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Obstetrics & Gynecology:
doi: 10.1097/AOG.0b013e3181945a4f
Original Research

Earlier Diagnosis and Serum Human Chorionic Gonadotropin Regression in Complete Hydatidiform Moles

Kerkmeijer, Linda G. W. MD1,2; Massuger, Leon F. A. G. MD, PhD2; ten Kate-Booij, Marianne J. MD, PhD3,4; Sweep, Fred C. G. J. PhD1; Thomas, Chris M. G. PhD1,2,4

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Author Information

From the Departments of 1Chemical Endocrinology and 2Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen; the 3Department of Obstetrics and Gynaecology, Amphia Medical Centre, Breda; and the 4Dutch Working Party on Trophoblastic Tumours, Utrecht, the Netherlands.

Corresponding author: Chris M. G. Thomas, PhD, Department of Chemical Endocrinology, 479, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands; e-mail: C.Thomas@ace.umcn.nl.

Financial Disclosure The authors did not report any potential conflicts of interest.

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Abstract

OBJECTIVE: To estimate serum human chorionic gonadotropin (hCG) regression in uneventful complete hydatidiform moles before and after the introduction of routine first-trimester ultrasonography.

METHODS: Gestational age, maternal age, preevacuation hCG concentrations, serum hCG regression, and hCG disappearance time among a recent group of 137 women with uneventful complete hydatidiform moles that were found between 1994 and 2006 were evaluated retrospectively and compared with a historical cohort of 106 patients with complete moles that were found between 1977 and 1989.

RESULTS: Gestational age, preevacuation hCG concentration, and hCG disappearance time were significantly lower in the recent complete hydatidiform mole cohort compared with the historic series. Ninety-nine percent of the recent cohort achieved hCG normalization within 19 weeks after uterine evacuation compared with 25 weeks in the historic group.

CONCLUSION: Earlier serum hCG regression in the recent cohort of complete hydatidiform moles probably is a result of widely used first-trimester ultrasonography leading to detection and evacuation of complete moles at younger gestational ages, resulting in lower hCG levels at time of evacuation.

LEVEL OF EVIDENCE: II

Hydatidiform moles have been diagnosed at younger gestational ages in the past 10 years owing to the widespread use of routine first-trimester ultrasound detection and ultrasound investigation of threatened miscarriage.1,2 Historically, hydatidiform moles presented in the second trimester of pregnancy, typically with symptoms of vaginal blood loss and increased uterine volume accompanied by theca lutein cysts and hyperemesis due to excessive human chorionic gonadotropin (hCG) levels in the blood. Seldom, patients were asymptomatic at time of presentation.3 Nowadays, high numbers of complete hydatidiform mole patients are diagnosed coincidentally at routine first-trimester ultrasound examination without any classical symptoms. Typical ultrasonographic features, such as a combination of hypo- and hyperechogenic areas, are also less clearly present in recent years. Partial moles are more difficult to diagnose ultrasonographically.2,4

Human chorionic gonadotropin, produced by the trophoblast, is a measure for trophoblastic activity. Therefore, hCG follow-up after evacuation of a hydatidiform mole is essential for all patients to detect those requiring further treatment. The frequency of preevacuation hCG levels of 100,000 international units/L or more is higher in diploid (complete) than in triploid (partial) moles.5 Moreover, the β-hCG is synthesized more abundantly in complete hydatidiform mole than in partial mole. The cause of this difference remains to be elucidated.6,7

According to the criteria of the International Federation of Gynecology and Obstetrics (FIGO), persistent trophoblastic disease is defined as 1) a plateau in serum hCG plus or minus 10% of the baseline for 3 consecutive weeks, 2) an increase in serum hCG level greater than 10% from the baseline for 2 weeks, or 3) persistence of detectable hCG levels for more than 6 months after evacuation.8 In the majority of hydatidiform mole patients, remaining trophoblastic tissue resolves spontaneously after uterine evacuation. Persistent trophoblastic disease (PTD) occurs in approximately 15% of all complete molar pregnancies.9

A report from The Netherlands, published in 1993, shows that 95% of complete hydatidiform mole patients achieved hCG normalization by 25 weeks after uterine evacuation of the molar tissue.10 First-trimester ultrasonography increasingly became part of basic Dutch prenatal care in the early 1990s to affirm gestational age.11 With diagnosis of complete hydatidiform mole at younger gestational ages, spontaneous serum hCG regression after evacuation may have changed, resulting in earlier normalization of serum hCG levels. The aim of the present study is to estimate serum hCG regression in uneventful complete hydatidiform mole before and after the introduction of routine ultrasonography in the first trimester of pregnancy.

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MATERIALS AND METHODS

The Dutch Central Registry of Hydatidiform Mole was established at the Radboud University Nijmegen Medical Centre in 1977. This registry serves mainly as an epidemiological database and provides advice and a national hCG assay service to local gynecologists. From 1977 through 1989 and from 1994 through 2006, respectively, 907 and 1,647 patients were registered at the Dutch Central Registry for Hydatidiform Mole. Routine first-trimester ultrasonography was introduced gradually in the early 1990s. To make a clear-cut differentiation between patients diagnosed in the years before and after the introduction of routine first-trimester ultrasonography, patients diagnosed between 1990 and 1994 were not included for further analysis. The following exclusion criteria were applied: histological diagnosis other than complete mole, PTD, recurrence of trophoblastic disease after normalization of hCG levels, hysterectomy after hydatidiform mole, and patients for whom fewer than three hCG measurements were performed at the Central Registry Laboratory. Persistent trophoblastic disease was defined as static or rising hCG levels for 2 weeks. The Dutch Society of Gynaecology and Obstetrics added an extra criterion to the criteria for PTD—at least one hCG level exceeding the normogram for hCG regression described by Yedema et al.10,12 One hundred six patients with uneventful complete hydatidiform mole who were registered from 1977 through 1989 fulfilled the inclusion criteria (historic cohort). One hundred thirty-seven patients with complete mole with uneventful hCG regression, all registered from 1994 through 2006, were eligible for analysis (recent cohort). Patients with a brief, temporary plateau or rise in the hCG regression curve beneath the 95th percentile line of the normal regression curve also were included, provided that they had not received chemotherapy and had not undergone hysterectomy or second curettage. Histopathologic criteria for the diagnosis of complete hydatidiform mole have been described recently.13 In case of doubt, the histopathological diagnosis was reviewed centrally by a specialized pathologist, including flow cytometric analysis or immunohistochemistry (p57 Kip). Gestational age, maternal age, preevacuation hCG, and hCG disappearance times among the recent cohort of patients with complete mole were compared with those among the historic cohort. The study has been carried out in The Netherlands in accordance with the applicable rules concerning the review of research, ethics committees, and informed consent.

Serum hCG was measured weekly until normal levels were obtained and then monthly for 6 months. All serum hCG measurements were performed by means of a sensitive and specific radioimmunoassay, developed at the Central Registry Laboratory, using a polyclonal antiserum that measures both intact hCG and free β-subunits (total hCG), as described previously.14 From here on, total hCG will be referred to as hCG. The assay has been calibrated against the Third International Standard for human Chorionic Gonadotropin for Immunoassay (World Health Organization, 75/537). The measuring range for the standard line of the assay was 1 to 80 ng/mL (0.027 to 2.14 nmol/L, equivalent to 9.29 to 743 international units/L). The hCG radioimmunoassay has a cross-reactivity of 100% on a mol/mol basis with intact hCG and 1,000% with β-hCG. All test results were expressed in ng/mL. The analytical sensitivity of the assay is 1.0 ng/mL. The cutoff value for normal hCG levels was established at 2.0 ng/mL, representing the cutoff serum concentration for normal levels at 95% specificity as found in postmenopausal women and hypergonadotropic men. The within-assay and between-assay coefficients of variation for means of duplicate measurements were at a level of 10 micrograms/L (equivalent to 0.267 nmol/L or 93 international units/L), 7.5% and 10.3%, respectively, and at a level of 56 micrograms/L (equivalent to 1.50 nmol/L or 520 international units/L), 7.3% and 12%.

For patients whose hCG titers fell progressively to undetectable levels, 95th, 50th, and 5th percentile lines of hCG regression were developed from serial weekly hCG levels sorted by week after evacuation (cross-sectional). Subsequently, a curve-fitting algorithm for exponential decay was used. Statistical analyses were performed using the SPSS 14.0 statistical software package for Windows (SPSS Inc, Chicago, IL). Human chorionic gonadotropin disappearance time is defined as the time from uterine evacuation until the time of the first normal hCG level. Normality of distributions was explored by use of the Kolmogorov-Smirnov test and frequency-distribution histograms. Differences in parametrical data were calculated by two-tailed Student t test. Nonparametric data were assessed by two-tailed Mann-Whitney U test. Frequency distributions were compared by Pearson's χ2 test and, in case of expected counts less than 5, by Fisher exact test. Longitudinal analysis of hCG regression curves was performed by repeatedmeasures analysis of variance. P values of less than .05 were considered statistically significant.

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RESULTS

From 1994 to 2006, 137 patients diagnosed with complete hydatidiform mole fulfilled the aforementioned inclusion criteria. For those patients, a total number of 1,402 hCG measurements was known. For the historic cohort of complete mole patients (n=106), 1,097 hCG concentrations were known. The preevacuation serum hCG levels in patients of the recent cohort were lower than in the historical cohort (median 4,100 ng/mL compared with 8,600 ng/mL, P=.001), as shown in Table 1. Patients with complete hydatidiform mole among the recent cohort had a significantly higher mean maternal age than did those with complete moles in the historic cohort (mean 29.9 compared with 28.3 years, P<.001). The percentage of patients with maternal ages below 20 years of age was not significantly different (3% in the recent group compared with 5% in the historic group); for patients older than 40 years, no statistically significant difference was observed (4% in the recent group compared with 5% in the historic cohort). Gestational ages were lower in the recent cohort of patients with complete mole when compared with the historical cohort (mean 11.7 compared with 13.8 weeks, P<.001). Significantly more patients underwent uterine evacuation within 14 weeks of gestation in the recent group than in the historical cohort of patients with complete hydatidiform mole (82% compared with 59%, P<.001). Human chorionic gonadotropin disappearance times were lower in the recent cohort (median 7.4 compared with 10.0 weeks, P<.001) than in the historic cohort.

Table 1
Table 1
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After evacuation of the molar tissue, 95% of all patients with complete mole in the recent series achieved hCG disappearance within 14 weeks; 95% of the historic cohort attained normal levels at 16 weeks after evacuation (Table 2). Ninety-nine percent of all patients with complete hydatidiform mole in the recent and historic cohorts attained hCG normalization within 19 and 25 weeks, respectively.

Table 2
Table 2
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Figure 1 shows the 5th, 50th, and 95th percentile lines for normal regression of hCG levels after molar evacuation in the recent and historic cohorts. The three dashed lines correspond to the 5th, 50th, and 95th percentiles of uneventful regression of the recent group of patients with complete moles; the three continuous lines represent the percentile lines of the historic cohort. The horizontal broken line represents the cutoff serum concentration of hCG (2.0 ng/mL).

Fig. 1
Fig. 1
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Linear regression repeated measures analysis revealed that, for patients with complete serial consecutive hCG levels until week 9 after evacuation (n=31 for the recent cohort, n=50 for the historic cohort), between-subject effects were significantly different (P=.003). When comparing hCG levels per week after evacuation, regression of serum hCG in the recent group has shifted to the left because serum hCG levels among the recent group were significantly lower than in the historic series (Table 3).

Table 3
Table 3
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DISCUSSION

The aim of the present study was to estimate serum hCG regression in uneventful complete hydatidiform mole in The Netherlands before and after the introduction of routine first-trimester ultrasonography. Serum hCG disappearance advanced when comparing regression curves of patients with complete mole before and after the introduction of routine first-trimester ultrasonography, which coincided with lower preevacuation hCG levels in the latter series. Ninety-nine percent of the recent cohort of patients with complete mole achieved hCG normalization within 19 weeks after uterine evacuation compared with 25 weeks in the historic group. As expected, gestational age at time of evacuation was significantly lower in the recent cohort of complete hydatidiform mole than in the historic group, and more patients underwent uterine evacuation within 14 weeks of conception. Because of the retrospective nature of the present study, hCG measurements on a weekly basis were not available for all patients. Ideally, a prospective cohort survey would have been performed, with hCG measurement at the Radboud University Nijmegen Medical Centre laboratory for all individual patients in all subsequent weeks, including a preevacuation hCG level. However, this was not feasible owing to the low incidence of complete hydatidiform mole. Uniformity in ultrasonographic diagnosis of complete mole might be distorted by interobserver variation because ultrasound examinations were performed in different hospitals (both academic and regional hospitals). Uniformity in hCG measurement, however, was achieved by hCG measurement at one central laboratory because absolute hCG levels measured by use of different assays are not comparable owing to differences in assay sensitivity and specificity. Complete hydatidiform moles terminated during the first trimester of pregnancy histologically resemble late partial moles, and early partial moles resemble hydropic abortion. It is not unlikely that misclassification occurred more often as a result of evacuation in the first trimester of pregnancy when compared with the moles evacuated later in pregnancy.13,15

The increase over time in maternal age observed in patients with complete mole is in line with the rise in maternal age in the general pregnant population. In the Dutch population, the mean maternal age at time of birth of the first child was 25.6 years in 1980, which increased to 29.4 years in 2006.16 The decrease in gestational age at time of evacuation of complete mole in recent years also has been reported by other authors.1

In 1993, Yedema et al reported on hCG normalization within 25 weeks after uterine evacuation in 95% of Dutch patients with complete hydatidiform mole.10 A normogram for serum hCG regression was developed from the 95th percentile line of hCG regression among 129 patients with uneventful complete hydatidiform mole. Until now, exceeding the serum hCG normogram is used as an additional criterion for diagnosis of PTD in The Netherlands.12 Recurrence of trophoblastic disease after spontaneous normalization of serum hCG levels occurred rarely.17

Ultrasonography has been a widely accepted, reliable method for the diagnosis of complete hydatidiform mole for several decades.18 The clinical presentation in uneventful complete moles has changed in the past 30 years, most likely owing to ultrasound detection at younger gestational ages by the widespread use of routine first-trimester ultrasonography and ultrasound investigation of vaginal blood loss in threatened miscarriage.1,2,4 Consequently, lower gestational age at time of evacuation caused lower preevacuation hCG levels and therefore shortened hCG disappearance times when compared with the historical cohort. Also, improved technology and increased experience in complete mole detection by early ultrasound examination might have contributed to this decrease in gestational age. Aside from the effect of younger gestational age at time of evacuation, other factors might have contributed to the reduction in hCG disappearance time after uneventful complete mole evacuation. For instance, it seems reasonable to assume that uterine curettage has become more complete in terms of evacuating trophoblastic tissue in recent years owing to the increased use of ultrasound-guided curettage. Nevertheless, earlier evacuation of complete hydatidiform mole did not result in a significant decrease in the incidence of PTD.1

In case this trend of earlier hCG disappearance in recent years also is observed in larger cohorts, the third FIGO criterion (ie, persistence of detectable hCG levels for more than 6 months after evacuation) might be outdated. However, the present findings alone do not justify modification of the third FIGO criterion because the number of patients diagnosed with PTD by this criterion is unknown. Presumably, this number is limited because no more than 10% of 86 patients with PTD were identified by the FIGO 2000 criteria more than 11 weeks after evacuation.19 Furthermore, the clinical relevance of diagnosis of PTD several weeks earlier remains to be investigated.

In conclusion, serum hCG disappearance occurred significantly earlier in the recent cohort than in the historic cohort of patients with complete hydatidiform mole. This is most probably a result of widely used first-trimester ultrasonography leading to earlier diagnosis and evacuation of complete hydatidiform mole, resulting in lower hCG levels at time of evacuation.

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REFERENCES

1. Soto-Wright V, Bernstein M, Goldstein DP, Berkowitz RS. The changing clinical presentation of complete molar pregnancy. Obstet Gynecol 1995;86:775–9.

2. Jauniaux E, Nicolaides KH. Early ultrasound diagnosis and follow-up of molar pregnancies. Ultrasound Obstet Gynecol 1997;9:17–21.

3. Curry SL, Hammond CB, Tyrey L, Creasman W, Parker RT. Hydatidiform mole: diagnosis, management and long-term follow-up of 347 patients. Obstet Gynecol 1975;45:1–8.

4. Mangili G, Garavaglia E, Cavoretto P, Gentile C, Scarfone G, Rabaiotti E. Clinical presentation of hydatidiform mole in northern Italy: has it changed in the last 20 years? Am J Obstet Gynecol 2008;198:302.e1–4.

5. Niemann I, Petersen LK, Hansen ES, Sunde L. Differences in current clinical features of diploid and triploid hydatidiform mole. BJOG 2007;114:1273–7.

6. Berkowitz R, Ozturk M, Goldstein D, Bernstein M, Hill L, Wands JR. Human chorionic gonadotropin and free subunits' serum levels in patients with partial and complete hydatidiform moles. Obstet Gynecol 1989;74:212–6.

7. Van Trommel NE, Sweep FC, Schijf CP, Massuger LF, Thomas CM. Diagnosis of hydatidiform mole and persistent trophoblastic disease: diagnostic accuracy of total human chorionic gonadotropin (hCG), free hCG {alpha}- and {beta}-subunits, and their ratios. Eur J Endocrinol 2005;153:565–75.

8. FIGO Oncology Committee. FIGO staging for gestational trophoblastic neoplasia 2000. FIGO Oncology Committee. Int J Gynecol Obstet 2002;77:285–7.

9. Wolfberg AJ, Feltmate C, Goldstein DP, Berkowitz RS, Lieberman E. Low risk of relapse after achieving undetectable hCG levels in women with complete molar pregnancy. Obstet Gynecol 2004;104:551–4.

10. Yedema KA, Verheijen RH, Kenemans P, Schijf CP, Borm GF, Segers MF, et al. Identification of patients with persistent trophoblastic disease by means of a normal human chorionic gonadotropin regression curve. Am J Obstet Gynecol 1993;168:787–92.

11. Dutch Society for Obstetrics and Gynaecology. Richtlijn Basis Prenatale Zorg 1.0 (Guideline basic prenatal care). Available at: http:/www.nvog.nl. Retrieved September 1, 2008.

12. Dutch Society for Obstetrics and Gynaecology. Richtlijn Molazwangerschap 1.2. (Guideline hydatidiform mole). Available at: http://www.nvog.nl. Retrieved September 1, 2008.

13. Sebire NJ, Makrydimas G, Agnantis NJ, Zagorianakou N, Rees H, Fisher RA. Updated diagnostic criteria for partial and complete hydatidiform moles in early pregnancy. Anticancer Res 2003;23:1723–8.

14. Thomas CM, Segers MF, Houx PC. Comparison of the analytical characteristics and clinical usefulness in tumour monitoring of fifteen hCG(-beta) immunoassay kits. Ann Clin Biochem 1985;22:236–46.

15. Mosher R, Goldstein DP, Berkowitz R, Bernstein M, Genest DR. Complete hydatidiform mole. Comparison of clinicopathologic features, current and past. J Reprod Med 1998;43:21–7.

16. Central Bureau for Statistics, Vruchtbaarheid in de 20e eeuw (Fertility in the 20th Century). Available at: http://www.cbs.nl. Retrieved September 1, 2008.

17. Kerkmeijer LG, Wielsma S, Massuger LF, Sweep FC, Thomas CM. Recurrent gestational trophoblastic disease after hCG normalization following hydatidiform mole in The Netherlands. Gynecol Oncol 2007;106:142–6.

18. Leopold GR. Diagnostic ultrasound in the detection of molar pregnancy. Radiology 1971;98:171–6.

19. Van Trommel NE, Ngo Duc H, Massuger LF, Schijf CP, Sweep CG, Thomas CM, et al. Early identification of persistent trophoblastic disease with serum hCG concentration ratios. Int J Gynecol Cancer 2008;18:318–23.

© 2009 by The American College of Obstetricians and Gynecologists.

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