ORIGINAL ARTICLES: FERTILITY PRESERVATION

Who will benefit fromuterus-sparing surgery inadenomyosis-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 andR40 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 oddsratios of 6.22, 0.18, and 0.77, respectively. In the younger group, 60.8% of women with history of IVF failure showed successfulpregnancy after surgery. We experienced 2 cases of placenta accreta in far advanced cases.Conclusion(s): This studydemonstrated age as a determinant in fertility outcomes. Surgery could be a beneficial treatment forwomenwhoexperienced IVF treatment failures, especially at ages of%39 years.We could not showa clear benefit of the surgery on fertility outcomes of

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the group aged R40 years. Extremely severe adenomyosis affecting a broad range of the uterinesubendomerial myometrium should be treated carefully on a pregnancy course. (Fertil Steril�2014;102:802–7.�2014 by American Society for Reproductive Medicine.)Key Words: Adenomyosis, surgery, subfertility, pregnancy, complication

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U terine adenomyosis is definedby the presence of endometrialglands and stroma surrounded

by the hypertrophic and hyperplasicmyometrium (1), and its pathogenesisis still not explained sufficiently.Generally, adenomyosis is accepted toresult from a direct invasion of theendometrium into the myometrium,and is thought to be found most likelyduring the fourth and fifth decades oflife and after childbearing activity.However, with the trend of delayedchildbearing, adenomyosis has cometo be diagnosed more frequently infertility clinics (2, 3). This is also

Received February 21, 2014; revised and accepted MY.K. has nothing to disclose. M.Y. has nothing to disReprint requests: Yohei Kishi, M.D., Department of

Hospital, U-Kyo 1-3-3, Nara 631-0805, Japan (E-

Fertility and Sterility® Vol. 102, No. 3, September 20Copyright ©2014 American Society for Reproductivehttp://dx.doi.org/10.1016/j.fertnstert.2014.05.028

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thought to be caused by the recentdevelopment of diagnostic tools suchas high-resolution transvaginal sonog-raphy and magnetic resonance imaging(MRI). With the aid of these diagnostictools, uterine adenomyosis is becominga more common disease among womenwith childbearing desire and showingmore diversity (4–9). Recently, thecorrelation between adenomyosis andendometriosis has gradually beenrevealed (4–9). We often encounteruterine adenomyosis withoutjunctional zone (JZ) changes. Thisatypical adenomyosis often coexistswith severe endometriosis and is

ay 16, 2014; published online June 19, 2014.close. F.T. has nothing to disclose.Obstetrics and Gynecology, Takanohara Centralmail: kishi@takanohara-ch.or.jp).

14 0015-0282/$36.00Medicine, Published by Elsevier Inc.

localized at the outer myometriumwithout aberrations of thesubendometrial myometrium (5, 7, 9).

Major treatment options forwomen wishing to preserve theirfertility are thought to be assistedreproductive technologies (ART) andsurgical removal of the adenomyosis.The impact of adenomyosis on in vitrofertilization (IVF) treatment outcomesis controversial (10–14). Two studiesshowed a positive effect of prolongeddown-regulation on IVF outcomes ofwomen with adenomyosis (10, 11),whereas another study reported anegative effect of adenomyosis on thefinal outcome of IVF treatment (12–14). Regarding surgical removal ofadenomyosis, a recent reviewconcluded that uterus-sparing surgeryfor adenomyosis appears to be feasibleand satisfactory although pointing outthe need of prospective well designed

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studies (15). At this stage, the true impact of various treat-ments on fertility outcomes of adenomyosis-associatedsubfertility has not been fully clarified (16).

We have applied laparoscopic excision surgery of theadenomyosis to symptomatic uterine adenomyosis, andamong these cases roughly 72% of the women desired postop-erative pregnancy. In the present study, we aimed to compilepregnancy outcomes following uterus-sparing surgery, andanalyzed the determining factors of successful pregnancy.Furthermore, to the best of our knowledge, there is no studythat has analyzed postoperative pregnancy outcomes in termsof the difference in localization of uterine adenomyosis. Wealso tried to incorporate this factor into the analysis of fertilityoutcomes.

MATERIALS AND METHODSWe retrospectively compiled the data of 141 women who un-derwent uterus-sparing surgery for uterine adenomyosis fromApril 2007 to December 2012 at the Department of Obstetricsand Gynecology, Takanohara Central Hospital, Nara, Japan.Among them, 102 had the desire for pregnancy at the timeof surgery. Surgical and patient background data wereretrieved from our surgical and patient database. Pregnancyoutcomes were collected from questionnaires or interviewsof outpatients. The median follow-up period was 24 months(range 9–60 months). We defined ‘‘clinical pregnancy’’ as thepresence of a fetal heart beat at 12 weeks of gestation. Alladenomyosis was diagnosed by preoperative MRI. The criteriaused for the definition of adenomyosis on MRI were: 1) a my-ometrial mass with indistinct margins of primarily lowintensity with all sequences; or 2) diffuse or local wideningof the junctional zone on T2-weighted images (>12 mm)(17–19). All the adenomyosis cases were confirmedhistologically. In the analysis of determining factors forclinical pregnancy, we used a univariable analysis and amultivariable regression analysis. In these analyses, we usedthe following variables: age at surgery, coexistingendometriosis, coexisting ovarian endometrioma, RevisedAmerican Fertility Society (r-AFS) scores, anterior wallinvolvements, posterior wall involvements, history of IVFtreatments, weight of adenomyotic nodule, presence of JZchange in MR imaging. There was one missing piece of data.We couldn't follow one patient who was categorized asR40 years old, and the patient's pregnancy outcome wastreated as ‘‘not pregnant.’’ This study was approved by theInstitutional Ethical Committee, and informed consent wasobtained from each of the patients.

Statistical Analysis

The c2 test was used for the comparison of groups regardingcategoric variables; the Fisher exact test was used in the caseof small cell counts. Parametric and nonparametric continuousvariables were compared with the use of the Student t test, andthe Mann-Whitney U test was applied when the variables didnot pass the normality test. P values of < .05 were consideredto be statistically significant. Stepwise logistic regressionanalysis was used for the analysis of the factors related to clin-ical pregnancy (IBM statistics software, version 16; SPSS).

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Surgical Procedures

The patient was placed in Trendelenburg position and triplepuncture laparoscopic surgery performed. We initiatedsurgery by observation of the pelvic cavity to diagnoseassociated disorders. In cases having severe rectovaginalendometriosis, causing posterior cul-de-sac obliteration,we initiated the procedure by excision of the rectal enodo-metriotic nodules from the anterior rectal wall, keeping therectal endometriotic nodules attached to the posterior wallof the uterus; the excised nodules are removed en blocwith the posterior wall adenomyosis foci. After these prepa-rations, we confirmed the boundary between the adenomyo-sis foci and healthy uterine myometrium to determine theextent of resection. An incision was made to the healthymyometrium just adjacent to the adenomyosis foci withthe use of a potassium titanyl phosphate laser. The incisionwas performed step by step by making traction between theadenomyosis foci and the healthy muscles; the differencebetween the adenomyotic nodule and healthy muscles couldbe distinguished by the difference in extensibility. Adeno-myosis tissues are less elastic than the normal uterinemuscles because of fibrotic changes. However, because theborder is unclear, we made incision to the healthy uterinemuscles just adjacent to the adenomyosis foci. In this way,we remove the adenomyosis foci en bloc as completely aspossible. After removal of the adenomyosis foci, the defectedspaces were carefully repaired with continuous stitches of2-0 synthetic absorbable sutures to close the residualmyometrium.

RESULTSPatients' Backgrounds and Surgical Data

Background aspects of the 102 women who had a desire forpregnancy are summarized in Table 1. When the womenwere divided into%39 andR40 years age groups, significantdifferences were found in the number of years of infertile andpercentages of women who had coexisting endometriosis.There was no significant difference in stages of endometriosisor r-AFS scores. The weight of adenomyotic nodules of theolder age group was relatively heavier than that of theyounger group (not significantly); however, blood loss andthe open conversion rate of the older group were significantlyhigher.

Pregnancy Outcomes

Pregnancy outcomes are presented in Table 2. The clinicalpregnancy rate was totally 31.4% (32/102). When the womenwere divided into %39 and R40 years, clinical pregnancyrates were 41.3% and 3.7%, respectively. In the older group,5/6 of the pregnancies ended in miscarriages. All of thewomen who succeeded in clinical pregnancy were deliveredwith the use of elective cesarean section. Next, we analyzedfertility outcomes on women who had a history of IVF fail-ures. In the younger group, 60.8% of the women succeededin postoperative clinical pregnancy. In contrast, the clinicalpregnancy rate of the older group was 7.1%. Most of thewomen had successful pregnancies with the use of IVF

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TABLE 1

Background aspects and surgical data of women who desired pregnancy.

£39 y (n [ 75) ‡40 y (n [ 27) P value

Age, median (range), y 36 (26–39) 42 (40–51)Married women, n (%) 75 (100) 27 (100)Parity, n (%) 7 (9.3) 0 (0) .099a

Preoperative miscarriage, n/n (%) 27 (36.0) 14 (51.9) .149a

Years infertile, mean � SD 2.98 � 1.46 6.58 � 5.78 .011b,c

History of IVF, n (%) 23 (30.6) 13 (48.1) .103a

Coexisting endometriosis, n (%) 54 (72.0) 12 (44.4) .010a,c

Stage 1, n (%) 9/54 (16.7) 1/12 (8.3) .479a

Stage 2, n (%) 8/54 (14.8) 1/12 (8.3) .553a

Stage 3, n (%) 12/54 (22.2) 1/12 (8.3) .273a

Stage 4, n (%) 25/54 (46.2) 9/12 (75.0) .071a

r-AFS score, median (range) 40 (2–120) 72 (4–98) .119b

Clinical symptoms, n (%)Menorrhagia 65 (86.7) 24 (88.9) .766a

Dysmenorrhea 71 (94.7) 26 (96.3) .736a

Dyschezia 43 (57.3) 14 (51.9) .622a

Dyspareunia 42 (56.0) 18 (63.0) .334a

Chronic pelvic pain 35 (46.7) 18 (63.0) .074a

Operation time, median, range (min) 149 (32–406) 146 (89–341) .718b

Blood loss, median, range (g) 150 (10–1,400) 279 (50–1,300) .0007b,d

Nodule weight, median, range (g) 33 (3–838) 92 (2–362) .068b

Open conversion, n (%) 4 (5.3) 5 (18.5) .038a,c

Transfusion, n (%) 1 (1.3) 0 (0) .546a

Note: r-AFS ¼ Revised American Fertility Society.a c2 test.b Mann-Whitney U test.c P%.05.d P%.01.

Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.

ORIGINAL ARTICLE: FERTILITY PRESERVATION

treatment (13/15). The maximum age of the women succeed-ing in clinical pregnancy was 42 years.

Statistical Analysis

The results and variables of the univariable and the multi-variable analyses for clinical pregnancy are presented inTables 3 and 4. The variables extracted in the multivariableregression analysis were: history of IVF treatments,posterior wall involvements, and age at surgery, withodds ratios of 6.22 (95% CI 1.90–20.33), 0.18 (95% CI

TABLE 2

Pregnancy outcomes.

£39 y (n [ 75) ‡40 y (n [ 27)

Overall pregnancy, n (%) 36 (48.0) 6 (22.2)Miscarriage, n 5 5Ectopic pregnancy, n 0 0

Clinical pregnancy, n (%) 31 (41.3) 1 (3.7)Spontaneous, n 16 0IVF, n 15 1

History of IVF treatments, n 23 14Overall pregnancy, n (%) 16/23 (69.5) 5/14 (35.7)

Miscarriage, n 2 4Ectopic pregnancy, n 0 0

Clinical pregnancy, n (%) 14/23 (60.8) 1/14 (7.1)Spontaneous, n 2 0IVF, n 12 1

Note: Median observation 24 months (range 9–60 months).

Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.

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0.09–0.63), and 0.77 (95% CI 0.67–0.88), respectively.We found significant differences of these variables alsoin the univariable analysis. With the use of univariableanalysis, there was a significant difference in r-AFS scoresbetween the groups.

Perinatal Complications

Perinatal complications are shown in Supplemental Table 1(available online at www.fertstert.org). Uterine rupture wasnot found in this series. There were two cases of placenta ac-creta; they underwent postpartum hysterectomies, withoutsevere maternal or fetal complications. Two cases of threat-ened preterm birth were managed by tocolytic treatmentand underwent elective cesarean sections at 35 and 36 weeksgestational age. There were no multiple pregnancies.

TABLE 3

Multivariable analysis for clinical pregnancy (stepwise logisticregression analysis; n [ 101).

Variable Odds ratio 95% CI P value

History of IVF treatments 6.22 1.90–20.33 .002Posterior wall involvements 0.18 0.09–0.63 .004Age at surgery 0.77 0.67–0.88 .002Note:Overall model fit significance level: P< .0001. Variables used: age at surgery, coexistingendometriosis, coexisting endometrioma, anterior wall involvement, posterior wall involve-ment, history of IVF treatments, nodule weight, presence of junctional zone change, RevisedAmerican Fertility Society score.

Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.

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TABLE 4

Univariable analysis for clinical pregnancy.

Clinicalpregnancy D(n [ 32)

Clinicalpregnancy L(n [ 69) P value

Age, median (range), y 33 (25–42) 38 (22–51) .0006b,d

Coexisting endometriosis,n (%)

22 (66.7) 36 (47.8) .117a

Coexisting endometrioma,n (%)

10 (31.2) 26 (37.6) .530a

Anterior wall involvements,n (%)

15 (46.8) 19 (23.2) .055a

Posterior wall involvements,n (%)

18 (56.2) 60 (86.9) .0015a,d

History of IVF treatments,n (%)

15 (46.8) 18 (26.1) .038a

Nodule weight, median(range), g

22 (3–316) 44 (2–838) .0891b

Presence of JZ change, n (%) 9 (28.1) 29 (42.0) .179a

r-AFS score, median (range) 24 (2–120) 64 (2–106) .022b,c

Note: Abbreviations as in Table 3.a c2 test.b Mann-Whitney U test.c P%.05.d P%.01.

Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.

Fertility and Sterility®

DISCUSSIONIn this study, we analyzed a variety of factors concerning thefertility outcomes following uterus-sparing surgery to combatuterine adenomyosis. The total clinical pregnancy rate in ourcases was 31.4% (32/102). Live birth rates following conser-vative surgery for uterine adenomyosis were reported to be32%–36% (16). Our results are thought to be consistent withthese fertility outcomes. Next, we analyzed pregnancy ratesdividing the cases into two groups by the age at surgery.When the cases were grouped into %39 year andR40 years age groups, the clinical pregnancy rates were41.3% and 3.7%, respectively. The clinical pregnancy rateof the R40 years group was significantly lower, and 5/6 ofthe pregnancies ended up with miscarriages. We also showedan adverse impact of age on clinical pregnancy with the use ofmultiple regression analysis (odds ratio 0.77). Our results mayindicate that an increased woman's age is a strong risk factorfor fertility outcomes, common to that of general populations.Generally, fertility declines after 35 years of age, and thechance of miscarriage increases (20). The influence of femaleage on fertility has been established by earlier studies thathave demonstrated a decline in pregnancy rates withadvancing maternal age (21–24). The decrease in thenumber and quality of oocytes is most commonlyconsidered to be the cause of age-related differences infertility outcomes.

Wenow further discuss thewomenwho experiencedpreop-erative IVF failures. ‘‘History of preoperative IVF treatments’’was extracted as a factor relating to clinical pregnancy inmulti-variable regression analysis. When we examine the details, inthe younger group (%39 years) a total of 60.8% of womenwith a history of preoperative IVF failures showed successfulpostoperative pregnancy. In contrast, the older age group(R40 years) resulted in only a 7.1% clinical pregnancy rate

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(1/14). In earlier reports, successful pregnancy rates followingIVF-ET of women with adenomyosis were reported to be11%–35% (10–14). Our study included 37 women who wererecommended to have surgical intervention because ofrepeated IVF failures. For these women we performed anadenomyomectomy, and roughly 60% of those in the youngergroup succeeded in postoperative IVF treatments. This resultsuggests a possible beneficial effect of adenomyomectomy onpatients who experience IVF failures, especially at ages %39years. At the same time, it should be noted that we could notshow a clear benefit of the surgery on fertility outcomes forpatients R40 years old. Also in an earlier study, the live birthrates per cycle of IVF were shown to be drop from 31% at35 years of age to <5% at 42 years of age (25). We shouldrecognize the fact that surgical and IVF treatments can notcompletely compensate for an age-related decline in fertility.

To the best of our knowledge, there have been no studiesthat evaluated the impact of the localization of uterineadenomyosis on fertility outcomes. In this study, we tried tocategorize the localization of adenomyosis in a two-way cate-gorization: ‘‘functional aspect’’ and ‘‘simple topologic aspect.’’In the functional aspect, uterine myometrium could bedivided into subendometrial myometrium (JZ) and outer my-ometrium, where the former is involved in preparation of theendometrium for implantation and uterine peristalsis: spermtransport and hemostasis during menstruation (26–31).Based on these findings, we categorized the present casesinto two groups according to the functional aspect: thepresence or not of JZ changes. Moreover, we added atopologic categorization: anterior and posterior wallinvolvements. As a result, only the topologic factor ofposterior wall involvement of adenomyosis was extracted asa negative factor relating to clinical pregnancy (odds ratio0.18). How should we interpret this result? In our previousstudy, we demonstrated that extrinsic adenomyosis has acharacteristic that it is found mostly on the posterior wall,coexisting with pelvic endometriosis (9).

Again, with the use of univariable analysis, r-AFS scoresof the unsuccessful group were significantly higher thanthose of the successful group, which means that there was atendency of women in the unsuccessful group to have moresevere forms of endometriosis. On the other hand, we caninterpret this result from another viewpoint. In the unsuccess-ful group, 19/69 (27.5%) of the women had adenomyosis atboth anterior and posterior wall; in the successful group,only one women was affected at both anterior and posteriorwall. From these details, the severity of endometriosis andextent of adenomyosis could be considered to be negativefactors relating to clinical pregnancy.

In addition, we would like to consider another theoryrelating to this result: Posterior wall involvements mayhave negatively affected the process of embryo implantation.Up to now, there have been no studies that evaluated thedifference between uterine anterior and posterior wall as adominant implantation site for human embryos. The onlyfindings so far were concerned about sites of human embryoimplantation are that implantation occurs dominantly aroundthe fundus area (32, 33). On the other hand, in mice,implantation of the embryo is known to always take place

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ORIGINAL ARTICLE: FERTILITY PRESERVATION

on the ventral wall of the uterus (34, 35). Gravity might beconsidered to be a reason of this ventral side–dominantimplantation. We consider it to be reasonable if there was adifference between mice as quadrupeds and humans asbipeds on the spacing of implantation sites under theinfluences of gravity. If so, there is no hard evidence tomake clear conclusions on this result. More research isrequired on this subject.

Finally, we should discuss the perinatal complications ofthe surgery. We experienced two cases of placenta accreta,and both of them resulted from extremely severe adenomyo-sis affecting a broad range of the uterine subendometrialmyometrium. In such cases, it is quite difficult to balancebetween complete removal and preservation of the endome-trium. Accordingly in the majority of the far advanced cases,we could not avoid small perforations of the endometrium,which may become a crucial cause of invasion of the placentainto the outer myometrium through the defected subendome-trial myometrium. Another important subject that should betaken account in this type of surgery is uterine rupture duringpregnancy or labor. In this study, we did not experience auterine rupture. However, recently we experienced a case ofuterine rupture after adenomyomectomy (this case was notin the present study period), and that case also was faradvanced. We consider that the size of adenomyosis is themost important factor linked to uterine ruptures. In the pres-ence of uterine adenomyosis, myocytes are widely separatedby a loose connective tissue matrix filled with less elasticcollagen fibrils (30). This structural change may cause adecline in elasticity of the tissues. When the adenomyotic tis-sues remained dense at the excised myometrium surface, therepaired uterine wall could be lower in tensile strength, whichmay increase the risk of uterine ruptures. Especially in faradvanced cases, it is quite difficult to balance between com-plete removal of adenomyosis and preservation of healthyuterine muscles: Fibrotic adenomyotic tissue can remaingrossly at the excised myometrium surface. The more com-plete removal of the adenomyotic nodule may ensure strongerwound healing on defected uterine myometrium, althoughthere must be a limit in size of adenomyosis regarding preser-vation of the uterine wall. From our experience, a noduleweight of >100 g might be relatively risky as an indicationfor uterus-sparing surgery for adenomyosis-associated infer-tility. On the other hand, it is thought to be relatively safe incases of small adenomyosis that localizes the intra or outermyometrium and keeps the JZ intact. We do not considerthat all cases have the same risk of perinatal complications.Precise diagnosis of the localization of each adenomyosiswould provide us with useful information regarding manage-ment of the surgery and assessment of the postoperative risk.Deliberate consideration should be given in each facility ofindications for this type of surgery.

Study Strengths and Limitations

The present study was a retrospective cohort study. Patient se-lection biases should be taken into consideration. It should benoted that there was sometimes no clear line between painand infertility in indications for surgery. Not all of the women

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were able to determine their desire for pregnancy at the timeof surgery, particularly those who were unmarried. We cate-gorized those subjects into the ‘‘no desire for pregnancy’’ cate-gory, and in this study none of them became pregnant afterthe operation. Also, there is one set of incomplete databecause of lost follow-up. As we mentioned, this case wastreated as ‘‘did not conceive.’’ Thus, we think we preventedour results from becoming overestimated.

Some factors related to infertility were difficult to be pre-cisely evaluated. Not all of the women were fully assessed forfemale and male factors, and their duration of infertility wassometimes subjective. For this reason, we used variables thatcould be assessed objectively. However, we consider that ourselection policy would not distort the results of the statisticalanalyses for determinants. Preferably, a well conducted ran-domized study is required to evaluate and analyze the trueefficacy of adenomyosis on fertility outcomes and the deter-mining factors.

CONCLUSIONThis study demonstrated the advantage of fertility outcomesin younger women after uterus-sparing surgery for the uter-ine adenomyosis. This type of surgery could be a beneficialtreatment for women who have experienced IVF treatmentfailures, especially at ages of %39 years. Unfortunately, wecould not show a clear benefit of the surgery on fertility out-comes for patients R40 years old. We experienced two casesof placenta accreta in far advanced cases. Extensive adeno-myosis with subendometrium myometrium involvementshould be treated carefully during pregnancy or labor.

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SUPPLEMENTAL TABLE 1

Perinatal complications.

Patient Age, y Complications Type of adenomyosis

1 35 Placenta accreta Anterior and posterior wall, with J2 31 Placenta accreta Anterior and posterior wall, with J3 34 Threatened preterm

birthPosterior wall, without JZ change

4 37 Threatened pretermbirth

Posterior wall, without JZ change

Note: C/S ¼ cesarean section; JZ ¼ junctional zone.

Kishi. Adenomyomectomy for infertile women. Fertil Steril 2014.

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Noduleweight, g Treatments Delivery data

Birthweight, g Other

Z change 273 Postpartum hysterectomy 35 wk elective C/S 2,095 Site of placenta: fundus posterior sideZ change 126 Postpartum hysterectomy 36 wk elective C/S 2,635 Site of placenta: posterior wall

30 Tocolytic treatment (27 wk) 36 wk elective C/S 2,286

26 Tocolytic treatment (26 wk) 36 wk elective C/S 2,364

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