{"paper_id":"6729c441-57f9-4a14-9444-988d4ce27db0","body_text":"Adenomyosis is a benign gynecological disease in which the endometrial glands and stroma are present in the myometrium, causing hypermenstruation, dysmenorrhea, infertility, and a significant reduction in quality of life.[ 1 , 2 ] For women of reproductive age, the negative impact of adenomyosis on fertility is a primary concern, and patients with adenomyosis often have intractable infertility, which has been treated with a variety of infertility treatments.[ 3 , 4 ]\nRecently, a number of reports have shown an association between adenomyosis and adverse pregnancy outcomes, including an increased risk of preterm delivery, hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), and placental malposition,[ 5 6 7 ] demonstrating that adenomyosis has adverse effects on pregnancy.\nAlthough hormone therapy has been considered a conservative treatment for adenomyosis,[ 8 9 10 ] controlling symptoms of dysmenorrhea and hypermenorrhea are often difficult through long-time drug therapies. While hysterectomy remains the primary treatment for adenomyosis, such a procedure may not be a viable therapeutic option for many women of reproductive age who desire children. The frequency of adenomyosis-complicated pregnancy has been increasing in recent years with the advancing age of pregnancy among women.[ 2 ] Therefore, women who want to preserve fertility would often be offered conservative surgical treatments for adenomyosis.[ 11 ] Adenomyomectomy, one of the surgical treatments for adenomyosis, has been reported to be effective in improving symptoms of dysmenorrhea and hypermenorrhea.[ 12 ] Initially, adenomyomectomy was performed under an open abdomen, but in recent years, more and more laparoscopic techniques have been reported.[ 13 ] However, whether it be open or laparoscopic, some reports have suggested that this procedure increases the risk of uterine rupture during a subsequent pregnancy.[ 11 ] Therefore, no consensus has yet been established regarding the treatment of adenomyomectomy before pregnancy.\nTo date, several reports have investigated the effects of adenomyomectomy on pregnancy outcomes, including rates of subsequent pregnancy, miscarriage, and live birth. However, only a few studies have comprehensively examined pregnancy outcomes after adenomyomectomy. The present study, therefore, retrospectively investigated the efficacy of laparoscopic surgical treatment on pregnancy outcomes by examining obstetric complications of pregnancies after laparoscopic adenomyomectomy.\n\nThis retrospective cohort study evaluated pregnancy outcomes in patients after laparoscopic adenomyomectomy between January 01, 2005 and December 31, 2020 at a single institution. A total of 43 pregnant cases with adenomyosis were enrolled in this study after excluding subsequent pregnancies ending in miscarriages or ectopic pregnancies and those with obvious recurrence of adenomyosis. The nonsurgery group consisted of pregnant patients with no history of surgery for adenomyosis who delivered a live infant ( N  = 26), excluding cases of miscarriage ( N  = 13) and ectopic pregnancy ( N  = 2). The surgery group consisted of pregnant patients who delivered after laparoscopic adenomyomectomy ( N  = 17), excluding the cases of miscarriage ( N  = 6), ectopic pregnancy ( N  = 2), and obvious recurrence of adenomyosis ( N  = 1) [ Figure 1 ]. Adenomyosis was diagnosed through magnetic resonance imaging (MRI) before pregnancy and confirmed through pathological examination in the surgery group. Based on previous reports, the following criteria were adopted for diagnosing adenomyosis through MRI: (1) a myometrial mass with indistinct margins of primarily low signal intensity or (2) thickening of the junctional zone forming an ill-defined area of low signal intensity on T2-weighted images.[ 14 ] Focal-type adenomyosis was defined as an adenomyotic lesion in the restricted area of the hypertrophic and distorted endometrium and myometrium, usually embedded within the normal myometrium. Diffuse-type adenomyosis was defined as an adenomyotic lesion developing at all layers of the myometrium that can be characterized by foci of endometrial mucosa (glands and stroma) scattered throughout the uterine musculature as previously reported.[ 11 ] Surgery was performed in cases of repeated assisted reproductive technology failures, repeated miscarriages, and cases of difficulty with infertility treatment due to severe pain. All surgeries were performed laparoscopically. Uterine sparing surgeries for adenomyosis can be divided into adenomyomectomy for focal adenomyosis and cytoreductive surgery for extensive adenomyosis.[ 15 ] In cases with focal adenomyosis, the adenomyotic lesion was enucleated. In cases with diffuse-type adenomyosis, a transverse incision was made on the uterine myometrium using an ultrasonic scalpel to reduce blood loss, followed by removal along the adenomyosis lesion. An incision was made at the site of the adenomyosis lesion approximately 1 cm outside the endometrium to not disrupt the endometrium. Based on the depth of the wound, the myometrium was sutured with a single or multilayer suture to ensure no dead space, while the uterus was reconstructed as described by Grimbizis  et al .[ 16 , 17 ] A representative image of laparoscopic adenomyomectomy is shown in  Figure 2 . All pregnant patients were managed at our institution, and the pregnant patients’ medical records were assessed. Some of the patients’ clinical data, such as type of adenomyosis (focal or diffuse), the position of adenomyosis (anterior or posterior), and history of endometriosis, were determined from the medical records. To investigate the influence of surgical treatment for adenomyosis on perinatal prognosis, obstetric complications, such as preterm delivery, FGR (FGR; defined FGR as estimated fetal weight <1.5 standard deviation [SD] of gestational age), HDP, placental malposition (includes from low to total placenta previa), oligohydramnios (amniotic fluid pocket <2 cm or amniotic fluid index <4.0), gestational diabetes mellitus (GDM), uterine rupture, abruptio placentae, postpartum hemorrhage (PPH; vaginal delivery: defined as >500 mL within 24 h postpartum and cesarean section: defined as >1,000 mL), and neonatal outcomes (e.g., gestational weeks, birth weight, Apgar score at 1 and 5 min, umbilical cord artery pH, neonatal intensive care unit (NICU) admission, and neonatal death) were compared between both groups. Moreover, we examined the influence of laparoscopic adenomyomectomy on overall obstetric complications by determining the number of obstetric events, such as preterm delivery, FGR, HDP, placental malposition, oligohydramnios, GDM, uterine rupture, abruptio, and PPH. We adopted “obstetric morbidity” as a composite criterion by compiling all nine events and compared it between the study groups as previously reported.[ 18 ] Each obstetric event was counted as one. Obstetric morbidity in each group was compared by summing the number of relevant events (0–9 events). We excluded the pregnant patients with multiple pregnancies, congenital abnormalities, chronic hypertension or diabetes mellitus, endocrine diseases, cardiovascular diseases, and other internal complications. This study was approved by the Institutional Review Board of Teine Keijinkai Hospital (2-020039-00) and was conducted in accordance with Ethical Guidelines for Medical and Health Research Involving Human Subjects. The requirement for obtaining written informed consent was waived given the retrospective nature of the study.\nFlow chart of this study\n(a) The representative photo imaging of adenomyomectomy during surgery After transverse incision of uterine myometrium using an ultrasonic scalpel, followed by removal along the adenomyosis lesion (a, b) An incision was made at the site of the adenomyosis lesion about 1 cm outside the endometrium not to disrupt the endometrium. According to the depth of the wound, the myometrium was sutured with a single or multilayer, not to make dead space (c)\nThe Mann–Whitney  U -test and Fisher’s exact test were used as appropriate. All statistical analyses were conducted using JUMP version 10 (JUMP, Chicago, IL, USA), with  P  < 0.05 indicating statistical significance.\n\nAmong the 20 patients who underwent laparoscopic adenomyomectomy at our institution to preserve fertility over the past 16 years, 19 became pregnant and 17 eventually had a live birth. The clinical data of all 20 patients who underwent adenomyomectomy are summarized in  Table 1 . During adenomyomectomy, the median maternal age (range) was 36 (24–42) years, parity was 0.25 ± 0.44 (mean ± SD), the weight of the adenomyosis lesion was 37.2 ± 9.5 g, duration of surgery was 149 (47–443) min, estimated blood loss at surgery was 50 (20–850) ml, and the period from surgery to pregnancy was 24 (6–78) months.\nClinical characteristics of the patients who underwent laparoscopic adenomyomectomy for pregnancy\n*Values are presented as median (IQR), mean±SD, or  n  (%). IQR: Interquartile range, SD: Standard deviation, GnRH: Gonadotropin-releasing hormone\nAfter excluding miscarriages, ectopic pregnancies, and one obvious case of recurrence, 43 pregnant women with adenomyosis were enrolled in the present study [ Table 2 ]. Among the included women, 17 and 26 in the surgery and nonsurgery groups were diagnosed with adenomyosis based on MRI before pregnancy, respectively [ Table 2 ]. Moreover, 26 cases (60.5%) became pregnant through assisted reproductive technology. Diffuse- and focal-type adenomyosis was observed in 18 (41.9%) and 25 cases (58.1%), respectively, whereas 12 cases (27.9%) had a history of endometriosis [ Table 2 ]. Among the 43 cases, 33 (76.7%) developed pregnancy complications, including preterm delivery (10 cases, 23.3%), FGR (7 cases, 16.3%), HDP (4 cases, 9.3%), placental malposition (6 cases, 14.0%), oligohydramnios (5 cases, 11.6%), GDM (5 cases, 11.6%), abruptio placentae (2 cases, 4.7%), and uterine rupture (1 cases, 2.3%) [ Table 3 ]. In addition, we compared the pregnancy outcomes between the nonsurgery ( N  = 26) and surgery groups ( N  = 17). Accordingly, no differences in clinical backgrounds were observed between both groups. Regarding obstetric complications, no FGR case was noted in the surgery group, which was significantly less than that in the nonsurgery group ( P  = 0.031). Regarding other obstetrics complications, no differences in preterm delivery (19.3%, 5/26 vs. 29.4%, 5/17), HDP (11.5%, 3/26 vs. 5.9%, 1/17), placental malposition (15.4%, 4/26 vs. 11.8%, 2/17), oligohydramnios (15.4%, 4/26 vs. 5.9%, 1/17), GDM (15.4%, 4/26 vs. 5.9%, 1/17), uterine rupture (0%, 0/26 vs. 5.9%, 1/17), abruptio placentae (7.7%, 1/26 vs. 5.9%, 1/17), and PPH (61.5%, 16/26 vs. 58.8%, 10/17) were found between both groups. No difference in obstetric morbidity was observed between the two groups (19.2%, 45/234 vs. 13.7%, 21/153). The surgery group had a significantly higher rate of cesarean sections compared to the nonsurgery group given that all pregnancies after adenomyomectomy were delivered through cesarean sections (nonsurgery vs. surgery: 53.8%, 14/26 vs. 100%, 17/17;  P  = 0.001), although no difference in gestational weeks (37.2 ± 2.4 vs. 36.4 ± 3.2) and birth weight (2573.6 ± 557.9 g vs. 2555.4 ± 680.8 g) was observed. No differences in Apgar score at 1 min (8.0 ± 0.7 vs. 7.7 ± 1.2) and 5 min (8.9 ± 0.6 vs. 8.5 ± 1.8), umbilical artery pH (UApH) (7.28 ± 0.08 vs. 7.28 ± 0.06), NICU admission (26.9%, 7/26 vs. 41.2%, 7/17), and neonatal death (0%, 0/26 vs. 0%, 0/17) were noted between both groups. One case had diffuse-type adenomyosis with intraoperative endometrial perforation developed uterine rupture at 34 weeks of gestation. The patient showed no uterine cavity defect on hysteroscopy 3 months after the adenomyomectomy, which permitted assisted reproductive technology pregnancy. Given her high risk for uterine rupture, she had been carefully managed and admitted to the hospital for threatened premature labor starting at 30 weeks of gestation. At 34 weeks of gestation, she complained of a sudden lower abdominal pain together with a decrease in the fetal heart rate, for which an emergency cesarean section was performed. Uterine rupture at uterine fundus due to placenta percreta was confirmed during surgery. The neonatal birth weight was 2039 g, with an Apgar score of 5/8 and UApH of 7.145. Fortunately, both mother and child recovered well and were subsequently discharged from the hospital.\nMaternal characteristics of patients with adenomyosis in the nonsurgery and surgery groups\nValues are presented as median (IQR), mean±SD, or  n  (%). IQR: Interquartile range, SD: Standard deviation, ART: Assisted reproductive technology, NS: Not significant\nPerinatal outcomes of the pregnant patients in the nonsurgery and surgery groups\nPlacental malposition includes placenta previa or low-lying placenta that required cesarean section. Values are presented as mean±SD or  n  (%). NICU: Neonatal intensive care unit, NS: Not significant, SD: Standard deviation\nTo examine the perinatal prognosis of each subtype of adenomyosis, the 43 patients were divided into those with focal-( N  = 25) and diffuse-type adenomyosis ( N  = 18). We investigated whether laparoscopic adenomyomectomy improves the pregnancy prognosis in focal and diffuse types, but found no difference in either case, although the small number of cases may have had an effect ( supplemental data 1 ).\nClinical characteristics and perinatal outcomes of pregnant patients according to adenomyosis type (focal and diffuse type)\nValues are presented as mean±SD or  n  (%). ART: Assisted reproductive technology, NS: Not significant, SD: Standard deviation\n\nTo the best of our knowledge, this is the first study to comprehensively investigate the effectiveness of laparoscopic surgical treatment for adenomyosis on pregnancy outcomes. To date, only a few reports have examined outcomes of subsequent pregnancies after adenomyomectomy. Kwack  et al . reported on the perinatal outcome of 22 pregnancies after adenomyomectomy, and found that seven cases (31.8%) had preterm delivery but none of them had FGR or preeclampsia.[ 19 ] From, their study, Li YT  et al . noted the safety of the perinatal outcome in women with adenomyosis treated with adenomyomectomy, although we still took much care about the preterm labor and pregnancy-related complications in these women.[ 20 ] The same study also observed one case of uterine rupture and four cases of placenta accreta Sugiyama  et al ., who investigated the outcomes of 10 pregnancies after abdominal adenomyomectomy, reported three cases (30%) of preterm delivery.[ 21 ] Among the pregnant women who underwent adenomyomectomy in the present study, 29.4% experienced preterm birth, which was almost the same as those reported previously, and one case developed HDP. However, none of our cases developed FGR and oligohydramnios, similar to the previous study. Among the patients with adenomyosis, alterations in the junctional zone of the myometrium, which plays an important role in placentation, have been reported to have a negative impact on subsequent placentation. Brosens  et al . suggested that adenomyosis lesions may disrupt the process of spiral artery remodeling in the myometrial junctional zone from the onset of decidualization, causing defective deep placentation.[ 22 , 23 ] Moreover, one study reported decreased placental blood flow in a case of FGR with adenomyosis during pregnancy,[ 24 ] suggesting that placental hypoperfusion also may be associated with insufficient placental development. Considering the aforementioned reports, resection of the adenomyosis lesion, albeit not completely, may reduce obstetric complications from adenomyosis lesions and consequently improve pregnancy outcomes. The present study excluded one case with obvious recurrence of adenomyosis after adenomyomectomy. However, this case ultimately developed FGR, suggesting the significance of immediate postoperative fertility treatment before adenomyosis recurrence among those who desire children. On the other hand, we found a significant difference in the prevalence of FGR, but contrary to expectations, no difference in birth weight. Comparing deliveries at <37 weeks with those after 37 weeks, there was no birth weight difference in the preterm period, but there was a trend toward heavier weight in the surgery group after 37 weeks ( P  = 0.09), which may be one of the reasons for the difference. In addition, once FGR is diagnosed at some point during pregnancy, many cases were admitted to the hospital for management. Therefore, this management may recover fetal growth in some cases, which ultimately eliminated the difference in birth weight. Furthermore, the clinical background of the patients in the surgical group may differ from that of the nonsurgical group, because in the surgery group, patients were received laparoscopic adenomyomectomy due to repeated implantation failure after embryo transfer, repeated miscarriages, and the inability to perform infertility treatment by severe pain. Therefore, there is a limitation in comparing the two groups. We need to pay attention to the fact that this is a retrospective cohort study, therefore, it cannot be said that surgery reduces FGR.\nUterine rupture remains a serious complication among pregnant women who had undergone adenomyomectomy, with reports showing an occurrence rate ranging from 2.8% to 12.5% after adenomyomectomy.[ 25 , 26 ] In the present study, only one case of uterine rupture was observed (5.9%), which was not as high as previously reported. Despite the lower rate of FGR in the surgery group, no difference in birth weight was observed between both groups. This may have been attributed to the high percentage of preterm births without FGR in the surgery group (nonsurgery 19.3% vs. surgery 29.4%), although no difference was found between both given the small number of samples included herein.\nTo date, few reports have examined the pregnancy prognosis for each of the focal and diffuse subtypes. Tan  et al ., in their review, mention the possibility that adenomyomectomy improves pregnancy and miscarriage rates with respect to the focal type;[ 27 ] however, no reports have comprehensively examined the perinatal prognosis other than pregnancy and miscarriage rates. Therefore, in the subanalysis, we examined perinatal outcomes according to focal and diffuse types and found no difference in obstetric complications between both groups. However, the number of cases is small and needs further study.\nThis study has several limitations worth noting. First, our surgical method may not have completely removed the adenomyosis lesions. Although reports have shown that pregnancy rates are higher when the lesion is closer to complete removal, this may also cause excessive removal of the normal myometrium, leading to a smaller remaining normal myometrium. Sugiyama  et al . reported some similarities between the condition of the uterus after adenomyomectomy and a small uterus, such as that during irradiation of the uterus in pediatric patients.[ 21 ] They indicated that a small uterus in which myometrial expansion during pregnancy was restricted, causes preterm delivery.[ 28 , 29 ] Complete resection of adenomyosis lesion may occasionally increase the risk of placenta accreta and Asherman syndrome due to endometrial failure. Moreover, the clinical background of the two groups may differ, as the weight of adenomyosis is not known in the nonsurgical group, and the degree of infertility in the surgical group may be more severe due to unsuccessful infertility treatment and eventual surgery. Therefore, this is simply a retrospective observational study, and data may vary due to the long observation period. In future, we need to perform a prospective multicenter study enrolling a large number of cases to solve these problems.\n\nThe present study showed that our method of volume reduction, in which a few adenomyosis lesions remained, reduced the risk of FGR and did not increase the overall incidence of obstetric complications, with only one case having developed uterine rupture. Although laparotomy for adenomyosis may be superior in terms of the amount of adenomyosis lesions resected, from the perspective of perinatal prognosis, preserving the volume of the normal uterus as much as possible without causing endometrial failure may be more important even when a small portion of the lesion remains.\nNil.\nThere are no conflicts of interest.","source_license":"CC0","license_restricted":false}