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What serial hCG can tell you, and cannot tell you, about an early pregnancy
What serial hCG can tell you, and cannot tell you, about an early pregnancy Beata E. Seeber, M.D., M.S.C.E. Department of Gynecologic Endocrinology and Reproductive Medicine, Innsbruck Medical University, Innsbruck, Austria
The serial measurement of serum hCG concentrations is an important clinical tool used to differentiate normal from abnormal pregnancies. At hCG values below which ultrasonography can be diagnostic, the comparison of a patient's hCG dynamics to those of established expected curves of rise or fall can aid the clinician in determining when to follow expectantly and when to intervene. Still, this method has some limitations and should never suUse your smartphone persede clinical judgment based on symptoms or signs. (Fertil SterilÒ 2012;98:1074–7. Ó2012 to scan this QR code by American Society for Reproductive Medicine.) and connect to the Key Words: Early pregnancy, ectopic pregnancy, serial hCG measurements Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/seeberbe-serial-hcg-early-pregnancy/
I
n medical school, most of us still learned the old adage that in a normally developing intrauterine pregnancy, the serum human chorionic gonadotropin (hCG) should double every 2 days. We were taught that deviations from this doubling time were thought to be suspect and could indicate an abnormally developing intrauterine pregnancy (IUP) or miscarriage, or an ectopic pregnancy (EP). In the last decade, dozens of publications have delved more deeply into this topic of how hCG really behaves in normally developing, compared to aberrant, pregnancies. What they have shown us is that the picture is much more complicated than it first appeared. It is well accepted that the initial evaluation of a woman with a symptomatic early pregnancy (bleeding and/or pain) includes transvaginal pelvic sonography (TVS) and measure-
ment of the serum hCG concentration. In many cases this is all that is needed to make the diagnosis of an intrauterine pregnancy (viable or nonviable pregnancy) or an ectopic gestation. However, in cases where the hCG value is below the critical threshold of 1500 to 2000 mIU/mL (often called the discrimination level) and ultrasound is not likely to be diagnostic, the pregnancy is of unknown location (PUL) (1, 2). As discussed in a recent consensus statement, PUL is a descriptive term only, not a diagnosis, and women with a PUL need to be followed until a diagnosis can be made (1, 2). This follow-up consists of repeated (serial) hCG values usually measured 48 hours apart until either the trajectory of hCG is diagnostic of a non-viable gestation and intervention may be required, or the hCG discrimination level is reached, a point at which an ultrasound can pro-
Received June 25, 2012; revised September 7, 2012; accepted September 13, 2012; published online September 29, 2012. B.E.S. has nothing to disclose. Reprint requests: Beata E. Seeber, M.D., M.S.C.E., Department of Gynecologic Endocrinology and Reproductive Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria (E-mail: [email protected]). Fertility and Sterility® Vol. 98, No. 5, November 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2012.09.014 1074
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
vide the diagnosis. It is critical to understand that the trajectory of the rise in hCG alone is not diagnostic of a viable pregnancy, and always needs to be followed by an ultrasound to establish the correct diagnosis.
RISING hCG LEVELS The clinical utility of following serial hCG concentrations is based on comparing the dynamics of a patient's hCG concentrations to those of published reports of the behavior of hCG in viable intrauterine pregnancies. Most of the initial studies were performed in small numbers of subjects, many of whom conceived following infertility treatment (3, 4). Thus, the generalizability of these data to the typical symptomatic patient presenting with bleeding and pain was unclear. A small study of only 20 women by Kadar et al. (5) in 1990 was one of the first to evaluate symptomatic women with spontaneously conceived pregnancies and reported that the rise of hCG for a viable IUP needed to be at least 66% in 2 days. Many clinicians adopted these findings to their clinical practice, diagnosing those women with a slower rise in hCG with an abnormal VOL. 98 NO. 5 / NOVEMBER 2012
Fertility and Sterility® pregnancy. What they failed to understand, however, was that the minimal 2-day rise of 66% was actually the lower limit of an 85% confidence interval, meaning that almost 8% of viable intrauterine pregnancies exhibited a slower rate of rise. With the more recent publication of larger cohort studies by Barnhart's group in the mid-2000's, the minimal expected rise of hCG in viable pregnancies became more clear. In a study of 287 subjects who presented with symptomatic early pregnancy, the rise in hCG could be as slow as 53% in 2 days and the pregnancy could still turn out to be viable (6). Adopting a lower limit based on a 99% confidence interval meant that less than 1% of viable pregnancies exhibited an hCG rise even slower than that. While an appropriate rise in hCG is reassuring and predicts that a pregnancy may turn out to be viable on further follow-up, it is in no way diagnostic of an IUP. This is the case because an initial normal rise in hCG does not exclude the possibility of a nonviable pregnancy, especially that of an EP. Horne et al. demonstrated this fact with their study of 340 women who presented with pain and/or bleeding at <12 weeks gestation and had an inconclusive initial ultrasound. Despite a normally rising hCG defined as at least R66% rise over 48 hours in 63 of the women, 10 (16%) of them went on to have an ectopic pregnancy (7). Silva et al. (8) reported in 2006 on the great variability of serial hCG values in women with EP. In their cohort of 200 women with EP, 60% of subjects had an initial rise in hCG over 2 days, with almost 21% having a rise that was at least equal to the minimal rise of 53% for a viable gestation. Thus, despite behaving like an IUP, a pregnancy may still turn out be an ectopic. For this reason it is critical to continue to follow any symptomatic pregnancy closely with serial hCG concentrations, no matter how ‘‘reassuring’’ the rise in hCG may be at first. Such follow-up should continue until a definitive diagnosis can be made, namely with ultrasound once the discriminatory hCG level is reached. In cases where an initially appropriately rising hCG does not rise at least 53% in 2 days on subsequent follow-up, a nonviable pregnancy (miscarriage or ectopic pregnancy) is almost certain. Further evaluation to discriminate between these two entities is then necessary, and a uterine evacuation may be needed. Evacuating the contents of the uterus followed by histologic evaluation for the presence of chorionic villi is the diagnostic test to confirm that intrauterine implantation had occurred.
DECLINING OR PLATEAUING hCG LEVELS What can we say about the opposite situation, when serial hCG levels taken 2 days apart plateau or decline? In such a case, barring the unlikely event of a laboratory error, or rare exceptions like pregnancies complicated by ovarian hyperstimulation syndrome (see below), the pregnancy is for certain nonviable. The key question is: can the rate of hCG decline help in distinguishing between a pregnancy that requires intervention (ectopic pregnancy, non-resolving miscarriage) and one that can be managed expectantly (spontaneously resolving miscarriage or spontaneously resolving ectopic)? A critical piece of information to answer this question was provided by Barnhart et al. (9) in their 2004 publication describing VOL. 98 NO. 5 / NOVEMBER 2012
the normal curve of decline in hCG in spontaneous complete abortion. In this study of 710 women ultimately diagnosed with a miscarriage due to spontaneous decline of hCG to <5 mIU/mL without medical or surgical intervention, the authors found that the rate of hCG decline is quadratic and exhibits a faster decline when the initial hCG value is higher. For example, the 2-day decline for a starting hCG of 5000 should be at minimum 35%, that for a starting hCG of 500, at minimum 24%. In a subsequent publication, this group was able to further demonstrate that when the intial hCG values are as low as 50 mIU/mL, then the subsequent hCG value 2 days later can decline by as little as 12% and still result in a spontaneous complete abortion (10). In both of the studies, the authors report the slowest decline as represented by the 95th percentile confidence intervals, meaning that there will still be individuals whose decline may be even slower. In all, these rates of decline are much slower than those following an induced abortion (11, 12). Table 1 summarizes for clinical use the slowest appropriate decline in hCG (according to initial hCG level) that most likely represents a spontaneously resolving pregnancy not requiring intervention. Condous et al. (13) compared the ratio of serum hCG taken at the time of presentation and a subsequent value measured 48 hours later in women with pregnancy of unknown location, dividing their study cohort into a training and test set. This method of creating two separate study cohorts allows the investigator to validate his or her findings by testing how well the algorithm created with the training set performs on the test set cohort. They calculated that a ratio of <0.87 between these two hCG measurements had a sensitivity and specificity of over 90% in both sub-sets for predicting a failing PUL which will resolve spontaneously. The authors advocate a non-interventional approach in these women unless deterioration in the woman's clinical condition was observed. Applying a similar logic to that previously described for viable pregnancies, as long as a patient's hCG declines at the minimum rate based on her starting hCG, she may be managed expectantly because there is a very good chance that her pregnancy will resolve without the need for intervention. However, it is again critical to understand that an appropriate rate of decline is not diagnostic of a nonviable intrauterine pregnancy because some ectopic pregnancies will exhibit a similar decline in hCG. According to the 2006 publication by Silva et al. (8), 8% of the 200 ectopic
TABLE 1 Expected minimal percentage of decline in serum hCG for nonviable pregnancies. Initial hCG (MIU/mL) 50 150 250 500 1000 2000 2500
% Decline after 2 d
% Decline after 4 d
12 18 21 24 28 31 32
26 39 44 50 55 60 62
Note: Adapted from Barnhart et al., Ob Gyn 2004 (9); and Chung et al., Fertil Steril 2006 (10). Seeber. hCG in early pregnancy. Fertil Steril 2012.
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VIEWS AND REVIEWS pregnancies in their study presented with a fall in hCG values similar to that seen in women with a completed spontaneous abortion. Similarly, Horne et al. reported that of the 214 women who had a fall in hCG of more than 10% on serial measurements, 6 (3%) had an ectopic pregnancy (7). Thus, women with declining hCG levels should be followed regularly and the hormonal declines should be compared to the published expected value, as summarized in Table 1 based on the publications of Barnhart's group (9). Only with consistent and complete follow-up until the hCG level is below 5 mIU/mL can one be certain that the pregnancy has resolved. If the percentage of decline is below that of the expected, then intervention is likely necessary to rule-out an ectopic gestation or to manage a non-resolving miscarriage. It is critical to point out that despite a decline in hCG, a resolving ectopic pregnancy may rupture. There have been cases reported where an ectopic pregnancy has ruptured despite continuously declining hCG values (14). Clearly, clinical monitoring for suspicious symptoms or signs of an ectopic pregnancy should always accompany laboratory monitoring in women with a PUL, even if it appears to be resolving.
a false-negative classification as being a non-viable pregnancy due to a too slow rise of hCG. Based on this, Morse et al. (16) conclude that a third hCG measurement may sometimes be needed to make the correct diagnosis, especially when the initial hCG values are low (around 500 mIU/mL). So, the critical question is, how should a clinician apply the data from these studies to the clinical care of a patient with a PUL? How important are serial hCG values to making a diagnosis and to choosing the correct management? The abbreviated answer is that serial hCG values are essential, but should never be used alone to diagnose a woman. Quoting Morse et al. (16), ‘‘.they should be used in combination with clinical judgment evaluation of symptoms, and repeat ultrasound (as needed).’’ There will always be exceptions to the rules, in this case, pregnancies in which the hCG follows a trajectory outside of the 99.9 confidence interval of ‘‘expected.’’ The practice of comparing a given patient's change in hCG to what would be expected has made the diagnostic process more logical and timely. But, ultimately, clinical judgment should always prevail over laboratory values and no patient should be treated based on hCG values alone.
ACCURACY OF DIAGNOSIS WHEN USING SERIAL hCG LEVELS
HCG MEASUREMENTS IN PREGNANCIES FOLLOWING IN VITRO FERTILIZATION (IVF)
The validity and accuracy of these recently redefined curves for IUP and resolving SAB, as published by Barnhart's group (6, 9), were confirmed in two subsequent publications. Applying the published curves for IUP and SAB, with their respective wide and liberal confidence intervals, to a cohort of 1,249 women with pregnancies of unknown location led to accurate and timely diagnosis (15). In fact, the authors report an improvement in the diagnosis of EP by about 2.5 days by using these rules. Still, not all EP could be diagnosed by aberrant behavior of hCG in serial evaluations, reiterating again that laboratory monitoring cannot replace clinical evaluation and judgment. In addition, the authors caution that in order to minimize the risk of interrupting a potentially viable gestation, an even more conservative rule than the rise of 53% over 2 days should be followed. This is the case because, according to the data from this study, a small number of pregnancies that end up viable may have a rise in hCG as slow as 35% over 2 days. In a subsequent multi-center study published in 2012, Morse et al. (16) applied the redefined curves to an ethnically and geographically diverse population of over 1,000 women. They used the very conservative rise of only 35% over 2 days for an IUP, representing the 99.9% confidence interval from the previous study (6), and a relatively sharp decline during 2 days, representing 90% of women with a miscarriage, to set the bounds of normal hCG behavior. They chose these curves as a balance of not of interrupting a viable IUP and not misclassifying an EP as a miscarriage. Still, despite the adoption of these conservative parameters to the analysis of the changes in serial hCG, the authors report that 30 EPs in this series would have been misclassified. Twenty-four of these 30 EPs would have been misclassified as potential IUPs because of an hCG that changed appropriately between the two time points measured. Conversely, 20 cases of IUPs would have received
Can the curves of expected hCG dynamics be applied to pregnancies conceived following IVF? Studies examining the predictive value of a single post-IVF hCG determination have shown that the values are higher for pregnancies that go on to be viable than for those that end in a pregnancy loss (17, 18). Additional studies have shown that hCG concentrations determined 13 and 15 days after fertilization are higher in pregnancies resulting from cleavage-stage day 3 embryos than those achieved through the transfer of blastocysts on day 5. Nonetheless, the percentage increase in serial measurements of hCG did not differ between these groups (19). Certainly, no distinction can be made between miscarriages and ectopic pregnancies with one single measurement. Chen et al. evaluated paired hCG levels on day 15 and 22 postembryo transfer (no details were given as to day of transfer) to test whether the ratio of these values was a better predictor of pregnancy outcome than hCG doubling time following IVF. They concluded that the best diagnostic accuracy was obtained by a combination of both hCG on day 15 R 150 mIU/mL and an hCG day 22/hCG day 15 ratio of R15 with a specificity of 94% and sensitivity of 47% for normal pregnancy. Conversely, when the hCG on day 15 was below 150 mIU/mL and the ratio of hCG on day 22/hCG on day 15 was below 15, there was an 84% chance of an abnormal pregnancy (20). A subsequent study of 143 women found that when an initial hCG concentration following IVF is less than 50% of the 5th percentile, then that pregnancy is certainly nonviable. (21) However, single measurements of hCG, even if low and suspicious for a non-viable pregnancy, cannot distinguish between non-viable intrauterine and ectopic gestations. Analyzing data from 6021 IVF pregnancies, Shamonki et al. (22) created logarithmic curves predicting live delivery rates given initial levels and percent 2-day rise of hCG after IVF. Consistent with previous publications, these authors
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Fertility and Sterility® showed that the higher the percentage of rise in hCG drawn 2 days following the initial value (days 14 and 16 following oocyte retrieval), the better the live delivery rate. These studies are important in that they establish the prognostic value of hCG for a successful pregnancy outcome following IVF. When compared to spontaneous conception cycles, the average doubling time of hCG following IVF-embryo transfer in viable pregnancies appears to be the same (1.4 0.3 versus 1.6 0.4 days, NS) (23). One recent study from 2006 described the profile of hCG in a large cohort of nearly 400 pregnancies conceived following IVF that resulted in a live birth (24). Within the hCG range, with its corresponding gestational age, at which ultrasound is non-diagnostic, hCG was shown to exhibit a log linear pattern of rise, comparable to that seen for spontaneously conceived intrauterine pregnancies. On average, hCG rose 50% in 1 day and 124% in 2 days, with documented extremes of as little as a 14% or 30% rise over 1 or 2 days, respectively, still resulting in a live birth. Of course, as described in detail above for the case of spontaneously conceived pregnancies, an initially normally rising hCG does not exclude the possibility of a nonviable gestation, including ectopic pregnancy. Thus, serial measurements of hCG followed by ultrasonography are just critical to establishing the definitive diagnosis in post-IVF as they are for spontaneously conceived pregnancies. Caution should be taken in interpreting hCG values in IVFconceived pregnancies complicated by ovarian hyperstimulation syndrome (OHSS), especially at low hCG values. Due to extra-vascular fluid shifts, and hemoconcentration followed post-hydration hemodilution, serum hCG values may be inaccurate. We have clinically observed multiple patients whose hCG values appeared to initially plateau, only to follow an expected trajectory once hemodynamic stability was established.
3.
4.
5. 6.
7.
8.
9.
10.
11.
12. 13.
14.
15.
16.
SERIAL hCG VALUES IN MULTIPLE GESTATIONS Several studies have shown that rates of rise of hCG are similar in multiple compared to singleton gestations, with only higher absolute values seen in higher fetal number gestations. Following IVF, 48 single pregnancies were compared to 50 multiple pregnancies with comparable hCG doubling times reported (23). Chung et al. evaluated 135 twin and 32 triplet pregnancies following IVF and likewise found that baseline hCG concentrations were higher for the multiple pregnancies than for the 224 singletons. But, the rate of rise in hCG was similar for both groups (24). Heterotopic pregnancies are a very rare form multiple gestation that are nonetheless more likely to occur after IVF than spontaneously. These pregnancies are inherently difficult to diagnose and no data has been published regarding the observed or expected behavior of hCG in these unusual cases.
REFERENCES 1.
2.
Barnhart KT, Simhan H, Kamelle SA. Diagnostic accuracy of ultrasound above and below the beta-hCG discriminatory zone. Obstet Gynecol 1999;94:583–7. Barnhart K, vam Mello NM, Bourne T, Kirk E, Van Calster B, Bottomley C, et al. Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome. Fertil Steril 2011;95:857–66.
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Kadar N, Freedman M, Zacher M. Further observations on the doubling time of human chorionic gonadotropin in early asymptomatic pregnancies. Fertil Steril 1990;54:783–7. Pittaway DE, Wentz AC. Evaluation of early pregnancy by serial chorionic gonadotropin determinations: a comparison of methods by receiver operating characteristic curve analysis. Fertil Steril 1985;43:529–33. Kadar N, Caldwell BV, Romero R. A method of screening for ectopic pregnancy and its indications. Obstet Gynecol 1981;58:162–6. Barnhart KT, Sammel MD, Rinaudo PF, Zhou L, Hummel AC, Guo W. Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined. Obstet Gynecol 2004;104:50–5. Horne AW, McBride R, Denison FC. Normally rising hCG does not predict live birth in women presenting with pain and bleeding in early pregnancy. Eur J Obstet Gynecol Reprod Biol 2011;156:120–1. Silva C, Sammel MD, Zhou L, Gracia C, Hummel AC, Barnhart K. Human chorionic gonadotropin profile for women with ectopic pregnancy. Obstet Gynecol 2006;107:605–10. Barnhart K, Sammel MD, Chung K, Zhou L, Hummel A, Guo W. Decline of serum human chorionic gonadotropin and spontaneous complete abortion: defining the normal curve. Obstet Gynecol 2004;104:975–81. Chung K, Sammel M, Zhou L, Hummel A, Guo W, Barnhart K. Defining the curve when initial levels of human chorionic gonadotropin in patients with spontaneous abortions are low. Fertil Steril 2006;85:508–10. Steier JA, Bergsjo P, Myking OL. Human chorionic gonadotropin in maternal plasma after induced abortion, spontaneous abortion, and removed ectopic pregnancy. Obstet Gynecol 1984;64:391–4. Aral K, Gurkan Zorlu C, Gokmen O. Plasma human chorionic gonadotropin levels after induced abortion. Adv Contracept 1996;12:11–4. Condous G, Kirk E, Van Calster B, Van Huffel S, Timmerman D, Bourne T. Failing pregnancies of unknown location: a prospective evaluation of the human chorionic gonadotrophin ratio. BJOG 2006;113:521–7. Montgomery Irvine L, Padwick ML. Case report: serial serum HCG measurements in a patient with an ectopic pregnancy: a case for caution. Hum Reprod 2000;15:1646–7. Seeber BE, Sammel MD, Guo W, Zhou L, Hummel A, Barnhart KT. Application of redefined human chorionic gonadotropin curves for the diagnosis of women at risk for ectopic pregnancy. Fertil Steril 2006;86:454–9. Morse CB, Sammel MD, Shaunik A, Allen-Taylor L, Oberfoell NL, Takacs P, et al. Performance of human chorionic gonadotropin curves in women at risk for ectopic pregnancy: exceptions to the rules. Fertil Steril 2012;97: 101–6. Bjercke S, Tanbo T, Dale PO, Morkid L, Abyholm T. Human chorionic gonadotrophin concentrations in early pregnancy after in-vitro fertilization. Hum Reprod 1999;14:1642–6. Confino E, Demir RH, Friberg J, Gleicher N. The predictive value of hCG beta subunit levels in pregnancies achieved by in vitro fertilization and embryo transfer: an international collaborative study. Fertil Steril 1986;45:526–31. Zhang X, Barnes R, Confino E, Milad M, Puscheck E, Kazer RR. Delay of emobryo transfer to day 5 results in decreased intial serum B-human chorionic gonadotropin levels. Fertil Steril 2003;80:1359–63. Chen CD, Ho HN, Wu MY, Chao KH, Chen SU, Yang YS. Paired human chorionic gonadotrophin determinations for the prediction of pregnancy outcome in assisted reproduction. Hum Reprod 1997;12:2538–41. Alahakoon TI, Crittenden T, Illingworth P. Value of single and paired serum human chorionic gonadotropin measurements in predicting outcome of in vitro fertilisation pregnancy. Aust N Z J Obstet Gynaecol 2004;44:57–61. Shamonki MI, Frattarelli JL, Bergh PA, Scott RT. Logarithmic curves depicting initial level and rise of serum beta human chorionic gonadotropin and live delivery outcomes with in vitro fertilization: an analysis of 6021 pregnancies. Fertil Steril 2009;91:1760–4. Zegers-Hochschild F, Altieri E, Fabres C, Fernandez E, Mackenna A, Orihuela P. Predictive value of human chorionic gonadotrophin in the outcome of early pregnancy after in-vitro fertilization and spontaneous conception. Hum Reprod 1994;9:1550–5. Chung K, Sammel MD, Coutifaris C, Chalian R, Lin K, Castelbaum AJ, et al. Defining the rise of serum HCG in viable pregnancies achieved through use of IVF. Hum Reprod 2006;21:823–8.
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The serial measurement of serum hCG concentrations is an important clinical tool used to differentiate normal from abnormal pregnancies. At hCG values below which ultrasonography can be diagnostic, the comparison of a patient's hCG dynamics to those of established expected curves of rise or fall can aid the clinician in determining when to follow expectantly and when to intervene. Still, this method has some limitations and should never suUse your smartphone persede clinical judgment based on symptoms or signs. (Fertil SterilÒ 2012;98:1074–7. Ó2012 to scan this QR code by American Society for Reproductive Medicine.) and connect to the Key Words: Early pregnancy, ectopic pregnancy, serial hCG measurements Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/seeberbe-serial-hcg-early-pregnancy/
I
n medical school, most of us still learned the old adage that in a normally developing intrauterine pregnancy, the serum human chorionic gonadotropin (hCG) should double every 2 days. We were taught that deviations from this doubling time were thought to be suspect and could indicate an abnormally developing intrauterine pregnancy (IUP) or miscarriage, or an ectopic pregnancy (EP). In the last decade, dozens of publications have delved more deeply into this topic of how hCG really behaves in normally developing, compared to aberrant, pregnancies. What they have shown us is that the picture is much more complicated than it first appeared. It is well accepted that the initial evaluation of a woman with a symptomatic early pregnancy (bleeding and/or pain) includes transvaginal pelvic sonography (TVS) and measure-
ment of the serum hCG concentration. In many cases this is all that is needed to make the diagnosis of an intrauterine pregnancy (viable or nonviable pregnancy) or an ectopic gestation. However, in cases where the hCG value is below the critical threshold of 1500 to 2000 mIU/mL (often called the discrimination level) and ultrasound is not likely to be diagnostic, the pregnancy is of unknown location (PUL) (1, 2). As discussed in a recent consensus statement, PUL is a descriptive term only, not a diagnosis, and women with a PUL need to be followed until a diagnosis can be made (1, 2). This follow-up consists of repeated (serial) hCG values usually measured 48 hours apart until either the trajectory of hCG is diagnostic of a non-viable gestation and intervention may be required, or the hCG discrimination level is reached, a point at which an ultrasound can pro-
Received June 25, 2012; revised September 7, 2012; accepted September 13, 2012; published online September 29, 2012. B.E.S. has nothing to disclose. Reprint requests: Beata E. Seeber, M.D., M.S.C.E., Department of Gynecologic Endocrinology and Reproductive Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria (E-mail: [email protected]). Fertility and Sterility® Vol. 98, No. 5, November 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2012.09.014 1074
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
vide the diagnosis. It is critical to understand that the trajectory of the rise in hCG alone is not diagnostic of a viable pregnancy, and always needs to be followed by an ultrasound to establish the correct diagnosis.
RISING hCG LEVELS The clinical utility of following serial hCG concentrations is based on comparing the dynamics of a patient's hCG concentrations to those of published reports of the behavior of hCG in viable intrauterine pregnancies. Most of the initial studies were performed in small numbers of subjects, many of whom conceived following infertility treatment (3, 4). Thus, the generalizability of these data to the typical symptomatic patient presenting with bleeding and pain was unclear. A small study of only 20 women by Kadar et al. (5) in 1990 was one of the first to evaluate symptomatic women with spontaneously conceived pregnancies and reported that the rise of hCG for a viable IUP needed to be at least 66% in 2 days. Many clinicians adopted these findings to their clinical practice, diagnosing those women with a slower rise in hCG with an abnormal VOL. 98 NO. 5 / NOVEMBER 2012
Fertility and Sterility® pregnancy. What they failed to understand, however, was that the minimal 2-day rise of 66% was actually the lower limit of an 85% confidence interval, meaning that almost 8% of viable intrauterine pregnancies exhibited a slower rate of rise. With the more recent publication of larger cohort studies by Barnhart's group in the mid-2000's, the minimal expected rise of hCG in viable pregnancies became more clear. In a study of 287 subjects who presented with symptomatic early pregnancy, the rise in hCG could be as slow as 53% in 2 days and the pregnancy could still turn out to be viable (6). Adopting a lower limit based on a 99% confidence interval meant that less than 1% of viable pregnancies exhibited an hCG rise even slower than that. While an appropriate rise in hCG is reassuring and predicts that a pregnancy may turn out to be viable on further follow-up, it is in no way diagnostic of an IUP. This is the case because an initial normal rise in hCG does not exclude the possibility of a nonviable pregnancy, especially that of an EP. Horne et al. demonstrated this fact with their study of 340 women who presented with pain and/or bleeding at <12 weeks gestation and had an inconclusive initial ultrasound. Despite a normally rising hCG defined as at least R66% rise over 48 hours in 63 of the women, 10 (16%) of them went on to have an ectopic pregnancy (7). Silva et al. (8) reported in 2006 on the great variability of serial hCG values in women with EP. In their cohort of 200 women with EP, 60% of subjects had an initial rise in hCG over 2 days, with almost 21% having a rise that was at least equal to the minimal rise of 53% for a viable gestation. Thus, despite behaving like an IUP, a pregnancy may still turn out be an ectopic. For this reason it is critical to continue to follow any symptomatic pregnancy closely with serial hCG concentrations, no matter how ‘‘reassuring’’ the rise in hCG may be at first. Such follow-up should continue until a definitive diagnosis can be made, namely with ultrasound once the discriminatory hCG level is reached. In cases where an initially appropriately rising hCG does not rise at least 53% in 2 days on subsequent follow-up, a nonviable pregnancy (miscarriage or ectopic pregnancy) is almost certain. Further evaluation to discriminate between these two entities is then necessary, and a uterine evacuation may be needed. Evacuating the contents of the uterus followed by histologic evaluation for the presence of chorionic villi is the diagnostic test to confirm that intrauterine implantation had occurred.
DECLINING OR PLATEAUING hCG LEVELS What can we say about the opposite situation, when serial hCG levels taken 2 days apart plateau or decline? In such a case, barring the unlikely event of a laboratory error, or rare exceptions like pregnancies complicated by ovarian hyperstimulation syndrome (see below), the pregnancy is for certain nonviable. The key question is: can the rate of hCG decline help in distinguishing between a pregnancy that requires intervention (ectopic pregnancy, non-resolving miscarriage) and one that can be managed expectantly (spontaneously resolving miscarriage or spontaneously resolving ectopic)? A critical piece of information to answer this question was provided by Barnhart et al. (9) in their 2004 publication describing VOL. 98 NO. 5 / NOVEMBER 2012
the normal curve of decline in hCG in spontaneous complete abortion. In this study of 710 women ultimately diagnosed with a miscarriage due to spontaneous decline of hCG to <5 mIU/mL without medical or surgical intervention, the authors found that the rate of hCG decline is quadratic and exhibits a faster decline when the initial hCG value is higher. For example, the 2-day decline for a starting hCG of 5000 should be at minimum 35%, that for a starting hCG of 500, at minimum 24%. In a subsequent publication, this group was able to further demonstrate that when the intial hCG values are as low as 50 mIU/mL, then the subsequent hCG value 2 days later can decline by as little as 12% and still result in a spontaneous complete abortion (10). In both of the studies, the authors report the slowest decline as represented by the 95th percentile confidence intervals, meaning that there will still be individuals whose decline may be even slower. In all, these rates of decline are much slower than those following an induced abortion (11, 12). Table 1 summarizes for clinical use the slowest appropriate decline in hCG (according to initial hCG level) that most likely represents a spontaneously resolving pregnancy not requiring intervention. Condous et al. (13) compared the ratio of serum hCG taken at the time of presentation and a subsequent value measured 48 hours later in women with pregnancy of unknown location, dividing their study cohort into a training and test set. This method of creating two separate study cohorts allows the investigator to validate his or her findings by testing how well the algorithm created with the training set performs on the test set cohort. They calculated that a ratio of <0.87 between these two hCG measurements had a sensitivity and specificity of over 90% in both sub-sets for predicting a failing PUL which will resolve spontaneously. The authors advocate a non-interventional approach in these women unless deterioration in the woman's clinical condition was observed. Applying a similar logic to that previously described for viable pregnancies, as long as a patient's hCG declines at the minimum rate based on her starting hCG, she may be managed expectantly because there is a very good chance that her pregnancy will resolve without the need for intervention. However, it is again critical to understand that an appropriate rate of decline is not diagnostic of a nonviable intrauterine pregnancy because some ectopic pregnancies will exhibit a similar decline in hCG. According to the 2006 publication by Silva et al. (8), 8% of the 200 ectopic
TABLE 1 Expected minimal percentage of decline in serum hCG for nonviable pregnancies. Initial hCG (MIU/mL) 50 150 250 500 1000 2000 2500
% Decline after 2 d
% Decline after 4 d
12 18 21 24 28 31 32
26 39 44 50 55 60 62
Note: Adapted from Barnhart et al., Ob Gyn 2004 (9); and Chung et al., Fertil Steril 2006 (10). Seeber. hCG in early pregnancy. Fertil Steril 2012.
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VIEWS AND REVIEWS pregnancies in their study presented with a fall in hCG values similar to that seen in women with a completed spontaneous abortion. Similarly, Horne et al. reported that of the 214 women who had a fall in hCG of more than 10% on serial measurements, 6 (3%) had an ectopic pregnancy (7). Thus, women with declining hCG levels should be followed regularly and the hormonal declines should be compared to the published expected value, as summarized in Table 1 based on the publications of Barnhart's group (9). Only with consistent and complete follow-up until the hCG level is below 5 mIU/mL can one be certain that the pregnancy has resolved. If the percentage of decline is below that of the expected, then intervention is likely necessary to rule-out an ectopic gestation or to manage a non-resolving miscarriage. It is critical to point out that despite a decline in hCG, a resolving ectopic pregnancy may rupture. There have been cases reported where an ectopic pregnancy has ruptured despite continuously declining hCG values (14). Clearly, clinical monitoring for suspicious symptoms or signs of an ectopic pregnancy should always accompany laboratory monitoring in women with a PUL, even if it appears to be resolving.
a false-negative classification as being a non-viable pregnancy due to a too slow rise of hCG. Based on this, Morse et al. (16) conclude that a third hCG measurement may sometimes be needed to make the correct diagnosis, especially when the initial hCG values are low (around 500 mIU/mL). So, the critical question is, how should a clinician apply the data from these studies to the clinical care of a patient with a PUL? How important are serial hCG values to making a diagnosis and to choosing the correct management? The abbreviated answer is that serial hCG values are essential, but should never be used alone to diagnose a woman. Quoting Morse et al. (16), ‘‘.they should be used in combination with clinical judgment evaluation of symptoms, and repeat ultrasound (as needed).’’ There will always be exceptions to the rules, in this case, pregnancies in which the hCG follows a trajectory outside of the 99.9 confidence interval of ‘‘expected.’’ The practice of comparing a given patient's change in hCG to what would be expected has made the diagnostic process more logical and timely. But, ultimately, clinical judgment should always prevail over laboratory values and no patient should be treated based on hCG values alone.
ACCURACY OF DIAGNOSIS WHEN USING SERIAL hCG LEVELS
HCG MEASUREMENTS IN PREGNANCIES FOLLOWING IN VITRO FERTILIZATION (IVF)
The validity and accuracy of these recently redefined curves for IUP and resolving SAB, as published by Barnhart's group (6, 9), were confirmed in two subsequent publications. Applying the published curves for IUP and SAB, with their respective wide and liberal confidence intervals, to a cohort of 1,249 women with pregnancies of unknown location led to accurate and timely diagnosis (15). In fact, the authors report an improvement in the diagnosis of EP by about 2.5 days by using these rules. Still, not all EP could be diagnosed by aberrant behavior of hCG in serial evaluations, reiterating again that laboratory monitoring cannot replace clinical evaluation and judgment. In addition, the authors caution that in order to minimize the risk of interrupting a potentially viable gestation, an even more conservative rule than the rise of 53% over 2 days should be followed. This is the case because, according to the data from this study, a small number of pregnancies that end up viable may have a rise in hCG as slow as 35% over 2 days. In a subsequent multi-center study published in 2012, Morse et al. (16) applied the redefined curves to an ethnically and geographically diverse population of over 1,000 women. They used the very conservative rise of only 35% over 2 days for an IUP, representing the 99.9% confidence interval from the previous study (6), and a relatively sharp decline during 2 days, representing 90% of women with a miscarriage, to set the bounds of normal hCG behavior. They chose these curves as a balance of not of interrupting a viable IUP and not misclassifying an EP as a miscarriage. Still, despite the adoption of these conservative parameters to the analysis of the changes in serial hCG, the authors report that 30 EPs in this series would have been misclassified. Twenty-four of these 30 EPs would have been misclassified as potential IUPs because of an hCG that changed appropriately between the two time points measured. Conversely, 20 cases of IUPs would have received
Can the curves of expected hCG dynamics be applied to pregnancies conceived following IVF? Studies examining the predictive value of a single post-IVF hCG determination have shown that the values are higher for pregnancies that go on to be viable than for those that end in a pregnancy loss (17, 18). Additional studies have shown that hCG concentrations determined 13 and 15 days after fertilization are higher in pregnancies resulting from cleavage-stage day 3 embryos than those achieved through the transfer of blastocysts on day 5. Nonetheless, the percentage increase in serial measurements of hCG did not differ between these groups (19). Certainly, no distinction can be made between miscarriages and ectopic pregnancies with one single measurement. Chen et al. evaluated paired hCG levels on day 15 and 22 postembryo transfer (no details were given as to day of transfer) to test whether the ratio of these values was a better predictor of pregnancy outcome than hCG doubling time following IVF. They concluded that the best diagnostic accuracy was obtained by a combination of both hCG on day 15 R 150 mIU/mL and an hCG day 22/hCG day 15 ratio of R15 with a specificity of 94% and sensitivity of 47% for normal pregnancy. Conversely, when the hCG on day 15 was below 150 mIU/mL and the ratio of hCG on day 22/hCG on day 15 was below 15, there was an 84% chance of an abnormal pregnancy (20). A subsequent study of 143 women found that when an initial hCG concentration following IVF is less than 50% of the 5th percentile, then that pregnancy is certainly nonviable. (21) However, single measurements of hCG, even if low and suspicious for a non-viable pregnancy, cannot distinguish between non-viable intrauterine and ectopic gestations. Analyzing data from 6021 IVF pregnancies, Shamonki et al. (22) created logarithmic curves predicting live delivery rates given initial levels and percent 2-day rise of hCG after IVF. Consistent with previous publications, these authors
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Fertility and Sterility® showed that the higher the percentage of rise in hCG drawn 2 days following the initial value (days 14 and 16 following oocyte retrieval), the better the live delivery rate. These studies are important in that they establish the prognostic value of hCG for a successful pregnancy outcome following IVF. When compared to spontaneous conception cycles, the average doubling time of hCG following IVF-embryo transfer in viable pregnancies appears to be the same (1.4 0.3 versus 1.6 0.4 days, NS) (23). One recent study from 2006 described the profile of hCG in a large cohort of nearly 400 pregnancies conceived following IVF that resulted in a live birth (24). Within the hCG range, with its corresponding gestational age, at which ultrasound is non-diagnostic, hCG was shown to exhibit a log linear pattern of rise, comparable to that seen for spontaneously conceived intrauterine pregnancies. On average, hCG rose 50% in 1 day and 124% in 2 days, with documented extremes of as little as a 14% or 30% rise over 1 or 2 days, respectively, still resulting in a live birth. Of course, as described in detail above for the case of spontaneously conceived pregnancies, an initially normally rising hCG does not exclude the possibility of a nonviable gestation, including ectopic pregnancy. Thus, serial measurements of hCG followed by ultrasonography are just critical to establishing the definitive diagnosis in post-IVF as they are for spontaneously conceived pregnancies. Caution should be taken in interpreting hCG values in IVFconceived pregnancies complicated by ovarian hyperstimulation syndrome (OHSS), especially at low hCG values. Due to extra-vascular fluid shifts, and hemoconcentration followed post-hydration hemodilution, serum hCG values may be inaccurate. We have clinically observed multiple patients whose hCG values appeared to initially plateau, only to follow an expected trajectory once hemodynamic stability was established.
3.
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5. 6.
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12. 13.
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SERIAL hCG VALUES IN MULTIPLE GESTATIONS Several studies have shown that rates of rise of hCG are similar in multiple compared to singleton gestations, with only higher absolute values seen in higher fetal number gestations. Following IVF, 48 single pregnancies were compared to 50 multiple pregnancies with comparable hCG doubling times reported (23). Chung et al. evaluated 135 twin and 32 triplet pregnancies following IVF and likewise found that baseline hCG concentrations were higher for the multiple pregnancies than for the 224 singletons. But, the rate of rise in hCG was similar for both groups (24). Heterotopic pregnancies are a very rare form multiple gestation that are nonetheless more likely to occur after IVF than spontaneously. These pregnancies are inherently difficult to diagnose and no data has been published regarding the observed or expected behavior of hCG in these unusual cases.
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