Adenomyosis, an estrogen-dependent chronic inflammatory gynecological benign disease, is defined as the presence of endometrial glands and stroma within the myometrium of the uterus, resulting in dysmenorrhea and infertility [1, 2, 3]. The exact pathogenesis of adenomyosis remains unclear, although the incidence of adenomyosis tends to occur in younger women and is rising [4, 5, 6]. Although there are many mechanisms to explain infertility caused by adenomyosis, such as abnormal endometrial receptivity and oviduct peristalsis, it is still not clear whether infertility is the result or the cause of adenomyosis [6, 7, 8, 9]. Recently, as more women delay their first pregnancy, adenomyosis, like endometriosis, is attracting more attention because of its increasing impact on fertility and pregnancy outcomes [10, 11, 12, 13, 14, 15, 16, 17]. Consequently, it is necessary to identify the high risk factors affecting the fertility and reproductive outcomes of patients with adenomyosis prior to pregnancy in order to minimize obstetric complications.

Increasing evidence from recent studies has demonstrated that many factors, including age, uterine size, disease severity, subtype and concomitant diseases, can affect the pregnancy outcomes of women with adenomyosis [18, 19, 20, 21, 22, 23, 24]. One study of uterus-sparing surgery for patients with adenomyosis by Kishi et al. [18] showed that the clinical pregnancy rate of women $\le$39 years old (41.3%) was significantly higher than that of women $\ge$40 years old (3.7%). Another study of frozen thawed embryo transfer for patients with adenomyosis by Li et al. [19] found that the miscarriage rate of women with large uterine volume ($>$98.81 cm${}^3$) was 8.5 times that of women with small uterine volume ($\le$98.81 cm${}^3$). Using the new ultrasonographic adenomyosis grading and severity scoring system, it was found that the higher the score of adenomyotic lesions was associated with higher infertility and miscarriage rates [20]. It has been shown that the clinical pregnancy rate of women with focal adenomyosis is higher than that of women with diffuse adenomyosis following uterus-sparing surgery [21]. Compared with women with adenomyosis alone, women with the combination of adenomyosis and endometriosis have a higher miscarriage rate and a lower live birth rate [22, 23, 24].

Many obstetric complications in pregnant women with adenomyosis, such as preeclampsia, preterm birth, premature rupture of membrane, small for gestational age, malpresentation and abruption have received more attention in recent years [25, 26, 27, 28]. More recently, a study by Ono et al. [29] of the positional relationship between the placenta and the adenomyosis lesion influenced the perinatal outcomes demonstrating that placental localization near or above adenomyotic lesions increased the risk of perinatal complications. Based on previous research, we performed a retrospective study [30], and found that our results were consistent with those reported by Ono et al. [29]. There was a significant increase in the obstetric morbidity and lower birth weight when the placenta overlaid an adenomyosis lesion. If women with severe diffuse adenomyosis do not have normal myometrium, their placenta will be implanted on the adenomyotic lesions. This may be the cause of infertility or pregnancy failure in patients with severe diffuse adenomyosis.

We investigated if the positional relationship between placenta and adenomyotic lesions could be identified in pregnant women with adenomyosis, and all patients were divided into two subgroups (Group 1: placenta on or above the adenomyotic lesion; Group 2: placenta far away from the adenomyotic lesion) according to the relationship between placental implantation site and the adenomyotic lesion. A comparative analysis was performed so as to clarify the influence of the relationship between placental implantation site and adenomyosis lesion on perinatal complications.

Recent publications have confirmed that adenomyosis was associated with increased risks of early miscarriage, second trimester miscarriage, preterm delivery, preeclampsia, FGR, placental malposition, postpartum bleeding, cesarean section rate and the incidence of pregnancy by ART [33, 34, 35]. In addition, the gestational age and neonatal birth weight at delivery were significantly lower than those of pregnant patients without adenomyosis and the placental attachment on the area of adenomyotic lesion could be associated with FGR [13, 25].

Our study drew similar conclusions and reconfirmed the conclusion that the relationship between placental implantation site and adenomyotic lesion location had a substantial impact on pregnancy outcome of adenomyosis patients [29]. In our study, the placenta implantation site above the uterine adenomyosis had a high correlation with preterm delivery, lower birth weight and placenta malposition. However, the incidence of FGR showed no significant difference.

Adenomyosis-associated lower neonatal birth weight and preterm delivery were thought to have a pathophysiological correlation with inflammation, free radicals and junctional zone alterations. Specifically, thickening of the myometrial junctional zone was the typical change noted in adenomyosis patients by magnetic resonance imaging (MRI). Placental dysplasia caused by impaired remodeling of spiral arteries in this area creates a hostile environment for the placenta that impedes adequate fetal exchange with the maternal blood supply, possibly through a vascular steal mechanism, leading to numerous adverse pregnancy complications [16, 36, 37, 38, 39]. Previous studies have suggested that fetuses with lower placental weight and smaller placental surface area were at higher risk of developing FGR [40, 41], a finding in accordance with the results of our study that birth weight was positively associated with placental surface area. The lower birth weight in women with placenta location overlapping adenomyosis may be related to the smaller placenta being caused by the adenomyosis.

Adenomyosis is also an independent risk factor for impaired reproductive function [42]. These patients have a higher incidence of infertility and the clinical pregnancy rate of assisted reproductive technology in adenomyosis patients is significantly reduced [36]. In our study, 69 cases (22.19%) underwent ART, with the percentage being much higher when compared with average women. Moreover, researchers have found that the adverse pregnancy outcome of patients whose pregnancy was complicated with adenomyosis was closely related to the severity of the disease and whether it was diffuse adenomyosis [43, 44]. A clinical trial from Japan recruited 272 pregnant women with adenomyosis and reported that the rates of miscarriage ($>$12 weeks) and cervical incompetency were positively related to the size of the adenomyosis, and that the rates of PIH and uterine infection in patients with diffuse adenomyosis were higher than that in patients with focal adenomyosis [45]. As related to whether the adenomyosis was surgically or medically treated prior to pregnancy, the rates of pregnancy complications did not differ to a statistically significant extent [45]. Another Japanese study of 325 pregnant women with adenomyosis (136 with co-existing endometriosis) demonstrated that the frequency of obstetric complications was as high as 60.0% and only pregnant women with a medical history of adenomyosis experienced adverse events of mild preeclampsia, placental abruption and FGR (adjusted odds ratio (aOR) = 1.86, aOR = 2.62, and aOR = 2.72, respectively) [46].

Although it is currently believed that the adverse pregnancy outcomes of adenomyosis patients are related to the severity and lesion type of adenomyosis [43, 44], the exact mechanism leading to the phenomenon is still unclear. Thickening of the myometrium and endometrial-myometrial junction, elevated inflammatory cytokines, such as IL-6 and TNF-$\alpha$, could lead to insufficient infiltration of trophoblast cells into the endometrium, leading to poor remodeling of the spiral artery and placental dysplasia, resulting in a small placenta and FGR [47, 48, 49, 50, 51]. Further investigations are needed to better understand the pathophysiologic mechanisms of the spectrum of adenomyotic lesion location-associated obstetric complications. Despite the low level of evidence, pregnant women with diffuse adenomyosis should be considered at high risk for adverse obstetric outcomes. The characteristics of adenomyosis affect the blood supply of the mother and fetus, which may be the main reason for the adverse outcomes of pregnancy [52]. Recently, Ono et al. [29] reported that the relationship between placental location and lesion location in pregnant patients complicated with adenomyosis markedly affected perinatal outcomes. The incidence of adverse perinatal outcomes such as FGR in patients with the placenta very close to or directly implanted on the adenomyotic lesion was significantly higher than that in patients with placenta far away from the lesion.

Our study retrospectively analyzed the clinical data of 311 pregnant patients complicated with adenomyosis. Our data demonstrated that the placental implantation site was closely related to pregnancy outcomes. If the placenta was located on or close to the adenomyotic lesion, the rate of preterm delivery and placental malposition were significantly increased, and the gestational age, neonatal birth weight and placental size were significantly decreased, which were consistent with the results reported in the literature [13, 53]. Thus, it was further confirmed that there were severe adverse pregnant outcomes in adenomyosis patients whose placenta was closely implanted to the lesion.

Our study detected that diffuse adenomyosis, endometriosis history and placenta malposition might increase the risk of placenta implantation site overlapping the uterine adenomyosis, this pathological mechanism needs to be further explored. This indicates that patients with adenomyosis are recommended to evaluate the severity and lesion type of adenomyosis before pregnancy, and offer early intervention, especially for those women co-existing with an endometriosis history. Once the patient is pregnant, ultrasound and other imaging techniques such as MRI should be utilized to identify the relationship between the embryo implantation site and the lesion position of adenomyosis, and to check the uterine artery pulsation index, in order to closely monitor and intervene when appropriate. An early intervention is the usage of aspirin, in order to prevent early placental dysplasia, including PIH [54] and recurrent miscarriage [55]. The study of Yamanaka [56] revealed that adenomyosis had a risk of activating the blood coagulation system and increased the risk of thrombosis, suggesting that aspirin be considered to be useful in pregnancy complicated by adenomyosis.

Our study determined that severe adverse pregnant outcomes in adenomyosis patients were closely related to the placenta implantation site if it was overlapping lesion. These conclusions are consistent with those reported by Ono et al. [29]. Due to the difficulty to distinguish junctional zone (JZ) in the pregnant uterus by ultrasound screening, it is hard for us to determine the relationship between adenomyosis lesion and JZ, as well as the exact distance between the placenta and the lesions. Thus, our recommendation is that pregnant patients complicated with adenomyosis should undergo MRI in late pregnancy to identify the relationship between placental implantation site and lesion location, uterine artery pulsation index and fetal growth.

In our study, there was no significant difference in the incidence of FGR and PIH, regardless of the location of the placenta. Other researchers have found that PIH was a maternal complication related to an autoimmune mechanism, so it might have something to do with immune pathogenesis of adenomyosis [57]. Although other literature reported that the incidence of FGR in pregnant patients complicated with adenomyosis was mainly related to diffuse adenomyosis [52], our data showed no difference, which might due to one of the limitations of the study (the relatively small number of cases and imperfect retrospective data). There are still other limitations. The history of cesarean section and ART may be associated with the risk of maternal and neonatal outcomes but these cases were not excluded from the study. Fortunately, the patients with the history of cesarean section or ART were symmetrically distributed in two groups. Furthermore, all patients merely had ultrasound images without MRI images since our study was a retrospective approach, so the specific data of the distance between the placental implantation site and the lesion of adenomyosis could not be acquired. Obviously, it is necessary to further comprehensively apply ultrasound and MRI to classify the types of adenomyosis, measure the size of uterus, evaluate the severity of the disease, measure the distance between the placental implantation site and the lesion, and implement a multicenter prospective study with a large sample size to evaluate the adverse pregnancy outcomes of pregnant patients complicated with adenomyosis.

Pregnant women whose pregnancy is complicated by adenomyosis are associated with adverse pregnancy outcomes. When the placental implantation site overlaps the adenomyotic lesion, adverse pregnancy outcomes are more likely to occur, and include preterm delivery and lower birth weight. Women with diffuse adenomyosis, endometriosis history and placenta malposition are more likely to have placental implantation site overlapping the adenomyotic lesion. Therefore, patients with adenomyosis need detailed and thorough evaluation prior to pregnancy. Imaging examinations should be performed during the pregnant process to determine the placental implantation site, uterine artery pulsation index and fetal growth. Close monitoring and early intervention such as consultant-led care when clinically appropriate should be carried out to improve pregnancy outcomes.

The data and materials generated during and analyzed during the present study are available from the corresponding author upon reasonable request.

XZ and PX designed the research study. PX, XH, YZ, YW and GZ performed the research. PX, XH, JW analyzed the data. PX, JW and XZ wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This study was approved by the Ethics Committee of Women’s Hospital, School of Medicine, Zhejiang University (No. IRB-20210310-R). All patients were exempt from informed consent because this study was retrospective.

We appreciate the staff at the Zhejiang University, women hospital for their diligent clinical work and precise data recording in the cases we reported in this article. We thank all the participants in the study.

This study was funded by National Key R&D Program of China (Grant number: 2022YFC2704003) and Zhejiang Provincial Natural Science Foundation of China (grant No. LY23H040005).

The authors declare no conflict of interest.