoneal cavity, the presence of cardiac activity on ultrasound, an initial serum βhCG greater than 5000 IU/l and a pretreatment increase in serum βhCG level of more than 50% over a 48-h period [8,88]. Ultimately, approximately one in 15 women treated with methotrexate will need surgery.
Where a miscarriage has not been excluded, methotrexate should be avoided in the management of a presumed ectopic preganancy as this could potentially result in unnecessary chemotherapy for a woman with a complete miscarriage or even a PUL that may progress to a viable intrauterine pregnancy. There is no evidence of adverse long-term effects of methotrexate with regards to miscarriage, future pregnancies or congenital malformations. The most common dose employed is 50 mg/m2 of body surface area or multiple doses of 1 mg/kg, alternating with folinic acid rescue. Serum βhCG levels should be monitored while it is being used. A combination of mifepristone 600 mg and methotrexate was suggested to increase successful resolution of unruptured ectopic pregnancy, but a recent randomized control trial showed little advantage over methotrexate alone [89].
Contraindications to the use of methotrexate are either absolute or relative. Absolute contraindications include known sensitivity to methotrexate, breast feeding, laboratory evidence of immunodeficiency, active pulmonary disease, pre-existing blood dyscrasias, peptic ulcer disease, hepatitis, renal or hematological dysfunction and alcoholism or alcoholic, or other chronic liver disease [12,90]. Among the relative contraindications are an ectopic mass of more than 3.5–4 cm in diameter, an embryonic cardiac motion detected by transvaginal ultrasound, a patient declining blood transfusion or not able to avail themselves for follow-up and high initial hCG levels (>5000 IU/l) [12,90]. Side effects of methotrexate occur in 20–30% of cases and include myelosuppression, abdominal pain, conjunctivitis, stomatitis, gastritis, diarrhea, alopecia, liver toxicity, pneumonitis, photosensitivity, renal toxicity and anaphylaxis.
Approximately 25–30% of the total number of ectopic pregnancies satisfy the criteria for medical treatment, making its role somewhat limited [91,92]. Those managed medically are at increased risk of major hemorrhage from rupture after the administration of methotrexate, hence, the need to be kept under surveillance as 10% will require intervention because of this [91]. Owing to the concerns regarding side effects of methotrexate on subsequent pregnancy, a minimum of 3 months is recommended after medical treatment.
Surgical versus medical therapy
Studies comparing medical therapy and laparoscopic salpingostomy for unruptured ectopic pregnancy have shown nonsignificantly higher success rates with multidose methotrexate (relative success rate: 1.8; 95% CI: 0.73–4.6) and significantly lower success rates with single dose methotrexate (relative success rate: 0.82; 95% CI: 0.72–0.84) compared with salpingostomy [83,84]. Systemic methotrexate therapy has, in a cost-analysis study been shown to be cheaper than laparoscopic surgical therapy, but only if the diagnosis of ectopic pregnancy does not require laparoscopy and serum βhCG values are greater than 1500 IU/l [93]. Follow-up studies after successful medical and surgical management have shown similar rates of tubal patency (62–90%) and recurrence rates of ectopic pregnancy (8–15%) [83,84].
Pregnancies of unknown location
These are cases where ultrasound has failed to conclusively localize the site of gestation (i.e., there are no signs of either an ectopic or an intrauterine pregnancy [94]. These pregnancies may progress into one of seven categories [94]. The final outcome groups include a visualized ectopic pregnancy, a visualized intrauterine pregnancy, a spontaneous resolved pregnancy of unknown location, a nonvisualized persistent PUL, a resolved persistent PUL, a persisting PUL and a histological intrauterine pregnancy [94]. Crucial to the management of PULs is the rise in HCG levels. While traditionally, a rise of 50–60% after 48 h has been consistent with an intrauterine pregnancy, there is increasing recognition of the accuracy of this rise with some studies, suggesting that it could be as low as 35% [95]. Whatever the rise, a high index of suspicion based on clinical signs is essential for appropriate and timely intervention, especially where this progresses to an ectopic pregnancy.
Nontubal ectopic pregnancies
Nontubal ectopic pregnancies make up less than 10% of ectopic pregnancies and the sites for these include the cervix, ovary, the interstitial portions of the tube, cesarean section scars and the abdominal cavity.
Cervical ectopic pregnancies
Cervical ectopic pregnancies contribute 0.2% of all nontubal types [96]. The diagnosis is based on the placenta and the entire chorionic sac containing the pregnancy being located below a close internal cervical os. An ultrasound scan will typically show no intrauterine gestational sac, a ballooned cervical canal-/barrel-shaped cervix and a gestational sac in the endocervix below the uterine arteries. The management of these may be conservative, surgical, medical or a combination [97].
Ovarian ectopic pregnancies
Ovarian ectopic pregnancies comprise 0.2–1% of all ectopic pregnancies. The diagnosis is based on Spielberg's 1878 four criteria [96], which state that the gestation sac must occupy the position of the ovary; it should be connected to the uterus by the ovarian ligament; it should have ovarian tissue in its wall and the ipsilateral tube must be unaffected [98]. Treatment is mainly surgical although in very exceptional circumstances methotrexate may be given as adjunct if there is persistent trophoblastic tissue [99].
Interstitial ectopic pregnancies
Interstitial ectopic pregnancies make up 2–3% of all ectopic pregnancies. They present late, usually at approximately 7–12 weeks of gestation, and rupture of the uterine wall is the most frequent outcome. The diagnosis is made by ultrasound visualization of the interstitial line adjoining the gestationial sac and the lateral aspect of the uterine cavity, and the continuation of the myometrial mantle around the ectopic sac [100]. They have to be distinguished from angular pregnancies, which are implanted in one of the lateral angles of the uterine cavity, medial to the utero–tubal junction and leading to asymmetric enlargement of the uterus. The bulge of the angular pregnancy is medial to the round ligament displacing it laterally, while the bulge of interstitial pregnancy is lateral to the round ligament. Angular pregnancies tend to end in early miscarriage but may lead to persistent vaginal bleeding, placental retention or uterine rupture.
The preferred treatment option is surgery involving either a laparoscopic resection or a salpingectomy; however, medical treatment (systemically or administered into the pregnancy) with methotrexate can also be used [101]. Owing to the risk of uterine rupture in subsequent pregnancy and decreased fertility rate, it is advised that the optimal mode of delivery for all pregnancies following interstitial pregnancy is via cesarean section [102].
Primary abdominal pregnancy
Less than 1% of ectopic pregnancies are implanted primarily within the abdominal cavity [103]. They are associated with a high maternal mortality rate of 0.5–18%, which is eight-times greater than for other ectopic pregnancies. They tend to progress until late diagnosis at greater than 20 weeks. They are associated with high perinatal mortality rate of 40–95% and a pressure malformations, such as pulmonary hypoplasia, facial asymmetry and talipes [103].
The mainstay of treatment is surgery, however, removal of the placenta may be difficult and a combination of medical and surgical treatment should be considered. The problem encountered at surgery is often the difficulty with removal of the placenta. The placenta may be left in situ and spontaneous natural resorption is awaited. However, this often causes a stormy postoperative course with ileus and infection owing to bowel obstruction, fistula formation, hemorrhage and peritonitis [10,104].
Cesarean section scar ectopic pregnancies
Cesarean scar ectopic pregnancies are occurring more frequently because of an increase in the number of cesarean section deliveries. Recognized risk factors include trauma from previous uterine surgery, for example, dilatation and curettage, metroplasty, hysteroscopy, myomectomy, manual removal of placenta and incomplete healing of the uterine scar. Medical treatment is the first option for treatment, but surgery in the form of evacuation is possible, although the risk of hemorrhage and subsequent hysterectomy is considerable. Under these circumstances, tamponade with balloons of catheters or hemostatic stitches (e.g., Shirodkar) may be effective [105].
Conclusion
Ectopic pregnancy continues to be an important cause of maternal morbidity and mortality. The etiopathogenesis is poorly understood in over 50% of cases and, while there has been an improvement in an understanding of the clinical presentation and management, a small number are atypical in their presentation. In this review, we have discussed these atypical cases and their management.
Future perspective
Current approaches to the accurate diagnosis of ectopic pregnancies may involve multiple visits and tests to the hospitals. Several biomarkers are currently being investigated and a combination of these is most likely to reduce the interval between presentation and diagnosis, consequently allowing more patients to be treated by expectant management or medically, thereby reducing morbidity and mortality from ectopic pregnancies.
Further research is required to identify markers that identify women at risk of ectopic pregnancies, especially in the 50% in whom there are no etiological factors. Such triaging in the community will allow for a focused approach to diagnosis on first presentation.
Randomized trials are required to determine the success rate and cost benefits of expectant versus medical versus surgical treatment of unruptured ectopic pregnancies.
Executive summary
Pelvic inflammatory disease, previous tubal surgery and smoking are the most common risk factors for ectopic pregnancy; however, assisted reproduction and increasing cesarean rates account for the increasing number of nontubal ectopic pregnancies.
Clinical features depend on whether the ectopic pregnancy is ruptured (30% of cases) or not (70% of cases). Approximately 80–90% of cases present subacutely. Abdominal pain, abnormal uterine bleeding and amenorrhea are the most common symptoms. However, this complication must be suspected in women in the reproductive age group presenting with acute gastrointestinal symptoms, such as diarrhea associated with nausea and vomiting.
Clinical examination findings also depend on the state and site of the ectopic pregnancy, but include those of shock where there is severe hemorrhage, although in a significant number of cases (those presenting as unruptured) findings vary from vague generalized/localized abdominal pain to minimal symptoms.
A single discriminatory β-human chorionic gonadotrophin (βhCG) value between 1500 and 3000IU/l should be used to improve the diagnosis of unruptured ectopic pregnancies. The higher the discriminatory value the higher its specificity in making a diagnosis.
Recent data show that βhCG levels rise after 48 h by 63% in only 85% of cases of intrauterine pregnancies, and more recently, by 53% in 99% of cases. This is contrary to the previously reported 66% rise over 2.2 days in 85% of cases of intrauterine pregnancies. By implications, a slower rise in βhCG levels does not imply an ectopic pregnancy as this may well be intrauterine.
Serum progesterone levels are useful in algorithms for the diagnosis of unruptured ectopic pregnancies, especially when combined with βHCG and ultrasound. Values >60 mmol/l are suggestive of a normal intrauterine pregnancy while those <25 mmol/l are suggestive of a failing pregnancy that is likely to be resolved spontaneously. Ectopic pregnancies tend to be associated with values between 25 and 60 mmol/l.
Transvaginal ultrasound scan is almost 100% accurate in diagnosing an intrauterine pregnancy after 6 weeks, and the absence of an intrauterine pregnancy should raised the suspicion of an ectopic pregnancy. Approximately 70% of ectopic pregnancies can be visualized on initial transvaginal ultrasound.
The four diagnostic features for diagnosis include a viable extrauterine pregnancy (7% of cases); the nonviable extrauterine pregnancy (13% of cases); a hyperechoic adnexal mass, the ring sign (20% of cases); and the nonhomogenous mass seen separate from the ovary (60% of cases). A pseudogestational sac is found in 25% of cases.
Doppler ultrasonograpy and 3D ultrasonography are not yet routinely used to diagnose ectopic pregnancies.
Three treatment options include expectant management, surgery and medical management. Expectant management is offered to relatively asymptomatic/mildly symptomatic cases with less than 100-ml hemoperitoneum, βhCG of <1000 IU/l and with access to follow-up.
Laparoscopic surgery is the preferred cost-effective approach to either salpingostomy or salpingectomy depending on the state of the affected tube, the contralateral adnexal and the fertility desires of the woman.
Medical management is preferably with a single dose of methotrexate (50 mg/m2) and is best for those who are clinically stable, with minimal hemoperitoneum, βhCG <5000 IU/l, absence of cardiac activity in the ectopic pregnancy and a sac that is less than 3.5 cm. Approximately 25–30% of cases are suitable for medical treatment provided they avail themselves to follow-up and understand that further surgery may be required.
Treatment for nontubal ectopic pregnancies depends on their location and clinical state of the patient.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.