Seventy patients had attempted to conceive, with 44 receiving treatments for infertility, including ovarian hyperstimulation. The mean (±SD) and median intervals to attempted conception after treatment were 7±7 and 5 months (range 1–31 months), respectively. The mean (±SD) and median ages of the patients who tried to conceive at the time of the pregnancy trial were 32.3±3.1 and 32.4 years (range 23–40 years), respectively. The types of infertility treatments included ovulation induction in four patients, controlled ovarian hyperstimulation with intrauterine insemination in 14 cases, in vitro fertilization with intracytoplasmic sperm injection in one case, and in vitro fertilization with embryo transfer in 25 patients. One patient underwent hysteroscopic lysis of an intrauterine adhesion. Figure 1 summarizes these pregnancy outcomes. Of the 44 women who received infertility treatments, 38 (86%) achieved 55 pregnancies and 35 patients (80%) gave birth to 46 live neonates. Of the 26 women who attempted natural pregnancy, 13 (50%) achieved 16 pregnancies and 11 (42%) gave birth to 12 live neonates. In total, 51 of the 70 women (73%) who tried to conceive were successful, and 46 (66%) gave birth to 58 live neonates. Hence, the pregnancy and live birth rates were 73% (95% CI 61–82%) and 66% (95% CI 54–76%), respectively, among 70 women.
The pregnancy rate (86.4% compared with 50%; P=.001) and live birth rate (70.5% compared with 42.3%; P=.020) were significantly higher in patients who received infertility treatment than in patients who attempted natural pregnancy. Of the 58 live neonates born to our patients, 56 were completely healthy; the remaining two neonates had minor congenital anomalies (clubfoot and polydactyly, respectively). In addition, 18 women achieved two pregnancies and one patient achieved three pregnancies in our study cohort. There were also five twin pregnancies and one triplet pregnancy among our patients. In addition, three patients succeeded in becoming pregnant after successful salvage treatment for recurrent disease. After the completion of their planned families, 11 women underwent prophylactic hysterectomy, but no evidence of tumor was found in the uterine specimens.
The spontaneous abortion, ectopic pregnancy, and preterm delivery rates of our present cohort were 24% (95% CI 15–35%), 2.8% (95% CI 0.2–10.3%), and 11.5% (95% CI 5–52.3%), respectively. The spontaneous abortion rate (18.8% compared with 25.5%; P=.745) and ectopic pregnancy rate (3.6% compared with 0%; P=1.000) were not different between patients who received or did not receive infertility treatment. However, the preterm delivery rate (10.9% compared with 0%; P=.326) was higher among patients who had received infertility treatment. When we stratified the occurrence of spontaneous abortions according to maternal age, we found that 10 (59%) and seven (41%) of spontaneous abortions occurred in patients younger than 35 years old and 35 years old or older, respectively. Nine of 40 patients (22.5%) who were younger than 35 years old and had a pregnancy, whereas seven of 11 patients (63.6%) who were 35 years old or older and had a pregnancy sustained a spontaneous abortion (P=.023).
To estimate the influence of pregnancy on the recurrence of endometrioid adenocarcinoma of the uterus after fertility-sparing management using progestin, we compared the disease-free survival outcomes between patients who achieved one or more pregnancies (n=51) and those who did not (n=90). Demographic factors including age (30.7 compared with 31 years; P=.720), body mass index (BMI [calculated as weight (kg)/[height (m)]2] 23.27 compared with 25.08 kg/m2; P=.100), and medical comorbidities (9.8% compared with 10%; P=.970) were found not to be significantly different between patients who achieved pregnancy and patients who did not. The median follow-up times of the patients who achieved pregnancy and those who did not were 91 months (range 38–159 months) and 58 months (range 14–194 months), respectively (P<.001). The 5-year disease-free survival rates for patients who achieved pregnancy and those who did not were 76% and 62%, respectively (P=.028; Fig. 2A).
To estimate the influence of the use of fertility drugs, including clomiphene citrate and gonadotropin, on the recurrence of endometrioid adenocarcinoma after fertility-sparing management using progestin, we compared the disease-free survival rates between patients who received fertility drugs (n=44) and those who did not (n=97). Demographic factors, including age (31 compared with 30.8 years; P=.765), BMI (23.33 compared with 24.93 kg/m2; P=.159), and the diagnosis of medical comorbidities (11.4% compared with 9.3%; P=.701) were not found to be significantly different between patients who did and did not receive fertility drugs. The median follow-up times for patients who received fertility drugs and those who did not were 87 months (range 45–159 months) and 58 months (range 14–194 months), respectively (P<.001). The 5-year disease-free survival rates of patients who received infertility drugs and patients who did not were 73% and 62%, respectively (P=.335; Fig. 2B).
In our present cohort of young women diagnosed with early-stage endometrial cancer, the incidence of infertility (38.3%) was higher than that of the general population (10–15%).14 Although many of our patients required assisted reproductive technology to become pregnant, the pregnancy outcomes of this group are very promising. The pregnancy rate (86.4% compared with 50%; P=.001) and live birth rate (70.5% compared with 42.3%; P=.020) were significantly higher among patients who received infertility treatment than patients who only tried to conceive naturally. The pregnancy rate may be important for estimating the potential effect of pregnancy on subsequent remission. However, the pregnancy results are rather irrelevant to the patients themselves, who are primarily interested in live birth rates.
In the present study, only 46 of 177 patients (26%) who initially tried fertility-sparing management achieved a live birth. However, 71 patients who did not attempt to get pregnant, either because they were not married (n=46) or for other reasons (n=25), may attempt to get pregnant at some time in the future. If all of these women do try to conceive at a later date, a similar number of patients may achieve a live birth. In addition, patients who tried to conceive but did not succeed may also achieve a live birth at some point in the future. Therefore, more of the patients in this study may go on to achieve a live birth.
The spontaneous abortion rate of our patients was 24%, a somewhat higher rate than the general population (15–20%).15,16 However, the spontaneous abortion rate of patients who achieved natural pregnancy was 18.8%, which was lower than the rate of patients who received infertility treatment (25.5%; P=.745) and similar to that of the general population. If we consider the preclinical pregnancy loss and spontaneous abortion rate together, the spontaneous abortion rate of the general population is as high as 30%.17 Compared with this figure, the spontaneous abortion rate of our present cohort is not particularly high. The ectopic pregnancy rate in our current cohort was 2.8%, which is comparable to that of the general population (2%).18 The ectopic pregnancy rate in the present cohort was not different between patients who received infertility treatment and those who did not (3.6% compared with 0%; P=1.000). The preterm delivery rate of our cohort was 11.5%, similar to the rate of 10% for the general population.19 The preterm delivery rate of our study cohort was higher among patients who received infertility treatment than patients who did not (10.9% compared with 0%; P=.326).
There are few reports in the literature on pregnancy outcomes after fertility-sparing management in young women with early endometrial cancer. A recent review reported that 86 (34.8%) of 280 patients who received fertility-sparing management achieved pregnancy and gave birth to 89 live neonates. Han et al20 reported promising pregnancy outcomes of 10 patients who received assisted reproductive technology after successful fertility-sparing management. In their series, nine of 10 patients (90%) achieved nine pregnancies. There was one ectopic pregnancy (11%), two miscarriages (22%), and six patients gave birth to six healthy neonates (67%), although three of these six live births were preterm (50%). Some other previous small case series also reported promising pregnancy outcomes using assisted reproductive technology after successful fertility-sparing management.21–23
The use of fertility drugs, including clomiphene citrate and gonadotropins, is associated with increased estrogen production during the follicular phase of the ovulation induction cycle.24 Some studies have suggested a relationship between the use of fertility drugs and the risk of endometrial cancer,25,26 but this is not supported by other studies.27,28 Hence, this relationship is not clearly understood and remains controversial. In our present series, the use of fertility drugs after successful fertility-sparing management did not result in an increased recurrence of endometrial cancer and therefore did not compromise the disease-free survival of our patients. In fact, the disease-free survival of our patients who succeeded in becoming pregnant was significantly better regardless of the use of fertility drugs. Hence, fertility drugs may be used safely in these patients. It is likely that the use of these drugs after fertility-sparing management will be recommended for women with a history of subfertility or infertility. However, further evaluations are still required.
As the reviewer suggests, the patients with endometrial cancer examined in the current study are thin compared with patients in the United States. However, the World Health Organization criteria for overweight and obesity is different for Western countries and Eastern countries; therefore, our patients are not particularly thin. In addition, we believe that this has little effect on the results of our study and that BMI has no significant effect on pregnancy outcomes.
Our study is limited by its retrospective nature, missing data related to BMI, and by the fact that several patients were lost to follow-up. Also, we were not able to reliably ascertain which patients had medical comorbidities. However, our study benefits greatly from the fact that it involves a large number of patients with endometrial cancer and also incorporates a long follow-up period.
In conclusion, although the proportion of our current patients with a history of subfertility or infertility was high, the pregnancy outcomes after the use of assisted reproductive technology are very promising. Importantly, the use of fertility drugs in our present cohort was not found to be associated with a higher incidence of endometrial cancer recurrence.
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© 2013 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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