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CME Practice CMAJ Cases Persistent mild increase of human chorionic gonadotropin levels in a 31-year-old woman after spontaneous abortion Jianing Chen, Sheri-Lee Samson MD, James Bentley MD, Yu Chen MD PhD Competing interests: None 31-year-old woman (gravida 2, para 1, of the patient’s uterus by hysteroscopy three declared. abortus 1), who had been attempting months after the spontaneous abortion showed a This article has been peer A pregnancy, underwent ultrasonography normal endometrial cavity with no evidence of reviewed. in the first trimester; results were suspicious for retained tissue. Results of endometrial biopsy The authors have obtained molar pregnancy, showing echogenic and lobu- were negative. Other investigations looking for patient consent. lated tissue inside an intrauterine gestational metastatic disease, including chest radiography, Correspondence to: sac. A few days later, she presented with an pelvic magnetic resonance imaging (MRI), and Yu Chen, yu.chen@ apparent spontaneous abortion, passing blood computed tomography (CT) of the chest, abdo- horizonNB.ca and tissue. Repeat ultrasonography showed that men and pelvis, all yielded negative results. CMAJ 2016. DOI:10.1503 the abnormal-appearing sac had been passed, The medical biochemistry service was con- /cmaj.151481 and there was a small amount of echogenic sulted for further investigations and to rule out the debris remaining, consistent with blood. The possibility of laboratory analytical error or assay adnexa were normal. interference. The patient’s serum was diluted at The gynecology service was consulted given ratios of 1:20 and 1:40 for an immunoassay inter- that initial ultrasonography was suspicious for ference study, which showed a linear response molar pregnancy. Because no tissue had been and about 90% recovery on hCG value. Serum obtained for pathology, serum human chorionic treated with a heterophilic blocking tube gener- gonadotropin (hCG) levels were monitored ated the same value as a neat specimen of weekly. The patient’s serum hCG levels ini- 103 IU/L. A urine qualitative strip test for preg- tially dropped from 10 000 to 23 IU/L within nancy was positive. Serum was sent to reference the first month; however, the level increased laboratories to test for hyperglycosylated hCG, and plateaued at about 100 IU/L two months which was undetectable (< 5.5 IU/L, the detection later (Figure 1). limit of the assay), and free β-hCG, which was The gynecologic oncology service was con- low at 3.6 IU/L. Serum luteinizing hormone and sulted because of the persistent low-level increase follicle-stimulating hormone levels were normal in serum hCG levels. The possibility of persistent at 4.1 and 6.4 IU/L, respectively. These results gestational trophoblastic disease was considered. indicated that the observed increase of hCG levels Repeat ultrasonography was normal. Inspection were true values, supporting a diagnosis of quiescent gestational trophoblastic disease. Key points The patient’s serum level of hCG was fol- lowed weekly; by two weeks, the level started • Pregnancy, ectopic pregnancy, retained products of conception, false- positive human chorionic gonadotropin (hCG) test results, pituitary to drop and returned to normal in one month. production of hCG, gestational trophoblastic disease and Her serum hCG level remained below the assay nontrophoblastic cancer are all possible causes of increases in serum detection limit (1 IU/L) for the next six months hCG levels. until she had another normal pregnancy, which • A false-positive result of serum hCG, if undetected, may lead to was conceived about 10 months after the initial unnecessary chemotherapy or hysterectomy. spontaneous abortion. • Quiescent gestational trophoblastic disease is a benign condition characterized by a low-level increase of serum hCG, undetectable Discussion hyperglycosylated hCG and low free β-hCG. • Levels of hCG should be monitored in patients with quiescent gestational trophoblastic disease; in most cases, the levels will gradually Clinicians should consider several diagnoses decrease to normal. when faced with the persistent presence of low- level serum hCG, as described in this case E504 CMAJ, December 6, 2016, 188(17–18) © 2016 Joule Inc. or its licensors Practice (Box 1).1–6 These include new pregnancy, retained bridge the capture antibody and the tracer anti- products of conception, a false-positive hCG body in the immunometric reaction of the hCG result, pituitary or menopausal hCG, non- assay, and lead to a false-positive result.7 trophoblastic cancer and gestational trophoblas- A 10-year report of the USA hCG Reference tic disease. Service identified 83 of 565 recorded consult- Our patient was diagnosed with quiescent ing cases to be false positives.2 In 62 of these gestational trophoblastic disease, a disease 83 cases, patients underwent unnecessary che- entity identified in 2001–2003, which is charac- motherapy or hysterectomy, which led to law- terized by persistent low-level hCG elevation suits.2 The American College of Obstetricians and usually has a benign prognosis.4–6 and Gynecologists recommends three procedures to rule out the presence of heterophilic Differential diagnosis of low-level hCG antibodies or other interfering substances:1 elevation 1. A urine test (either quantitative or qualitative). Interference is confirmed if the urine New pregnancy pregnancy test is negative and the serum hCG Serum hCG is the most sensitive marker for value is at least 50 IU/L. pregnancy. If a patient has actively been trying 2. Serial dilutions to check for linearity and to get pregnant, the presence of low-level recovery. Lack of linearity and recovery con- serum hCG could be consistent with a new via- firms interference because the interfering anti- ble pregnancy, an ectopic pregnancy or a recur- body or substance usually presents a different rent molar pregnancy. However, in the case of dynamic reaction to reagent antibodies com- our patient, the serum hCG pattern did not sup- pared with the analyte in an immunoassay. port a new viable pregnancy. Her sexual history 3. Pretreatment of serum to remove hetero- did not support a new conception, and thus philic antibodies (e.g., with a heterophilic pregnancy was thought to be an unlikely cause blocking tube). If the result becomes nega- of her rise in serum hCG levels. tive after removal of the heterophilic antibody, interference is present. Retained products of conception We performed these procedures and con- Retained products of conception can cause mild cluded that there was neither evidence of assay persistent hCG, but the levels should not interference nor any other laboratory error in this increase as seen with our patient (from 23 to case. Additionally, the serum can be tested with about 100 IU/L). Persistent heterotopic preg- a different commercial hCG immunoassay to see nancy is rare but should be considered (Box 1). if this results in a substantially discrepant level. In the case of our patient, repeat ultrasonography, endometrial biopsy and hysteroscopy were Pituitary or menopausal hCG all negative for retained products of conception. Pituitary hCG is produced in the anterior pituitary gland, along with luteinizing hormone and Phantom hCG False-positive serum hCG, so-called phantom hCG, due to heterophilic antibody interference on 100 000 the hCG immunoassay, is another possible cause of low-level increase in serum hCG level. Hetero- 10 000 philic antibodies are human antibodies that have the capability to bind to other species’ immuno- 1000 globulins; among them, the most important ones 100 noted in laboratory and clinical medicine, are human anti-animal antibodies and human anti- hCG, IU/L 10 mouse antibodies. Most heterophilic antibodies 1 are common, naturally occurring antibodies with low affinities. However, human anti-animal anti- 0 bodies and human anti-mouse antibodies are high- –4 –2 02468 affinity and high-specificity antibodies, which are Time, mo encountered in individuals who have had prior sensitization to an animal species, through occu- pational animal exposure, animal products in diet Figure 1: Serum human chorionic gonadotropin (hCG) levels of a 31-year-old woman after spontaneous abortion of a possible molar pregnancy. Month 0 or therapeutic intervention. These two antibodies indicates when she was referred to the gynecology service and medical bio- may bind to reagent antibodies used in the immu- chemistry was consulted. Values from months 1 to 6 were below the assay noassay (e.g., mouse monoclonal antibody) to detection limit (1 IU/L). CMAJ, December 6, 2016, 188(17–18) E505 Practice follicle-stimulating hormone, when production ease (e.g., partial and complete moles of gesta- of gonadotropin-releasing hormone becomes tional trophoblastic disease have an average unrestricted owing to the absence of sex steroid hCG serum level of 49 000 and up to feedback to the hypothalamus. Pituitary hCG 100 000 IU/L, respectively).4 Choriocarcinomas usually increases mildly (≤ 39 IU/L) along with may have even higher levels of hCG production rising follicle-stimulating hormone (> 30 IU/L) (e.g., > 600 000 IU/L).4 during the peri- and postmenopausal period.2,3 When gestational trophoblastic disease is Because our patient was 31 years of age, without present, the secretion of β subunits of hCG premature ovarian failure and with normal folli- increases. Moreover, invasive cytotrophoblast cle-stimulating hormone and luteinizing hor- cells secrete hyperglycosylated hCG. Studies mone levels, we

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