To properly evaluate the vast majority of patients in whom an early ectopic pregnancy is suspected, it is absolutely imperative to correlate the sonographic findings with the results of a quantitative serum pregnancy test. In addition, it is important for the sonographer and sonologist to know the type of assay used and its relative sensitivity.
The enzyme-linked immunoassays that detect urine human chorionic gonadotropin (hCG) are nonquantitative but very sensitive and may easily be performed in an office or clinic. These tests are useful for determining the presence or absence of a pregnancy and are routinely positive when the serum hCG level is at least 50 mIU/mL (8 to 10 days postconception). They are positive in about 99% of patients with a symptomatic ectopic pregnancy. The enzyme-linked immunoabsorbant assays (ELISAs) detecting the β subunit of the serum hCG molecule are quantitative and most helpful in cases where a problem arises during an early pregnancy, such as suspected ectopic pregnancy or threatened abortion.
All commercially available kits that measure serum hCG now use nonradioactive technology and the older radioimmunoassays (RIAs) have been replaced. In addition, the earlier confusion over different "international standards" has been resolved, and all kits now use the same standard.
Most of the urine pregnancy tests assay for the whole intact hCG molecule. They may, however, also detect metabolized core fragments of hCG, which contain portions of both the α and β chains of the molecule, but where the β subunit is "nicked." These "nicked" β subunit chains may not be detected by a serum hCG assay, thereby giving the impression of a "false-positive" urine pregnancy test.25 Clinically, this may be encountered when a patient has a nonviable pregnancy (usually intrauterine) that is in the process of resolving.26 The trophoblast has ceased producing hCG, and has often been expelled, and the serum hCG level is very low. Such patients may present with complaints of pain and abnormal bleeding, and an ectopic pregnancy is in the differential diagnosis. Usually, the urine pregnancy test also becomes negative when repeated in 48 hours.
Most laboratories test for the whole hCG molecule when performing a quantitative serum assay. At Duke University Medical Center, a whole-molecule electrochemiluminescent immunoassay is used. The assay that detects both the whole molecule and free β subunit is generally only used when following patients with gestational trophoblastic disease. An ectopic pregnancy does not produce free β-hCG subunits and testing for this is not necessary. What is critically important, however, is that when performing serial quantitative hCG assays, the same assay should be used throughout.
The ability to quantitate serum levels of hCG allows the clinician to grossly approximate the gestational age of the pregnancy, assuming it is normal. The hCG level can then be correlated with the sonographic findings in looking for certain developmental "milestones" (Table 4-1). Transvaginal sonographic features that are expected at the various hCG levels are summarized in Figure 4-1. Correlating the serum hCG level with the sonographic findings enables the clinician to evaluate the normalcy of the pregnancy in question. However, there appears to be significant overlap in these values, and they are limited in multiple gestations.
Table 4-1TRANSVAGINAL ULTRASOUND AND EMBRYOLOGIC MILESTONES ||Download (.pdf) Table 4-1 TRANSVAGINAL ULTRASOUND AND EMBRYOLOGIC MILESTONES
|Gestational Age (weeks) ||Range of Chorionic Sac Mean Dimension (mm)a ||Embryo Length (mm)b ||Mean β-hCG mIU/mLb,c |
|4 ||1.5 × 2.8 ||0.5 ||28 |
|5 ||8–15 ||1.5–3 ||300 |
|6 ||15–40 ||4–8 ||3000 |
|7 ||40–100 ||9–16 ||50,000 |
β-hCG and TAS milestones. (Cartwright P, DiPietro D. Ectopic pregnancy: change in serum hCG concentrations. Obstet Gynecol 1984;63:76.) (I.R.P., international reference preparation)
The sonographic "milestones" that are helpful and more commonly used include the delineation of a "chorionic sac" at the fifth week, detection of a yolk sac within the gestational sac of approximately 1 cm at 5 to 6 weeks, and an embryo within a sac of approximately 1.5 mm at 6 weeks.
A discriminatory zone for the level of serum hCG has been defined for discerning an intrauterine pregnancy from an ectopic pregnancy by means of TVS. This varies somewhat depending on the sonographer's expertise and equipment used. With an experienced sonographer, this level is between 1500 and 2000 mIU/mL. This means every viable singleton intrauterine pregnancy should be visible sonographically by the time the serum hCG is 1500-2000 mIU/mL or more. An exception to this is multiple gestation. The absence of an intrauterine gestational sac when the serum level is above the discriminatory zone is highly suspicious for an ectopic pregnancy. If no intrauterine gestational sac is seen while the serum hCG is below the discriminatory zone, the pregnancy may be either very early intrauterine or ectopic. Even when an adnexal mass is visualized, this may simply be a self-contained hemorrhagic corpus luteum cyst. Measuring the thickness of the endometrial stripe is a limited value. Some have observed that normal, early intrauterine pregnancies tend to be associated with a thickened (>6 mm) endometrium, whereas the stripe is thinner with an ectopic pregnancy or spontaneous abortion.17 When ambiguity persists, serial hCG determinations should be drawn to look for a normal or abnormal progression, and the sonogram should be repeated once the level has risen above the discriminatory zone.
It must be emphasized, however, that these criteria represent guidelines, not absolute end points.18 It is possible for a viable intrauterine pregnancy to demonstrate a low hCG level and/or slow progression. Conversely, a normal rise in the hCG level may sometimes be associated with an ectopic pregnancy.18 Also, a multiple gestation or a heterotopic pregnancy may show an uncharacteristically elevated hCG level for any given gestational age.
The amount of hCG produced by an ectopic pregnancy is generally less than that by a viable intrauterine pregnancy of the same gestational age,26 which may be due to an unfavorable location for trophoblast proliferation. This fact is useful, however, only if the date of conception is known. The serum hCG level for 192 women with a proven ectopic pregnancy at the time of their initial presentation is shown in Figure 4-2. It is clear that the majority of these patients presented with the serum hCG level below the discriminatory zone.
β-hCG at time of presentation in 192 surgically proven ectopic pregnancies. (Cartwright P, DiPietro D. Ectopic pregnancy: change in serum hCG concentrations. Obstet Gynecol 1984;63:76.) (I.R.P.)
The level of serum hCG tends to be proportional to the size of a tubal pregnancy (Figure 4-3). A ruptured tubal pregnancy tends to be associated with a higher level than one that has not ruptured. The range of serum hCG levels for any given situation, however, is so broad that this observation has little clinical relevance.
β-hCG versus size of mass. (I.R.P.)
Visualizing an intrauterine sac when the serum hCG is below the discriminatory zone may signify an abnormal gestation (Figure 4-4). An intrauterine "blighted ovum" may appear this way. Also, there is the "pseudogestational sac," which is sometimes associated with an ectopic pregnancy. A pseudogestational sac lacks the "double-sac" sign and is smaller and more irregular than a true gestational sac at a comparable gestational age.
β-hCG, ultrasound (TA) findings in 46 proven ectopic pregnancies. (Cartwright P, DiPietro D. Ectopic pregnancy: change in serum hCG concentrations. Obstet Gynecol 1984;63:76.)
, ruptured. (I.R.P.)
Serial determinations of the serum hCG level have proven useful in the clinically stable patient when ambiguity persists even after the sonographic findings have been correlated with a single quantitative hCG. Figure 4-5 shows the hCG progression in 19 clinically stable patients with an ectopic pregnancy.26 The first known value is arbitrarily placed on the standard line, and subsequent values are plotted accordingly. It is apparent that most patients showed a plateau or fall in the level during the period of preoperative evaluation. This plateau or fall is diagnostic of a nonviable pregnancy when it occurs at levels below 3000 mIU/mL during at least a 48-hour period. It does not, however, distinguish between a nonviable intrauterine and an ectopic pregnancy. It is also apparent from Figure 4-5 that some ectopic pregnancies may show an initial "normal" rise in the level of hCG. This normal rise, however, is usually short-lived, and an abnormal progression soon develops.
Serial β-hCG in 19 clinically stable patients. (Cartwright P, DiPietro D. Ectopic pregnancy: change in serum hCG concentrations. Obstet Gynecol 1984;63:76.) (I.R.P.)
Serial hCG determinations are also essential after treatment of an ectopic pregnancy by either medical or surgical means. A plateau or rise in the level may be the first indication of a persistent ectopic pregnancy indicating the need for further treatment.27 Furthermore, a negative hCG may signify a resolution of the ectopic pregnancy, which may proceed normalization of any sonographic findings.
Some groups consider a nondiagnostic TVS to represent a "pregnancy of unknown location" and advocate a repeat hCG after 48 hours. In normal intrauterine pregnancies, hCG increases by an average of 66% in 48 hours. Not all intrauterine pregnancies (IUPs) have this expected increase, and up to 15% of normal IUPs will have less than the expected rise.28