Clinical characteristics and outcomes of women with adenomyosis pain during pregnancy: a retrospective study

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Recent case reports show that some women with adenomyosis experience pain at the adenomyosis lesion during pregnancy and have detrimental perinatal outcomes. However, the prevalence of pain onset in women with adenomyosis has not been studied, nor has its influence on perinatal outcomes. This study aimed to clarify the clinical characteristics of pain developing in adenomyosis lesions during pregnancy and the perinatal outcomes associated with this phenomenon. Methods This was a single-center retrospective analysis of a cohort of women with adenomyosis who delivered between 2011 and 2021. The incidence of pain onset at adenomyosis lesions among women with adenomyosis during pregnancy was analyzed retrospectively from medical records. Pain during pregnancy was defined as persistent pain at the adenomyosis site with administration of analgesics for pain relief, and its association with perinatal outcomes was analyzed. Results Among 91 singleton pregnancies with adenomyosis, 12 pregnancies (13.2%) presented with pain at the adenomyosis site during pregnancy. In total, 5 of the 12 pregnancies (41.7%) developed preeclampsia, which resulted in preterm delivery, and only 3 of the 12 pregnancies (25.0%) achieved term delivery. The incidence of preeclampsia and preterm delivery was higher in those who experienced pain than in those who did not (41.7% vs. 13.9%; p < 0.05, and 66.7% vs. 31.7%; p < 0.05, respectively). Among the women who had pain during pregnancy, the maximum C-reactive protein level was significantly higher in women who developed preeclampsia than in those who did not (5.45 vs. 0.12 mg/dL, p < 0.05). Conclusion Our study revealed that adenomyosis can cause pain in over one of eight pregnancies with adenomyosis, which may be associated with the increased incidence of preeclampsia resulting in preterm delivery. Women who present with pain at the adenomyosis lesion, especially those with high C-reactive protein levels, may be at a high risk for the future development of preeclampsia and consequent preterm delivery. pregnancy adenomyosis degeneration preeclampsia preterm delivery Figures Figure 1 Figure 2 Background Uterine adenomyosis is a benign disorder in which endometrial tissues are present within the myometrium, and it is associated with abnormal uterine bleeding, dysmenorrhea, pelvic pain, and infertility.( 1 ) ( 2 ) Moreover, adenomyosis is also known to be associated with unfavorable perinatal outcomes, with increased incidence of preterm delivery, preeclampsia (PE), cesarean delivery, postpartum hemorrhage, and small for gestational age infants. ( 3 – 8 ) However, the pathophysiology underlying this etiology remains to be elucidated, along with the clinical factors associated with adenomyosis that are responsible for these outcomes. Several cases of adenomyosis accompanied by severe pain and enhanced inflammatory response during pregnancy that showed degenerative changes, which were confirmed with magnetic resonance imaging, have been reported since 2006, including one from our institution.( 9 ) ( 10 ) ( 11 ) Intriguingly, all of the cases developed either preterm delivery, miscarriage, preeclampsia, or non-reassuring fetal status. Although fibroids are reported to degenerate during pregnancy and cause pain and enhanced inflammation in 12.6–28.0% of these women,( 12 ) , ( 13 ) the incidence of pain and enhanced inflammation during pregnancy among women with adenomyosis has not been reported, nor has its degeneration during pregnancy and its impact on perinatal outcomes. Our main objective was to evaluate the clinical characteristics of pain at the adenomyosis site during pregnancy. We also compared perinatal outcomes between those who experienced pain and those who did not among pregnant women with adenomyosis to investigate whether this pain, suggesting degeneration during pregnancy, affects perinatal outcomes. Methods This was a retrospective cohort study of 91 singleton pregnancies in 73 women with adenomyosis, who were managed at a single institution. Clinical information was retrospectively obtained from the medical records of pregnant women with adenomyosis who were managed and delivered after 12 weeks of gestation at the University of Tokyo Hospital between January 2011 and December 2021. Women with artificial abortions, multiple gestations, fetal abnormalities, or uterine malformations were excluded from this study. Pain during pregnancy was judged based on medical records as those having persisting pain at the adenomyosis site with administration of analgesics for pain relief during pregnancy; C-reactive protein (CRP) was measured while the pain persisted. The following maternal background information and perinatal outcomes were reviewed for those who experienced pain at the adenomyosis site: maternal age, parity, mode of conception, maximum CRP during pain, duration of pain, delivery week, onset of PE, spontaneous preterm delivery, delivery method, blood loss, postpartum hemorrhage, neonatal weight, and light for gestational age infants. Spontaneous preterm delivery was defined as delivery followed by spontaneous onset of labor or prelabor rupture of the membrane.( 14 ) The duration of pain was judged by the time period in which the analgesics were prescribed and the patient’s claim of the pain from the medical record. Postpartum hemorrhage was defined as blood loss of ≥ 500 g for vaginal delivery and ≥ 1000 g for cesarean delivery. Light for gestational age infant was defined as an infant with a birth weight below the 10th percentile. PE was diagnosed based on the diagnostic criteria of the International Society for the Study of Hypertension in Pregnancy.( 15 ) The diagnosis of adenomyosis was based on transvaginal ultrasound and/or MRI performed before conception and/or during the first or second trimester of pregnancy. On transvaginal ultrasound, adenomyosis was diagnosed based on the Morphological Uterus Sonographic Assessment (MUSA) criteria established in 2019: asymmetrical thickening, cysts, hyperechoic islands, fan-shaped shadowing, echogenic subendometrial lines and buds, translesional vascularity, irregular junctional zone, and interrupted junctional zone.( 16 ) On MRI, adenomyosis was diagnosed when one of the following two diagnostic criteria were met: 1) presence of a myometrial mass with indistinct margins with primarily low signal intensity, or 2) diffuse or focal thickening of the junctional zone forming an ill-defined area of low signal intensity on T2-weighted images.( 17 ) Statistical analysis Statistical analyses were performed using the JMP Pro 16 software (SAS Institute Inc.). Frequencies of obstetric complications and other categorical variables were analyzed using Fisher's exact test, while blood loss and other continuous variables were analyzed using the Mann-Whitney U test. For these tests, p < 0.05 was considered to indicate a significant difference. Results There were 91 pregnancies in 73 women with adenomyosis during the study period of 11 years. Among these 91 pregnancies, 12 pregnancies (11 women) (13.2%) presented with pain at the adenomyosis site during pregnancy, and were given oral acetaminophen. None of the 12 pregnancies had coexisting fibroids. Maternal background and perinatal outcomes of the 12 pregnancies are shown in Table 1 . In total, 5 pregnancies (41.7%) developed PE, which resulted in preterm delivery, and only 3 out of 12 pregnancies (25.0%) achieved term delivery. Among the 12 pregnancies with pain, the median gestational week at which the pain started was 19 weeks (interquartile range: 14–23 weeks), and the median duration of the pain was 42 days (interquartile range: 28–148 days) (Fig. 1 ). To quantitatively assess inflammation, CRP level was measured in each of the 12 pregnancies who developed pain, and the maximum CRP level is also shown in Table 1 . The median value of the maximum CRP level in the 12 pregnancies was 1.67 mg/dL (interquartile range: 0.11–4.89 mg/dL). Table 1 Maternal background and pregnancy outcomes of 12 pregnancies with adenomyosis pain during pregnancy # age Parity Mode of conception Max CRP (mg/dL) Delivery week PE Delivery method Blood loss (ml) PPH Neonatal weight (g) LGA 1 41 1 natural 2.37 17 no VD 1722 yes 180 no 2 43 0 ART 5.45 23 yes CS 780 no 293 yes 3 39 1 ART 25.9 27 yes CS 940 no 1000 no 4 38 0 ART 3.1 33 yes CS 1140 yes 1351 yes 5 39 0 ART 10.29 33 yes CS 2730 yes 1639 no 6 38 0 ART 0.97 34 yes CS 1480 yes 2750 no 7 40 0 ART 0.46 35 no CS 1090 yes 2066 no 8 34 0 natural 0.12 36 no CS 1390 yes 2416 no 9 36 0 natural 3.2 36 no CS 750 no 2164 no 10 39 0 ART 0.04 37 no CS 1550 yes 1847 yes 11 36 1 natural 0.53 37 no CS 1520 yes 2446 no 12 38 0 ART 0.11 37 no CS 1755 yes 3126 no ART, assisted reproductive technology; CRP, C-reactive protein; CS, cesarean delivery; Max, maximum; PE, preeclampsia; PPH, postpartum hemorrhage; LGA, light for gestational age infants; VD, vaginal delivery Comparison Between Those Who Did And Did Not Develop Pain During Pregnancy To assess the impact of pain during pregnancy on perinatal outcomes, we compared the maternal backgrounds and pregnancy outcomes between those who did and did not develop pain at the adenomyosis site among 91 pregnancies with adenomyosis, as shown in Table 2 . There was no difference in the maternal backgrounds, but those who experienced pain during pregnancy had a significantly higher incidence of PE (41.7% vs. 13.9%; p < 0.05). The cesarean section and preterm delivery rates were also significantly higher in those with pain (91.7% vs. 51.9%; p < 0.05, and 66.7% vs. 31.7%; p < 0.05, respectively), but the rate of spontaneous preterm delivery was not significantly higher in women who experienced pain than that in those who did not (25.0% vs. 11.9%; p = 0.19). Table 2 Maternal background and pregnancy outcomes of 91 pregnancies with adenomyosis pain + (12) pain – (79) p value Age, median, years (IQR) 38.5 (36.5–39.8) 37.0 (34.0–40.0) 0.27 primiparity 75.0 (%) 67.1 (%) 0.80 ART 66.7 (%) 50.6 (%) 0.29 Preterm delivery 66.7 (%) 31.7 (%) 0.02 Spontaneous preterm delivery 25.0 (%) 11.4 (%) 0.19 Preeclampsia 41.7 (%) 13.9 (%) 0.03 Cesarean section rate 91.7 (%) 51.9 (%) 0.01 Blood loss, median (IQR) 1435 (978–1679) ml 930 (435–1500) ml 0.07 Postpartum hemorrhage 75.0 (%) 58.2 (%) 0.22 LGA 25.0 (%) 13.9 (%) 0.27 ART, assisted reproductive technology; IQR, interquartile range; LGA, light for gestational age infants To assess whether the extent of inflammation was associated with the onset of PE, we compared the maximum CRP level, which was measured before the onset of PE, among the 12 pregnancies who developed pain during pregnancy. The median maximum CRP level was significantly higher in patients with PE than that in those without PE (5.45 vs. 0.12 mg/dL, p < 0.05) (Fig. 2 ). Among the 5 cases who developed PE, the maximum CRP level preceded the onset of PE as early as 6 days and as late as 47 days, with the median time from the maximum CRP level to the onset of PE being 15 days (interquartile range: 9–45 days). Discussion The current study revealed that pain at the adenomyosis site occurred in 13.2% of all pregnancies with adenomyosis. Moreover, the onset of adenomyosis pain was associated with adverse perinatal outcomes, including PE that resulted in preterm delivery and a high cesarean delivery rate. Among women with adenomyosis pain, the maximum CRP level was significantly high among those who developed PE, which preceded the onset of PE for a median of 15 days. We have provided a new insight that adenomyosis can trigger abdominal pain during pregnancy. Fibroids cause abdominal pain in up to 28% of cases during pregnancy,( 12 ) but whether the same physiologic changes occur in adenomyosis during pregnancy is not well understood. The pathophysiology underlying pain mechanism in fibroids is degeneration, which occurs predominantly during the second and early third trimesters.( 18 ) It is generally diagnosed by confirming the presence of pain directly over the fibroid correlating with ultrasound examination findings, and further accurate diagnosis can be made with MRI.( 19 , 20 ) The degeneration of fibroids is often accompanied by enhanced inflammation and an increase in CRP levels,( 12 ) , ( 13 ) which decrease with the amelioration of pain, usually within two weeks.( 12 ) , ( 19 ) However, whether this phenomenon is linked to adverse perinatal outcomes has not been conclusive.( 21 ) Considering the similarity between fibroids and adenomyosis, the timing of pain onset that we reported in this study and the past reports of degeneration of adenomyosis during pregnancy indicate that the pain followed by the enhanced inflammatory response observed in our cohort mimics the degeneration of fibroids.( 11 , 22 , 23 ) Nevertheless, it seems unquestionable that some proportion of women with adenomyosis develop pain during pregnancy. A recent meta-analysis showed that women with adenomyosis had an increased likelihood of PE (odds ratio: 4.35; 95% confidence interval, 1.07–17.72; p < 0.05), although the pathophysiology underlying this result is unknown.( 5 ) In our study, the adenomyosis pain onset was associated with the onset of PE, which intriguingly was more conspicuous in patients with elevated CRP levels. Interestingly, the median time from the maximum CRP level to the onset of PE was 15 days, and the CRP level decreased in the days before PE development. Several mouse models of PE have been reported that were induced by inflammatory cytokines.( 24 – 26 ) Although CRP cannot be used as a marker for predicting the onset of PE, circulating CRP is reported to be elevated in some groups of women, such as those with periodontal disease or obesity, before the onset of PE. ( 27 – 29 ) Although the number of cases is limited, considering that the maximum CRP preceded the onset of PE in our cohort and that previous reports show an association with inflammation and the onset of PE, enhanced inflammation at the utero-placental unit may be the key factor to induce the onset of PE in women with adenomyosis pain. Our findings suggest that adenomyosis can trigger abdominal pain during pregnancy, but as with fibroid degeneration, it is essential to rule out other diseases when uterine tenderness and enhanced inflammation are observed among pregnant women, especially threatened preterm labor with intra-amniotic infection (IAI). In the case with prominent inflammation and severe pain at onset (#3 in Table 1 ), IAI was initially suspected when the patient presented with acute abdominal pain and an enhanced inflammatory response. Therefore, we performed amniocentesis to rule out IAI, followed by MRI, which showed hemorrhagic degeneration of the adenomyosis, as previously reported.( 11 ) In the other 11 cases, the patients had confined pain at the adenomyosis site on primary presentation without shortening of the cervix; therefore, we clinically diagnosed these patients with adenomyosis pain. Moreover, all placentae from 15 pregnancies underwent pathological examination, of which only two cases (#2 and #3 in Table 1 ) showed histological chorioamnionitis of stage 1 based on Blanc’s classification( 30 ) in the absence of any sign suggestive of clinical IAI, which implies that the pain observed in 12 pregnancies is likely to be distinct from IAI. Consequently, we believe that the diagnosis of adenomyosis pain should be based on clinical symptoms by carefully excluding IAI. Of note, even after the pain resolves and a decrease in CRP level is confirmed, women with adenomyosis pain accompanied by elevated CRP levels warrant close follow-up for the onset of PE as a high-risk group of patients. A strength of our study is that, to the best of our knowledge, this is the first report to show the clinical characteristics of pain at the adenomyosis site during pregnancy. Another limitation is that we did not confirm the imaging findings that are linked to the manifestation of adenomyosis pain. However, as with degeneration in fibroids, diagnosis of adenomyosis pain during pregnancy seems sufficient to confirm the tenderness over the adenomyosis lesion with ultrasound after carefully excluding the possibility of IAI. Moreover, to elucidate the pathophysiology of pain at the adenomyosis site, pathological confirmation of the histological change in adenomyosis is warranted in future studies. Conclusions We have delineated one aspect of the perinatal pathophysiology of adenomyosis that can cause pain in more than one of eight pregnancies with adenomyosis, which may be associated with an increased incidence of PE resulting in preterm delivery. The risk of adverse perinatal outcomes in a patient population with adenomyosis is not well known, but our findings have provided new insights, indicating that those who develop adenomyosis pain during pregnancy, especially those with high CRP levels, may be at high risk for the later development of PE and consequently warrant special attention in perinatal care. Abbreviations preeclampsia (PE), C-reactive protein (CRP), intra-amniotic infection (IAI) Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board of the University of Tokyo (approval number: 3053-1) and informed consent was obtained using the opt-out method of our hospital website, which was also approved by the Institutional Review Board of the University of Tokyo (approval number: 3053-1).All methods were performed in accordance with the Declarations of Helsinki. Consent for publication Not applicable. Availability of data and materials The datasets generated and/or analysed during the current study are not publicly available for legal or ethical reasons, but are available from the corresponding author on reasonable request. Authors’ contribution S.S. collected data, conducted statistical analysis, and drafted the article. T.I. conceived the study, drafted the article, and reviewed the final version. YT and AH assisted in collecting data. MT, MI, TS, KS, KeK, TN, KaK, and YO supervised and reviewed the final version. Competing interests The authors declare that they have no competing interests. Funding No funding source was involved in this research. Acknowledgements Not applicable. References Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511-9. Vannuccini S, Tosti C, Carmona F, Huang SJ, Chapron C, Guo SW, et al. Pathogenesis of adenomyosis: an update on molecular mechanisms. Reprod Biomed Online. 2017;35(5):592-601. Mochimaru A, Aoki S, Oba MS, Kurasawa K, Takahashi T, Hirahara F. Adverse pregnancy outcomes associated with adenomyosis with uterine enlargement. J Obstet Gynaecol Res. 2015;41(4):529-33. Hashimoto A, Iriyama T, Sayama S, Nakayama T, Komatsu A, Miyauchi A, et al. Adenomyosis and adverse perinatal outcomes: increased risk of second trimester miscarriage, preeclampsia, and placental malposition. 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Tokyo","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Keiichi","middleName":"","lastName":"KUMASAWA","suffix":""},{"id":171760786,"identity":"cffc00d9-0b45-4371-bebc-1c3c07f59b23","order_by":9,"name":"Takeshi NAGAMATSU","email":"","orcid":"","institution":"The University of Tokyo","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"NAGAMATSU","suffix":""},{"id":171760787,"identity":"0a877ffe-f756-4e22-87f4-b74031b6e3d6","order_by":10,"name":"Kaori KOGA","email":"","orcid":"","institution":"The University of Tokyo","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kaori","middleName":"","lastName":"KOGA","suffix":""},{"id":171760788,"identity":"acf1bda6-1424-455c-a0d9-4041090f442a","order_by":11,"name":"Yutaka OSUGA","email":"","orcid":"","institution":"The University of Tokyo","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yutaka","middleName":"","lastName":"OSUGA","suffix":""}],"badges":[],"createdAt":"2023-01-19 06:14:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2494154/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2494154/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":32350118,"identity":"6db9db62-d25e-4ccb-babf-e708b420fa22","added_by":"auto","created_at":"2023-02-01 20:37:54","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":37456,"visible":true,"origin":"","legend":"\u003cp\u003eTiming and duration of pain in 12 pregnancies with pain at the adenomyosis site.\u003c/p\u003e\n\u003cp\u003eThe case number (#) represents the patients listed in Table 1, and the patient numbers with “*” represent those who developed preeclampsia. The duration of pain is indicated with black arrow (→), and the delivery is indicated with a star (☆).\u003c/p\u003e","description":"","filename":"fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2494154/v1/f57b5b9ce92f36428e85c7e1.jpg"},{"id":32350117,"identity":"9b27d61c-f008-4959-aaaa-594cf37871ca","added_by":"auto","created_at":"2023-02-01 20:37:54","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":15189,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of maximum CRP levels between those who did and did not develop preeclampsia among the patients with pain at the adenomyosis site.\u003c/p\u003e\n\u003cp\u003eCRP was measured during the time period in which the pain at the adenomyosis lesion persisted, and the maximum value of the CRP during the time period was recorded as maximum CRP, which was significantly higher in those who developed PE compared with that of those who did not (5.45 vs. 0.12 mg/dL, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05). (n=6 and n=5 for non-PE and PE groups, respectively).\u003c/p\u003e\n\u003cp\u003eCRP, C-reactive protein; Max, maximum; PE, preeclampsia; * \u003cem\u003ep\u003c/em\u003e \u0026lt;0.05.\u003c/p\u003e","description":"","filename":"fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2494154/v1/5928d144d2e2db578589086d.jpg"},{"id":33730701,"identity":"28b88583-521f-445d-a9da-9c8c7c3a4a4f","added_by":"auto","created_at":"2023-03-03 07:14:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":430253,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2494154/v1/a60a309a-175d-4c19-be8b-028702dc3dcd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical characteristics and outcomes of women with adenomyosis pain during pregnancy: a retrospective study","fulltext":[{"header":"Background","content":"\u003cp\u003eUterine adenomyosis is a benign disorder in which endometrial tissues are present within the myometrium, and it is associated with abnormal uterine bleeding, dysmenorrhea, pelvic pain, and infertility.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Moreover, adenomyosis is also known to be associated with unfavorable perinatal outcomes, with increased incidence of preterm delivery, preeclampsia (PE), cesarean delivery, postpartum hemorrhage, and small for gestational age infants. (\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) However, the pathophysiology underlying this etiology remains to be elucidated, along with the clinical factors associated with adenomyosis that are responsible for these outcomes.\u003c/p\u003e \u003cp\u003eSeveral cases of adenomyosis accompanied by severe pain and enhanced inflammatory response during pregnancy that showed degenerative changes, which were confirmed with magnetic resonance imaging, have been reported since 2006, including one from our institution.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) Intriguingly, all of the cases developed either preterm delivery, miscarriage, preeclampsia, or non-reassuring fetal status. Although fibroids are reported to degenerate during pregnancy and cause pain and enhanced inflammation in 12.6\u0026ndash;28.0% of these women,(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003csup\u003e,\u003c/sup\u003e(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) the incidence of pain and enhanced inflammation during pregnancy among women with adenomyosis has not been reported, nor has its degeneration during pregnancy and its impact on perinatal outcomes.\u003c/p\u003e \u003cp\u003eOur main objective was to evaluate the clinical characteristics of pain at the adenomyosis site during pregnancy. We also compared perinatal outcomes between those who experienced pain and those who did not among pregnant women with adenomyosis to investigate whether this pain, suggesting degeneration during pregnancy, affects perinatal outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis was a retrospective cohort study of 91 singleton pregnancies in 73 women with adenomyosis, who were managed at a single institution. Clinical information was retrospectively obtained from the medical records of pregnant women with adenomyosis who were managed and delivered after 12 weeks of gestation at the University of Tokyo Hospital between January 2011 and December 2021. Women with artificial abortions, multiple gestations, fetal abnormalities, or uterine malformations were excluded from this study. Pain during pregnancy was judged based on medical records as those having persisting pain at the adenomyosis site with administration of analgesics for pain relief during pregnancy; C-reactive protein (CRP) was measured while the pain persisted.\u003c/p\u003e \u003cp\u003eThe following maternal background information and perinatal outcomes were reviewed for those who experienced pain at the adenomyosis site: maternal age, parity, mode of conception, maximum CRP during pain, duration of pain, delivery week, onset of PE, spontaneous preterm delivery, delivery method, blood loss, postpartum hemorrhage, neonatal weight, and light for gestational age infants. Spontaneous preterm delivery was defined as delivery followed by spontaneous onset of labor or prelabor rupture of the membrane.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) The duration of pain was judged by the time period in which the analgesics were prescribed and the patient\u0026rsquo;s claim of the pain from the medical record. Postpartum hemorrhage was defined as blood loss of \u0026ge;\u0026thinsp;500 g for vaginal delivery and \u0026ge;\u0026thinsp;1000 g for cesarean delivery. Light for gestational age infant was defined as an infant with a birth weight below the 10th percentile. PE was diagnosed based on the diagnostic criteria of the International Society for the Study of Hypertension in Pregnancy.(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe diagnosis of adenomyosis was based on transvaginal ultrasound and/or MRI performed before conception and/or during the first or second trimester of pregnancy. On transvaginal ultrasound, adenomyosis was diagnosed based on the Morphological Uterus Sonographic Assessment (MUSA) criteria established in 2019: asymmetrical thickening, cysts, hyperechoic islands, fan-shaped shadowing, echogenic subendometrial lines and buds, translesional vascularity, irregular junctional zone, and interrupted junctional zone.(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) On MRI, adenomyosis was diagnosed when one of the following two diagnostic criteria were met: 1) presence of a myometrial mass with indistinct margins with primarily low signal intensity, or 2) diffuse or focal thickening of the junctional zone forming an ill-defined area of low signal intensity on T2-weighted images.(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using the JMP Pro 16 software (SAS Institute Inc.). Frequencies of obstetric complications and other categorical variables were analyzed using Fisher's exact test, while blood loss and other continuous variables were analyzed using the Mann-Whitney U test. For these tests, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to indicate a significant difference.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThere were 91 pregnancies in 73 women with adenomyosis during the study period of 11 years. Among these 91 pregnancies, 12 pregnancies (11 women) (13.2%) presented with pain at the adenomyosis site during pregnancy, and were given oral acetaminophen. None of the 12 pregnancies had coexisting fibroids. Maternal background and perinatal outcomes of the 12 pregnancies are shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. In total, 5 pregnancies (41.7%) developed PE, which resulted in preterm delivery, and only 3 out of 12 pregnancies (25.0%) achieved term delivery. Among the 12 pregnancies with pain, the median gestational week at which the pain started was 19 weeks (interquartile range: 14\u0026ndash;23 weeks), and the median duration of the pain was 42 days (interquartile range: 28\u0026ndash;148 days) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). To quantitatively assess inflammation, CRP level was measured in each of the 12 pregnancies who developed pain, and the maximum CRP level is also shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The median value of the maximum CRP level in the 12 pregnancies was 1.67 mg/dL (interquartile range: 0.11\u0026ndash;4.89 mg/dL).\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMaternal background and pregnancy outcomes of 12 pregnancies with adenomyosis pain during pregnancy\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e#\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eage\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParity\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMode of\u003c/p\u003e\n \u003cp\u003econception\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMax CRP\u003c/p\u003e\n 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\u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eART\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2730\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1639\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eART\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1480\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2750\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eART\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enatural\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1390\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2416\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enatural\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e750\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2164\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eART\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1550\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1847\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enatural\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1520\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2446\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eART\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1755\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\"\u003eART, assisted reproductive technology; CRP, C-reactive protein; CS, cesarean delivery; Max, maximum; PE, preeclampsia; PPH, postpartum hemorrhage; LGA, light for gestational age infants; VD, vaginal delivery\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ch3\u003eComparison Between Those Who Did And Did Not Develop Pain During Pregnancy\u003c/h3\u003e\n\u003cp\u003eTo assess the impact of pain during pregnancy on perinatal outcomes, we compared the maternal backgrounds and pregnancy outcomes between those who did and did not develop pain at the adenomyosis site among 91 pregnancies with adenomyosis, as shown in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. There was no difference in the maternal backgrounds, but those who experienced pain during pregnancy had a significantly higher incidence of PE (41.7% vs. 13.9%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The cesarean section and preterm delivery rates were also significantly higher in those with pain (91.7% vs. 51.9%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, and 66.7% vs. 31.7%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, respectively), but the rate of spontaneous preterm delivery was not significantly higher in women who experienced pain than that in those who did not (25.0% vs. 11.9%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.19).\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMaternal background and pregnancy outcomes of 91 pregnancies with adenomyosis\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003epain + (12)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003epain \u0026ndash; (79)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge, median, years (IQR)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e38.5 (36.5\u0026ndash;39.8)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e37.0 (34.0\u0026ndash;40.0)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eprimiparity\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e75.0 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e67.1 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eART\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e66.7 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e50.6 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePreterm delivery\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e66.7 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e31.7 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSpontaneous preterm delivery\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e25.0 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e11.4 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePreeclampsia\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e41.7 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e13.9 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCesarean section rate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e91.7 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e51.9 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBlood loss, median (IQR)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e1435\u003c/p\u003e\n \u003cp\u003e(978\u0026ndash;1679) ml\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e930\u003c/p\u003e\n \u003cp\u003e(435\u0026ndash;1500) ml\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePostpartum hemorrhage\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e75.0 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e58.2 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLGA\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e25.0 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e13.9 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n\u003c/table\u003e\n\u003cp\u003eART, assisted reproductive technology; IQR, interquartile range; LGA, light for gestational age infants\u003c/p\u003e\n\u003cp\u003eTo assess whether the extent of inflammation was associated with the onset of PE, we compared the maximum CRP level, which was measured before the onset of PE, among the 12 pregnancies who developed pain during pregnancy. The median maximum CRP level was significantly higher in patients with PE than that in those without PE (5.45 vs. 0.12 mg/dL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Among the 5 cases who developed PE, the maximum CRP level preceded the onset of PE as early as 6 days and as late as 47 days, with the median time from the maximum CRP level to the onset of PE being 15 days (interquartile range: 9\u0026ndash;45 days).\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe current study revealed that pain at the adenomyosis site occurred in 13.2% of all pregnancies with adenomyosis. Moreover, the onset of adenomyosis pain was associated with adverse perinatal outcomes, including PE that resulted in preterm delivery and a high cesarean delivery rate. Among women with adenomyosis pain, the maximum CRP level was significantly high among those who developed PE, which preceded the onset of PE for a median of 15 days.\u003c/p\u003e \u003cp\u003eWe have provided a new insight that adenomyosis can trigger abdominal pain during pregnancy. Fibroids cause abdominal pain in up to 28% of cases during pregnancy,(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) but whether the same physiologic changes occur in adenomyosis during pregnancy is not well understood. The pathophysiology underlying pain mechanism in fibroids is degeneration, which occurs predominantly during the second and early third trimesters.(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) It is generally diagnosed by confirming the presence of pain directly over the fibroid correlating with ultrasound examination findings, and further accurate diagnosis can be made with MRI.(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) The degeneration of fibroids is often accompanied by enhanced inflammation and an increase in CRP levels,(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003csup\u003e,\u003c/sup\u003e(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) which decrease with the amelioration of pain, usually within two weeks.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003csup\u003e,\u003c/sup\u003e(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) However, whether this phenomenon is linked to adverse perinatal outcomes has not been conclusive.(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) Considering the similarity between fibroids and adenomyosis, the timing of pain onset that we reported in this study and the past reports of degeneration of adenomyosis during pregnancy indicate that the pain followed by the enhanced inflammatory response observed in our cohort mimics the degeneration of fibroids.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) Nevertheless, it seems unquestionable that some proportion of women with adenomyosis develop pain during pregnancy.\u003c/p\u003e \u003cp\u003eA recent meta-analysis showed that women with adenomyosis had an increased likelihood of PE (odds ratio: 4.35; 95% confidence interval, 1.07\u0026ndash;17.72; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), although the pathophysiology underlying this result is unknown.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) In our study, the adenomyosis pain onset was associated with the onset of PE, which intriguingly was more conspicuous in patients with elevated CRP levels. Interestingly, the median time from the maximum CRP level to the onset of PE was 15 days, and the CRP level decreased in the days before PE development. Several mouse models of PE have been reported that were induced by inflammatory cytokines.(\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) Although CRP cannot be used as a marker for predicting the onset of PE, circulating CRP is reported to be elevated in some groups of women, such as those with periodontal disease or obesity, before the onset of PE. (\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) Although the number of cases is limited, considering that the maximum CRP preceded the onset of PE in our cohort and that previous reports show an association with inflammation and the onset of PE, enhanced inflammation at the utero-placental unit may be the key factor to induce the onset of PE in women with adenomyosis pain.\u003c/p\u003e \u003cp\u003eOur findings suggest that adenomyosis can trigger abdominal pain during pregnancy, but as with fibroid degeneration, it is essential to rule out other diseases when uterine tenderness and enhanced inflammation are observed among pregnant women, especially threatened preterm labor with intra-amniotic infection (IAI). In the case with prominent inflammation and severe pain at onset (#3 in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), IAI was initially suspected when the patient presented with acute abdominal pain and an enhanced inflammatory response. Therefore, we performed amniocentesis to rule out IAI, followed by MRI, which showed hemorrhagic degeneration of the adenomyosis, as previously reported.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) In the other 11 cases, the patients had confined pain at the adenomyosis site on primary presentation without shortening of the cervix; therefore, we clinically diagnosed these patients with adenomyosis pain. Moreover, all placentae from 15 pregnancies underwent pathological examination, of which only two cases (#2 and #3 in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) showed histological chorioamnionitis of stage 1 based on Blanc\u0026rsquo;s classification(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) in the absence of any sign suggestive of clinical IAI, which implies that the pain observed in 12 pregnancies is likely to be distinct from IAI. Consequently, we believe that the diagnosis of adenomyosis pain should be based on clinical symptoms by carefully excluding IAI. Of note, even after the pain resolves and a decrease in CRP level is confirmed, women with adenomyosis pain accompanied by elevated CRP levels warrant close follow-up for the onset of PE as a high-risk group of patients.\u003c/p\u003e \u003cp\u003eA strength of our study is that, to the best of our knowledge, this is the first report to show the clinical characteristics of pain at the adenomyosis site during pregnancy. Another limitation is that we did not confirm the imaging findings that are linked to the manifestation of adenomyosis pain. However, as with degeneration in fibroids, diagnosis of adenomyosis pain during pregnancy seems sufficient to confirm the tenderness over the adenomyosis lesion with ultrasound after carefully excluding the possibility of IAI. Moreover, to elucidate the pathophysiology of pain at the adenomyosis site, pathological confirmation of the histological change in adenomyosis is warranted in future studies.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe have delineated one aspect of the perinatal pathophysiology of adenomyosis that can cause pain in more than one of eight pregnancies with adenomyosis, which may be associated with an increased incidence of PE resulting in preterm delivery. The risk of adverse perinatal outcomes in a patient population with adenomyosis is not well known, but our findings have provided new insights, indicating that those who develop adenomyosis pain during pregnancy, especially those with high CRP levels, may be at high risk for the later development of PE and consequently warrant special attention in perinatal care.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003epreeclampsia (PE), C-reactive protein (CRP), intra-amniotic infection (IAI)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the\u0026nbsp;Institutional Review Board of the University of Tokyo\u0026nbsp;(approval number: 3053-1) and informed consent was obtained using the opt-out method of our hospital website, which was also approved by the\u0026nbsp;Institutional Review Board of the University of Tokyo\u0026nbsp;(approval number: 3053-1).All methods were performed in accordance with the Declarations of Helsinki.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available for legal or ethical reasons, but are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS.S. collected data, conducted statistical analysis, and drafted the article. T.I. conceived the study, drafted the article, and reviewed the final version. YT and AH assisted in collecting data. MT, MI, TS, KS, KeK, TN, KaK, and YO supervised and reviewed the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding source was involved in this research.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBurney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511-9.\u003c/li\u003e\n\u003cli\u003eVannuccini S, Tosti C, Carmona F, Huang SJ, Chapron C, Guo SW, et al. 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Maternal periodontal disease, systemic inflammation, and risk for preeclampsia. American Journal of Obstetrics \u0026amp; Gynecology. 2008;198(4):389.e1-.e5.\u003c/li\u003e\n\u003cli\u003eHamadeh R, Mohsen A, Kobeissy F, Karouni A, Akoum H. C-Reactive Protein for Prediction or Early Detection of Pre-Eclampsia: A Systematic Review. Gynecol Obstet Invest. 2021;86(1-2):13-26.\u003c/li\u003e\n\u003cli\u003eWolf M, Kettyle E, Sandler L, Ecker JL, Roberts J, Thadhani R. Obesity and preeclampsia: the potential role of inflammation. Obstetrics \u0026amp; Gynecology. 2001;98(5, Part 1):757-62.\u003c/li\u003e\n\u003cli\u003eBlanc WA. Pathology of the placenta, membranes, and umbilical cord in bacterial, fungal, and viral infections in man. Monogr Pathol. 1981(22):67-132.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"pregnancy, adenomyosis, degeneration, preeclampsia, preterm delivery","lastPublishedDoi":"10.21203/rs.3.rs-2494154/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2494154/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAdenomyosis is known to be associated with unfavorable perinatal outcomes, but the patient population among women with adenomyosis who is at high risk for adverse perinatal outcomes remains unclear. Recent case reports show that some women with adenomyosis experience pain at the adenomyosis lesion during pregnancy and have detrimental perinatal outcomes. However, the prevalence of pain onset in women with adenomyosis has not been studied, nor has its influence on perinatal outcomes. This study aimed to clarify the clinical characteristics of pain developing in adenomyosis lesions during pregnancy and the perinatal outcomes associated with this phenomenon.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis was a single-center retrospective analysis of a cohort of women with adenomyosis who delivered between 2011 and 2021. The incidence of pain onset at adenomyosis lesions among women with adenomyosis during pregnancy was analyzed retrospectively from medical records. Pain during pregnancy was defined as persistent pain at the adenomyosis site with administration of analgesics for pain relief, and its association with perinatal outcomes was analyzed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong 91 singleton pregnancies with adenomyosis, 12 pregnancies (13.2%) presented with pain at the adenomyosis site during pregnancy. In total, 5 of the 12 pregnancies (41.7%) developed preeclampsia, which resulted in preterm delivery, and only 3 of the 12 pregnancies (25.0%) achieved term delivery. The incidence of preeclampsia and preterm delivery was higher in those who experienced pain than in those who did not (41.7% vs. 13.9%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, and 66.7% vs. 31.7%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, respectively). Among the women who had pain during pregnancy, the maximum C-reactive protein level was significantly higher in women who developed preeclampsia than in those who did not (5.45 vs. 0.12 mg/dL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur study revealed that adenomyosis can cause pain in over one of eight pregnancies with adenomyosis, which may be associated with the increased incidence of preeclampsia resulting in preterm delivery. Women who present with pain at the adenomyosis lesion, especially those with high C-reactive protein levels, may be at a high risk for the future development of preeclampsia and consequent preterm delivery.\u003c/p\u003e","manuscriptTitle":"Clinical characteristics and outcomes of women with adenomyosis pain during pregnancy: a retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-02-01 20:37:49","doi":"10.21203/rs.3.rs-2494154/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"646f79ce-bfb0-4ff9-9482-0c4459cf818d","owner":[],"postedDate":"February 1st, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-03-03T07:14:30+00:00","versionOfRecord":[],"versionCreatedAt":"2023-02-01 20:37:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2494154","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2494154","identity":"rs-2494154","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}