Ectopic Pregnancy

An ectopic pregnancy occurs when an embryo implants outside of the uterus. In 98% of cases, the ectopic implantation takes place in the fallopian tube. Ectopic pregnancies occur in 1% to 2% of all pregnancies and remain an important cause of maternal morbidity and mortality in the first trimester. Although the etiology of ectopic pregnancy is poorly understood, epidemiologic studies have identified several risk factors for ectopic pregnancy: cigarette smoking, tubal damage from previous surgery, and Chlamydia trachomatis infection. These risk factors have been hypothesized to lead to embryo implantation within the fallopian tube by altering tubal smooth muscle contractility and the tubal microenvironment, leading to arrest of the embryo within the fallopian tube and an environment more apt to facilitate implantation. Ectopic pregnancy can be difficult to diagnose, and most women present with pain and bleeding in the first trimester. These symptoms, however, are relatively common in early pregnancy, are not specific to ectopic pregnancy, and may be associated with other conditions, such as miscarriage. There are currently no specific biomarkers for ectopic pregnancy, and diagnosis relies on serial measurements of serum β-human chorionic gonadotropin (β-hCG)9 to monitor the β-hCG doubling time, as well as transvaginal ultrasound (TVS), to rule out the presence of an intrauterine pregnancy. In some cases, serum β-hCG concentration and ultrasound results may be inconclusive, and laparoscopy is required to make a diagnosis. In this Q&A, 4 experts discuss recent advances that help us understand the etiology of ecto- pic pregnancy and the available methods for diagnosing and treating ectopic pregnancy. How is ectopic pregnancy currently being diagnosed in your institution? Andrew W. Horne: In our institution, ectopic pregnancy is diagnosed with a combination of TVS and serial serum β-hCG monitoring. Kurt Barnhart: The majority of women with ectopic pregnancy are identified with ultrasound. Some women will be identified as having an ectopic pregnancy, and others will be identified as having an intrauterine pregnancy, therefore virtually eliminating the possibility of concomitant ectopic pregnancy. However, there remain up to 20% of women at risk who have nonspecific ultrasound findings, and further testing is warranted to ultimately distinguish the location of the gestation. This follow-up usually occurs as an outpatient. Tom Bourne: In our unit, the majority of ectopic pregnancies are diagnosed with TVS. We can detect 74% of ectopic pregnancies on the basis of a single TVS. After follow-up scans, 91% of ectopic pregnancies can be visualized before surgery. The reasons some ectopic pregnancies are not seen initially are that the fetuses are simply too small and it is too early in the disease course for them to be visualized. A proportion of women undergo a TVS, and still the location of the pregnancy cannot be identified. This pregnancy is classified as a pregnancy of unknown location (PUL). In these circumstances, serial serum β-hCG concentrations are measured to determine the intensity of follow-up, and further scans are arranged until the location of the pregnancy is identified. In the event that the serum β-hCG continues to rise and the rate of rise is too slow to be associated with a viable intrauterine pregnancy, a presumptive diagnosis of ectopic pregnancy may be made, and medical treatment with methotrexate is begun. Laparoscopy is rarely used to make a diagnosis of ectopic pregnancy but is used for treatment. If a laparoscopy is carried out in our institution on the basis of the prior visualization of an ectopic pregnancy with TVS and no ectopic pregnancy is then seen at surgery, this would be considered a risk issue and a potential indicator of there being a problem with the quality of the scan that had been carried out. Ioannis E. Messinis: The diagnosis of ectopic pregnancy is straightforward only in the case of rupture, with symptoms of acute abdominal pain and hemodynamic shock. In that case, history and physical examination are enough for the diagnosis. In the case of a suspected ectopic pregnancy without symptoms, the diagnosis is based on history, physical examination, TVS, and serum β-hCG measurement. The limitations of all these methods are well known. An ectopic pregnancy is highly suspected if the serum β-hCG is >2000 IU/L with no sac in the uterine cavity on ultrasound and is diagnosed by laparoscopy. When the serum β-hCG on the first visit is <2000 IU/L, the doubling time of β-hCG values is estimated. In these cases, methotrexate, uterine curettage, and laparoscopy are considered for treatment. What are the difficulties in diagnosing ectopic pregnancy? How do these affect patient care? Andrew W. Horne: The diagnosis of ectopic pregnancy remains problematic and often results in treatment delays. In our unit, fewer than 50% of tubal ectopic pregnancies are diagnosed at the patient's initial presentation. Despite the clinical advances in imaging, ultrasound is nonconclusive in up to 20% of women, for whom measurement of serial β-hCG concentrations is necessary to guide management. Further difficulties are encountered because serial β-hCG determination cannot accurately separate arrested intrauterine from ectopic pregnancies. Decelerated increases in β-hCG concentrations cannot be used to discriminate between a miscarriage and an ectopic pregnancy. Moreover, laparoscopy can be occasionally required to confirm the diagnosis, and this procedure is not without risk to the patient. Kurt Barnhart: Ectopic pregnancy, if not identified or considered, can be a life-threatening event. However, clinicians are now very good at identifying women at risk, and the clinical dilemma has shifted from the possibility of missing an ectopic pregnancy to determining the acuity of follow-up and/or interventions. Paramount is the determination that a woman at risk for an ectopic pregnancy does not have a desired viable intrauterine pregnancy. This is necessary because the diagnosis and treatment of ectopic pregnancy will often result in termination of a pregnancy. The second step is to distinguish if a nonviable pregnancy is an ectopic pregnancy or a miscarriage. Tom Bourne: In developed countries, most ectopic pregnancies will be diagnosed before there are serious acute complications. However, the problem is with diagnosing ectopic pregnancy at a point in the disease process when relatively conservative treatment approaches remain an option. As indicated earlier, at a certain point ectopic pregnancies are simply too small to visualize with current imaging techniques. Furthermore, at least 10% of early ectopic pregnancies have a rise in β-hCG similar to that seen in a normal viable intrauterine pregnancy. Using the β-hCG ratio is certainly not diagnostic and only can help us focus on a PUL that requires a closer follow-up until the location of the pregnancy is known. We can use progesterone, but while this might help with viability, it does not inform us about pregnancy location. So the problem is in diagnosing ectopic pregnancies at a very early stage when treatment is likely to be straightforward and not involve surgery or require treatment at all. The use of laparoscopy as a diagnostic test is a very invasive approach and should be unnecessary in most cases, and even when a laparoscopy is performed, it may be impossible to visualize a small ectopic pregnancy within a fallopian tube. More recently, the problem of diagnosing “nontubal” ectopic pregnancy has become more of an issue. By this I mean pregnancies that have implanted outside the endometrial cavity but not in the tube. Of particular concern are pregnancies that are implanted in cesarean section scars. In the early stages, these pregnancies are relatively easy to treat, but if advanced, they are associated with significant morbidity and mortality. The ultrasound-based diagnostic criteria for these pregnancies are not clear yet, and the risk of a false-positive diagnosis and intervention is not known. Ioannis E. Messinis: Apart from the usual clinical manifestations of the normal pregnancy, there are no specific symptoms associated with ectopic pregnancy. In some cases, mild abdominal pain and vaginal bleeding are present. Except in the case of acute abdominal pain and hemodynamic shock, a physical examination is not diagnostic, and the ectopic sac is rarely visible on ultrasound. An ectopic pregnancy is likely if there is less than a 66% rise in β-hCG values over 48 h. Nevertheless, even with stable values, at a β-hCG concentration <2000 IU/L the differential diagnosis from a missed or incomplete abortion is difficult. In the majority of cases, the ectopic pregnancy is a diagnosis of exclusion. As a result, a patient's treatment may be delayed, which may predispose to the rupture of the ectopic, while in other cases a precipitate action may lead to an unnecessary surgical intervention. This might cause substantial psychological morbidity. What would an ideal biomarker for ectopic pregnancy look like? Andrew W. Horne: An ideal serum biomarker would be one that could be assayed accurately and quickly, preferably in an emergency department setting. However, it would also have to be an inexpensive measure to have true value clinically. Fundamentally, the question of whether a serum biomarker exists that can accurately and specifically detect a tubal ectopic pregnancy remains unanswered. Furthermore, with the advent of better imaging techniques, a serum biomarker may be superseded by ultrasound-related technology. Kurt Barnhart: An ideal biomarker needs to be noninvasive and highly accurate. However, the test characteristics of the biomarker can certainly be taken advantage of, as there could be a variety of uses. For example, a valuable biomarker could distinguish between an intrauterine and an extrauterine (ectopic) pregnancy. Alternatively, a biomarker could also be valuable if it could distinguish between a viable and a nonviable pregnancy, especially when the location of that pregnancy is not known. Finally, a biomarker could also be used to identify the aggressiveness and prognosis of a PUL, distinguishing a patient who may be treated with expectant from a patient for medical or surgical Tom Bourne: An ideal biomarker would have a of the required for testing would be to it would be a test that could be carried out by the women at as a If a it would be if the test could be carried out in the the patient is seen the patient could be without the in to a A focus on diagnostic would be for such a important of such a would be to the of the ectopic pregnancy. the ectopic pregnancy it to methotrexate or a the pregnancy with tubal rupture and A that could help these monitor would the morbidity of ectopic pregnancy. is likely that ectopic pregnancies are currently treated or when they would without intervention. The problem with β-hCG concentration over time as a of ectopic is that are the pregnancies only over a of time in The β-hCG concentration may rise for a and then However, with current intervention will occur before in β-hCG concentration is Ioannis E. Messinis: An ideal biomarker would be a by the ectopic and in from other that have been for the diagnosis of an ectopic pregnancy and and factors by the and or endometrial and have been Nevertheless, of these is considered an ideal biomarker for ectopic pregnancy. the in diagnosing ectopic pregnancy substantial to the and would a biomarker Andrew W. Horne: The and currently necessary are a for As an example, to from a recent in that that in are up to diagnosing and ectopic pregnancy, with an in to the Using a diagnostic serum that could up to in Kurt Barnhart: when the location of a is not identified by a woman needs with the These diagnostic at presumptive treatment. This to the on the especially when a woman to a clinical and of these are A biomarker that would accurately identify the location of a pregnancy, the of the pregnancy, or the prognosis of the pregnancy would the of and time to diagnosis, Tom Bourne: there is a associated with this The issue to a between 10% and of women with in early pregnancy will be classified as women undergo and/or ultrasound scans before a diagnosis is than a there is also a to the women and in of time and The psychological morbidity of such follow-up while being about the is not but may be the of has also the now may they are before they have even missed a As a result, are for scans in for or with symptoms when there is no possibility that a pregnancy will be seen by ultrasound. they are then classified as a PUL and may up having a of unnecessary as a The between the of an scan and the when the scan is carried out in a by A further to a or missed diagnosis of ectopic pregnancy. This may be in of surgery and or the on treatment with methotrexate is also a issue. The of methotrexate to women with a PUL who are to have a viable intrauterine pregnancy is an cause of with associated Ioannis E. Messinis: The methods used for the diagnosis of an ectopic pregnancy are is that no more than 50% of the cases of ectopic pregnancies are diagnosed at the first the other the biomarkers used have a diagnostic and diagnostic leading to a process of with the for or even an Furthermore, on several an unnecessary laparoscopy can be performed, which an risk for the patient. of these a substantial to the that are for with The of a biomarker specific for the ectopic pregnancy would certainly these In your factors have the or of an ectopic pregnancy Andrew W. Horne: serum biomarkers have been identified to in an to diagnosis of ectopic pregnancy, the of and a in The clinical of these biomarkers has been because of results for the most to limitations in In the very and the of ectopic pregnancy within the not In some not accurately for gestation. This the in determining the of an ectopic pregnancy. Some of the serum biomarkers have also use because they not a or with a normal gestation. Moreover, in the and the used to detect biomarkers have to results between Kurt Barnhart: There have been a of studies identifying biomarkers for ectopic pregnancy. 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Ioannis E. Messinis: In this is to the of specific from the ectopic that would be to this and not from the may valuable on this An would also be the of a specific from the tubal by the implanted Although the majority of ectopic pregnancies occur in the fallopian a from the tubal will not all other and abdominal such as the or the abdominal ectopic implantation may also Furthermore, are to the of a combination of factors in the of a for an early diagnosis of the ectopic pregnancy. is about the etiology of ectopic pregnancy. What are this Andrew W. Horne: studies on the etiology of ectopic pregnancy have been and on or fallopian from women with ectopic pregnancy and fallopian from women or women with a There has been very of the of the in or in these to the that the etiology of ectopic pregnancy is difficult to There are no because ectopic is in the of fallopian tube from women with intrauterine it difficult to the ideal for to fallopian from women with ectopic pregnancy. In on from fallopian tube from women with ectopic pregnancy than before the event. is difficult to whether the predispose to ectopic pregnancy, or whether they are simply the result of tubal implantation and/or the presence of the Furthermore, the risk factors for ectopic pregnancy cigarette have been well the by which or to tubal implantation remains Kurt Barnhart: The of pregnancy is very difficult for there is an epidemiologic risk factors for ectopic pregnancy, it is difficult to identify Moreover, have in our our of normal as well as ectopic implantation. We also do not understand the risk of ectopic pregnancy is by concomitant or Finally, the of has the to this Tom Bourne: Some of the risk such as and are but the these factors lead to tubal pregnancy remain The is that studies of the fallopian tube will on However, studies are often to the fallopian tube of women the tube has been because of an ectopic pregnancy, which are difficult to In these circumstances, of the tube is not there are often difficulties in of would be or before in or the fallopian of women who or who have had Chlamydia and are The ectopic pregnancy is not but may to the of cesarean section in the case of and pregnancy, to of the A of to section has been a problem when to whether the ultrasound of a to and/or the risk of ectopic pregnancy. Ioannis E. Messinis: clinical have been associated with the of an ectopic pregnancy, such as previous previous tubal pregnancy, previous tubal surgery for and current use of an intrauterine In the majority of the cases, damage of the tubal can the ectopic implantation. risk factors such as and in An of the implantation at other than the fallopian tube is difficult. however, is and this is to the of these of them for of ectopic pregnancies. the other tubal the most common cause of damage to an ectopic pregnancy, may even treatment. of the tube is not How are ectopic pregnancies at your institution, and would an the of this Andrew W. Horne: In ectopic pregnancy is or have and to whether the ectopic pregnancy will without the for intervention. This conservative approach is used only if the patient is is has a risk of rupture, and has serum β-hCG of ectopic pregnancy is to with symptoms who are have no more than a of on ultrasound and have a β-hCG concentration the of methotrexate, usually in a single After methotrexate, undergo until serum β-hCG concentration is indicated if the patient is not for methotrexate or has symptoms or of tubal This a if the tube is or a when this is not the In the of acute hemodynamic a approach is the of medical with methotrexate with ectopic and this only of women with ectopic pregnancies are for medical in An would a of women to have medical management. Kurt Barnhart: most ectopic pregnancies are with the methotrexate to the ectopic pregnancy. In this treatment is often to women with a of, but without of, a diagnosis of ectopic pregnancy. has become less However, surgical of an ectopic pregnancy has some the and of treatment. also a better of prognosis for the pregnancy. treated with medical until the has This can up to If a biomarker could accurately identify the location of a could have and if a biomarker could a of woman might be to be treated therefore the morbidity from the medical and surgical Tom Bourne: A of surgery, medical treatment with methotrexate, and expectant and with no of tubal ectopic pregnancies are on and a or is performed, on the of damage to the tube and the of the tube. Laparoscopy can be carried out even in the event of hemodynamic but may be necessary in these circumstances, on the of the are for surgery if they are if they have a to if an embryo with a is visible within the sac of the pregnancy, or if the ectopic is very can be considered if the patient is and there are in place for In use the β-hCG ratio to women for expectant a with treatment with methotrexate, the are up with the serum β-hCG concentration taken on 4 and to the by We use a for ectopic pregnancy could management. diagnosis could make more women for medical which might involve of methotrexate or other of There is also a that women methotrexate for ectopic pregnancies that would without intervention if to an β-hCG concentration in will lead to methotrexate treatment than expectant management. in some of these the β-hCG will the pregnancy will without the for and are simply the pregnancy at a single point in We this methotrexate, in the 4 treatment there is often an rise in serum only for it to between 4 and a biomarker that would the of an ectopic pregnancy, the risk of tubal rupture, and the to methotrexate or other would lead to in for a of The use of such a would patient and us to better treatment. Ioannis E. Messinis: We measure β-hCG and the doubling We also use to or an intrauterine pregnancy. If the β-hCG concentration is >2000 IU/L and no intrauterine sac is do a laparoscopy. If the β-hCG concentration is <2000 IU/L with at least a 66% rise over 48 the patient is up until the β-hCG concentration that If there is or no and no intrauterine sac is methotrexate treatment or laparoscopy uterine are with the vaginal bleeding and β-hCG concentrations In these cases, uterine may be The of an would certainly help the This is to the of and the is also that the use of medical treatment will at the of surgery. there a woman can to having an ectopic pregnancy? Andrew W. Horne: Although women with ectopic pregnancy have no risk it has been that of ectopic pregnancy and a of the associated risk factors help identify women at a risk to facilitate an early and more diagnosis. risk factors are associated with of prior damage to the fallopian tube. These factors previous or abdominal surgery, and infection. Chlamydia trachomatis has been to of all ectopic pregnancies. The of this is not but it has been that in to of tubal it may be to an on the tubal In of all cases of ectopic pregnancy are to be associated with There is a with the ratio of when are a for this have been one or more of the tubal and uterine and microenvironment, and women should be to early treatment for suspected and to Kurt Barnhart: there are no for ectopic pregnancy. least of all ectopic pregnancies occur in women without risk the of ectopic pregnancy, it is for a woman to the and symptoms of a potential ectopic pregnancy, which vaginal bleeding and pain in the first of pregnancy. to an will early diagnosis of a potential ectopic pregnancy. However, it should be that women present early in a that diagnostic have and an intervention is often by the A who the of ectopic pregnancy can a and intervention and can be Tom Bourne: the risk factors would be a in the Using may but needs to be to some of our A on is especially in Using methods of in to the will the risk of Chlamydia and other for Chlamydia may lead to whether this the risk of ectopic pregnancy or other is not and women to have a of for Chlamydia and clinicians to the diagnosis for woman with bleeding or The that a recent that of women having had a Chlamydia the could be at risk of ectopic pregnancy should also be of the risk and be to an early scan to identify the location of the pregnancy. If an ectopic pregnancy cannot be it may at least be diagnosed is to the risk of ectopic pregnancy. having had a cesarean section is a risk and should be considered as a potential risk for women to this Ioannis E. Messinis: specific to ectopic pregnancy. What is to serious by an early diagnosis and treatment. women with one or more risk factors for an ectopic pregnancy should be the first until an intrauterine sac visible on ultrasound. Nevertheless, a time, help such as women to ectopic pregnancy. women should be to before and pregnancy. In this of have studies been to identify potential factors to ectopic pregnancy? Andrew W. Horne: no studies to ectopic pregnancy have been However, have in a small that women with ectopic pregnancy in the of of the the of these in a is to the that the and has a in ectopic implantation. Kurt Barnhart: is that there have been no studies to identify factors to ectopic pregnancy. However, it should be that studies have not been as as and have medical to than for a which may or may not be should be for a for the early diagnosis of ectopic pregnancy. In other it do us good to that has a when the is still a event of a in a that a to an pregnancy or an ectopic pregnancy would be of value to an woman and to the Ioannis E. Messinis: So there are no such studies in ectopic pregnancy. There are only some on of specific For example, serum concentrations are usually in ectopic no between of the and ectopic pregnancy In certain have been associated with tubal damage in by Chlamydia a potential cause of ectopic pregnancy. had a between and ectopic pregnancy, but this has not been In no has been between and ectopic pregnancy in in β-human chorionic gonadotropin transvaginal ultrasound pregnancy of unknown location.

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