Numerous clinical guidelines and algorithms advise using the human chorionic gonadotropin (hCG) discriminatory level as a means of ruling out a viable intrauterine pregnancy early in pregnancy when a gestational sac cannot be seen via transvaginal sonography. The recommended hCG discriminatory level has steadily declined in concert with advances in transvaginal sonography, but some clinicians have questioned its sensitivity. This issue of Strategies reports on one institution’s examination of pregnancy outcomes in cases with discrepant hCG and ultrasound results.

Early in pregnancy hCG levels rise rapidly in parallel with the developing placenta, reaching median concentrations of about 100,000 IU/L between 8-10 weeks’ gestation, gradually declining during the next 12-16 weeks, and thereafter remaining at about 10% of peak concentration until delivery. With development and refinement of transvaginal sonography, the concept of an hCG discriminatory level was first proposed in 1981 as the hCG concentration which suggests either an ectopic pregnancy or abnormal intrauterine pregnancy when no gestational sac is observed via sonography. This level, initially put forward as 6500 IU/L and lowered over time to 1000-2000 IU/L, has been widely adopted in professional guidelines and medical textbooks.

“The idea of the hCG discriminatory level is the hCG measurement at which you should always see the gestational sac in the uterus via transvaginal ultrasound if the mother has a normal intrauterine pregnancy,” explained Peter Doubilet, MD, PhD, senior vice chair for physician affairs in radiology at Brigham and Women's Hospital and professor of radiology at Harvard Medical School in Boston. “The reason the discriminatory level has gone down over the years is that ultrasound equipment has gotten better, which means that we see pregnancies earlier in pregnancy than we did 30 years ago when the hCG discriminatory level was first described.”

Doubilet was the lead author of a retrospective study at Brigham and Women’s Hospital that assessed whether women with hCG levels >2000 IU/L and no gestational sac observed on transvaginal sonography were subsequently found to have a live intrauterine pregnancy (J Ultrasound Med 2011;30:1637-1642). He and his coauthor, Carol Benson, MD, identified all instances of women undergoing serum hCG testing and transvaginal sonography on the same day, having positive hCG results but no intrauterine fluid collection observed on transvaginal sonography, and in whom a follow-up sonogram showed a live intrauterine pregnancy. During an 11-year period, the authors found 202 such patients, nine of whom had hCG concentrations >2000 IU/L, 12 with levels between 1500-1999 IU/L, and 19 with levels between 1000-1499 IU/L. The majority of women (80.2%) had hCG concentrations <1000 IU/L. Logistic regression analysis showed no significant relationship between either initial hCG level and outcome or high or low hCG level and outcome. Of the nine patients who had hCG levels >2000 IU/L, seven had live intrauterine pregnancies at the end of the first trimester, and six delivered liveborn babies. The highest hCG level was 6567 IU/L, and the highest value that preceded a liveborn baby was 4336 IU/L.

Doubilet explained that the findings have implications for how most clinicians evaluate suspected ectopic pregnancies. “When a woman comes in to her doctor or the emergency department complaining of pelvic pain or vaginal bleeding and her hCG level is above the discriminatory level, say above 2000 IU/L, and an ultrasound shows no pregnancy, the common teaching is, she doesn’t have a normal intrauterine pregnancy. It’s either an ectopic pregnancy or an abnormal intrauterine pregnancy that isn’t going to make it, and therefore you should either give methotrexate to treat the ectopic pregnancy or do a D and C—dilatation and curettage—to treat the abnormal pregnancy,” he said. “However, we wanted to get our findings in the literature, because our concern is that practices that use an hCG discriminatory level of 2000 IU/L and treat women with methotrexate when hCG is higher than that and they see nothing in the uterus by sonography are doing harm to some potentially normal intrauterine pregnancies.”

Many hospitals and professional guidelines have algorithms that call for treatment of suspected ectopic pregnancy when women have hCG values above the discriminatory level—typically >2000 IU/L—and no gestational sac visible on transvaginal ultrasonography. However, Brigham and Women’s Hospital some years ago changed it protocol for managing patients with an hCG level above 2000 IU/ml and no visible intrauterine gestational sac, based on concerns that using a lower threshold to exclude normal pregnancies might expose healthy pregnancies to harm from methotrexate, D and Cs, or other interventions.

“Going back almost 10 years we established a protocol which said you don’t give methotrexate unless the hCG level is at least 4000 IU/L, which is double the normal discriminatory level,” said Doubilet. “We wanted to avoid the possibility of damaging a normal intrauterine pregnancy, and we decided that 2000 IU/L was too low.”

Both Doubilet and David Grenache, PhD, DABCC, agreed that Brigham and Women’s is unusual in having implemented a higher discriminatory zone. “What got my attention about this study was that there actually are women who have serum hCG concentrations above the discriminatory zone, with no evidence of pregnancy on ultrasound, who then go on to have intrauterine pregnancies. That was surprising, because in textbooks and guidelines it’s often cited that an hCG concentration above 2000 IU/L should be 100 percent sensitive, and that’s not the case,” said Grenache. “I suspect many healthcare providers aren’t necessarily aware of this possibility because the concept of an hCG discriminatory zone is so widely taught, accepted, and believed.” An associate professor of pathology at the University of Utah and medical director of special chemistry at ARUP Laboratories in Salt Lake City, Grenache was not involved in the study.

Doubilet argued that some providers have erroneously viewed the hCG discriminatory level as a hard-and-fast cutoff. “Where I think people have gotten the message somewhat wrong, and which has lead to treatment protocols I think are wrong, is in turning an almost always into an absolute. It’s correct to say that when the hCG level is above 2000 IU/L you will almost always see a gestational sac. But people have taken it as a given that under those circumstances there’s no chance of a normal intrauterine pregnancy and that the patient therefore can take methotrexate.”

Grenache also suggested that laboratorians look at the cutoffs used with their hCG assays. “Since hCG assays are not harmonized, you could take the same serum sample and quantitate hCG in it using different assays and you wouldn’t get the same value. So that begs the question of what effect the analytical variation between hCG assays might have on the hCG discriminatory zone,” he explained. “If a hospital, based on the literature, uses a discriminatory level of 2000 IU/L, but doesn’t bother to validate that cutoff with the hCG assay used in the lab, how will it know that’s an appropriate cutoff for that assay? Maybe it should be 2500 or 3000 or 1500 IU/L. This analytical variation between hCG assays could influence how the hCG discriminatory zone is interpreted. That question hasn’t been addressed as far as I can tell.” Grenache’s lab has just started investigating that issue. He also observed that the study underscored the need for better biomarkers of ectopic pregnancy, an area of active research.

Doubilet and Grenache concurred that laboratorians would do well to review the study findings with clinicians and work with them to reassess algorithms for evaluating suspected ectopic pregnancies. “The least you could do is have a dialogue about what discriminatory zones they’re using. But more importantly, you’d want to know what they do with patients with hCG results above the discriminatory zone but in whom they don’t see a fetus in the uterus,” said Grenache. “If the next step is, we wait, do serial hCG monitoring or look at hCG doubling times, that’s probably the smart approach. But if the answer is, we assume it’s an ectopic pregnancy and give methotrexate, then that opens the door to ask whether they’re aware of this study.”