Download 39. Shoni M, Nagymanyoki Z, Vitonis AF, Jimenez C, Ng SW

Modern hormone contraceptive use before hCG remission does not
increase the risk of gestational trophoblastic neoplasia following
complete hydatidiform mole
Antonio Braga PhD a,b, Izildinha Maestá PhD b, Dee Short BSc c, Philip Savage FRCP c,
Richard Harvey PhD c, Michael J Seckl FRCP c
a
Trophoblastic Disease Center, Maternity School of Rio de Janeiro Federal University
and Antonio Pedro University Hospital at Fluminense Federal University, Rio de
Janeiro, Brazil. Postdoctoral Program of Science without Borders (Brazilian
Government) – Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross
Hospital, Imperial College School of Medicine, London, UK and Postdoctoral Program
of Gynecology, Obstetrics and Mastology Postgraduate of Botucatu Medical School,
UNESP- São Paulo State University, Botucatu, São Paulo, Brazil.
b
Trophoblastic Disease Center, Department of Gynecology and Obstetrics, Botucatu
Medical School, UNESP- São Paulo State University, Botucatu, São Paulo, Brazil
c
Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Hospital,
Imperial College School of Medicine, London, UK
Correspondence to: Prof Michael J Seckl, Department of Medical Oncology, Charing
Cross Hospital Campus, Imperial College NHS Healthcare Trust, London W6 8RF, UK
email: [email protected]
Contributors
MJS conceived and designed the study. AB and DS participated in data collection. RH
did hCG assays. PS and MJS treated the patients. AB, IM, PS and MJS contributed to
data analysis and interpretation. AB, IM and MJS wrote the report. All authors have
seen and approved the final version of the report.
Conflicts of interest
We declare that we have no conflicts of interest.
Acknowledgments
MJS thanks the National Commissioning Group and Department of Health for
continuing support of the GTD service. MJS is supported by the Imperial College
Experimental Cancer Medicine Centre (ECMC) grant from Cancer Research UK, the
Department of Health, and the Imperial College National Institute for Health Research
Biomedical Research Centre (NIHR BRC).
AB thanks the Postdoctoral Program of Science without Borders – Brazilian
Government.
Abstract
Objective To re-evaluate the safety of low dose hormone contraceptives (HC) after
uterine evacuation of complete hydatidiform mole (CHM).
Design Non-concurrent cohort study.
Setting Charing Cross Hospital Gestational Trophoblastic Disease Centre, London,
United Kingdom.
Participants 2,423 women with CHM of whom 154 commenced HC whilst their
human chorionic gonadotropin (hCG) was still elevated, followed between 2003 and
2012.
Main outcome measures Time to hCG remission, risk of developing postmolar
gestational trophoblastic neoplasia (GTN) and proportion of patients with high FIGO
risk score.
Results No relationship was observed between HC use with time to hCG remission
(HC users verses non-users: 12 weeks in both, p = 0.192), GTN development (HC users
verses non-users: 20.1% and 16.7%, p = 0.266) or high-risk FIGO score (HC users vs
nonusers: 0% and 8%, p = 0.152). Moreover, no association between HC and GTN
development was found, even when an age-adjusted model was used (OR = 1.37, 95%
CI = 0.91 to 2.08, p = 0.132)
Conclusions The use of modern HC is not associated with development of postmolar
GTN or delayed time to hCG remission. Therefore, HC can be safely used for birth
control following CHM regardless of hCG level.
Introduction
Gestational trophoblastic disease (GTD) comprises a spectrum of pregnancyrelated disorders that result from genetic abnormalities often established at conception.
GTD consists of the premalignant entities of complete (CHM) and partial hydatidiform
mole (PHM), and the malignant condition of gestational trophoblastic neoplasia (GTN).
GTN includes invasive mole, choriocarcinoma, placental-site trophoblastic tumor, and
the extremely rare epithelioid trophoblastic tumor. 1–3
Although hydatidiform mole is a self-limited process that completely resolves
4–6
following uterine evacuation in most cases, 15-20% of CHM and 0.5-5% PHM
behave malignantly. This is usually clinically detected by a plateaued or rising human
chorionic gonadotropin (hCG) on three and two consecutive weekly samples,
respectively. 6 Consequently, monitoring with serial determinations of quantitative hCG
values is essential for the early detection and prompt treatment of post-molar GTN.
5,7,8
In the vast majority of GTN cases, single-agent chemotherapy is highly effective and
the overall cure rate is around 100%. 1–3 Such high survival rates allows giving patients
the least toxic therapy first, and thus avoids exposure to more harmful treatments. 1
Because pregnancy interferes with monitoring hCG levels and may delay the
diagnosis of post-molar GTN, the use of a reliable contraception method for up to 6
months from normalization of the hCG level is very important. 9
Among the several forms of contraceptives available, hormonal contraception
(HC) remains one of the most common reversible methods in many countries.
However, early population based and reasonably large studies
11–13
10
suggested that HC
used whilst the hCG was still elevated increased the incidence of developing GTN
following molar pregnancy. In contrast several smaller non-population based studies
have shown no significant association between the use of HC and the risk of postmolar
GTN or the abnormal elimination of hCG14–24. Whilst these discrepant results might
reflect case ascertainment bias in the smaller non-population based studies, it is also
conceivable that the differences observed are due to the use of more modern low dose
HCs. Nevertheless, the controversy persists with some national and/or institutional
guidelines recommending HC avoidance at least until the hCG is normal whilst other do
not. 23
We have therefore re-evaluated the use of HC in a cohort of patients exposed to
modern low dose HC after molar evacuation in a large population.
Methods
The Charing Cross Hospital Gestational Trophoblastic Disease Centre electronic
data base was screened to identify all registered CHM between Jan 2003 and Dec 2012.
Patients with a normal initial hCG value after uterine evacuation of their CHM were
excluded as the purpose of the study was to assess the effect of HCs on risk of
developing GTN in patients who still had an elevated hCG. Furthermore, patients where
HC status on the molar registration document was not completed or where there was
uncertainty as to when HC use had begun were excluded. Of 2,777 patients, 2,423 met
these entry criteria (Figure 1). A non-commercial one-site in-house competitive hCG
radioimmunoassay using a rabbit polyclonal antibody was utilized for detecting and
monitoring hCG as previously described.
1,25
Serum and urine hCG levels <5 IU/L and
< 25 IU/L, respectively, were considered normal. 1,25
Information regarding age at registration, HC use, development of CHM into
GTN requiring chemotherapy, time to hCG remission, and FIGO risk score were
collected from our GTD electronic database and medical records. Low-dose HC were
defined as birth control pills, injectables, skin patches, implants and vaginal rings
containing <50micrograms estrogen, in either a combination of estrogen and progestin
or progestin alone. Time to hCG remission (weeks) was defined as the period between
CHM evacuation and first normal serum hCG value ( 5 IU/L). Patient follow-up was
conducted according to the Royal College of Obstetricians and Gynecologists
guidelines.
26
Briefly, if hCG reverted to normal ≤56 days after uterine evacuation of
the CHM then follow up continued for 6 months from the date of uterine evacuation.
However, if the hCG reverted to normal > 56 days after the evacuation then follow-up
was for 6 months from normalization of the hCG levels. All histopathological samples
were centrally reviewed as previously described.
1
The criteria used for indicating
chemotherapy / making a GTN diagnosis are listed in Box 1. All identified GTN cases
were reviewed and discussed in weekly multidisciplinary meetings until treatment was
completed. 27,28 The study was approved by the local institution review board.
Statistical analysis
Outliers were checked by exploratory analysis before statistical analysis. The
Mann-Whitney test was used to compare time to hCG remission between HC users and
nonusers. The relationship between HC use and GTN development was assessed using
the Chi-square test and an age-adjusted logistic model. The relationship between HC
use and FIGO risk score was assessed by Fisher’s exact test. Significance level was set
at p  0.05. A retrospective analysis showed that our sample size of 2,423 patients of
whom 154 were using HC was sufficient to detect a difference of 8% in GTN risk with
80% power and a type I error of 5%. Statistical analyses were performed using SPSS
software (version 21.0, SPSS, Inc, Chicago, IL).
Results
A total of 2,777 patients with CHM were registered during the study period, of
which, postmolar hCG regression curve information was available for 2,509, the
remainder already having a normal hCG as their first value following CHM evacuation.
Information regarding HC use was available for 2,423 (154= HC users, 2,269= non-HC
users), and so these were included in the subsequent analysis (Figure 1).
Median patient age was 30 years (range 15-56). GTN requiring chemotherapy
was detected in 409 patients (17%), of whom 378 (92%) were classified as low-risk and
31 (8%) as high risk.
Table 1 demonstrated that no relationship was observed between HC use and
any of the following: time to hCG remission (HC users: 12 weeks verses (vs) HC
nonusers: 12 weeks, p = 0.192); post-CHM GTN development (HC users: 20.1% vs HC
nonusers: 16.7%, p = 0.266); and high-risk FIGO score (HC users: 0% vs HC nonusers:
8%, p = 0.152).
The risk of developing GTN after CHM increased 3% for every one-year
increase in patient age (OR = 1.03, 95% CI = 1.02 to 1.04, p <0.001). However, no
association between HC and GTN development was found, even when an age-adjusted
model was used (OR = 1.37, 95% CI = 0.91 to 2.08, p = 0.132) (Table 2).
Discussion
This study provides strong evidence that HC may be safely initiated immediately
after uterine evacuation, even whilst the hCG concentration is still elevated. Our results
show that besides not affecting time to GTD remission, HC had no influence on the risk
of developing postmolar GTN or on FIGO risk score.
The use of HC during postmolar follow-up has several advantages: promotes
effective contraception (99.0-99.7% with perfect use and 92-97% with typical use),
with high level of user satisfaction, which contributes to better compliance,
30
29
and
blocks the synthesis of pituitary derived hCG or LH that can cause false positive hCG
results.
31,32
Nevertheless, even in referral centers where HC is routinely recommended,
the pregnancy rate before the completion of molar pregnancy surveillance occurred in
12-23%, indicating the difficulty of maintaining contraception during the post-molar
follow-up. 33,34
Strengths and limitations of study
Despite its retrospective nature, this study represents the largest series
comparing the effects of HC on the prognosis of patients with GTD. In order to
minimize the limitations of the design of our investigation, we included all patients with
CHM followed at the Charing Cross Trophoblastic Disease Center between 2003 and
2012. Nearly all of these women had sufficient information for inclusion in the study
and because this was UK population based case ascertainment bias seems less likely to
be an issue here than in other studies. 21
Comparison with other studies
In our study, the type of contraception had no influence on time to hCG
remission (12 weeks for both HC users and nonusers). Stone and colleagues,
11
in their
early study of the relationship of oral conception to GTN development after molar
evacuation, reported that time to hCG normalization was longer in patients taking HC
compared to those using other methods of contraception. This could be explained as a
consequence of the higher doses of hormones used. 21,23 In contrast, and consistent with
our findings, other studies found no association between HC and time to hCG
regression.
14,19,21
The only exception was Morrow and colleagues,
16
who reported a
significant difference in hCG regression time. However, they observed each treatment
group during a different time period, and used different hCG-assays in each group.
23
The latter point is important as it is now well recognised that using different hCG assays
can have significant impact on the actual hCG results obtained.
1,25
A strength of the
present study is that we have used the same hCG assay throughout.
Certainly, the most important finding to emerge from this investigation is that HC use
was not associated with the occurrence of postmolar GTN, a result similar to others
studies.
14–22
In contrast, the original Stone et al paper showed the opposite. Why is
there such a discrepancy? One of the explanations that Stone and colleagues, 11 used to
justify a higher occurrence of GTN in users of HC was that these contraceptive methods
would promote a downregulation in the immunologic reaction of the receptor against
trophoblastic disease, resulting in exacerbated cell proliferation. However, in vitro
studies using trophoblastic cell lines treated with estrogen and progestin did not change
the rate of cell proliferation or even the production of hCG. 35,36 Nevertheless, placental
tissue and trophoblastic tumours do express estrogen receptor beta and progesterone
receptors and others have shown effects of hormones on these tissues. 37,38 Interestingly,
recent work shows that estrogen receptor alpha is not nuclear in GTD tissues but did
not examine estrogen receptor beta. 39 If ostrogens do play a role in GTD biology then
the most likely explanation for the marked difference in results between the early work
of Stone and the more recent papers including this study is the reduction in dose of
modern hormone contraceptives.
Conclusion
This study indicates that use of modern HC is not associated with development
of postmolar GTN or delayed time to hCG remission. Therefore, HC can be safely used
for birth control following CHM regardless of hCG level.
What this paper adds box
Section 1: What is already known on this subject
During postmolar follow up, the use of a reliable contraception method for
several months is essential to enable early detection of postmolar GTN. Conflicting data
exist regarding the safety of hormone contraceptives with some showing an increased
risk of GTN development particularly when started whilst the hCG is still elevated.
Section 2: What this study adds
The use of modern hormone contraceptive is not associated with development of
postmolar GTN or delayed time to human chorionic gonadotropin remission.
Hormone contraceptive can be safely used for birth control following CHM
regardless of hCG level.
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Box 1. Indications for chemotherapy
Plateaued or rising hCG after evacuation*
Heavy vaginal bleeding or evidence of gastrointestinal or peritoneal hemorrhage
Histological evidence of choriocarcinoma
Evidence of metastases in the brain, liver or gastrointestinal tract, or radiological opacities of >2
cm on chest X-ray
Serum hCG of ≥ 20,000 IU/L > 4 weeks after evacuation, because of the risk of uterine
perforation
Raised hCG 6 months after evacuation even if still falling (now omitted)
*Plateaued or rising is defined as four or more equivalent values of hCG over at least 3 weeks (days 1,
7, 14, and 21) and two consecutive rises in hCG of 10% or greater over at least 2 weeks (days 1, 7, and
14) respectively).
Figure 1. Overview of study population
CHM
N = 2,777
Exclusions
hCG normal N = 186
no hCG information N = 82
no HC information N = 86
Elevated hCG
N = 2,423
HC users
non-HC users
N = 154
N = 2,269
Table 1. Relationship between use of hormonal contraceptives and gestational
trophoblastic neoplasia in patients with complete hydatidiform mole.
Variables
Hormonal contraceptive use
1
CHM Outcome
Spontaneous remission
GTN development2
GTN 2 FIGO risk score
Low-risk FIGO score
High-risk FIGO score
Time to hCG normalisation (weeks)
No (N = 2269)
1891 (83,3%)
378 (16,7%)
No (N = 378)
347 (91,8%)
31 (8,2%)
No (N = 2269)
12 [8;16] (1 – 204)6
p
Yes (N = 154)
123 (79,9%)
31 (20,1%)
Yes (N = 31)
31 (100,0%)
0 (0,0%)
Yes (N = 154)
12 [8;16] (4 – 88) 6
0,266 (3)
0,152 (4)
0,192 (5)
(1) CHM – complete hydatidiform mole
(2) GTN – gestational trophoblastic neoplasia
(3 Chi-square test
(4) Fisher’s exact test
(5) Mann-Whitney test
(6) Median [1st Quartil; 3rd Quartil] (Minimum-Maximum)
Table 2. Adjusted logistic model to explain the occurrence of postmolar GTN
depending on patient's age and hormonal contraceptive use.
Variable
β
SE
Wald test
P
OR
CI (OR;95%)
HC use
0,32
0,21
2,27
0,132
1,37
(0,91 to 2,08)
Age (years)
0,03
0,01
31,72
0,000
1,04
(1,02 to 1,05)
Constant
-2,72
0,21
167,78
0,000
0,07
Key:  estimate; SE standard error; OR overall risk; CI confidence interval