Pregnancy of unknown location: Evaluation and management

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Pregnancy of Unknown Location: Evaluation and Management Daniela Carusi MD, MSc PII: DOI: Reference:

S0146-0005(18)30142-3 https://doi.org/10.1053/j.semperi.2018.12.006 YSPER 51107

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Seminars in Perinatology

Please cite this article as: Daniela Carusi MD, MSc , Pregnancy of Unknown Location: Evaluation and Management, Seminars in Perinatology (2018), doi: https://doi.org/10.1053/j.semperi.2018.12.006

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Pregnancy of Unknown Location: Evaluation and Management Daniela Carusi, MD, MSc* Brigham & Women’s Hospital and Harvard Medical School, Boston, MA

Corresponding author at: Department of Obstetrics & Gynecology, Brigham & Women’s

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*

Hospital, 75 Francis St., Boston, MA 02115, [email protected], 617-732-5452, 617-2326346 (fax)

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Abstract

Early diagnosis of an extrauterine pregnancy is important for safe and effective management. However, a pregnancy’s location often cannot be easily determined with abnormal implantations or prior to 5-6 weeks’ gestation. Multiple testing strategies exist to diagnose an abnormal

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pregnancy when location is unknown, but caution needs to be used to avoid a false diagnosis. Medical treatment is optimal when an abnormal pregnancy is diagnosed early. Because most of

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these pregnancies are intrauterine, additional testing to localize the pregnancy will allow the

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correct choice of therapy and avoids unnecessary exposure to a toxic therapy. This testing strategy should be reserved for patients with significant concern for ectopic pregnancy, based on

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either risk factors or clinical findings. Overuse of this approach can lead to interruption of

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normal pregnancies.

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The term “Pregnancy of Unknown Location,” or PUL can apply to any pregnancy in the first five weeks following a woman’s last menstrual period, or three weeks following conception. During this time an embryo will have implanted but is too small to be seen on imaging. While 98% of pregnancies will be normally implanted in the uterine cavity, abnormal or ectopic implantations

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can occur in the fallopian tubes, cervix, uterine cornua, within a cesarean section scar, or, even more rarely, in the ovaries, pelvis or abdomen.1 Ectopic implantations are at risk for organ

rupture and massive bleeding, so early diagnosis is critical to their safe management. When this diagnosis is suspected for any reason, close follow-up and a systematic approach to diagnosis

Confirming Pregnancy Location

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can hasten pregnancy localization and minimize maternal morbidity.

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There are two means of knowing a pregnancy’s location: Visual and histologic. Both methods have limitations, given that radiologic confirmation cannot happen before 5-6 weeks’ gestation,

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and histologic confirmation often requires disruption of the pregnancy. This may leave an

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interval of one to two weeks between confirmation that a woman is pregnant and affirming that it is in the proper location.

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Visual Confirmation

Transvaginal ultrasound (TVUS) is the radiologic method of choice for visualizing a pregnancy. The first sign of an intrauterine pregnancy (IUP) is a small sac located eccentrically within the decidua. This then evolves into a “double decidual” sign, with two rings of tissue around the sac. While an intradecidual sac may be apparent prior to five weeks’ gestation, its sensitivity and

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specificity may be too low to confirm an IUP.2 During the fifth week the double decidual sign will become visible on abdominal ultrasound, while a yolk sac will become visible on TVUS. Subsequently, an embryonic pole will appear at approximately six weeks. These findings are much more specific for IUP but should be confirmed by an experienced sonologist. An IUP can

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be absolutely confirmed by the presence of an intrauterine sac with an embryo that has a

detectable heartbeat; however, the earliest that this can occur is the sixth week of pregnancy with transvaginal ultrasound (TVUS).

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It is important to consider the quality of the ultrasound when interpreting the images.3 Patients with significant uterine fibroids or high body mass index may have more limited imaging, which should be considered when an IUP cannot be seen. In such situations IUP confirmation may need to take place at an even later gestational age. MRI has been used to identify a pregnancy’s

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location in extreme situations, such as with large obstructing fibroids. However, the sensitivity and specificity of specific MRI features have not been well studied.4 Furthermore, the potential

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risks of gadolinium contrast exposure need to be weighed against the importance of improved

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diagnosis on a case-by-case basis.5

When imaging cannot confirm an IUP, it may be able to confirm an ectopic implantation in the

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eyes of an experienced examiner. Because treatment of the ectopic pregnancy often involves

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pregnancy-harming procedures (medical or surgical), it is important to have high diagnostic confidence prior to intervention. As with IUP confirmation, the best diagnostic confirmation comes with detection of a fetal heartbeat (FH) outside of the endometrial cavity, though an FH does not develop in all ectopic gestations. Other signs include a gestational sac with or without a yolk sac in an ectopic location, or a complex adnexal mass that appears inconsistent with a hemorrhagic corpus luteum. While these findings may be seen earlier than an FH, their accuracy

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depends on the experience of the sonologist, and they are necessarily less specific than a fetal pole or heartbeat for diagnosing ectopic pregnancy. When location cannot be confirmed with high enough radiologic certainty, direct visualization

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may be an option. This is usually accomplished with a diagnostic laparoscopy, with visualization of a suspicious mass in the pelvis. As with radiologic confirmation, this requires experience on the part of the surgeon, and may be limited by the presence of pelvic adhesions or otherwise abnormal anatomy. Very early and small ectopic gestations may be missed with this method, as

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well as cervical or cesarean scar implantations. Surgical confirmation is generally employed when there is very high suspicion for ectopic implantation, or when immediate diagnosis is necessary at an early gestation. The method carries the advantage of simultaneous treatment when the location is confirmed, though drawbacks include the inherent risks of surgery and

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general anesthesia.

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Histologic Confirmation

Histologic confirmation involves removing tissue from a specific location and confirming the

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presence of trophoblast or chorionic villi. This approach is most often used to confirm an

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intrauterine implantation by sending endometrial curettings or spontaneously passed tissue to a pathologist. Ectopic location is confirmed when placental tissue is identified from an extrauterine

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source. Absence of trophoblastic or villi in an endometrial sample does not necessarily confirm ectopic location, as 15-40% of early or failed intrauterine pregnancies can be missed with histologic analysis.6, 7 Patient and Test Selection

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Short of visualizing a fetal heartbeat radiologically or an ectopic mass surgically, none of the tests described here has perfect diagnostic accuracy. Interpretation of these diagnostic tests involves a tradeoff between falsely calling a normal IUP abnormal, leading to its interruption, or missing an ectopic pregnancy diagnosis, leading to maternal harm or a foregone opportunity for

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medical management. Selecting appropriate tests and setting a threshold for calling a pregnancy abnormal involves individualized patient assessment and counseling.

At one extreme, patients who verify that the pregnancy is undesired can be assessed as

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candidates for pregnancy interruption. With appropriate termination counseling and consent, the uterus can be evacuated, and the tissue examined to confirm IUP. At the opposite extreme, patients may set a very high personal threshold for labeling a pregnancy abnormal. This may be especially true for patients with an infertility history. These patients should be carefully

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counseled about the risk of inaccurate diagnosis, which may involve discussion with the radiologists about diagnostic certainty of a suspected ectopic gestation or absence of IUP

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confirmation. For these patients, confirmation of multiple abnormal test findings will produce

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more certainty than reliance on a single study.8 As with any assay, the positive predictive value for a test of abnormal or ectopic pregnancy

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depends on the pretest probability of the diagnosis. Importantly, these tests generally have not

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been studied in women with no risk factors for or symptoms of an abnormal pregnancy. Such women are more likely to experience a false positive result if subjected to the above testing. This is evidenced in studies of the -hCG Discriminatory Zone: Studies showing a lower (1500 mIU/mL) cutoff looked at women with concern for ectopic pregnancy, while those showing failed visualization of a normal IUP at higher -hCG cutoffs included any patients undergoing simultaneous laboratory testing and ultrasound.9, 10 For this reason, this testing algorithm should

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be reserved for women at increased concern for ectopic implantation. Significant risk factors for and clinical signs of abnormal pregnancy are listed in Table 1. Finally, any patient who has clinical concern for active bleeding or pregnancy rupture – including hemodynamic instability, orthostasis, peritoneal signs on exam, or a hemoperitoneum

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on imaging – should go directly to surgical confirmation and treatment. This also applies to patients who cannot comply with close follow-up or cannot access emergency care. Such patients should either complete their diagnostic workup as inpatients or undergo surgical diagnosis and

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treatment, with the decision based on the level of concern for ectopic pregnancy. Diagnostic Workup

Three possibilities exist when an IUP is not seen by ultrasound: (1) The pregnancy is ectopic, (2)

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The pregnancy is intrauterine but too early for ultrasound detection, or (3) The pregnancy is intrauterine but abnormal. Any intrauterine pregnancy may be left alone, and viability can be

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later confirmed without significant maternal morbidity. However, if the pregnancy is ectopic, delays in diagnosis can lead to major hemorrhage and/or diminished fertility. Therefore, location

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may need to be confirmed before an IUP can be practically visualized. Because this often

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involves either evacuation of uterine contents or empiric treatment with toxic medications, it is critical to confirm that the pregnancy is abnormal (either ectopic or abnormal IUP) before

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intervening further with a desired pregnancy. One or, preferably, multiple tests can be used to confirm pregnancy abnormality prior to an invasive diagnostic or therapeutic intervention. Failed visualization with confirmed pregnancy dating As described above, an intrauterine pregnancy should be seen by transvaginal ultrasound by six weeks’ gestational age. Thus, the absence of a visualized gestational sac by this time is

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concerning for ectopic location. In addition to limits of image quality and provider experience, using this criterion requires confirmed pregnancy dating. This is best accomplished with laboratory confirmation of ovulation timing or known date of embryo transfer. While last menstrual period dating is generally reliable for women with regular menstrual cycles, variation

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can occur, and this should not be relied upon for ectopic pregnancy confirmation. With the

availability of quantitative serum β-hCG testing, reliance on known conception timing for nonIVF patients has become nearly obsolete.

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Failed visualization plus quantitative -hCG

Due to limitations in pregnancy dating, quantitative levels of serum β-hCG can be used to estimate gestational age prior to pregnancy visualization. The level of -hCG at which a viable IUP should be seen radiologically is known as the Discriminatory Zone (DZ); absence of a

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visualized IUP at a -hCG level above this level is suspicious for ectopic location or nonviable

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IUP.

Based on a review of -hCG levels with known pregnancy locations, a level of 1500 IU/ml has

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been proposed as the appropriate DZ with TVUS.9 A higher level (6500-7000) needs to be used

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with transabdominal imaging. The authors of this original publication recommended that each center should determine a DZ using its own radiologists and laboratory; however, this is not

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practical for most centers. While many institutions use the published DZ of 1500-2000 to diagnose abnormal implantation, cautionary publications have documented viable IUPs that were not seen by ultrasound with -hCG levels as high as 4000 IU/ml.10, 11 Thus, caution should be used when using this tool in isolation with desired pregnancies. Serial -hCG levels

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The above diagnostic tools have the advantage of completion in a single patient encounter – an important consideration with a time-sensitive diagnosis. However, additional data is needed when dating is uncertain or the -hCG level is below an acceptable discriminatory zone.

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Following serial -hCG levels is a commonly used method in these settings. With this method, -hCG levels are drawn 48 hours apart, and the level should roughly double if the pregnancy is normal. As with any other test, patient and laboratory variation can produce imperfect results, and lesser degrees of rise can be seen with normal IUPs. The predictive value

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of -hCG rise has been studied: a rise of < 67% predicts abnormal pregnancy with 95%

certainty, while a rise of <53% gives 99% certainty.8, 12 Because misdiagnosis and interruption of a normal pregnancy is unacceptable to most patients, the lower cutoff is generally used. For some patients, even this 1% possibility of incorrect diagnosis is not acceptable; in this case, a rise

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of 35% or less can be used to obtain a 99.9% level of certainty.12 However, using the lower

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cutoffs necessarily risks delayed or missed diagnosis of an ectopic pregnancy. These considerations should be discussed carefully with individual patients in determining a course of

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action.

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Serum progesterone level

The absolute level of serum progesterone has been used as an additional test to diagnose an

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abnormal pregnancy. A metanalysis of cohort studies showed that for women with symptoms of abnormal pregnancy and an indeterminate ultrasound, a very low progesterone level (3-6 ng/ml) indicated an abnormal gestation with 99% certainty.13 As with the other tests, this single reading will not always be accurate, and will not be useful if the patient is using exogenous sources of progesterone.

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Intervention Once the provider and patient feel convinced that a pregnancy is abnormal, either medical or surgical treatment options are available. The specific treatments will vary based on an

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intrauterine or ectopic location. Medical treatment of an abnormal intrauterine pregnancy involves a drug (misoprostol) that will allow expulsion of the trophoblast, with or without the addition of a drug to interrupt implantation (mifepristone).14 Alternatively, medical treatment of an ectopic pregnancy involves a direct cytotoxic agent, systemic methotrexate, or directly

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injected methotrexate or potassium chloride. Surgical treatment of an intrauterine pregnancy requires uterine evacuation; alternatively, surgical ectopic pregnancy treatment is accomplished via pelviscopy or occasionally laparotomy.

Some controversy exists as to whether an ectopic location should be confirmed before treating an

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abnormal pregnancy. Without ultrasound confirmation of ectopic pregnancy, localization will

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require surgical evacuation of the uterus, which may risk patient discomfort and, rarely, endometrial or uterine damage. In avoiding this step, giving empiric systemic methotrexate is

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expected to interrupt the pregnancy in any location, with a small intrauterine pregnancy passing

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when withdrawal bleeding ensues. Alternatively, some argue against empiric ectopic pregnancy treatment because most abnormal

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pregnancies are intrauterine.15 Based on this argument, uterine evacuation will fill both a diagnostic and often therapeutic role. Follow-up -hCG laboratory testing can help to confirm that a pregnancy was interrupted with uterine evaluation: A fall of 15-20% in 12-24 hours strongly suggests pregnancy interruption, and the levels can then be serially followed until undetectable.16 Additional arguments against empiric treatment include appropriate expectations and follow-up with future pregnancy, as patients who are labeled as having a prior ectopic

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pregnancy will be followed differently than those with a prior failed IUP. From an academic perspective, erroneously labeling failed intrauterine pregnancies as ectopic leads to overestimations of medical therapy’s success rate.17

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Once an ectopic implantation is confirmed, medical or surgical treatment may be selected. Beyond the requirement of hemodynamic stability, this choice is driven by two main factors: the absolute level of -hCG, and the patient’s ability to undergo treatment with a chemotherapeutic agent and comply with weeks of follow-up. Medical therapy usually involves systemic

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administration of methotrexate, a folinic acid inhibitor that blocks cell division. Prior to this treatment, renal, liver, pulmonary, and peptic ulcer disease must be excluded, and the visualized adnexal mass, if seen, should be less than 4 cm. Medical management is generally offered when the serum -hCG level is less than 5000 IU/ml, and has a success rate greater than 90% in this

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setting.18 Success rates fall and rupture rates increase with higher hCG levels. When a patient has medical contraindications to methotrexate or a high hCG level, but surgery is undesirable, direct

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injection of the pregnancy with potassium chloride has been successful.19 This treatment may be

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combined with systemic methotrexate with particularly challenging pregnancies. This requires an experienced operator with ultrasound guided injections/ aspirations.

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The protocols for Methotrexate therapy are shown in Table 2. The regimen names refer to the

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intended number of doses, “Single,-” “Multi-“ and “Two-“ Dose, though the single-dose regimen can be repeated if not successful the first time. The “Multi-Dose” methotrexate regimen has been proposed for cases with higher -hCG levels (3000-5000), and the “Two-Dose” regimen may be used when the -hCG level rises between Day 0 and Day 4 of the single-dose regimen.17, 20 Comparisons of single and non-single dose regimens show possibly more effectiveness with nonsingle dose regimens, but this comes with more toxicity as well.21, 22

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Surgical therapy is accomplished with laparoscopy, with laparotomy reserved for settings where a skilled laparoscopic team is unavailable, or the patient has medical or surgical restrictions to the laparoscopic approach. In the case of tubal ectopic, the pregnancy and its implantation site can be removed completely with a unilateral salpingectomy. Alternatively, the tube can be

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retained with a linear salpingostomy and extraction of the trophoblast. Less common ectopic implantations (abdominal, ovarian, interstitial, cesarean section scar) may also be excised with the implantation site left in place. This risks incomplete removal of the pregnancy, but conserves

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pelvic organs.

Surgical management is first-line when there is any concern for tubal rupture or intraabdominal bleeding. These include patients with hemodynamic instability, significant pain or peritoneal signs on exam, or evidence of moderate to large hemoperitoneum on ultrasound. It also should

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be strongly considered if a patient’s ability to comply with frequent laboratory follow-up comes into question. Patients who desire permanent sterilization may also prefer surgical removal of the

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ectopic pregnancy, with ligation or removal of the contralateral tube to accomplish sterilization.

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Patients desiring rapid resolution of the ectopic pregnancy and a quick return to conception attempts may also prefer this approach. In general, cervical, cornual, abdominal, and cesarean

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scar implantations are less amenable to safe surgical removal and should be referred to providers

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with expertise in their treatment. Expectant Management Expectant management is an option for some patients with PUL, or even for some with confirmed extrauterine pregnancies. This may be considered for hemodynamically stable, asymptomatic patients whose -hCG levels are falling with serial assessments. Randomized trials have shown this approach to be reasonable with -hCG levels up to 1500-2000 mIU/mL,

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though up to 40% of women intending expectant management ultimately needed medical or surgical treatment.23, 24 A fall in hCG level of at least 15-30% over 48 hours suggests that the pregnancy is nonviable, regardless of location, which can justify withholding treatment. The threshold hCG decline for considering expectant management depends on the initial level: A

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30% drop is appropriate for a starting level of 2000 mIU/mL, 20% with a level of 500 mIU/mL, and 15% when starting at 50 mIU/mL.12

Some patients with tubal ectopic gestations will pass the pregnancy into the pelvis – an event

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sometimes termed a “tubal abortion.” These patients may experience sudden pain that quickly improves, followed by a rapid drop in -hCG level. Complex fluid or blood may be visible on pelvic ultrasound. It is essential to confirm that these patients have no ongoing bleeding, which may require a period of inpatient observation with serial examinations and laboratory

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evaluations. Concern for bleeding often leads to laparoscopic evaluation for these patients. However, if the pregnancy is identified free in the pelvis and removed, with no evidence of gross

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tubal rupture or ongoing bleeding, it may be possible to manage these patients without tubal

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surgery or medical therapy. Postoperative methotrexate administration may be considered if there is any concern for residual trophoblastic tissue at the implantation site.

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Patient Follow-up

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Laboratory Follow-up

Patients with a PUL or ectopic pregnancy are generally followed until the -hCG level becomes undetectable. Depending on the initial level and rate of fall, this may take many weeks. Laboratory testing should continue weekly, with at least a 15% fall considered adequate. If at any point the level fails to fall by 15% in one week, medical or surgical intervention should be

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offered. Surgery should be the preferred option at this point with higher -hCG levels (particularly if over 5,000 mIU/mL), the presence of a suspicious adnexal mass on imaging, or the patient’s reluctance to continue with medical treatment and prolonged follow-up.

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If the uterus was not evacuated prior to initial PUL treatment, then this should be performed if the -hCG level fails to fall appropriately. Removal of an abnormal IUP may precipitate a rapid fall in serum hCG levels, while failure to observe this should prompt repeat medical or surgical ectopic pregnancy treatment.

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Following surgical management of an ectopic pregnancy, follow-up of -hCG levels depends on the likelihood of retained trophoblastic tissue. Patients who undergo removal of the pregnancy with retention of the implantation site – such as with salpingostomy, resection of a cesarean scar

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implantation, or removal of a cervical or interstitial pregnancy – should have their -hCG levels followed. Alternatively, if an entire pregnancy-containing fallopian tube is removed with

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Patient Counseling

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salpingectomy and confirmed histologically, laboratory follow-up is usually not necessary.

Though PUL evaluation and treatment focuses on laboratory testing, treatments, and the medical

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risks of ectopic pregnancy, it is important to acknowledge the anxiety and loss that come with this process. Patients may fear an emergency hemorrhage while waiting for a diagnosis and

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confirmed resolution of an ectopic pregnancy. Additionally, those diagnosed with ectopic pregnancies may feel the same sadness as any patient experiencing a miscarriage. Thus, it is important to periodically assess patients’ wellbeing and support systems, and to offer formal counseling to those in need. Future Pregnancy

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Many patients want to attempt a new conception as soon as they are cleared to do so. Intercourse should be avoided while the -hCG level is detectable. If the patient was treated with methotrexate she should postpone pregnancy until the medication is reliably cleared from her system, and is advised to wait at least three months.17 This duration should also allow for tubal

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healing and recanalization after salpingostomy or medical treatment. Patients treated with

complete surgical removal (salpingectomy) and no methotrexate may attempt pregnancy as soon as surgical healing is complete. While this duration is not clearly defined, 4-6 weeks should be

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generally safe.

Patients with a confirmed ectopic pregnancy should be counseled about the possibility of recurrence. They should be advised to contact a healthcare provider as soon as a future pregnancy test becomes positive, and to again have PUL follow-up until the pregnancy’s location

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is confirmed. History of ectopic pregnancy should be clearly documented in the patient’s medical

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record.

In many cases the exact location of the pregnancy may never be known, particularly when

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expectant management or medical treatment without localization is used. Even when a uterine curettage returns with no evidence of an IUP an ectopic pregnancy has not been definitively

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confirmed, especially if there are no signs of extrauterine location on imaging. Such patients

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should be counseled that the pregnancy’s location is uncertain, that it is statistically most likely to be intrauterine, and that this should be communicated to future pregnancy caregivers. Conclusions

Pregnancy of unknown location can be a challenging clinical scenario, as false diagnosis can lead to major patient harm. Careful consideration of individual patient risk, test interpretation,

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and the harms of intervention versus expectant management must take place, and consultation with experienced providers should occur when a diagnosis is in doubt. The choice of medical, surgical or expectant management depends largely on the initial -hCG level. Ultimate treatment

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choice should be individualized to a patient’s circumstances and preferences. Disclosures

The author reports no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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References

1. Marion LL, Meeks GR. Ectopic pregnancy: History, incidence, epidemiology, and risk factors. Clin Obstet Gynecol 2012 Jun;55(2):376-86.

2. Laing FC, Brown DL, Price JF, Teeger S, Wong ML. Intradecidual sign: is it effective in diagnosis of

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an early intrauterine pregnancy? Radiology 1997 Sep;204(3):655-60.

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3. Goldstein SR, Snyder JR, Watson C, Danon M. Very early pregnancy detection with endovaginal ultrasound. Obstet Gynecol 1988;72(2):200-4.

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4. Tamai K, Koyama T, Togashi K. MR features of ectopic pregnancy. Eur Radiol 2007 Dec;17(12):3236-46.

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5. Ray JG, Vermeulen MJ, Bharatha A, Montanera WJ, Park AL. Association Between MRI Exposure During Pregnancy and Fetal and Childhood Outcomes. JAMA 2016 Sep 6;316(9):952-61.

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6. Lindahl B, Ahlgren M. Identification of chorion villi in abortion specimens. Obstet Gynecol 1986 Jan;67(1):79-81. 7. Insogna IG, Farland LV, Missmer SA, Ginsburg ES, Brady PC. Outpatient endometrial aspiration: an alternative to methotrexate for pregnancy of unknown location. Am J Obstet Gynecol 2017 Aug;217(2):185 e1- e9.

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8. Morse CB, Sammel MD, Shaunik A, Allen-Taylor L, Oberfoell NL, Takacs P, et al. Performance of human chorionic gonadotropin curves in women at risk for ectopic pregnancy: exceptions to the rules. Fertil Steril 2012 Jan;97(1):101-6 e2. 9. Barnhart KT, Simhan H, Kamelle SA. Diagnostic accuracy of ultrasound above and below the beta-

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hCG discriminatory zone. Obstet Gynecol 1999;94(4):583-7. 10. Doubilet PM, Benson CB. Further evidence against the reliability of the human chorionic gonadotropin discriminatory level. J Ultrasound Med 2011 Dec;30(12):1637-42.

11. Connolly A, Ryan DH, Stuebe AM, Wolfe HM. Reevaluation of discriminatory and threshold levels

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for serum beta-hCG in early pregnancy. Obstet Gynecol 2013 Jan;121(1):65-70.

12. Barnhart KT, Sammel MD, Rinaudo PF, Zhou L, Hummel AC, Guo W. Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined. Obstet Gynecol 2004;104(1):50-5. 13. Verhaegen J, Gallos ID, van Mello NM, Abdel-Aziz M, Takwoingi Y, Harb H, et al. Accuracy of

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single progesterone test to predict early pregnancy outcome in women with pain or bleeding: metaanalysis of cohort studies. BMJ 2012 Sep 27;345:e6077.

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14. Schreiber CA, Creinin MD, Atrio J, Sonalkar S, Ratcliffe SJ, Barnhart KT. Mifepristone Pretreatment for the Medical Management of Early Pregnancy Loss. N Engl J Med 2018 Jun 7;378(23):2161-70.

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15. Barnhart KT, Katz I, Hummel A, Gracia CR. Presumed diagnosis of ectopic pregnancy.[see comment]. Obstet Gynecol 2002;100(3):505-10.

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16. Barnhart KT. Clinical practice. Ectopic pregnancy. N Engl J Med 2009;361(4):379-87. 17. Practice Committee of American Society for Reproductive M. Medical treatment of ectopic

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pregnancy: a committee opinion. Fertil Steril 2013 Sep;100(3):638-44. 18. Lipscomb GH, McCord ML, Stovall TG, Huff G, Portera SG, Ling FW. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 1999 Dec 23;341(26):1974-8. 19. Doubilet PM, Benson CB, Frates MC, Ginsburg E. Sonographically guided minimally invasive treatment of unusual ectopic pregnancies. J Ultrasound Med 2004 Mar;23(3):359-70.

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20. Barnhart K, Hummel AC, Sammel MD, Menon S, Jain J, Chakhtoura N. Use of "2-dose" regimen of methotrexate to treat ectopic pregnancy. Fertil Steril 2007 Feb;87(2):250-6. 21. Yuk JS, Lee JH, Park WI, Ahn HS, Kim HJ. Systematic review and meta-analysis of single-dose and non-single-dose methotrexate protocols in the treatment of ectopic pregnancy. Int J Gynecol Obstet

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2018;141(3):295-303. 22. Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing "single dose" and "multidose" regimens. Obstet Gynecol 2003 Apr;101(4):77884.

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23. van Mello NM, Mol F, Verhoeve HR, van Wely M, Adriaanse AH, Boss EA, et al. Methotrexate or expectant management in women with an ectopic pregnancy or pregnancy of unknown location and low serum hCG concentrations? A randomized comparison. Hum Reprod 2013 Jan;28(1):60-7. 24. Jurkovic D, Memtsa M, Sawyer E, Donaldson AN, Jamil A, Schramm K, et al. Single-dose systemic

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methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled

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randomized trial. Ultrasound Obstet Gynecol 2017 Feb;49(2):171-6.

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Table 1. Criteria for initiating a pregnancy of unknown location workup

Positive Pregnancy Test plus Any of the Following: Acute pelvic pain Vaginal bleeding Imaging shows hemoperitoneum with no IUP seen Suspicious pelvic mass on imaging without definite EP or IUP

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  

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Signs and Symptoms



Significant Risk Factors     

IUP = intrauterine pregnancy; EP = ectopic pregnancy

Prior confirmed ectopic pregnancy Known tubal damage (prior tubal surgery or pelvic inflammatory disease; known obstruction) Current use of intrauterine device Pregnancy conceived with infertility treatment

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Table 2. Medical treatment regimens for ectopic pregnancies

hCG Give Mtx 1 mg/kg

2



Give Lkv 0.1 mg/kg

3

 

hCG Give Mtx 1 mg/kg if < 15% fall from Day 1 If fall  15%, move to Follow-up

hCG Give Mtx 50 mg/m2

4

 

hCG

5

 

Give Lkv 0.1 mg/kg



hCG



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

 

hCG Give Mtx 50 mg/m2

 hCG  Mtx 50 mg/m2 if hCG level rising

Give Mtx 1 mg/kg if < 15% fall from Day 3 If fall  15%, move to Follow-up

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

“Two-Dose”

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 

1

 

“Multi-Dose”

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“Single Dose”

Day

Give Lkv 0.1 mg/kg

 

hCG Give Mtx 1 mg/kg if < 15% fall from Day

 

hCG: If fall  15% from Day 4, move to Follow-up



5



If fall insufficient,



If fall  15%, move to  Follow-up

8



Give Lkv 0.1 mg/kg

9



hCG



hCG: If fall  15% from Day 4, move to Follow-up If fall insufficient, consider second round of treatment

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7

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

6

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

consider surgical management

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Follow-  up  

Repeat hCG 7 days  after appropriate response confirmed If fall  15%, repeat  every 7 days until undetectable If fall insufficient,  consider second round of treatment or surgery

Repeat hCG 7 days after appropriate response confirmed If fall  15%, repeat every 7 days until undetectable If fall insufficient, consider surgery

hCG = laboratory evaluation of quantitative serum -hCG Mtx = methotrexate IM injection

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Lkv = leucovorin IM injection

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Repeat hCG 7 days after appropriate response confirmed If fall  15%, repeat every 7 days until undetectable If fall insufficient, consider surgery

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If < 15% fall in hCG from Day 7, consider surgical management If fall  15%, move to Follow-up

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