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Psychologic Impact of Follow-up After LowRisk Gestational Trophoblastic Disease Christine A. R. Lok, M.D., Ph.D., Mariëlle Donker, M.D., Mart M. Calff, Leon F. A. G. Massuger, M.D., Ph.D., and Anca C. Ansink, M.D., Ph.D.
OBJECTIVE: To discuss the length of follow-up of pahCG measurement, compared to 51% during weekly tients with molar pregnancy and spontaneous normalmeasurements. The majority of women (80%) completed ization of the human chorionic gonadotropin (hCG) level, the follow-up and confirmed that they would come for in consideration of the low weekly and monthly hCG incidence of recurrent dismeasurements if it would be ease. The aim of this study [F]ollow-up after low-risk GTD optional. was to investigate the psyCONCLUSION: Follow-up has psychological consequences after low-risk GTD has psychologic consequences of hCG measurements in paconsequences but but provides reassurance as well, chologic tients with low-risk gestaprovides reassurance as well. particularly if sufficient tional trophoblastic disease Therefore, women tend to ac(GTD) during follow-up. psychosocial support is provided. cept the offered surveillance STUDY DESIGN: Patients and refrain from pregnancy. registered in the Dutch CenWomen with GTD should be tral Registry of Hydatidicounseled about the minor form Mole between January 2006 and December 2007 risk of recurrence and the consequences of follow-up. (J were eligible for this study. Patients received a questionReprod Med 2011;56:0000–0000) naire containing questions about follow-up and anxiety and stress during this period. Keywords: follow up, GTD, hydatidiform mole, paRESULTS: Seventy-six patients were eligible for the tient preference, psychologic impact. study. An inverted correlation (r = −0.35, p = 0.003) was found between the age of patients and the level of anxiety. Over the last 15 years, the benefits of follow-up in Anxious patients scored higher for fear of recurrence certain malignancies have become a matter of de(r = 0.49, p < 0.0001), of infertility (r = 0.40, p = 0.001) bate. There are four aims that are considered to be and of conceiving again (r = 0.30, p = 0.01). They experigood reasons to carry out follow-up surveillance: enced the measurements as a burden (r = 0.35, p = 0.003). (1) early detection of residual or recurrent disease, Fewer patients (24%) were insecure before the monthly (2) detection of late physical and psychologic side From the Departments of Obstetrics and Gynecology and of Medical Psychology, Academic Medical Center, Amsterdam; the Department of Obstetrics and Gynecology, University Medical Center St. Radboud, Nijmegen; and the Comprehensive Cancer Center Rotterdam, Rotterdam, the Netherlands. Address correspondence to: Christine A. R. Lok, M.D., Ph.D., Department of Obstetrics and Gynecology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands (
[email protected]). Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.
0024-7758/11/5600-0000/$18.00/0 © Journal of Reproductive Medicine®, Inc. The Journal of Reproductive Medicine®
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effects of therapy, (3) support of the patient including providing advice and information on the disease and its consequences, and (4) the collection of outcome data obtained from follow-up visits. On the other hand, follow-up may cause anxiety in patients and imposes financial consequences on the health care system. Furthermore, follow-up does not always result in earlier detection of recurrence and an improved prognosis. Recently, the length of follow-up after low-risk gestational trophoblastic disease (GTD) has become an issue of debate. Early diagnosis and immediate treatment of GTD improves the patient’s prognosis, and this observation has traditionally been extrapolated to recurrent disease as well. Other factors relating to the development and persistence of recurrent disease include poor prognosis of metastatic disease, inadequate initial staging and therapy, lack of adequate maintenance chemotherapy beyond the first negative hCG level, and prolonged intervals between cycles of chemotherapy.1 Recurrent GTD after spontaneous normalization of hCG has been reported.2 Therefore, in most follow-up protocols continued hCG monitoring is recommended for at least 6 months after achieving undetectable levels of the hCG. However, in recent papers no recurrences at all were reported during follow-up surveillance.3,4 During the follow-up period women are advised to refrain from pregnancy. This may be difficult to accept for a considerable proportion of women as they are often eager to conceive again and the inci-
dence of recurrent disease after low-risk GTD is minimal2-11 (Table I). Thus, the level of evidence for a follow-up period of 6 months during which pregnancy is not recommended is not high. In such a situation, the patient’s preference can be considered an important factor in the decision of whether to begin a surveillance program. Minimal research has been performed to investigate patient preferences in GTD. In patients with colorectal cancer, a preference for routine followup was apparent.12 The aim of the present study was to investigate the psychologic consequences of weekly and monthly hCG measurements in patients with low-risk GTD and their opinion on the benefits and disadvantages of a follow-up surveillance program. Materials and Methods
All patients with a complete or partial molar pregnancy between January 2006 and December 2007 were eligible for this study. Patients were identified through the Central Molar Registry of Hydatidiform Mole in Nijmegen. Approval from the Medical Ethical Committee of the University Medical Centre, St. Radboud in Nijmegen was obtained. Gynecologists were contacted and requested to send a questionnaire to their patients or to provide contact details to the researchers. All patients received a questionnaire containing 30 questions about followup, completion of follow-up and anxiety and stress during this time. No existing validated questionnaires were available for this study. Therefore a
Table I Literature Overview of Recurrent GTD After Spontaneous hCG Normalization Recurrences
Author
Patients (N)
Bagshaw, 1986
Feltmate, 2003 Batorfi, 2004 Wolfberg, 2004
Lavie, 2005 Wielsma, 2006 Kerkmeijer, 2006 Wolfberg, 2006 Kerkmeijer, 2007 Sebire, 2007 a Normalization bNormalization cPrior
2,169a 2,585b 320 120 876c 82d 74 344 433 238 265 6,279
GTD
No.
%
CM/PM CM/PM CM/PM CM/PM CM CM PM PM CM PM CM/PM CM/PM
0 27 0 0 2 0 0 0 0 0 1 3
0% 1% 0% 0% 0.2% 0% 0% 0% 0% 0% 0.38% 0.05%
in < 56 days after evacuation. in > 56 days after evacuation.
to 1993. 1993 when more sensitive hCG assays were used. CM = complete hydatidiform mole, PM = partial hydatidiform mole.
dAfter
Time of recurrence
After 1–12 hCG measurements
— — Not stated — — — — — 4 Weeks after hCG normalization 402, 677, and 1,267 days after evacuation
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questionnaire was developed in cooperation with the department of medical psychology of the Academic Medical Center (Amsterdam, the Netherlands). The questionnaire contained multiplechoice questions. Patients were allowed to give multiple answers because several mood changes could be applicable. The questionnaire also contained statements for which patients were asked to score their agreement or disagreement on a scale, ranging from zero to ten. The scales were visualized in the questionnaire. A literature search was performed to obtain all available research data on follow-up in GTD. A computerized database was constructed and the obtained data were analyzed with SPSS for Windows 16.0 (Statistical Package for the Social Sciences, SPSS Inc., Benelux BV, Gorinchem, the Netherlands). Data from multiple-choice questions are presented as observational data. Mean scores and standard deviations were calculated from the qualitative results and provided where appropriate. To assess relations between variables, Pearson bivariate correlation coefficients were calculated. Results Patients
We identified 127 patients who were eligible for this study. Questionnaires were sent to these patients from hospitals throughout the Netherlands. Seventysix patients returned the questionnaire, which is a response rate of 60%. The patients had a mean age of 31.5 (± 4.8) years. All patients had an uncomplicated molar pregnancy with spontaneous normalization of the hCG level. Twenty-four patients (32%) were primigravida. The suspicion of hydatidiform mole was based on an early dating scan in 40% (30/76) of the patients and confirmed by histologic examination of the evacuated specimen. Only 21% (16/76) of the patients were symptomatic. In 36% (27/76) of the women, the diagnosis was established only after histologic examination of evacuated specimen.
Table II Reported Psychologic Consequences of Weekly and Monthly hCG Measurements Weekly measurements (n = 76)
Monthly measurements (n = 76)
Psychologic consequence
No. (%)
No. (%)
Insecure Anxious Not different Confident Depressed Tense Reassured Burden Different feeling/mood
32 (42) 25 (33) 2 (3) 5 (7) 10 (13) 39 (51) 42 (55) 11 (15) 8 (11)
18 (24) 8 (1) 14 (18) 13 (17) 9 (12) 22 (29) 38 (50) 12 (16) 8 (11)
Patients were asked about their moods and feelings for the hCG measurements. Multiple answers were possible; therefore the total percentage exceeds 100%.
not having felt any different compared to normal (3%). Patients were asked to record the extent of their anxiety on a scale ranging from 0 to 10. These results are presented in Figure 1. About 25% of all patients reported an anxiety of six on this scale (mean, 6.1 ± 2.3). Seventy-five percent (57/76) of the women noticed a reduction in anxiety after the weekly hCG measurement. The mean score for reassurance after hCG measurement is also presented in Figure 1 (7.3 ± 2.0). A significant inverted correlation (r = −0.35, p = 0.003) was found between the age of patients and the level of anxiety (Figure 2). Patients who were anxious scored higher for fear of recurrence (r = 0.49, p < 0.0001), fear of infertility (r = 0.40, p = 0.001) and fear of conceiving again (r = 0.30, p = 0.01). They also experienced the mea-
Psychologic Consequences of Weekly and Monthly hCG Measurements
The psychologic consequences of weekly and monthly follow-up are shown in Table II. More than half of the patients (51%) reported in retrospect to have felt tense before the weekly measurements, but even more patients were reassured after learning the result. Many patients were either insecure (42%) or anxious (33%). Only a minority reported
Figure 1 Anxiety and reassurance following weekly hCG follow-up. The percentage of patients reporting a certain level of anxiety (black bars) and reassurance (white bars) are presented in this figure.
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women reported insufficient psychologic support from either the medical staff or family. Support from medical staff was rated as 6 (SD ± 3) on a scale from 0 to 10, and support from family was rated as 9 (SD ± 2). Obtainment of information was considered to be of importance, and 73% of the patients felt that enough information was provided about their disease and the subsequent period. Completion of Follow-up
Figure 2 Correlation between age and anxiety. This figure presents a dot plot for the correlation between the age of a patient and the level of anxiety. A significant inverted correlation (r = −0.35, p = 0.003) was found between the age of patients and the level of anxiety. The curved lines represent the 95% mean confidence intervals.
surements as a greater burden (r = 0.35, p = 0.003). The patients who considered the likelihood of recurrence to be small also rated fear of infertility and fear to conceive lower (r = −0.38, p = 0.001 and r = 0.36, p = 0.002). A correlation between parity and anxiety was not found. Fewer patients were insecure before monthly hCG measurement (24%). More patients reported feeling no different (11%). Still, 29% of the women experienced tension, and 50% were reassured after the measurement. Medical Counseling and Support
About 80% of the patients reported that they either ‘always’ or ‘most of the time’ could approach their physician if they had questions. Furthermore, 68% had the option to contact their doctor by telephone. Many women were prepared to travel to the hospital in order to have blood samples taken (mean score, 4.7 ± 3.0). Most women (73%) had (almost) always contact with the same gynecologist throughout their treatment. A third of all women knew exactly what to expect during treatment and followup. Only 7% reported that they never knew what was going to happen. The majority of patients were satisfied with their gynecologist’s knowledge of GTD. Psychologic support, especially from medical staff, was not always adequate. About 50% of the
Many women are eager to conceive again and may not refrain from pregnancy as advised. In the present study, 80% of the women completed the followup of 6 months. Forty-nine women reported a score of ≥ 7 on this issue and 16 patients even noted the maximal score (10 of 10). Women were asked whether they would come for a weekly follow-up if it were optional. Eighty-seven percent of the patients confirmed that they certainly would visit the hospital on a weekly basis, and another 10% reported that they were likely to do so. When asked about the monthly follow-up schedule, 60% of the women would certainly visit the hospital and another 29% were likely to do so. Subsequent Pregnancy
Because of the molar pregnancy, it is possible that women would think differently about a new pregnancy. Therefore, they were asked whether it would be likely that they would conceive again. Only 8% replied that they would not. However, 16% did not conceive anymore. Some women (24%) were eager to have a subsequent pregnancy immediately after the evacuation of the GTD. Another 30% would prefer to become pregnant once the hCG level had become undetectable. Finally, 27% wanted to conceive immediately after the 6 months’ follow-up period, and the remaining women needed more than 6 months. Women were not really worried about infertility (mean score, 4.2 ± 3.4) and agreed to a certain extent that the likelihood of recurrence was minimal (mean score, 5.9 ± 2.6). Although there were some concerns in the subsequent pregnancy, only a few women were anxious enough that they avoided getting pregnant again (mean score, 1.9 ± 2.7). Once a pregnancy was achieved, many women (mean score, 7.6 ± 3.1) reported not being assured until an ultrasound scan confirmed an intact (nonmolar) pregnancy. Discussion
The incidence of complete molar pregnancy in the
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Netherlands is about 1:2000 pregnancies. The majority of patients can be cured with evacuation. After evacuation hCG is monitored weekly until the level is undetectable. Then monthly hCG monitoring is advised for a period of 6 months. During this period patients are seen by their physician to discuss the hCG level, or patients are informed by telephone. The incidence of recurrent disease after lowrisk GTD is minimal. In 15–20% of the patients there is no spontaneous regression of hCG.13 These patients need additional treatment and close followup surveillance for at least one year after completion of treatment. Hence, the discussion about reducing the length of follow-up applies only to women with GTD and a spontaneous normalization of hCG. The influence of quality of life (QOL) after molar pregnancy has been shown by several authors.14,15 Recently Ferreira et al16 published their study on the assessment of QOL and psychologic aspects in patients with GTD. However, they did not address the aspects of follow-up, and both women with spontaneous normalization and women with PTD were included (n = 54). Most patients rated their QOL as good (44%) and were satisfied with their health status (43%). However, there were indications for dysphoria and medium-high anxiety. We aimed for a more specific group: women with spontaneous normalization of hCG and completed follow-up. We selected this well-defined study group because a more protruded course of the disease could easily influence the perception of followup in these patients. From psychosocial studies in cancer patients we can learn that factors influencing QOL are age, social support, race, marital status, education, less advanced disease17 and the presence of children.15 The significant (inverted) correlation between age and the level of anxiety in the present study is in line with this previous research. In contrast, parity and anxiety were not related in our study. The presence of depressive symptoms and reduced QOL in early (normal) pregnancy is 15%.18 In women experiencing a miscarriage between 10 and 14 weeks’ gestational age, anxiety and depression were observed in 45% and 15% of women, respectively. These women report a desire for at least one follow-up appointment (92%) and for psychologic counseling (35%).19 Patients with a molar pregnancy not only lose their pregnancy but also suffer from a potentially dangerous disease and are advised to refrain from pregnancy during the follow-up peri-
od. They are also weekly and later monthly confronted with their disease. Our study suggests that follow-up is appreciated because the majority of the women would still come for the weekly and monthly follow-up if it were optional, even though they report a variety of psychologic symptoms from follow-up. Sufficient support should be provided during this period. This should be incorporated in follow-up protocols because our results show that support from medical staff was not always sufficient. Optimally, a multidisciplinary team including members trained in psychosocial counseling should be available. This is the first population-based study investigating patients’ opinions on follow-up after GTD. We included a homogeneous group of patients with low-risk GTD and spontaneous normalization of hCG. The response rate was reasonably high and therefore the results are likely to represent the general opinion of this patient group with low-risk GTD. From a psychologic point of view it would also be of great interest to investigate anxiety in women who need additional monochemotherapy with methotrexate and require 12 months of followup after hCG becomes negative but who also have a good prognosis. Future research may enable a comparison of anxiety levels between these patients and our patient group. A difficulty of the present study was the lack of validated questionnaires available for research on this specific topic. In most studies assessing QOL, standard validated questionnaires are used. These questionnaires were not applicable to our study because they are not suitable for retrospective studies and do not address patient preferences. Furthermore, they are not specifically constructed for GTD, which has some specific features different from other (malignant) diseases. We used a questionnaire that was specifically designed to review followup in GTD patients. A limitation of this study is its retrospective character. The results of the study may be influenced by recall bias. Hence, further prospective research on this topic is warranted. Prior to the year 2000, re-elevation of hCG may have been associated with problems with the hCG assay. Furthermore, we cannot eliminate the possibility that some of the patients with re-elevation of hCG suffered from quiescent GTD instead of recurrent disease. Quiescent GTD is a benign disease with persistent low levels of hCG not requiring chemotherapy or surgery. The incidence of quies-
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cent GTD is low, but careful monitoring with sensitive hCG tests and longer follow-up is required.20,21 The actual recurrence rate of low-risk GTD may therefore be even lower than that reported in Table I. In conclusion, follow-up after low-risk GTD has psychologic consequences but provides reassurance as well, particularly if sufficient psychosocial support is provided. Counseling of women with low-risk GTD should include a discussion about the minor risk of recurrence after normalization of the hCG level and thus about the minor consequences of pregnancy before follow-up is completed. If women are eager to conceive or if they are of advanced age, a follow-up period shorter than 6 months seems acceptable. References
1. Mutch DG, Soper JT, Babcock CJ, et al: Recurrent gestational trophoblastic disease: Experience of the Southeastern Regional Trophoblastic Center. Cancer 1990;66:978–982 2. Bagshawe KD, Dent J, Webb J: Hydatidiform mole in England and Wales 1973–1983. Lancet 1986;2:673–677
3. Kerkmeijer LGW, Wielsma S, Massuger LFAG, et al: Recurrent gestational trophoblastic disease after hCG normalization following hydatidiform mole in the Netherlands. Gynecol Oncol 2007;106:142–146
4. Sebire NJ, Foskett M, Short D, et al: Shortened duration of human chorionic gonadotrophin surveillance following complete or partial hydatidiform mole: Evidence for revised protocol of a UK regional trophoblast disease unit. BJOG 2007:760–762
5. Feltmate CM, Batorfi J, Fulop V, et al: Human chorionic gonadotrophin follow-up in patients with molar pregnancy: A time for reevaluation. Obstet Gynecol 2003;101:732–736 6. Batorfi J, Vegh G, Szepesi J, et al: How long should patients be followed after molar pregnancy? Analysis of serum hCG follow-up data. Obstet Gynecol 2004;112:95–97 7. Wolfberg AJ, Feltmate C, Goldstein DP, et al: Low risk of relapse after achieving undetectable hCG levels in women with complete molar pregnancy. Obstet Gynecol 2004;104: 551–554 8. Lavie I, Rao GG, Diego HC, et al: Duration of human chorionic gonadotropin surveillance for partial hydatidiform
moles. Am J Obstet Gynecol 2005;192:1362–1364
9. Wielsma S, Kerkmeijer L, Bekkers R, et al: Persistent trophoblast disease following partial molar pregnancy. Austr N Z J Obstet Gynaecol 2006;46:119–123
10. Kerkmeijer L, Wielsma S, Bekkers R, et al: Guidelines following hydatidiform mole: A reappraisal. Austr N Z J Obstet Gynaecol 2006;46:112–118 11. Wolfberg AJ, Growdon WB, Feltmate CM, et al: Low risk of relapse after achieving undetectable hCG levels in women with partial molar pregnancy. Obstet Gynecol 2006;108:393– 396
12. McCool J, Morris J: Focus of doctor-patient communication in follow-up consultations for patients treated surgically for colorectal cancer. J Manag Med 1999;12:169–177 13. Van Trommel NE, Massuger LF, Schijf CP, et al: Early identification of resistance to first-line single-agent methotrexate in patients with persistent trophoblastic disease. J Clin Oncol 2006;24:52–58 14. Wenzel L, Berkowitz R, Robinson S, et al: The psychological, social, and sexual consequences of gestational trophoblastic disease. Gynecol Oncol 1992;46:74–81
15. Peterson RW, Ung K, Holland C, et al: The impact of molar pregnancy on psychological symptomatology, sexual function, and quality of life. Gynecol Oncol 2005;97:535–542 16. Ferreira EG, Maesta I, Michelin OC, et al: Assessment of quality of life and psychologic aspects in patients with gestational trophoblastic disease. J Reprod Med 2009;54:239–244 17. Parker PA, Baile WF, de Moor C, et al: Psychosocial and demographic predictors of quality of life in a large sample of cancer patients. Psychooncology 2003;12:183–193 18. Nicholson WK, Setse R, Hill-Briggs F, et al: Depressive symptoms and health-related quality of life in early pregnancy. Obstet Gynecol 2006;107:798–806
19. Nikcevic AV, Tunkel SA, Nicolaides KH: Psychological outcomes following missed abortions and provision of followup care. Ultrasound Obstet Gynecol 1998;11:123–128 20. Khanlian SA, Cole LA: Management of gestational trophoblastic disease and other cases with low serum levels of human chorionic gonadotropin. J Reprod Med 2006;51:812– 818
21. Cole LA, Khanlian SA, Giddings A, et al: Gestational trophoblastic diseases: Presentation with persistent low positive human chorionic gonadotropin test results. Gynecol Oncol 2006;102:165–172
