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Pregnancy outcomes after fertility preservation in women with endometrial carcinoma and atypical endometrial hyperplasia: A systematic review and meta-analysis
  1. Zerui Xiaoa,1,
  2. Ziyi Songa,1,
  3. Jianliu Wanga,
  4. Huixin Liub,** and
  5. Qun Lua,*
  1. aDepartment of Obstetrics and Gynecology, Peking University People’s Hospital, China
  2. bDepartment of Clinical Epidemiology, Peking University People's Hospital, China
  1. ↵*Corresponding author. Department of Obstetrics and Gynecology, Peking Univeristy People's Hospital, Beijing, 100044, China. luqun1023{at}sina.com
  2. ↵**Corresponding author. Department of Clinical Epidemiology, Peking Univeristy People's Hospital, Beijing, 100044, China. liuhuixin{at}bjmu.edu.cn

Abstract

Objective The objective of the study was to compare the effects of assisted reproductive technology (ART) and spontaneous pregnancy on pregnancy outcomes in women with endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) following fertility-sparing treatments.

Methods Relevant studies published through July 2020 were identified from PubMed and Web of Science literature searches. The pregnancy outcomes of ART and spontaneous pregnancy were summarized and compared for women with complete remission of EC/AEH after fertility-sparing treatments. A subgroup analysis was performed based on whether patients had received in vitro fertilization and embryo transfer (IVF-ET) treatment. The complete remission and recurrence rates of EC/AEH following fertility-sparing treatments were estimated. The effect of pregnancy on recurrence rates of EC/AEH was also calculated.

Results Sixteen observational studies reporting pregnancy outcomes or recurrence with ART or spontaneous pregnancy for women with EC/AEH after fertility-sparing treatments were included. The complete remission rate of EC/AEH was 81.5% (95%CI, 78%–85%). Compared with spontaneous pregnancy, the pregnancy rate of ART was significantly higher (66.8% vs. 43.7%, OR ​= ​2.64, 95%CI 1.71–4.05, P<0.00001, I2 ​= ​14%). Subgroup analysis showed that the pregnancy rate of IVF-ET was significantly higher than that of spontaneous pregnancy (62.7% vs. 35.1%, OR ​= ​2.85, 95%CI 1.44-5.63, P ​= ​0.003, I2 ​= ​29%). The live birth rate of ART was significantly higher than that of spontaneous pregnancy (75.3% vs. 47.8%, OR ​= ​3.96, 95%CI1.76-8.77, P ​= ​0.0009, I2 ​= ​45%). The recurrence rate of EC/AEH was 31% (95%CI 24%–39%). Clinical pregnancy could reduce the recurrence rate of EC/AEH, but there was no significant evidence of an association.

Conclusions ART, especially IVF-ET, could significantly improve pregnancy outcomes in women with EC/AEH receiving fertility-sparing treatments. Following complete remission, ART treatment might be a better option for women with EC/AEH than spontaneous pregnancy.

  • Endometrial carcinoma
  • Atypical endometrial hyperplasia
  • Fertility sparing treatment
  • Assisted reproductive technology
  • In vitro fertilization and embryo transfer
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

https://doi.org/10.1016/j.gocm.2021.07.004

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    1 Introduction

    Endometrial carcinoma (EC) is the fourth most common malignant tumor in women.1 Atypical endometrial hyperplasia (AEH) is a known precursor of endometrial carcinoma.2 About 5% of women with EC and AEH are younger than 40 years old.3 With delays in childbearing age, many young women diagnosed with EC/AEH do not have children, so there is a strong desire to preserve fertility. High-dose progesterone therapy of EC and AEH achieves a remission rate ranging from 76.2% to 81.4% and preserves fertility for these women.4–7

    Considering the high recurrence rate of EC/AEH, it is recommended that women should conceive as soon as achieving remission after fertility-sparing therapy.8 Also, pregnancy provides a high progesterone level environment for women with EC/AEH, which has a similar effect on the uterus just like high-dose progesterone treatment. Therefore, it can be speculated that pregnancy and live birth have protective effect on women with EC/AEH and might decrease the recurrence rate.

    After complete remission of EC and AEH, achieving pregnancy in these women is a challenging issue. The two main ways by which these women can conceive are through assisted reproductive technology (ART) and spontaneous pregnancy. Spontaneous pregnancy usually arises from a single follicle during the natural menstrual cycle with physiological levels of estrogen, but the pregnancy rate is low. However, young women with EC or AEH usually have a history of infertility, obesity, chronic anovulation, polycystic ovary syndrome (PCOS) and multiple endometrial biopsies during high-dose progesterone treatment,9,10 which further reduce fertility. In addition, ART especially in vitro fertilization and embryo transfer (IVF-ET) achieve high pregnancy rate among infertile couples.11 Therefore, ART is highly recommended for women diagnosed with EC and AEH who are intending to pregnancy. However, controlled ovarian stimulation generates multiple follicles and high estrogen levels, and whether the high estrogen levels increase the risk of recurrence in patients with EC/AEH is a source of worry among clinicians. Hence, there is a need to explore whether the benefits of ART outweigh its risks and if spontaneous pregnancy is a better option.

    Due to the small sample sizes of observational studies of fertility preservation and pregnancy outcomes, these studies have often failed to provide robust evidence on pregnancy outcomes for women with EC/AEH. Whether spontaneous pregnancy or ART is the most suitable for women with EC/AEH following fertility preservation remains uncertain. Therefore, we conducted a systematic review and meta-analysis to compare the effects of ART and spontaneous pregnancy on pregnancy outcomes in women with EC/AEH following fertility-sparing treatments.

    2 Materials and methods

    2.1 Search strategy

    This systematic review focused on women willing to conceive after receiving fertility-sparing treatments for EC and AEH. The interventions were ART and spontaneous pregnancy. Outcomes were pregnancy outcomes, complete remission and recurrence rates of EC/AEH between the two interventions. Given that it was a review of published data, institutional review board approval and patients' consent were not required.

    We searched PubMed and Web of Sciences electronic databases. A combination of medical subject headings (MeSH) and text words was used to generate 2 subsets of citations, 1 including studies of “endometrial atypical hyperplasia” (“endometr* atypical hyperplas*”, “premalignant endometr*”, “precancer* endometr*”) or “endometrial carcinoma” (“endometri* cancer*”, “malignant endometri*”, “endometri* carcino*”, “endometri* neoplasm”) and the other including studies of “fertility sparing” (“Fertility preserve*”, “fertility reserve”, “conservative”, “fertility sparing”) or “pregnancy” (“pregnancy”, “reproductive”, “in vitro fertilization”, “assisted reproductive technology”). We searched the databases from inception to July 2020. These subsets were combined with the Boolean expression “AND” to generate a subset of citations. No language or geographical restrictions were applied during the search or selection.

    2.2 Study selection

    2.2.1 Inclusion criteria

    • 1) Women diagnosed histologically with EC or AEH based on the International Federation of Gynecology and Obstetrics (FIGO) staging system. There was no suspicious or metastatic disease on imaging examination.

    • 2) The interventions were different pregnancy methods - ART and spontaneous pregnancy.

    • 3) The studies reported at least one of the following: clinical pregnancy rate, live birth rate or recurrence rate of EC/AEH due to ART and spontaneous pregnancy.

    • 4) Study designs were randomized controlled trials (RCT) or cohort studies.

    • 5) The study reported the number of women with fertility intention after fertility-sparing treatments and reported the conception methods (spontaneous pregnancy or ART), the relationships of conception methods with pregnancy outcomes or recurrence, or the relationship between pregnancy and recurrence of EC/AEH.

    2.2.2 Exclusion criteria

    • 1) Cases reports, case-control studies or series with fewer than 20 cases.

    • 2) Studies that combined patients with other tumors or diseases of the cardiovascular, liver, kidney and hematopoietic systems.

    • 3) Animal studies, qualitative studies, letters, news articles, editorials, commentaries, reviews or duplicate publications.

    2.2.3 Data extraction

    Two reviewers (XZR and SZY) independently screened the retrieved citations and extracted data. The titles and abstracts were initially screened and citations that did not fit the inclusion criteria were excluded. If the title or abstract appeared to meet the inclusion criteria, the citations' full texts were obtained for further evaluation. For duplicate studies, the most recent or the most comprehensive publication was used. Any discrepancies about inclusion were resolved by consensus or arbitration by a third reviewer (LQ). The data extraction contents included: first author, corresponding author, publication year, survey area, publishing journals, research methods, sample size and outcome indicators.

    Two reviewers (XZR and SZY) completed the quality assessment. For observational studies, the Methodological Index for Non-Randomized Studies (MINORS) was used to assess the quality of the included studies. The following outcomes were defined:

    Complete remission (CR) was defined as the absence of residual EC or complex hyperplasia during follow-up of fertility-sparing treatments. Recurrence was defined as the reappearance of AEH or cancerous cells that had initially disappeared. Clinical pregnancy was defined as at least one intrauterine pregnancy sac with yolk sac or original cardiac pulsations by B-ultrasound examination; the rate was the number of women who had clinical pregnancy divided by the total number of women having a pregnancy desire of CR after fertility-sparing treatments. Live birth was defined as the birth of at least a healthy infant at 28 weeks or more of gestation during the follow-up period, and the rate was the number of women giving birth to healthy babies divided by the total number of women having pregnancy desire of CR after fertility-sparing treatments.

    2.2.4 Statistical analysis

    Meta-analysis was performed using Review Manager 5.4 and R3.6.1 software. The degree of heterogeneity between studies was quantitatively assessed using I2, with values >50% considered to represent substantial heterogeneity. A random effects model was used when I2 >50%; otherwise, the fixed-effects model was employed. We conducted a sensitivity analysis using the leave-one-out approach if there was substantial heterogeneity between studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to compare pregnancy rates between spontaneous pregnancy and ART for women with EC/AEH. P<0.05 was regarded as statistically significant. Complete remission, recurrence, pregnancy and live birth rates were extracted from each study and pooled. We compared the clinical pregnancy and live birth rates of women with ART and spontaneous pregnancy and conducted a subgroup analysis based on whether the patients had received IVF-ET. We also compared recurrence rates between pregnant and non-pregnant women. Publication bias was assessed using funnel plots.

    3 Results

    3.1 Study selection and characteristics of the included studies

    The study selection process is shown in Fig. 1. A total of 1090 citations were acquired from PubMed (n ​= ​515) and Web of Science (n ​= ​575). ​After screening titles and abstracts and removing duplicates, 720 citations were excluded following inability to fulfill the inclusion criteria. A total of 92 articles were included for full-text evaluation and 16 eligible studies were finally included.12–27

    Fig. 1
    Fig. 1

    Flow chart of literature screening and study selection.

    The characteristics of the included studies are described in Table 1. Overall, 16 studies were included in our meta-analysis, comprising 854 women, of which 570 were diagnosed with EC and 284 with AEH. In the primary studies, 422 women with well-differentiated EC were classified as G1, 55 cases were moderately or poorly differentiated EC (G2 or G3), and 93 ​EC women were of unknown pathological grade. In 12 of these 16 studies, 402/493 (81.5%) women with EC/AEH achieved CR after treatment with hysteroscopy, oral high-dose progestin or LNG-IUD.12–15,17–22,25,26

    View this table:
    Table 1

    Characteristics of eligible studies investigating reproductive outcomes after fertility-sparing management for AEH/EC.

    All studies clearly stated the purpose of the study and defined the outcome of the study. No studies had a blinded assessment of the outcomes. All the 16 studies were cohort studies; no RCT met the inclusion criteria. A total of 13 studies reported conception methods, which were either ART or spontaneous pregnancy.12–21,25–27 Of the 13 studies, 7 reported the pregnancy outcomes of IVF-ET.12,14,15,18,20,25,27 Eleven of 16 studies clearly stated the duration of follow-up,12–14,16,18–22,25,27 of which only 4 studies had a median follow-up duration of more than 5 years.16,20,21,25

    3.2 Complete remission and recurrence

    A meta-analysis of 12 studies on fertility-sparing treatments for EC/AEH found that 402 women achieved complete remission with a pooled CR rate of 81.5% (95% CI, 77.9%–84.7%, P ​= ​0.06, I2 ​= ​41%, Fig. 2).12–15,17–22,25,26 In 14 studies, the recurrence rate was reported; 225 women relapsed after the initial CR for EC/AEH during follow up, with a pooled recurrence rate of 31.3% (95% CI, 24.7%–38.9%, P ​= ​0.01, I2 ​= ​71%, Fig. 3).12–14,16–20,22–27

    Fig. 3
    Fig. 3

    Forest plot of meta-analysis of recurrence rates for fertility-sparing treatments of EC/AEH.

    Fig. 2
    Fig. 2

    Forest plot of meta-analysis of complete remission rates for fertility-sparing treatment of EC/AEH.

    3.3 Clinical pregnancy rates of ART vs. spontaneous pregnancy

    A total of 13 studies reporting the clinical pregnancy rates of ART or spontaneous pregnancy after fertility-sparing treatments for EC/AEH were included.12–21,25–27 Of the 235 women who had undergone ART, 157 achieved at least one successful clinical pregnancy, with a clinical pregnancy rate of 66.8%. Another 183 women were presumed to try spontaneous pregnancy, and 80 achieved at least one successful clinical pregnancy, with a clinical pregnancy rate of 43.7%. Meta-analysis of clinical pregnancy rate showed a significant difference between ART and spontaneous pregnancy (OR ​= ​2.64, 95% CI 1.72–4.05, P<0.00001, I2 ​= ​14%, Fig. 4).

    Fig. 4
    Fig. 4

    Forest plot of ART vs. spontaneous pregnancy and clinical pregnancy rates.

    To assess the potential for publication bias, a funnel plot was constructed. As shown in Fig. 5, the funnel plot was approximately symmetrical, suggesting no publication bias for the difference between ART and spontaneous pregnancy in clinical pregnancy (Fig. 5).

    Fig. 5
    Fig. 5

    Funnel plot of ART vs. spontaneous pregnancy and clinical pregnancy rates.

    3.4 Clinical pregnancy rates of IVF-ET vs. spontaneous pregnancy

    Seven studies12,14,15,18,20,25,27 reported ART methods in patients who achieved complete remission after AEH/EC. They all reported that women who were willing to have children underwent IVF-ET. The clinical pregnancy rate of IVF-ET (62.7%) was higher than that of spontaneous pregnancy (35.1%), and a significant difference was observed (OR ​= ​2.85, 95% CI 1.44–5.63, P ​= ​0.003, I2 ​= ​29%, Fig. 6). A funnel plot showed no evidence of publication bias (Fig. 7).

    Fig. 7
    Fig. 7

    Funnel plot of IVF vs. spontaneous pregnancy and clinical pregnancy rates.

    Fig. 6
    Fig. 6

    Forest plot of IVF vs. spontaneous pregnancy and clinical pregnancy rates.

    3.5 Live birth rates of ART vs. spontaneous pregnancy

    Five articles reported data on the differences in live birth rates between ART and spontaneous pregnancy.12,16,17,19,21 Women undergoing ART (75.3%) had more live births than that of spontaneous pregnancy (47.8%), but this was not significantly different (OR ​= ​1.87, 95% CI 0.36–9.69, P ​= ​0.45, I2 ​= ​56%, Fig. 8). In a sensitivity analysis that excluded Hahn et al.,12 a significant difference in the live birth rate was observed between ART and spontaneous pregnancy (OR ​= ​3.96, 95% CI 1.76–8.77, P ​= ​0.0009, I2 ​= ​45%).

    Fig. 8
    Fig. 8

    Forest plot of ART vs. spontaneous pregnancy and live birth rates.

    3.6 Clinical pregnancy and recurrence of EC/AEH

    Three studies reported the effect of clinical pregnancy on the recurrence of EC/AEH.16,22,23 Women who had at least one clinical pregnancy had a lower recurrence rate of EC/AEH (26.9%) than those who have never been pregnant (43.4%), but this was not significantly different (OR ​= ​0.51, 95% CI 0.18–1.44, P ​= ​0.20, I2 ​= ​56%, Fig. 9). We aimed to explore the effect of ART treatment on recurrence; however, only one study reported this. According to Tamauchi et al.,22 during a median follow-up of 52 (16–128) months, none of the 5 women who underwent ART had tumor recurrence; whereas 5 of 10 women who had a spontaneous pregnancy had EC/AEH recurrence.

    Fig. 9
    Fig. 9

    Forest plot of clinical pregnancy vs. no pregnancy and recurrence rates.

    4 Discussion

    With the development of fertility-sparing treatments and the increasing rates of complete remission for EC/AEH, conceiving and delivering live births are significant concerns for young women with EC/AEH. Whether conceiving through spontaneous pregnancy or ART in women with EC/AEH is a controversial topic. Choosing a conception method for women with EC/AEH depends on the balance between a high pregnancy rate and a low recurrence rate. This systematic review and meta-analysis synthesized data on women with EC/AEH who received fertility-sparing treatments and desired to conceive. We demonstrated higher pregnancy and live birth rates for ART than for spontaneous pregnancy. Also, there were low recurrence rates of EC/AEH for women who had a clinical pregnancy.

    Compared with women who conceived spontaneously, ART significantly improved the clinical pregnancy rate, resulting in good pregnancy outcomes. We demonstrated that IVF-ET had a positive effect on pregnancy outcomes for patients with EC/AEH. Our findings were consistent with those of previous studies.11,28 However, the studies we included did not report detailed data on ovarian stimulation protocol, embryo quality, endometrial thickness, pregnancy rate, embryo implantation rate or the number of embryo transfer. This meta-analysis only calculated the proportion of pregnancies in women receiving IVF-ET treatment but not the pregnancy rate per cycle. If a woman received multiple embryo transfers in several COH cycles, the pregnancy rate in this paper might be unreasonably high. Therefore, further studies are required to clarify this.

    ART not only improved the pregnancy rate of women with EC/AEH but also increased the live birth rate. Kim et al. reported an acceptable (50%) cumulative pregnancy rate following IVF-ET,24 while all women who delivered successfully had no obstetric complications, such as placental hyperplasia or postpartum hemorrhage. A recent study by Xu et al. also confirmed that ART could improve the pregnancy rate and live birth rate of patients with EC/AEH after fertility preservation.26 A recent study reported that the live birth rate of women receiving fertility preservation was 11.6%,29 which was lower than that reported in our study. This study included women who received fertility-sparing treatments but did not have family planning, so the live birth rate was low. In general, ART, as a safe and feasible method, enables women to obtain considerable live birth rate. Women with EC/AEH should be encouraged to undergo ART after complete remission to achieve clinical pregnancy and live birth.

    For women with EC/AEH, fertility-sparing treatments has a high remission rate, but its recurrence rate of 31% in the present study is also noteworthy. This meta-analysis also analyzed the relationship between pregnancy and recurrence of EC/AEH. The recurrence rate of women with clinical pregnancy was lower than that of women without pregnancy, but there was no statistical difference. Unfortunately, data on live births was limited; hence, the association between live births and recurrence could not be investigated. During pregnancy, it is well known that progesterone levels naturally increase, which might have a similar protective effect on the endometrium compared to high-dose progesterone treatment.30,31 This high hormonal environment continues throughout pregnancy. A previous study by Park et al. showed that women who had at least one pregnancy had a significantly higher 5-year relapse-free survival rate than those who were not pregnant.16,17 Ichinose et al. also reported that women who delivered had a lower risk of recurrence.31 Therefore, pregnancy and live births seem to have a protective effect on women with EC/AEH and reduce the recurrence rate.

    The influence of ART on the recurrence of EC/AEH has been widely debated. It has been reported in several previous studies that ART therapy did not increase the risk of EC/AEH recurrence, and the recurrence rate of women with ART pregnancy after fertility-sparing treatments is comparable to that of women with spontaneous pregnancy.32,33 In the process of controlled ovarian hyperstimulation, some strategies can keep estrogen at low levels to ensure the safety of estrogen-dependent cancer patients and avoid cancer recurrence.34 Currently, there is no evidence that ART is a risk factor for the recurrence of EC/AEH.28 ART treatment is safe and feasible for women with fertility preservation.

    The strengths of this meta-analysis include the comprehensive literature search, robust statistical methods and synthesis of data. We included a total of 16 studies and comprehensively analyzed the data. We conducted a sensitivity analysis to explore the sources of heterogeneity between studies and we also explored for potential publication bias. Finally, we evaluated potential factors affecting recurrence and live birth in patients with EC/AEH and fertility-sparing treatments, which could be used as a reference for further clinical research.

    Some limitations deserve consideration. Since there were no RCTs that met the inclusion criteria, we only included observational cohort designs, which has limitations. Due to the lack of detailed data on ART from the original literature, the robustness of our results is limited. The short-term follow-up duration, small sample sizes and wide confidence intervals reduced the strength of our inferences. Specifically, the relapse and live birth rates may be higher if women were followed up for at least 5 years following their diagnosis.

    5 Conclusion

    For women diagnosed with EC/AEH and complete remission after fertility-sparing treatments, ART (especially IVF-ET) could improve their pregnancy rate and increase the live birth rate. The recurrence rate of EC/AEH in women with clinical pregnancy was lower than that of women without pregnancy. There was no evidence suggesting that ART was associated with recurrence. Given the limitations, the current results should be interpreted with caution.

    Declaration of competing interest

    The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

    Acknowledgement

    This work was supported by the National Key Technology R&D Program of China (no. 2019YFC1005200 and 2019YFC1005203) and the National Natural Science Foundation of PR China (no. 82071715)

    The authors declared no potential conflicts of interest with respect to the research, authorship, or publication of this article.

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    Footnotes

    • ↵1 These two authors have equal contributions to this work