There are three reference standards for β-hCG measurement. The World Health Organization introduced the First International Standard (1st IS) in the 1930s. Testing for hCG and its subunits improved over the years. The Second International Standard (2nd IS), introduced in 1964, has varying amounts of β-hCG and β subunits. A purified preparation of β-hCG is now available. Originally referred to as the First International Reference Preparation (1st IRP), the test standard is now referred to as the Third International Standard (3rd IS). Although each standard has its own scale, the 2nd IS is about one-half of the 3rd IS. For example, if a level is reported as 500 mIU/mL (2nd IS), it is equivalent to a level of 1,000 mIU/mL (3rd IS). The assay standard used must be known to interpret hCG results correctly (106). In several recent articles, attention was drawn to a problem known as phantom hCG, in which the presence of heterophile anti bodies or proteolytic enzymes causes a false-positive hCG result. Because the antibodies are large glycoproteins, significant quantities of the antibody are not excreted in the urine. In the patient with hCG levels less than 1,000 mIU/mL, a urine pregnancy test should be performed and confirmatory positive results obtained before instituting treatment (107,108).
The hCG level correlates somewhat with the gestational age (109). During the first 6 weeks of amenorrhea, serum hCG levels increase exponentially. During this period, the doubling time of hCG is relatively constant, regardless of the initial level. After the sixth week of gestation, when hCG levels are higher than 6,000 to 10,000 mIU/mL, the hCG rise is slower and not constant (110).
The hCG doubling time can help to differentiate an ectopic pregnancy from an intrauterine pregnancy—a 66% rise in the hCG level over 48 hours (85% confidence level) represents the lower limit of normal values for viable intrauterine pregnancies (111). About 15% of patients with viable intrauterine pregnancies have less than a 66% rise in hCG level over 48 hours, and a similar percentage with an ectopic pregnancy have more than a 66% rise. If the sampling interval is reduced to 24 hours, the overlap between normal and abnormal pregnancies is even greater. Patients with normal intrauterine pregnancies usually have more than a 50% rise in their hCG levels over 48 hours when the starting level is less than 2,000 mIU/mL. The hCG pattern that is most predictive of an ectopic pregnancy is one that has reached a plateau (a doubling time of more than 7 days). For falling levels, a half-life of less than 1.4 days is rarely associated with an ectopic pregnancy, whereas a half-life of more than 7 days is most predictive of ectopic pregnancy.