Beta HCG Discriminatory Zone Time for a Re think

Author: Learning in 10

Today I will be talking about Beta-hCG discriminatory zone-- is it time for a rethink? I will be focusing on the use of Beta-hCG in the initial stage of the diagnostic algorithm for women with ectopic pregnancies who present to the emergency department. This is the outline of our presentation. I will first present the distribution of hCG level in pregnancy. Next, I will discuss the correlation of hCG level with ectopic pregnancy, risk of rupture, before I introduce the role of the hCG discriminatory zone. I will then discuss about the advance of technology in lowering the hCG discriminatory zone and effect of increasing the zone, followed by the conclusion. Ectopic pregnancy is a common and potentially fatal condition. It has a prevalence of around 2%.

Early diagnosis of a type of pregnancy is a medical dilemma. Beta-hCG is used as one of the tools to help in the diagnosis of ectopic pregnancy. Distribution of Beta-hCG in ectopic pregnancies. This is a study done by Kohn et al., published in 2003.

They investigated the distribution of Beta-hCG in ectopic pregnancies in emergency department patients presenting with abdominal pain or vaginal bleeding. The mean Beta-hCG is 1,886 in ectopic pregnancy, while the level is over 30,000 in normal intrauterine pregnancy. Is hCG level correlated with ectopic pregnancy? In the same paper by Kohn et al., they concluded that the risk of ectopic pregnancy is substantially increased in symptomatic women with Beta-hCG levels less than 1,5000. Is Beta-hCG level correlated with risk of rupture? Two studies done in the 1990s, in France and Canada, respectively, show that more than 10,000 is associated with increased risk of rupture in ectopic pregnancy. Importantly, rupture can still occur even with Beta-hCG less than 100.

This study by Downey et al., 2011, also shows that Beta-hCG more than 10,000 is associated with ectopic pregnancy rupture. So in 1981, Kadar et al., proposed a discriminatory zone of serum Beta-hCG level, whereby above which one should always visualize an intrauterine sac on ultrasound. A study done by this group detected viable gestational sac in the uterine cavity via transabdominal ultrasound at Beta-hCG between 6000 and 6500.

Beta HCG Discriminatory Zone Time for a Re think

Therefore, the absence of an intrauterine sac in conjunction with hCG values above this level signifies ectopic pregnancy at 95% probability. Over the years, we have progressed in technology and techniques, leading to a lowering of the upper limit of discriminatory zone. From 6,500, we have decreased it to 3,600 in 1985, by Nyberg. Then Bernaschek and Bree lowered it to about 2,000, using transvaginal ultrasound, which has a better resolution than transabdominal ultrasound. Using transvaginal ultrasound, we managed to lower it to 1,000. And finally, Barnhart, who publishes on ectopic pregnancy, established a level of 1,500, based on the phase 1 of his clinical trial to study detection of ectopic pregnancy.

From then on, the majority of us have set 1,500 as our discriminatory zone to detect ectopic pregnancy. Now we shall discuss about whether a high hCG level increases transvaginal ultrasound detection rate of a gestational sac. As shown in this table, Barnhat showed that at Beta-hCG below 1,500, there were 14 transvaginal ultrasound scans where a gestational sac is absent, and only three scans which show a presence of a sac. Above about 1,500, almost all the transvaginal ultrasound scans show presence of a gestational sac. Therefore, 1,500 is the bare minimum that will allow us to identify a gestational sac by transvaginal ultrasound.

Going higher, above 1,500, would not further improve our detection of a gestational sac significantly. Having appreciated the ability of Beta-hCG in predicting the presence of a gestational sac, we shall now assess how well can we use it as a diagnostic criteria for ectopic pregnancy. Here we have a table taken from a paper published by Condous et al. On sensitivity and specificity of various level of cut off for Beta-hCG to be used as discriminatory zone to predict ectopic pregnancy in women. They may or may not present with symptoms.

Before we discuss the table, here is some information on understanding sensitivity and specificity. Sensitivity is as shown in the green boxes. True positive in disease, which means number of ectopic pregnancy detected in people with ectopic pregnancy. Specificity is in red.

It shows the number of true negative in people who are well, which means detection of people with intrauterine pregnancy. At 1000 units, we have sensitivity of 21.7 and specificity of 87.3. At 1,500 units, which a majority of the hospitals use, sensitivity fell by 6%, to 15.2 and specificity increased by 10%, to 93.4.

At 2000 units, the sensitivity fell by another 5%, to 10.9, and specificity only rose by 2%, to 95.2. As mentioned earlier, 1,500 is a good cutoff to detect a gestational sac since 1994. And at 15.2%, sensitivity has already lost 6% of people with ectopic pregnancy in exchange for 10% increased detection of intrauterine pregnancy. Raising the level for discriminatory zone would further reduce detection of 5% of patients with ectopic pregnancy, with only a mere 2% rise in detection of normal pregnancy. Here we have another paper by Wang et al. And that study is on diagnostic performance of a discriminatory zone of 3,000 units.

And here, they show a sensitivity of 35% and specificity of 58%. Here, the rise in sensitivity and fall in specificity is due to the selected patient population, which is all symptomatic, with vaginal bleeding and abdominal pain. Here, we are trying to show you that symptoms of pain and bleeding will increase the sensitivity of our detection, and this element in clinical judgment needs to be exercised in using a discriminatory zone. In summary for this section, increase in discriminatory zone from 1500 to 2000 decreases sensitivity from 15.2% to 10.9%, which means that any increase would result in sending more women with ectopic pregnancy home, only to come back with symptoms of exacerbation of ectopic pregnancy. The decrease in specificity only means a small percentage of decrease in women being sent to diagnostic imaging for detailed checkup. However, with a significant rise in risk of rupture when hCG is above 10,000 units, such a change should not make a significant change in risk of rupture for the women. Therefore, some of the guidelines suggest hCG trending to be done before the diagnosis of ectopic pregnancy.

And 90% sensitivity, intrauterine pregnancy would show a 53% rise in Beta-hCG within 48 hours. On the other hand, a majority of Beta-hCG in women with ectopic pregnancy will either decrease or will not increase by more than 50%. Therefore, if the Beta-hCG rises by half after two days, it is not likely to be an ectopic pregnancy. Therefore, we ask the question, is the discriminatory still relevant in detecting ectopic pregnancy? So here are some critiques on using Beta-hCG as discriminatory zone.

In this paper by Wang et al., there is no consistent trend of increase in detection of intrauterine pregnancy with increasing serum Beta-hCG level below 10,000 units. Above 10,000, the detection rate improved dramatically. Therefore, cast doubts on the usefulness of such a test and whether we can replace this with something more reliable, like hCG trending.

A point to note is that the design of this study has two flaws. Firstly, not all the ultrasonographers are trained in ultrasonography. However, the author also did not find any significant difference in their accuracy. Secondly, all the participants had a transabdominal ultrasound followed by a transvaginal ultrasound. However, not every sonographer performed the transvaginal ultrasound.

Thus, this may affect the accuracy of the study. Coincidentally, Wang's opinion was supported by a paper from Harvard, done by Doubilet et al. They a study over 10 years, following up on the outcome of women who had a Beta-hCG level below the discriminatory zone and yet ended up with an intrauterine pregnancy. They showed that the outcome of the pregnancy is independent of hCG level.

This does not restrict to multiple gestation, which is known to have a high hCG level that crosses the discriminatory zone, but will not present with a gestational sac. Usually, a twin peak sign will appear in a few days later. Yet, this paper showed that singletons can also have the same presentation, and in fact, the majority of them are singletons in this study. Therefore, we cannot entirely attribute missing the intrauterine pregnancy to multiple pregnancy. So in conclusion, we find that increase in hCG discriminatory zone will result in more false negatives, while not decreasing false positives significantly. Therefore, we suggest to keep the current hCG discriminatory zone at 1500, and perform trending using an updated value of 50% as the cutoff, based on a study done in 2005, which has replaced the previous cutoff of 67% in the majority of the guidelines in the world.

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