Does hormonal contraception during molar pregnancy follow-up influence the risk and clinical aggressiveness of gestational trophoblastic neoplasia after controlling for risk factors?
Introduction
Molar pregnancy is a reproductive anomaly that affects 1 in 200–400 pregnant women in Brazil [1], an incidence 5 to 10 times higher than in the United States and Europe [2], [3]. This disease may present as either of two different clinical and cytogenetic forms, characterized by complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM), which represent the benign spectrum of gestational trophoblastic disease (GTD) [4].
The clinical importance of molar pregnancy is the risk of progression to gestational trophoblastic neoplasia (GTN), the malignant form of GTD, that occurs in about 15–20% of women following CHM and 1–5% of women after PHM [2], [3], [4]. The main strategy to diagnose GTN is to evaluate the levels of human chorionic gonadotropin (hCG) in the postmolar follow-up. The increase of hCG levels over two consecutive weeks, or a plateau (changes < 10%) for three consecutive weeks confirms the progression of molar pregnancy into GTN [5]. Fortunately, the early treatment of GTN achieves cure in > 98% of cases, even with the presence of multiple metastases [1], [6].
To maintain the reliability of hCG as a biological marker for GTN, including making the initial diagnosis of GTN, monitoring the response to chemotherapy, and surveilling for recurrent GTN after chemotherapy (which happens in 3% of patients with low risk GTN and in 7–10% of patients with high risk GTN), patients are advised to avoid pregnancy during the postmolar follow-up. In general, this means until 6 months after hCG level normalization without a diagnosis of GTN and until 12 months after the last cycle of chemotherapy if a patient requires GTN treatment [7], [8], [9].
Despite the World Health Organization (WHO) guidelines which maintain that the use of hormonal contraception (HC) does not increase the risk of postmolar GTN or retard hCG normalization [10], some medical associations such as the Royal College of Obstetricians and Gynaecologists [11] and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists [12] have concerns about initiating HC after molar evacuation, when hCG levels are still high. This concern is based on studies from the 1970s, which suggested that the use of HC increased the risk for postmolar GTN and postponed hCG normalization [13], [14], [15]. However, the contemporary relevance of those studies has been questioned, as patients at that time used contraception with higher hormonal levels than today [16].
Although many studies about the impact of HC in patients with molar pregnancy and the risk of postmolar GTN attest to its safety [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], a recent metanalysis compiling all data on contraception in this population has shown that fewer than 800 patients with molar pregnancy using HC were effectively evaluated for the risks of this contraceptive method [16]. In the largest single study about this subject, although it included 2777 patients with CHM, only 154 were using HC, which sustains the concern about the use of HC immediately after molar evacuation [27]. It is also important to highlight that none of these previous studies evaluated the effect of different compositions or hormonal doses, or even the impact of confounding risk factors for GTN on their results, maintaining uncertainty about the safety of HC among women with molar pregnancy and postmolar GTN.
Therefore, the aim of this paper is to evaluate the potential influence of HC on the occurrence and clinical aggressiveness of GTN as well as the time for hCG normalization controlling for risk factors for GTN among Brazilian women with molar pregnancy. We also wanted to evaluate specifically the safety of HC, analyzing not only its formulations, but also the impact of different dosages when compared to the patients using barrier methods of contraception (BM).
Section snippets
Study design
This is a retrospective cohort study of patients with molar pregnancy followed at the Rio de Janeiro Trophoblastic Disease Center (33a Maternity Ward of Santa Casa da Misericórdia in Rio de Janeiro, Antonio Pedro University Hospital of Fluminense Federal University and Maternity School of Rio de Janeiro Federal University) between January 2005 and January 2015.
The local Institutional Review Board approved this study under the protocol number 1.842.895.
Patients
The participants in this study were women
Results
The flow diagram in Fig. 1 illustrates the derivation of the study population. In total, 2828 patients were included in the final analysis, with 148 (5%) patients in the barrier method group and 2680 (95%) patients in the HC group.
Table 1 shows the demographic characteristics of patients with molar pregnancy according to contraception type. Rates of progression to GTN were similar among BM users when compared to those using HC (14.9% versus 12.9%, p = 0.500), respectively. Patients using HC
Discussion
This study indicates that there is no significant association between the use of modern HC and the development of postmolar GTN. This is in agreement with some prior reports, however, previous studies failed to control for GTN risk factors [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]. Controlling for underlying GTN risk factors is important. Patients using BM included in our study had two well-recognized high risk factors for progression to GTN, namely advanced
Conclusion
This paper reinforces the importance of HC in the follow-up of women with molar pregnancy and postmolar GTN, due to its high contraceptive effectiveness. Furthermore, HC does not increase the occurrence of postmolar GTN, the clinical aggressiveness of GTN, or the time to spontaneous hCG remission, and these findings are not affected by varied HC formulations (progestin-only versus combination oral contraceptive) or varied dosages of ethinyl estradiol.
The following are the supplementary data
Disclosures
The authors report no conflicts of interest.
Funding
This research was supported by the Carlos Chagas Filho Foundation for Research Support in the State of Rio de Janeiro/Brazil (FAPERJ) (E-26/112.070/2012) – an agency under the Brazilian Ministry of Science and Technology; and the Donald P. Goldstein MD Trophoblastic Tumor Registry Endowment and the Dyett Family Trophoblastic Disease Research and Registry Endowment. The funding agencies had no direct role in the generation of the data or manuscript.
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