ORIGINAL ARTICLES: FERTILITY PRESERVATION
Who will benefit from uterus-sparing surgery in adenomyosis-associated subfertility? Yohei Kishi, M.D., Maki Yabuta, M.D., and Fumiaki Taniguchi, M.D. Department of Obstetrics and Gynecology, Takanohara Central Hospital, Nara, Japan
Objective: To analyze the determinants of successful pregnancy following laparoscopic adenomyomectomy. Design: Retrospective cohort study. Setting: A general hospital. Patient(s): A total of 102 women who had a desire for pregnancy underwent laparoscopic adenomyomectomy from 2007 to 2012. Intervention(s): Surgical excision of the uterine adenomyosis; statistical analysis for fertility outcomes. Main Outcome Measure(s): Pregnancy rates and the results of univariable and multivariable analyses. Result(s): When the women were divided into %39 years and R40 years age groups, clinical pregnancy rates were 41.3% and 3.7%, respectively. Factors associated with clinical pregnancy were: history of IVF treatments, posterior wall involvements, and age, with odds ratios of 6.22, 0.18, and 0.77, respectively. In the younger group, 60.8% of women with history of IVF failure showed successful pregnancy after surgery. We experienced 2 cases of placenta accreta in far advanced cases. Conclusion(s): This study demonstrated age as a determinant in fertility outcomes. Surgery could be a beneficial treatment for women who experienced IVF treatment failures, especially at ages of %39 years. We could not show a clear benefit of the surgery on fertility outcomes of the group aged R40 years. Extremely severe adenomyosis affecting a broad range of the uterine Use your smartphone subendomerial myometrium should be treated carefully on a pregnancy course. (Fertil SterilÒ to scan this QR code 2014;102:802–7. Ó2014 by American Society for Reproductive Medicine.) and connect to the Key Words: Adenomyosis, surgery, subfertility, pregnancy, complication Discuss: You can discuss this article with its authors and other ASRM members at http:// fertstertforum.com/kishiy-uterus-sparing-surgery-adenomyosis-subfertility/
U
terine adenomyosis is defined by the presence of endometrial glands and stroma surrounded by the hypertrophic and hyperplasic myometrium (1), and its pathogenesis is still not explained sufficiently. Generally, adenomyosis is accepted to result from a direct invasion of the endometrium into the myometrium, and is thought to be found most likely during the fourth and fifth decades of life and after childbearing activity. However, with the trend of delayed childbearing, adenomyosis has come to be diagnosed more frequently in fertility clinics (2, 3). This is also
thought to be caused by the recent development of diagnostic tools such as high-resolution transvaginal sonography and magnetic resonance imaging (MRI). With the aid of these diagnostic tools, uterine adenomyosis is becoming a more common disease among women with childbearing desire and showing more diversity (4–9). Recently, the correlation between adenomyosis and endometriosis has gradually been revealed (4–9). We often encounter uterine adenomyosis without junctional zone (JZ) changes. This atypical adenomyosis often coexists with severe endometriosis and is
Received February 21, 2014; revised and accepted May 16, 2014; published online June 19, 2014. Y.K. has nothing to disclose. M.Y. has nothing to disclose. F.T. has nothing to disclose. Reprint requests: Yohei Kishi, M.D., Department of Obstetrics and Gynecology, Takanohara Central Hospital, U-Kyo 1-3-3, Nara 631-0805, Japan (E-mail: [email protected]). Fertility and Sterility® Vol. 102, No. 3, September 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.05.028 802
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localized at the outer myometrium without aberrations of the subendometrial myometrium (5, 7, 9). Major treatment options for women wishing to preserve their fertility are thought to be assisted reproductive technologies (ART) and surgical removal of the adenomyosis. The impact of adenomyosis on in vitro fertilization (IVF) treatment outcomes is controversial (10–14). Two studies showed a positive effect of prolonged down-regulation on IVF outcomes of women with adenomyosis (10, 11), whereas another study reported a negative effect of adenomyosis on the final outcome of IVF treatment (12– 14). Regarding surgical removal of adenomyosis, a recent review concluded that uterus-sparing surgery for adenomyosis appears to be feasible and satisfactory although pointing out the need of prospective well designed VOL. 102 NO. 3 / SEPTEMBER 2014
Fertility and Sterility® studies (15). At this stage, the true impact of various treatments on fertility outcomes of adenomyosis-associated subfertility has not been fully clarified (16). We have applied laparoscopic excision surgery of the adenomyosis to symptomatic uterine adenomyosis, and among these cases roughly 72% of the women desired postoperative pregnancy. In the present study, we aimed to compile pregnancy outcomes following uterus-sparing surgery, and analyzed the determining factors of successful pregnancy. Furthermore, to the best of our knowledge, there is no study that has analyzed postoperative pregnancy outcomes in terms of the difference in localization of uterine adenomyosis. We also tried to incorporate this factor into the analysis of fertility outcomes.
MATERIALS AND METHODS We retrospectively compiled the data of 141 women who underwent uterus-sparing surgery for uterine adenomyosis from April 2007 to December 2012 at the Department of Obstetrics and Gynecology, Takanohara Central Hospital, Nara, Japan. Among them, 102 had the desire for pregnancy at the time of surgery. Surgical and patient background data were retrieved from our surgical and patient database. Pregnancy outcomes were collected from questionnaires or interviews of outpatients. The median follow-up period was 24 months (range 9–60 months). We defined ‘‘clinical pregnancy’’ as the presence of a fetal heart beat at 12 weeks of gestation. All adenomyosis was diagnosed by preoperative MRI. The criteria used for the definition of adenomyosis on MRI were: 1) a myometrial mass with indistinct margins of primarily low intensity with all sequences; or 2) diffuse or local widening of the junctional zone on T2-weighted images (>12 mm) (17–19). All the adenomyosis cases were confirmed histologically. In the analysis of determining factors for clinical pregnancy, we used a univariable analysis and a multivariable regression analysis. In these analyses, we used the following variables: age at surgery, coexisting endometriosis, coexisting ovarian endometrioma, Revised American Fertility Society (r-AFS) scores, anterior wall involvements, posterior wall involvements, history of IVF treatments, weight of adenomyotic nodule, presence of JZ change in MR imaging. There was one missing piece of data. We couldn't follow one patient who was categorized as R40 years old, and the patient's pregnancy outcome was treated as ‘‘not pregnant.’’ This study was approved by the Institutional Ethical Committee, and informed consent was obtained from each of the patients.
Statistical Analysis The c2 test was used for the comparison of groups regarding categoric variables; the Fisher exact test was used in the case of small cell counts. Parametric and nonparametric continuous variables were compared with the use of the Student t test, and the Mann-Whitney U test was applied when the variables did not pass the normality test. P values of < .05 were considered to be statistically significant. Stepwise logistic regression analysis was used for the analysis of the factors related to clinical pregnancy (IBM statistics software, version 16; SPSS). VOL. 102 NO. 3 / SEPTEMBER 2014
Surgical Procedures The patient was placed in Trendelenburg position and triple puncture laparoscopic surgery performed. We initiated surgery by observation of the pelvic cavity to diagnose associated disorders. In cases having severe rectovaginal endometriosis, causing posterior cul-de-sac obliteration, we initiated the procedure by excision of the rectal enodometriotic nodules from the anterior rectal wall, keeping the rectal endometriotic nodules attached to the posterior wall of the uterus; the excised nodules are removed en bloc with the posterior wall adenomyosis foci. After these preparations, we confirmed the boundary between the adenomyosis foci and healthy uterine myometrium to determine the extent of resection. An incision was made to the healthy myometrium just adjacent to the adenomyosis foci with the use of a potassium titanyl phosphate laser. The incision was performed step by step by making traction between the adenomyosis foci and the healthy muscles; the difference between the adenomyotic nodule and healthy muscles could be distinguished by the difference in extensibility. Adenomyosis tissues are less elastic than the normal uterine muscles because of fibrotic changes. However, because the border is unclear, we made incision to the healthy uterine muscles just adjacent to the adenomyosis foci. In this way, we remove the adenomyosis foci en bloc as completely as possible. After removal of the adenomyosis foci, the defected spaces were carefully repaired with continuous stitches of 2-0 synthetic absorbable sutures to close the residual myometrium.
RESULTS Patients' Backgrounds and Surgical Data Background aspects of the 102 women who had a desire for pregnancy are summarized in Table 1. When the women were divided into %39 and R40 years age groups, significant differences were found in the number of years of infertile and percentages of women who had coexisting endometriosis. There was no significant difference in stages of endometriosis or r-AFS scores. The weight of adenomyotic nodules of the older age group was relatively heavier than that of the younger group (not significantly); however, blood loss and the open conversion rate of the older group were significantly higher.
Pregnancy Outcomes Pregnancy outcomes are presented in Table 2. The clinical pregnancy rate was totally 31.4% (32/102). When the women were divided into %39 and R40 years, clinical pregnancy rates were 41.3% and 3.7%, respectively. In the older group, 5/6 of the pregnancies ended in miscarriages. All of the women who succeeded in clinical pregnancy were delivered with the use of elective cesarean section. Next, we analyzed fertility outcomes on women who had a history of IVF failures. In the younger group, 60.8% of the women succeeded in postoperative clinical pregnancy. In contrast, the clinical pregnancy rate of the older group was 7.1%. Most of the women had successful pregnancies with the use of IVF 803
ORIGINAL ARTICLE: FERTILITY PRESERVATION
TABLE 1 Background aspects and surgical data of women who desired pregnancy. £39 y (n [ 75) Age, median (range), y Married women, n (%) Parity, n (%) Preoperative miscarriage, n/n (%) Years infertile, mean SD History of IVF, n (%) Coexisting endometriosis, n (%) Stage 1, n (%) Stage 2, n (%) Stage 3, n (%) Stage 4, n (%) r-AFS score, median (range) Clinical symptoms, n (%) Menorrhagia Dysmenorrhea Dyschezia Dyspareunia Chronic pelvic pain Operation time, median, range (min) Blood loss, median, range (g) Nodule weight, median, range (g) Open conversion, n (%) Transfusion, n (%)
36 (26–39) 75 (100) 7 (9.3) 27 (36.0) 2.98 1.46 23 (30.6) 54 (72.0) 9/54 (16.7) 8/54 (14.8) 12/54 (22.2) 25/54 (46.2) 40 (2–120) 65 (86.7) 71 (94.7) 43 (57.3) 42 (56.0) 35 (46.7) 149 (32–406) 150 (10–1,400) 33 (3–838) 4 (5.3) 1 (1.3)
‡40 y (n [ 27)
P value
42 (40–51) 27 (100) 0 (0) 14 (51.9) 6.58 5.78 13 (48.1) 12 (44.4) 1/12 (8.3) 1/12 (8.3) 1/12 (8.3) 9/12 (75.0) 72 (4–98)
.099a .149a .011b,c .103a .010a,c .479a .553a .273a .071a .119b
24 (88.9) 26 (96.3) 14 (51.9) 18 (63.0) 18 (63.0) 146 (89–341) 279 (50–1,300) 92 (2–362) 5 (18.5) 0 (0)
.766a .736a .622a .334a .074a .718b .0007b,d .068b .038a,c .546a
Note: r-AFS ¼ Revised American Fertility Society. a 2 c test. b Mann-Whitney U test. c P%.05. d P%.01. Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.
treatment (13/15). The maximum age of the women succeeding in clinical pregnancy was 42 years.
Statistical Analysis The results and variables of the univariable and the multivariable analyses for clinical pregnancy are presented in Tables 3 and 4. The variables extracted in the multivariable regression analysis were: history of IVF treatments, posterior wall involvements, and age at surgery, with odds ratios of 6.22 (95% CI 1.90–20.33), 0.18 (95% CI
TABLE 2 Pregnancy outcomes.
Overall pregnancy, n (%) Miscarriage, n Ectopic pregnancy, n Clinical pregnancy, n (%) Spontaneous, n IVF, n History of IVF treatments, n Overall pregnancy, n (%) Miscarriage, n Ectopic pregnancy, n Clinical pregnancy, n (%) Spontaneous, n IVF, n
£39 y (n [ 75)
‡40 y (n [ 27)
36 (48.0) 5 0 31 (41.3) 16 15 23 16/23 (69.5) 2 0 14/23 (60.8) 2 12
6 (22.2) 5 0 1 (3.7) 0 1 14 5/14 (35.7) 4 0 1/14 (7.1) 0 1
0.09–0.63), and 0.77 (95% CI 0.67–0.88), respectively. We found significant differences of these variables also in the univariable analysis. With the use of univariable analysis, there was a significant difference in r-AFS scores between the groups.
Perinatal Complications Perinatal complications are shown in Supplemental Table 1 (available online at www.fertstert.org). Uterine rupture was not found in this series. There were two cases of placenta accreta; they underwent postpartum hysterectomies, without severe maternal or fetal complications. Two cases of threatened preterm birth were managed by tocolytic treatment and underwent elective cesarean sections at 35 and 36 weeks gestational age. There were no multiple pregnancies.
TABLE 3 Multivariable analysis for clinical pregnancy (stepwise logistic regression analysis; n [ 101). Variable History of IVF treatments Posterior wall involvements Age at surgery
Odds ratio
95% CI
P value
6.22 0.18 0.77
1.90–20.33 0.09–0.63 0.67–0.88
.002 .004 .002
Note: Median observation 24 months (range 9–60 months).
Note: Overall model fit significance level: P< .0001. Variables used: age at surgery, coexisting endometriosis, coexisting endometrioma, anterior wall involvement, posterior wall involvement, history of IVF treatments, nodule weight, presence of junctional zone change, Revised American Fertility Society score.
Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.
Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.
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TABLE 4 Univariable analysis for clinical pregnancy. Clinical Clinical pregnancy D pregnancy L (n [ 32) (n [ 69) P value Age, median (range), y Coexisting endometriosis, n (%) Coexisting endometrioma, n (%) Anterior wall involvements, n (%) Posterior wall involvements, n (%) History of IVF treatments, n (%) Nodule weight, median (range), g Presence of JZ change, n (%) r-AFS score, median (range)
33 (25–42) 22 (66.7)
38 (22–51) 36 (47.8)
.0006b,d .117a
10 (31.2)
26 (37.6)
.530a
15 (46.8)
19 (23.2)
.055a
18 (56.2)
60 (86.9)
.0015a,d
15 (46.8)
18 (26.1)
.038a
22 (3–316)
44 (2–838)
.0891b
9 (28.1) 24 (2–120)
29 (42.0) 64 (2–106)
.179a .022b,c
Note: Abbreviations as in Table 3. a 2 c test. b Mann-Whitney U test. c P%.05. d P%.01. Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.
DISCUSSION In this study, we analyzed a variety of factors concerning the fertility outcomes following uterus-sparing surgery to combat uterine adenomyosis. The total clinical pregnancy rate in our cases was 31.4% (32/102). Live birth rates following conservative surgery for uterine adenomyosis were reported to be 32%–36% (16). Our results are thought to be consistent with these fertility outcomes. Next, we analyzed pregnancy rates dividing the cases into two groups by the age at surgery. When the cases were grouped into %39 year and R40 years age groups, the clinical pregnancy rates were 41.3% and 3.7%, respectively. The clinical pregnancy rate of the R40 years group was significantly lower, and 5/6 of the pregnancies ended up with miscarriages. We also showed an adverse impact of age on clinical pregnancy with the use of multiple regression analysis (odds ratio 0.77). Our results may indicate that an increased woman's age is a strong risk factor for fertility outcomes, common to that of general populations. Generally, fertility declines after 35 years of age, and the chance of miscarriage increases (20). The influence of female age on fertility has been established by earlier studies that have demonstrated a decline in pregnancy rates with advancing maternal age (21–24). The decrease in the number and quality of oocytes is most commonly considered to be the cause of age-related differences in fertility outcomes. We now further discuss the women who experienced preoperative IVF failures. ‘‘History of preoperative IVF treatments’’ was extracted as a factor relating to clinical pregnancy in multivariable regression analysis. When we examine the details, in the younger group (%39 years) a total of 60.8% of women with a history of preoperative IVF failures showed successful postoperative pregnancy. In contrast, the older age group (R40 years) resulted in only a 7.1% clinical pregnancy rate VOL. 102 NO. 3 / SEPTEMBER 2014
(1/14). In earlier reports, successful pregnancy rates following IVF-ET of women with adenomyosis were reported to be 11%–35% (10–14). Our study included 37 women who were recommended to have surgical intervention because of repeated IVF failures. For these women we performed an adenomyomectomy, and roughly 60% of those in the younger group succeeded in postoperative IVF treatments. This result suggests a possible beneficial effect of adenomyomectomy on patients who experience IVF failures, especially at ages %39 years. At the same time, it should be noted that we could not show a clear benefit of the surgery on fertility outcomes for patients R40 years old. Also in an earlier study, the live birth rates per cycle of IVF were shown to be drop from 31% at 35 years of age to 100 g might be relatively risky as an indication for uterus-sparing surgery for adenomyosis-associated infertility. On the other hand, it is thought to be relatively safe in cases of small adenomyosis that localizes the intra or outer myometrium and keeps the JZ intact. We do not consider that all cases have the same risk of perinatal complications. Precise diagnosis of the localization of each adenomyosis would provide us with useful information regarding management of the surgery and assessment of the postoperative risk. Deliberate consideration should be given in each facility of indications for this type of surgery.
were able to determine their desire for pregnancy at the time of surgery, particularly those who were unmarried. We categorized those subjects into the ‘‘no desire for pregnancy’’ category, and in this study none of them became pregnant after the operation. Also, there is one set of incomplete data because of lost follow-up. As we mentioned, this case was treated as ‘‘did not conceive.’’ Thus, we think we prevented our results from becoming overestimated. Some factors related to infertility were difficult to be precisely evaluated. Not all of the women were fully assessed for female and male factors, and their duration of infertility was sometimes subjective. For this reason, we used variables that could be assessed objectively. However, we consider that our selection policy would not distort the results of the statistical analyses for determinants. Preferably, a well conducted randomized study is required to evaluate and analyze the true efficacy of adenomyosis on fertility outcomes and the determining factors.
CONCLUSION This study demonstrated the advantage of fertility outcomes in younger women after uterus-sparing surgery for the uterine adenomyosis. This type of surgery could be a beneficial treatment for women who have experienced IVF treatment failures, especially at ages of %39 years. Unfortunately, we could not show a clear benefit of the surgery on fertility outcomes for patients R40 years old. We experienced two cases of placenta accreta in far advanced cases. Extensive adenomyosis with subendometrium myometrium involvement should be treated carefully during pregnancy or labor.
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Study Strengths and Limitations The present study was a retrospective cohort study. Patient selection biases should be taken into consideration. It should be noted that there was sometimes no clear line between pain and infertility in indications for surgery. Not all of the women 806
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807
Perinatal complications. Patient Age, y 1 2 3
35 31 34
4
37
Complications
Type of adenomyosis
Nodule weight, g
Placenta accreta Placenta accreta Threatened preterm birth Threatened preterm birth
Anterior and posterior wall, with JZ change Anterior and posterior wall, with JZ change Posterior wall, without JZ change
273 126 30
Postpartum hysterectomy 35 wk elective C/S Postpartum hysterectomy 36 wk elective C/S Tocolytic treatment (27 wk) 36 wk elective C/S
2,095 2,635 2,286
26
Tocolytic treatment (26 wk) 36 wk elective C/S
2,364
Posterior wall, without JZ change
Note: C/S ¼ cesarean section; JZ ¼ junctional zone. Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.
Treatments
Delivery data
Birth weight, g
Other Site of placenta: fundus posterior side Site of placenta: posterior wall
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807.e1
SUPPLEMENTAL TABLE 1
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Who will benefit from uterus-sparing surgery in adenomyosis-associated subfertility? Yohei Kishi, M.D., Maki Yabuta, M.D., and Fumiaki Taniguchi, M.D. Department of Obstetrics and Gynecology, Takanohara Central Hospital, Nara, Japan
Objective: To analyze the determinants of successful pregnancy following laparoscopic adenomyomectomy. Design: Retrospective cohort study. Setting: A general hospital. Patient(s): A total of 102 women who had a desire for pregnancy underwent laparoscopic adenomyomectomy from 2007 to 2012. Intervention(s): Surgical excision of the uterine adenomyosis; statistical analysis for fertility outcomes. Main Outcome Measure(s): Pregnancy rates and the results of univariable and multivariable analyses. Result(s): When the women were divided into %39 years and R40 years age groups, clinical pregnancy rates were 41.3% and 3.7%, respectively. Factors associated with clinical pregnancy were: history of IVF treatments, posterior wall involvements, and age, with odds ratios of 6.22, 0.18, and 0.77, respectively. In the younger group, 60.8% of women with history of IVF failure showed successful pregnancy after surgery. We experienced 2 cases of placenta accreta in far advanced cases. Conclusion(s): This study demonstrated age as a determinant in fertility outcomes. Surgery could be a beneficial treatment for women who experienced IVF treatment failures, especially at ages of %39 years. We could not show a clear benefit of the surgery on fertility outcomes of the group aged R40 years. Extremely severe adenomyosis affecting a broad range of the uterine Use your smartphone subendomerial myometrium should be treated carefully on a pregnancy course. (Fertil SterilÒ to scan this QR code 2014;102:802–7. Ó2014 by American Society for Reproductive Medicine.) and connect to the Key Words: Adenomyosis, surgery, subfertility, pregnancy, complication Discuss: You can discuss this article with its authors and other ASRM members at http:// fertstertforum.com/kishiy-uterus-sparing-surgery-adenomyosis-subfertility/
U
terine adenomyosis is defined by the presence of endometrial glands and stroma surrounded by the hypertrophic and hyperplasic myometrium (1), and its pathogenesis is still not explained sufficiently. Generally, adenomyosis is accepted to result from a direct invasion of the endometrium into the myometrium, and is thought to be found most likely during the fourth and fifth decades of life and after childbearing activity. However, with the trend of delayed childbearing, adenomyosis has come to be diagnosed more frequently in fertility clinics (2, 3). This is also
thought to be caused by the recent development of diagnostic tools such as high-resolution transvaginal sonography and magnetic resonance imaging (MRI). With the aid of these diagnostic tools, uterine adenomyosis is becoming a more common disease among women with childbearing desire and showing more diversity (4–9). Recently, the correlation between adenomyosis and endometriosis has gradually been revealed (4–9). We often encounter uterine adenomyosis without junctional zone (JZ) changes. This atypical adenomyosis often coexists with severe endometriosis and is
Received February 21, 2014; revised and accepted May 16, 2014; published online June 19, 2014. Y.K. has nothing to disclose. M.Y. has nothing to disclose. F.T. has nothing to disclose. Reprint requests: Yohei Kishi, M.D., Department of Obstetrics and Gynecology, Takanohara Central Hospital, U-Kyo 1-3-3, Nara 631-0805, Japan (E-mail: [email protected]). Fertility and Sterility® Vol. 102, No. 3, September 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.05.028 802
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localized at the outer myometrium without aberrations of the subendometrial myometrium (5, 7, 9). Major treatment options for women wishing to preserve their fertility are thought to be assisted reproductive technologies (ART) and surgical removal of the adenomyosis. The impact of adenomyosis on in vitro fertilization (IVF) treatment outcomes is controversial (10–14). Two studies showed a positive effect of prolonged down-regulation on IVF outcomes of women with adenomyosis (10, 11), whereas another study reported a negative effect of adenomyosis on the final outcome of IVF treatment (12– 14). Regarding surgical removal of adenomyosis, a recent review concluded that uterus-sparing surgery for adenomyosis appears to be feasible and satisfactory although pointing out the need of prospective well designed VOL. 102 NO. 3 / SEPTEMBER 2014
Fertility and Sterility® studies (15). At this stage, the true impact of various treatments on fertility outcomes of adenomyosis-associated subfertility has not been fully clarified (16). We have applied laparoscopic excision surgery of the adenomyosis to symptomatic uterine adenomyosis, and among these cases roughly 72% of the women desired postoperative pregnancy. In the present study, we aimed to compile pregnancy outcomes following uterus-sparing surgery, and analyzed the determining factors of successful pregnancy. Furthermore, to the best of our knowledge, there is no study that has analyzed postoperative pregnancy outcomes in terms of the difference in localization of uterine adenomyosis. We also tried to incorporate this factor into the analysis of fertility outcomes.
MATERIALS AND METHODS We retrospectively compiled the data of 141 women who underwent uterus-sparing surgery for uterine adenomyosis from April 2007 to December 2012 at the Department of Obstetrics and Gynecology, Takanohara Central Hospital, Nara, Japan. Among them, 102 had the desire for pregnancy at the time of surgery. Surgical and patient background data were retrieved from our surgical and patient database. Pregnancy outcomes were collected from questionnaires or interviews of outpatients. The median follow-up period was 24 months (range 9–60 months). We defined ‘‘clinical pregnancy’’ as the presence of a fetal heart beat at 12 weeks of gestation. All adenomyosis was diagnosed by preoperative MRI. The criteria used for the definition of adenomyosis on MRI were: 1) a myometrial mass with indistinct margins of primarily low intensity with all sequences; or 2) diffuse or local widening of the junctional zone on T2-weighted images (>12 mm) (17–19). All the adenomyosis cases were confirmed histologically. In the analysis of determining factors for clinical pregnancy, we used a univariable analysis and a multivariable regression analysis. In these analyses, we used the following variables: age at surgery, coexisting endometriosis, coexisting ovarian endometrioma, Revised American Fertility Society (r-AFS) scores, anterior wall involvements, posterior wall involvements, history of IVF treatments, weight of adenomyotic nodule, presence of JZ change in MR imaging. There was one missing piece of data. We couldn't follow one patient who was categorized as R40 years old, and the patient's pregnancy outcome was treated as ‘‘not pregnant.’’ This study was approved by the Institutional Ethical Committee, and informed consent was obtained from each of the patients.
Statistical Analysis The c2 test was used for the comparison of groups regarding categoric variables; the Fisher exact test was used in the case of small cell counts. Parametric and nonparametric continuous variables were compared with the use of the Student t test, and the Mann-Whitney U test was applied when the variables did not pass the normality test. P values of < .05 were considered to be statistically significant. Stepwise logistic regression analysis was used for the analysis of the factors related to clinical pregnancy (IBM statistics software, version 16; SPSS). VOL. 102 NO. 3 / SEPTEMBER 2014
Surgical Procedures The patient was placed in Trendelenburg position and triple puncture laparoscopic surgery performed. We initiated surgery by observation of the pelvic cavity to diagnose associated disorders. In cases having severe rectovaginal endometriosis, causing posterior cul-de-sac obliteration, we initiated the procedure by excision of the rectal enodometriotic nodules from the anterior rectal wall, keeping the rectal endometriotic nodules attached to the posterior wall of the uterus; the excised nodules are removed en bloc with the posterior wall adenomyosis foci. After these preparations, we confirmed the boundary between the adenomyosis foci and healthy uterine myometrium to determine the extent of resection. An incision was made to the healthy myometrium just adjacent to the adenomyosis foci with the use of a potassium titanyl phosphate laser. The incision was performed step by step by making traction between the adenomyosis foci and the healthy muscles; the difference between the adenomyotic nodule and healthy muscles could be distinguished by the difference in extensibility. Adenomyosis tissues are less elastic than the normal uterine muscles because of fibrotic changes. However, because the border is unclear, we made incision to the healthy uterine muscles just adjacent to the adenomyosis foci. In this way, we remove the adenomyosis foci en bloc as completely as possible. After removal of the adenomyosis foci, the defected spaces were carefully repaired with continuous stitches of 2-0 synthetic absorbable sutures to close the residual myometrium.
RESULTS Patients' Backgrounds and Surgical Data Background aspects of the 102 women who had a desire for pregnancy are summarized in Table 1. When the women were divided into %39 and R40 years age groups, significant differences were found in the number of years of infertile and percentages of women who had coexisting endometriosis. There was no significant difference in stages of endometriosis or r-AFS scores. The weight of adenomyotic nodules of the older age group was relatively heavier than that of the younger group (not significantly); however, blood loss and the open conversion rate of the older group were significantly higher.
Pregnancy Outcomes Pregnancy outcomes are presented in Table 2. The clinical pregnancy rate was totally 31.4% (32/102). When the women were divided into %39 and R40 years, clinical pregnancy rates were 41.3% and 3.7%, respectively. In the older group, 5/6 of the pregnancies ended in miscarriages. All of the women who succeeded in clinical pregnancy were delivered with the use of elective cesarean section. Next, we analyzed fertility outcomes on women who had a history of IVF failures. In the younger group, 60.8% of the women succeeded in postoperative clinical pregnancy. In contrast, the clinical pregnancy rate of the older group was 7.1%. Most of the women had successful pregnancies with the use of IVF 803
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TABLE 1 Background aspects and surgical data of women who desired pregnancy. £39 y (n [ 75) Age, median (range), y Married women, n (%) Parity, n (%) Preoperative miscarriage, n/n (%) Years infertile, mean SD History of IVF, n (%) Coexisting endometriosis, n (%) Stage 1, n (%) Stage 2, n (%) Stage 3, n (%) Stage 4, n (%) r-AFS score, median (range) Clinical symptoms, n (%) Menorrhagia Dysmenorrhea Dyschezia Dyspareunia Chronic pelvic pain Operation time, median, range (min) Blood loss, median, range (g) Nodule weight, median, range (g) Open conversion, n (%) Transfusion, n (%)
36 (26–39) 75 (100) 7 (9.3) 27 (36.0) 2.98 1.46 23 (30.6) 54 (72.0) 9/54 (16.7) 8/54 (14.8) 12/54 (22.2) 25/54 (46.2) 40 (2–120) 65 (86.7) 71 (94.7) 43 (57.3) 42 (56.0) 35 (46.7) 149 (32–406) 150 (10–1,400) 33 (3–838) 4 (5.3) 1 (1.3)
‡40 y (n [ 27)
P value
42 (40–51) 27 (100) 0 (0) 14 (51.9) 6.58 5.78 13 (48.1) 12 (44.4) 1/12 (8.3) 1/12 (8.3) 1/12 (8.3) 9/12 (75.0) 72 (4–98)
.099a .149a .011b,c .103a .010a,c .479a .553a .273a .071a .119b
24 (88.9) 26 (96.3) 14 (51.9) 18 (63.0) 18 (63.0) 146 (89–341) 279 (50–1,300) 92 (2–362) 5 (18.5) 0 (0)
.766a .736a .622a .334a .074a .718b .0007b,d .068b .038a,c .546a
Note: r-AFS ¼ Revised American Fertility Society. a 2 c test. b Mann-Whitney U test. c P%.05. d P%.01. Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.
treatment (13/15). The maximum age of the women succeeding in clinical pregnancy was 42 years.
Statistical Analysis The results and variables of the univariable and the multivariable analyses for clinical pregnancy are presented in Tables 3 and 4. The variables extracted in the multivariable regression analysis were: history of IVF treatments, posterior wall involvements, and age at surgery, with odds ratios of 6.22 (95% CI 1.90–20.33), 0.18 (95% CI
TABLE 2 Pregnancy outcomes.
Overall pregnancy, n (%) Miscarriage, n Ectopic pregnancy, n Clinical pregnancy, n (%) Spontaneous, n IVF, n History of IVF treatments, n Overall pregnancy, n (%) Miscarriage, n Ectopic pregnancy, n Clinical pregnancy, n (%) Spontaneous, n IVF, n
£39 y (n [ 75)
‡40 y (n [ 27)
36 (48.0) 5 0 31 (41.3) 16 15 23 16/23 (69.5) 2 0 14/23 (60.8) 2 12
6 (22.2) 5 0 1 (3.7) 0 1 14 5/14 (35.7) 4 0 1/14 (7.1) 0 1
0.09–0.63), and 0.77 (95% CI 0.67–0.88), respectively. We found significant differences of these variables also in the univariable analysis. With the use of univariable analysis, there was a significant difference in r-AFS scores between the groups.
Perinatal Complications Perinatal complications are shown in Supplemental Table 1 (available online at www.fertstert.org). Uterine rupture was not found in this series. There were two cases of placenta accreta; they underwent postpartum hysterectomies, without severe maternal or fetal complications. Two cases of threatened preterm birth were managed by tocolytic treatment and underwent elective cesarean sections at 35 and 36 weeks gestational age. There were no multiple pregnancies.
TABLE 3 Multivariable analysis for clinical pregnancy (stepwise logistic regression analysis; n [ 101). Variable History of IVF treatments Posterior wall involvements Age at surgery
Odds ratio
95% CI
P value
6.22 0.18 0.77
1.90–20.33 0.09–0.63 0.67–0.88
.002 .004 .002
Note: Median observation 24 months (range 9–60 months).
Note: Overall model fit significance level: P< .0001. Variables used: age at surgery, coexisting endometriosis, coexisting endometrioma, anterior wall involvement, posterior wall involvement, history of IVF treatments, nodule weight, presence of junctional zone change, Revised American Fertility Society score.
Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.
Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.
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TABLE 4 Univariable analysis for clinical pregnancy. Clinical Clinical pregnancy D pregnancy L (n [ 32) (n [ 69) P value Age, median (range), y Coexisting endometriosis, n (%) Coexisting endometrioma, n (%) Anterior wall involvements, n (%) Posterior wall involvements, n (%) History of IVF treatments, n (%) Nodule weight, median (range), g Presence of JZ change, n (%) r-AFS score, median (range)
33 (25–42) 22 (66.7)
38 (22–51) 36 (47.8)
.0006b,d .117a
10 (31.2)
26 (37.6)
.530a
15 (46.8)
19 (23.2)
.055a
18 (56.2)
60 (86.9)
.0015a,d
15 (46.8)
18 (26.1)
.038a
22 (3–316)
44 (2–838)
.0891b
9 (28.1) 24 (2–120)
29 (42.0) 64 (2–106)
.179a .022b,c
Note: Abbreviations as in Table 3. a 2 c test. b Mann-Whitney U test. c P%.05. d P%.01. Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.
DISCUSSION In this study, we analyzed a variety of factors concerning the fertility outcomes following uterus-sparing surgery to combat uterine adenomyosis. The total clinical pregnancy rate in our cases was 31.4% (32/102). Live birth rates following conservative surgery for uterine adenomyosis were reported to be 32%–36% (16). Our results are thought to be consistent with these fertility outcomes. Next, we analyzed pregnancy rates dividing the cases into two groups by the age at surgery. When the cases were grouped into %39 year and R40 years age groups, the clinical pregnancy rates were 41.3% and 3.7%, respectively. The clinical pregnancy rate of the R40 years group was significantly lower, and 5/6 of the pregnancies ended up with miscarriages. We also showed an adverse impact of age on clinical pregnancy with the use of multiple regression analysis (odds ratio 0.77). Our results may indicate that an increased woman's age is a strong risk factor for fertility outcomes, common to that of general populations. Generally, fertility declines after 35 years of age, and the chance of miscarriage increases (20). The influence of female age on fertility has been established by earlier studies that have demonstrated a decline in pregnancy rates with advancing maternal age (21–24). The decrease in the number and quality of oocytes is most commonly considered to be the cause of age-related differences in fertility outcomes. We now further discuss the women who experienced preoperative IVF failures. ‘‘History of preoperative IVF treatments’’ was extracted as a factor relating to clinical pregnancy in multivariable regression analysis. When we examine the details, in the younger group (%39 years) a total of 60.8% of women with a history of preoperative IVF failures showed successful postoperative pregnancy. In contrast, the older age group (R40 years) resulted in only a 7.1% clinical pregnancy rate VOL. 102 NO. 3 / SEPTEMBER 2014
(1/14). In earlier reports, successful pregnancy rates following IVF-ET of women with adenomyosis were reported to be 11%–35% (10–14). Our study included 37 women who were recommended to have surgical intervention because of repeated IVF failures. For these women we performed an adenomyomectomy, and roughly 60% of those in the younger group succeeded in postoperative IVF treatments. This result suggests a possible beneficial effect of adenomyomectomy on patients who experience IVF failures, especially at ages %39 years. At the same time, it should be noted that we could not show a clear benefit of the surgery on fertility outcomes for patients R40 years old. Also in an earlier study, the live birth rates per cycle of IVF were shown to be drop from 31% at 35 years of age to 100 g might be relatively risky as an indication for uterus-sparing surgery for adenomyosis-associated infertility. On the other hand, it is thought to be relatively safe in cases of small adenomyosis that localizes the intra or outer myometrium and keeps the JZ intact. We do not consider that all cases have the same risk of perinatal complications. Precise diagnosis of the localization of each adenomyosis would provide us with useful information regarding management of the surgery and assessment of the postoperative risk. Deliberate consideration should be given in each facility of indications for this type of surgery.
were able to determine their desire for pregnancy at the time of surgery, particularly those who were unmarried. We categorized those subjects into the ‘‘no desire for pregnancy’’ category, and in this study none of them became pregnant after the operation. Also, there is one set of incomplete data because of lost follow-up. As we mentioned, this case was treated as ‘‘did not conceive.’’ Thus, we think we prevented our results from becoming overestimated. Some factors related to infertility were difficult to be precisely evaluated. Not all of the women were fully assessed for female and male factors, and their duration of infertility was sometimes subjective. For this reason, we used variables that could be assessed objectively. However, we consider that our selection policy would not distort the results of the statistical analyses for determinants. Preferably, a well conducted randomized study is required to evaluate and analyze the true efficacy of adenomyosis on fertility outcomes and the determining factors.
CONCLUSION This study demonstrated the advantage of fertility outcomes in younger women after uterus-sparing surgery for the uterine adenomyosis. This type of surgery could be a beneficial treatment for women who have experienced IVF treatment failures, especially at ages of %39 years. Unfortunately, we could not show a clear benefit of the surgery on fertility outcomes for patients R40 years old. We experienced two cases of placenta accreta in far advanced cases. Extensive adenomyosis with subendometrium myometrium involvement should be treated carefully during pregnancy or labor.
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Study Strengths and Limitations The present study was a retrospective cohort study. Patient selection biases should be taken into consideration. It should be noted that there was sometimes no clear line between pain and infertility in indications for surgery. Not all of the women 806
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807
Perinatal complications. Patient Age, y 1 2 3
35 31 34
4
37
Complications
Type of adenomyosis
Nodule weight, g
Placenta accreta Placenta accreta Threatened preterm birth Threatened preterm birth
Anterior and posterior wall, with JZ change Anterior and posterior wall, with JZ change Posterior wall, without JZ change
273 126 30
Postpartum hysterectomy 35 wk elective C/S Postpartum hysterectomy 36 wk elective C/S Tocolytic treatment (27 wk) 36 wk elective C/S
2,095 2,635 2,286
26
Tocolytic treatment (26 wk) 36 wk elective C/S
2,364
Posterior wall, without JZ change
Note: C/S ¼ cesarean section; JZ ¼ junctional zone. Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.
Treatments
Delivery data
Birth weight, g
Other Site of placenta: fundus posterior side Site of placenta: posterior wall
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807.e1
SUPPLEMENTAL TABLE 1
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