eMedicine Specialties > Obstetrics and Gynecology > General Gynecology

Ectopic Pregnancy: Workup

Author: Vicken P Sepilian, MD, MSc, Medical Director, Reproductive Endocrinology and Infertility, CHA Fertility Center
Coauthor(s): Ellen Wood, DO, FACOOG, Voluntary Assistant Professor, University of Miami School of Medicine
Contributor Information and Disclosures

Updated: Aug 2, 2009

Workup

Laboratory Studies

  • Patients with early normal intrauterine pregnancies often present with signs and symptoms similar to those encountered in patients with ectopic pregnancies and other gynecological or gastrointestinal conditions. The availability of various biochemical, ultrasonographic, and surgical modalities can aid the health care provider today in establishing a definitive diagnosis and differentiating among various conditions.
  • In order to reduce the morbidity and mortality associated with ectopic pregnancy, a high index of suspicion is necessary to make a prompt and early diagnosis. As mentioned earlier, neither risk factors nor signs and symptoms of ectopic pregnancy are sensitive or specific enough to establish a definitive diagnosis. Hence, screen any female patient in the reproductive years presenting with abdominal pain, cramping, or vaginal bleeding for pregnancy. In recent years, serum and urine assays for the beta subunit of human chorionic gonadotropin (bhCG) have been developed to detect a pregnancy before the first missed period. While some commercial urine test kits are able to detect bhCG in early gestation, they are associated with varying false-negative rates. In addition, the need for a quantitative value makes serum bhCG the criterion standard for biochemical testing.
  • Beta–human chorionic gonadotropin
    • In early healthy intrauterine pregnancies, serum levels of bhCG double approximately every 2 days (1.4-2.1 d). Kadar et al established that the lower limit of the reference range to which serum bhCG should increase during a 2-day period is 66%.1 For example, a pregnant patient with a serum bhCG level of 100 mIU/mL should have a serum bhCG level of at least 166 mIU/mL 2 days later. An increase in bhCG of less than 66% is associated with an abnormal intrauterine pregnancy or an extrauterine pregnancy. Remember that 15% of healthy intrauterine pregnancies do not increase by 66% and that 13% of all ectopic pregnancies have normally rising bhCG levels of at least 66% in 2 days.
    • Shepherd et al demonstrated that 64% of very early ectopic pregnancies initially may have normal doubling bhCG levels.2 Barnhart et al more recently reported that the minimum rise in bhCG for a potentially viable pregnancy in women who present with vaginal bleeding or pain is 53% per 2 days (up to5,000IU/L).3 Hence, intervention when the bhCG level rises less than 66% but more than 53% should be undertaken according to other clinical and biochemical criteria.
    • Furthermore, even though ectopic pregnancies have been established to have lower mean serum bhCG levels than healthy pregnancies, no single serum bhCG level is diagnostic of an ectopic pregnancy. In short, serial serum bhCG levels are necessary to differentiate between normal and abnormal pregnancies and to monitor resolution of ectopic pregnancy once therapy has been initiated.
    • The major disadvantage in relying on serial titers to distinguish between normal and abnormal pregnancies is the potential for delay in reaching the diagnosis. Furthermore, while serial bhCG titers may be used to differentiate between a normal and an abnormal gestation, the test does little to indicate the location of the pregnancy. Hence, additional diagnostic modalities, including US and other biochemical markers, are needed.
  • Progesterone
    • A single serum progesterone level is another tool that is useful in differentiating abnormal gestations from healthy intrauterine pregnancies. Serum progesterone levels are not gestational age–dependent, they remain relatively constant during the first trimester of normal and abnormal pregnancies, they do not return to the reference range if initially abnormal, and they do not correlate with bhCG levels. However, no consensus on a single value that differentiates between a normal and an abnormal pregnancy currently exists. Several authors have proposed different cutoffs with varying sensitivity and specificity. A progesterone value of greater than 25 ng/mL excluded ectopic pregnancy with 97.4% certainty in one large study. Furthermore, levels of less than or equal to 5 ng/mL indicated a nonviable pregnancy, ectopic or intrauterine, and excluded normal pregnancy with 100% sensitivity.
    • Although inexpensive, the usefulness of serum progesterone is limited in that a significant number of results fall in the equivocal range of 5-25 ng/mL. Also, this test is unreliable in differentiating between normal and abnormal pregnancies in patients who conceive after IVF because of excessive progesterone production from multiple corpora lutea, as well as the practice of pharmacologic progesterone supplementation
  • Other markers
    • Several other serum and urine markers are currently under investigation to help distinguish normal and abnormal pregnancies. These include serum estradiol, inhibin, pregnancy-associated plasma protein A, pregnanediol glucuronide, placental proteins, creatinine kinase, and a quadruple screen of serum progesterone, bhCG, estriol, and alfa-fetoprotein.
    • At present, use each of these markers only as a research tool until substantial clinical evidence proves their role in clinical medicine.

Imaging Studies

  • Ultrasonography
    • US probably is the most important tool in diagnosing an extrauterine pregnancy. More frequently, it is used to confirm an intrauterine pregnancy. Visualization of an intrauterine sac, with or without fetal cardiac activity, often is adequate to exclude ectopic pregnancy. The exception to this is in the case of heterotropic pregnancies, which occur from 1 in 4000 to 1 in 30,000 spontaneous pregnancies. Screening the adnexa by US is mandatory despite visualization of an intrauterine pregnancy in patients undergoing ovarian stimulation and assisted reproduction because they have a 10-fold increased risk of heterotropic pregnancy.
    • Transvaginal US, with its greater resolution, can be used to visualize an intrauterine pregnancy by 24 days postovulation, or 38 days after last menstrual period, which is about 1 week earlier than transabdominal US. The gestational sac, which is a sonographic term and not an anatomic term, is the first structure that is recognizable on transvaginal US. It has a thick echogenic rim surrounding a sonolucent center corresponding to the trophoblastic decidual reaction surrounding the chorionic sac. Structures that represent a developing embryo cannot be recognized until a later time.
    • A pseudosac is a collection of fluid within the endometrial cavity created by bleeding from the decidualized endometrium often associated with an extrauterine pregnancy and should not be mistaken for a normal early intrauterine pregnancy. The true gestational sac is located eccentrically within the uterus beneath the endometrial surface, whereas the pseudosac fills the endometrial cavity.
    • The yolk sac is the first visible structure within the gestational sac, and it resembles a distinct circular structure with a bright echogenic rim and a sonolucent center. It can first be recognized 3 weeks postconception, about 5 weeks after last menstrual period. The embryo is recognized first as a thickening along the edge of the yolk sac, and embryonic cardiac motion can be observed 3.5-4 weeks postconception, about 5.5-6 weeks after the last menstrual period.
    • In the absence of reliable menstrual and ovulatory history, a discriminatory zone of bhCG levels validates the US findings. The discriminatory zone is the level of bhCG, using the Third International Standard for quantitative bhCG, at which all intrauterine pregnancies should be visible on US. With abdominal US, that level is 6000-6500 mIU/mL, but high-resolution transvaginal US has reduced this level to 1500-1800 mIU/mL. If transvaginal US does not reveal an intrauterine pregnancy when the discriminatory bhCG levels are reached, the pregnancy generally can be considered extrauterine.
    • An exception to this is multiple gestations. Kadar et al reported that patients with normal multiple gestates were found to have levels of bhCG above the discriminatory zone before any US evidence of the gestation was apparent.1 They showed multiple gestations with bhCG levels of up to 2300 mIU/mL before transvaginal US recognition. Therefore, if a multiple gestation is suspected, as in pregnancies resulting from assisted reproduction, the bhCG discriminatory zone must be used cautiously. Remember that a discriminatory zone is operator and institution dependent, and the clinician must be aware of the zone used by that institution prior to interpreting results.
    • The effectiveness of using US with discriminatory zone of bhCG levels has been well established in the literature.
      • In one large study of more than 1200 patients by Barnhart et al, 78.8% of patients were diagnosed definitively at the initial visit using an algorithm that included the use of US along with serum bhCG levels above the discriminatory zone.4 According to this study, if the patient's serum bhCG level was above the established discriminatory zone at initial presentation and an intrauterine sac was not identified, an operative approach involving curettage and possible operative laparoscopy was used to diagnose ectopic pregnancy.
      • If the patient's serum bhCG levels were below the discriminatory zone, serial bhCG titers were performed every 2 days. Once a patient's levels reached the discriminatory zone, US was performed. If, however, the patient's bhCG levels failed to rise appropriately (ie, at least 66% in 2 d), operative intervention was undertaken with dilatation and curettage or laparoscopy to exclude the diagnosis of ectopic pregnancy. With this protocol, Barnhart et al reported 100% sensitivity and a specificity of 99.9%.4
    • The value of US is highlighted further in its ability to demonstrate free fluid in the cul-de-sac. While free fluid could represent hemoperitoneum, it is not specific for ruptured ectopic pregnancy. Free fluid on US can represent physiological peritoneal fluid or blood from retrograde menstruation and unruptured ectopic pregnancies. Furthermore, US can be used to detect the presence of other pathological conditions that may display the signs and symptoms of ectopic pregnancy.
  • Doppler US
    • Color-flow Doppler US has been demonstrated to improve the diagnostic sensitivity and specificity of transvaginal US, especially in cases where a gestational sac is questionable or absent. A study of 304 patients at high risk for ectopic pregnancy found that the use of color-flow Doppler US, compared with transvaginal US alone, increases the diagnostic sensitivity from 71-87% for ectopic pregnancy, from 24-59% for failed intrauterine pregnancy, and from 90-99% for viable intrauterine pregnancy.
    • The addition of color-flow Doppler US may expedite earlier diagnosis and eliminate delays caused by using levels of bhCG for diagnosis. Furthermore, color-flow Doppler US can potentially be used to identify involuting ectopic pregnancies that may be candidates for expectant management.

Diagnostic Procedures

  • Dilatation and curettage
    • A simple way to rule out an ectopic pregnancy is to establish an intrauterine pregnancy. Dilation and curettage is a rapid cost-effective method to diagnose ectopic pregnancy. Once an abnormal pregnancy is established by bhCG or progesterone levels, curettage can help differentiate between an intrauterine or ectopic pregnancy. If tissue obtained is positive for villi by floating in saline or by histological diagnosis on frozen or permanent section, then a nonviable intrauterine pregnancy has occurred. In the absence of villi, the diagnosis of ectopic pregnancy is made. Laparoscopy can be performed at that time, or the case may be followed by serial serum bhCG levels and treated medically or surgically at a later time, depending on the clinical setting.
    • This method of diagnostic dilatation and curettage may only be used, of course, in cases where continuation of a pregnancy is not desired even if it were an intrauterine gestation.
    • In a patient undergoing a dilatation and curettage for the diagnosis of ectopic pregnancy, obtaining consent for a diagnostic, and possibly operative, laparoscopy is also necessary in case the diagnosis of ectopic pregnancy is made; this spares the patient exposure to an additional operative procedure.
    • While dilatation and curettage is easy and effective, it can provide false reassurance in cases of heterotropic pregnancies where multiple gestations are present, with at least one being intrauterine and one being extrauterine.
  • Culdocentesis
    • Culdocentesis is another rapid and inexpensive method of evaluation for ruptured ectopic pregnancy. It is performed by inserting a needle through the posterior fornix of the vagina into the cul-de-sac and attempting to aspirate blood. When nonclotting blood is found in conjunction with a suspected ectopic pregnancy, operative intervention is indicated because the likelihood of a ruptured ectopic pregnancy is high.
    • Culdocentesis is of historical interest because its use today is rare. It is associated with a high false-negative rate (10-14%) usually reflecting blood from an unruptured ectopic pregnancy, ruptured corpus luteum, incomplete abortion, and retrograde menstruation. Furthermore, the improved technology with US and hormonal assays is far superior in sensitivity and specificity in reaching the correct diagnosis.
  • Laparoscopy
    • Patients in pain and/or those who are hemodynamically unstable should proceed to laparoscopy. Laparoscopy allows assessment of the pelvic structures, size and exact location of ectopic pregnancy, presence of hemoperitoneum (see Media file 2), and presence of other conditions, such as ovarian cysts and endometriosis, which, when present with an intrauterine pregnancy, can mimic an ectopic pregnancy. Furthermore, laparoscopy provides the option to treat once the diagnosis is established.

      Ectopic pregnancy. Laparoscopic picture of an unr...

      Ectopic pregnancy. Laparoscopic picture of an unruptured right ampullary tubal pregnancy with bleeding out of the fimbriated end resulting in hemoperitoneum.

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      Ectopic pregnancy. Laparoscopic picture of an unr...

      Ectopic pregnancy. Laparoscopic picture of an unruptured right ampullary tubal pregnancy with bleeding out of the fimbriated end resulting in hemoperitoneum.

    • Laparoscopy remains the criterion standard for diagnosis; however, its routine use on all patients suspected of ectopic pregnancy may lead to unnecessary risks, morbidity, and costs. Moreover, laparoscopy can miss up to 4% of early ectopic pregnancies, and, as more ectopic pregnancies are diagnosed earlier in gestation, the rate of false-negative results with laparoscopy would be expected to rise.

More on Ectopic Pregnancy

Overview: Ectopic Pregnancy
Workup: Ectopic Pregnancy
Treatment: Ectopic Pregnancy
Follow-up: Ectopic Pregnancy
Multimedia: Ectopic Pregnancy
References
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Further Reading

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Keywords

tubal pregnancy, extrauterine pregnancy, ectopic gestation, pelvic inflammatory disease, PID, Chlamydia trachomatis, salpingitis, Neisseria gonorrhoeae, salpingostomy, neosalpingostomy, fimbrioplasty, tubal reanastomosis, tubal ligation, clomiphene citrate, injectable gonadotropin therapy, in vitro fertilization, IVF, gamete intrafallopian transfer, GIFT, intrauterine device, IUD, salpingitis isthmica nodosum, pain

amenorrhea, vaginal bleeding, methotrexate, pregnancy-related death, abnormally implanted gestation, pelvic infection, cigarette smoking, diethylstilbestrol exposure, DES exposure, T-shaped uterus, prior abdominal surgery, failure with progestin-only contraception, ruptured appendix, adnexal mass, culdocentesis, hematosalpinx, hemoperitoneum, tubal rupture, uterine rupture, shock, disseminatedintravascular coagulopathy, DIC, laparoscopic salpingectomy

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Contributor Information and Disclosures

Author

Vicken P Sepilian, MD, MSc, Medical Director, Reproductive Endocrinology and Infertility, CHA Fertility Center
Vicken P Sepilian, MD, MSc is a member of the following medical societies: American College of Obstetricians and Gynecologists and American Society for Reproductive Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Ellen Wood, DO, FACOOG, Voluntary Assistant Professor, University of Miami School of Medicine
Ellen Wood, DO, FACOOG is a member of the following medical societies: American Society for Reproductive Medicine
Disclosure: Nothing to disclose.

Medical Editor

Robert K Zurawin, MD, Associate Professor, Director of Baylor College of Medicine Program for Minimally Invasive Gynecology, Director of Fellowship Program, Minimally Invasive Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine
Robert K Zurawin, MD is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Harris County Medical Society, North American Society for Pediatric and Adolescent Gynecology, and Texas Medical Association
Disclosure: Johnson and Johnson Honoraria Speaking and teaching; Conceptus Honoraria Speaking and teaching; Biosphere Medical Honoraria Speaking and teaching; Eli Lilly Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

A David Barnes, MD, PhD, MPH, FACOG, Consulting Staff, Department of Obstetrics and Gynecology, Mammoth Hospital (Mammoth Lakes, California), Pioneer Valley Hospital (Salt Lake City, Utah), Warren General Hospital (Warren, Pennsylvania), and Mountain West Hospital (Tooele, Utah)
A David Barnes, MD, PhD, MPH, FACOG is a member of the following medical societies: American College of Forensic Examiners, American College of Obstetricians and Gynecologists, American Medical Association, Association of Military Surgeons of the US, and Utah Medical Association
Disclosure: Nothing to disclose.

CME Editor

Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Hancock Medical Center
Frederick B Gaupp, MD is a member of the following medical societies: American Academy of Family Physicians
Disclosure: Nothing to disclose.

Chief Editor

Michel E Rivlin, MD, Professor, Coordinator of Quality Assurance/Quality Improvement, Department of Obstetrics and Gynecology, University of Mississippi School of Medicine
Michel E Rivlin, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association, Mississippi State Medical Association, and Royal College of Surgeons of Edinburgh
Disclosure: Nothing to disclose.

 
 
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