Category Archives: Ectopic Pregnancy

Ectopic Pregnancy

The hCG discriminatory zone in ectopic pregnancy: does assay harmonization matter?

Ectopic_Pregnancy_DiagramEctopic pregnancy is a potentially life threatening complication of pregnancy. It occurs when the embryo implants outside the uterine cavity, most commonly in the fallopian tube. Common symptoms include nausea, abdominal pain, and slight vaginal bleeding. Approximately 2% of all pregnancies are ectopic pregnancies and they require emergency treatment to either prevent rupture of the fallopian tube or treat a woman with a ruptured ectopic pregnancy.

Diagnosis of an ectopic pregnancy requires the exclusion of a normal, intrauterine pregnancy. This is often facilitated by the use of transvaginal ultrasound (TVUS) to visualize the location of the yolk sac or embryo, which should be able to be seen by the end of the 6th week of gestation. However, such precise dating is often not available for patients that seek medical attention with symptoms of ectopic pregnancy and so hCG testing is often used as a surrogate marker for gestational age. The serum hCG result is interpreted against the “hCG discriminatory zone.” This is the hCG concentration that, once exceeded, means that the embyro should be large enough for TVUS to always detect it. However, it is inappropriate to diagnose a patient with an ectopic pregnancy even if no embryo is observed in the uterus when the hCG concentration has exceeded the discriminatory zone. 

The hCG discriminatory zone is commonly described as an hCG concentration between 1,500 and either 2,000, 2,500 or 3,000 IU/L. Guidelines from the American College of Obstetricians and Gynecologists define it as 1,500 to 2,000 IU/L.

The management of patients with a suspected ectopic pregnancy would be easier if hCG assays were harmonized, meaning that, regardless of the assay used to measure the hCG concentration, the results would be equivalent. In other words, it would be ideal if a sample tested for hCG on one manufacturer’s test platform was equivalent to the result obtained from another manufacturer’s test platform. Unfortunately, hCG assays are not harmonized, yet many clinicians are unaware of this limitation.

Along with colleagues, I recently published the results of a study that evaluted if the lack of hCG test harmonization would affect the interpretation of an hCG result with regards to the hCG discriminatory zone. The findings confirmed that there was, indeed, a lack of harmonization between 7 commonly used hCG assays. However, when we calculated what the expected hCG discriminatory zone should be for the different assays, all of them, with one exception, would have been within 9% of the frequently cited hCG discriminatory zone cutoffs of 1,500 to 3,500 IU/L. That amount of variation is very reasonable and is not cause for alarm. The single exception was an hCG assay for which a discriminatory zone of 2,000 to 4,900 IU/L would be estimated to be equivalent. We concluded that, despite significant differences in hCG concentrations across different hCG tests, an hCG result within a discriminatory zone of 1,500–3,500 IU/L could be used without regard to a specific assay for all but one commonly used hCG test.

Watch a short video of me explaining this study!

Is it time to abandon the hCG discriminatory zone?

I've written about ectopic pregnancy a few times now (see this and this).  The use of hCG testing in the evaluation of a woman with a suspected ectopic pregnancy is invaluable.  For many years doctors have relied upon the concept of a "discriminatory zone."  That is, an hCG concentration above which an intrauterine pregnancy should always be visible using transvaginal ultrasound.  The hCG concentration that is often used as the discriminatory zone is between 1,000 and 2,000 IU/L.  If no fetus is seen then the woman may receive treatment for a presumed ectopic pregnancy.

Early recognition and treatment of an ectopic pregnancy is critical because it is a leading cause of maternal death in the first trimester.  Ectopic pregnancies are terminated by the use of the drug methotrexate or surgery.  Methotrexate is a folic acid antagonist and a powerful teratogen that causes malformations in a developing fetus.  The use of methotrexate has increased substantially in the last few years because it has fewer risks and is less expensive than surgery.  However, methotrexate is sometimes given to women with an erroneous diagnosis of ectopic pregnancy which results in the loss of a viable pregnancy or the delivery of infants with birth defects.

Two recent reports have shown a spotlight on this problem:

  • The first study reported the outcomes of 8 pregnancies that were incorrectly diagnosed as ectopic and in whom the mother was treated with methotrexate.  Sadly and unsurprisingly, all 8 pregnancies had terrible outcomes.  Two pregnancies resulted in severely malformed infants.  One was liveborn at 37 weeks and had Tetralogy of Fallot, pulmonary atresia, congenital scoliosis, 7 ribs on left side and 11 ribs on right side, and a single kidney.  The other was stillborn at 30 weeks and had Tetralogy of Fallot, horseshoe kidney, and a single umbilical artery.  The other 6 pregnancies were aborted, 3 spontaneously and 3 deliberately.
  • The second study addressed the reliability of the hCG discriminatory zone by evaluting 202 patients that met the following criteria: 1) a transvaginal sonogram showing no intrauterine pregnancy; 2) an hCG test performed on the same day as the ultrasound; 3) documentation of a subsequent viable intrauterine pregnancy.  80% had an hCG concentration less than 1,000 IU/L (well below the discriminatory zone), in 9% it was between 1,000 and 1,499 IU/L, in 6% it was between 1,500 and 1,999 IU/L, and in 5% it was 2,000 IU/L or greater (above the discriminatory zone).  The highest hCG concentration observed was 6,567 IU/L.

While the idea of an hCG discriminatory zone is an appealing one, it is clearly not something that can be relied on to make an important therapeutic decision.  The authors of the second study (above) concluded exactly that and recommend using follow-up sonography and serial hCG testing in hemodynamically stable patients before treating for presumed ectopic pregnancy.

        Ectopic pregnancy and the hCG discriminatory zone

        I’ve written about the use of hCG testing in the evaluation of patients with suspected ectopic pregnancies.  As a reminder, the diagnostic tests used in the work-up of a woman with symptoms of an ectopic pregnancy include a combination of transvaginal ultrasound and the laboratory measurement of serum hCG concentrations.

        Transvaginal ultrasound is used to visualize the fluid-filled, gestational sac in which the embryo is growing. Ultrasound may reveal 1) a normal, intrauterine pregnancy, 2) an ectopic pregnancy, or 3) neither. The latter finding would be considered an indeterminate result and occurs in about 10-30% of women being evaluated for ectopic pregnancy. An indeterminate result could represent early intrauterine pregnancy, ectopic pregnancy, or fetal loss.

        These indeterminate results are often interpreted against the hCG “discriminatory zone,” the concentration of serum hCG above which a gestational sac in the uterus should be readily observed. The discriminatory zone is often considered to be between 1,500 and 3,000 IU/L.

        A recent study investigated how well a serum hCG concentration ≥3,000 IU/L worked to differentiate an ectopic pregnancy from a normal pregnancy in women with symptoms of ectopic pregnancy but with indeterminate ultrasound findings. What they reported was quite interesting.

        There were 141 women with an indeterminate ultrasound result and 57 of these had an hCG concentration ≥3,000 IU/L. Of these, 82% actually did have intrauterine pregnancies even though their hCG concentrations were above the discriminatory zone.

        There is a very important methodological consideration to consider in this study. Pelvic rather than transvaginal ultrasonography was used and emergency department physicians and not radiologists performed it. The study purposely used pelvic ultrasound because its use in an emergency department allows for the rapid and accurate detection of an intrauterine pregnancy in the majority of cases. It also can result in a shorter stay for the patient, which, presumably, would result in lower costs. In this same study, 99% of 115 women with an intrauterine pregnancy were identified as having one using pelvic ultrasound.

        The main conclusion of this study is that in women with an indeterminate pelvic ultrasound, the use of an hCG discriminatory zone does not provide information to help differentiate ectopic from intrauterine pregnancy.

        Laboratory testing in ectopic pregnancy investigation

        What’s the leading cause of maternal death in the first trimester? That would be an ectopic pregnancy, which occurs when the fertilized egg implants someplace other than the inside of the uterus. In the vast majority of ectopic pregnancies the zygote implants in the fallopian tube, an organ that, unlike the uterus, can’t expand to accommodate the growing embryo. If not diagnosed early, an ectopic pregnancy can cause the fallopian tube to rupture that can result in massive internal bleeding and death.

         Diagnosing an ectopic pregnancy is challenging. The typical symptoms of abdominal pain and vaginal bleeding are not present in all patients and can be due to reasons other than an ectopic pregnancy. Also, the risk factors of ectopic pregnancy are absent in about half of all women who have an ectopic pregnancy. Fortunately there are laboratory tests that assist in identifying an ectopic pregnancy.

         hCG testing is first used to confirm that the patient is, indeed, pregnant. Although a rapid, point-of-care urine test may be used to detect hCG, I think it is much safer to perform a serum hCG test because it can detect lower concentrations of hCG than a urine test can. If the test is negative, that is hCG is not present, then the patient isn’t pregnant at all. If hCG is detected then pregnancy is confirmed but, all by itself, a single hCG test cannot identify a normal from an ectopic pregnancy.

         To do that, other investigations are commonly put to use:

        1. Transvaginal ultrasound. Ultrasound imaging is used to visually observe if an embryo is in the uterus or the fallopian tube but it can also be inconclusive if no embryo is observed anywhere. If the ultrasound is inconclusive then the concentration of serum hCG can be useful. That’s because an intrauterine pregnancy should always be able to be seen by ultrasound when the serum hCG concentration is greater than 1500 to 2000 IU/L. If that threshold is reached and no embryo is seen in the uterus then the patient is likely to have an ectopic pregnancy. If that threshold is not present at the initial evaluation, then serial hCG testing is considered.
        2. Serial hCG testing. Collecting more than 1 blood sample over time for hCG testing is helpful because in a normal pregnancy serum concentrations of hCG increase by 53% or more every 2 days. An increase that is less than 53% is cause for concern. That’s because an abnormal increase in indicates an abnormal pregnancy. In an ectopic pregnancy, hCG can show a normal or abnormal increase so an abnormal increase by itself it isn’t diagnostic of an ectopic pregnancy.

         These two tests are usually used together in an algorithm that looks something like this:



        Ectopic algorithm


        The take home message here is that, as helpful as lab tests are, the diagnosis of ectopic pregnancy cannot be accomplished by lab tests alone. All clinical data must be evaluated in order to arrive at the final diagnosis.