{"paper_id":"c762abf4-11d7-4f96-a594-dd2d69b0af71","body_text":"In vitro  fertilization (IVF) has revolutionized the treatment of\ninfertility, offering hope to individuals facing complex reproductive challenges.\nSince its introduction into clinical practice in the late 1970s ( Fishel, 2018 ), IVF has significantly evolved in\nterms of efficacy and safety, becoming a widely used technique in cases of\nendometriosis, ovulatory disorders, tubal-peritoneal factors, and male infertility\nfactors. Between 2020 and 2024, in Brazil 544,983 embryos have been vitrified,\nacross 216 assisted reproduction centers, with 68% of these procedures performed in\nthe southeastern region. Of these, 65,627 were transferred, resulting in a clinical\npregnancy rate of approximately 27.4% in patients under 35 years old and 18.5% in\nthose aged 35 or older ( ANVISA - Agência\nNacional de Vigilância Sanitária, 2025 ). In parallel with\nthe increased use of the technique, there has been a growing incidence of obstetric\ncomplications in pregnancies resulting from IVF, raising concerns among patients,\nhealth professionals and researchers.\nPlacenta accreta is histologically defined as the complete or partial absence of the\ndecidua basalis at the placental insertion site ( Jauniaux  &  Ayres-de-Campos, 2018 ). Currently, PAS\ndisorders are divided into three categories, as postulated by  Luke  et al.  (1966)  ( Imafuku  et al. , 2021 ): placenta accreta, when\nthe villus only adheres to the myometrium; placenta increta, when the villus invades\nthe myometrium; and placenta percreta, when the invasion includes the uterine serosa\nor adjacent organs. Prenatal diagnosis of this condition is essential for safe birth\nplanning. A multidisciplinary approach in highly complex centers is essential to\nreduce morbidity and mortality in these cases ( Jauniaux  &  Ayres-de-Campos, 2018 ). This obstetric\ncomplication has been increasingly associated with pregnancies resulting from\nassisted reproduction techniques, especially IVF. The relationship between IVF and\nplacenta accreta has been the subject of intensive studies to understand the\nunderlying mechanisms and mitigate the associated risks.\nThis review explores the complex intersection between in vitro fertilization and\nplacenta accreta, examining the risk factors, pathophysiological mechanisms\ninvolved, and the most frequent complications. In addition, recent advances in\nunderstanding the pathogenesis of placenta accreta in pregnancies after IVF are\npresented, emphasizing strategies to minimize maternal and fetal complications. By\nelucidating the complex interactions between assisted reproductive technologies and\nadverse obstetric consequences, this article seeks to contribute to the advancement\nof scientific and clinical knowledge, promoting best practices in reproductive and\ngestational health care.\n\nSystematic review with comprehensive research in the electronic databases PubMed,\nCochrane Library, BVS, Embase, Web of Science, Scopus. The search did not limit\nthe initial date of publication, with the final date being January 8, 2025. The\nsearch terms used are listed in  Table\n1 .\nSearch Terms.\nThe inclusion criteria were: original studies published and fully avaiable in\nscientific databases or in printed versions; studies comparing an intervention\ngroup (pregnancy through IVF) to a control group (spontaneous pregnancy) in\nrelation to the occurrence of placenta accreta; and original language English or\nPortuguese.\nThe exclusion criteria were: isolated case studies or case series with fewer than\n10 patients; studies not fully available in the databases searched; articles not\npeer-reviewed, such as opinions, editorials and letters to the editor; review\nstudies; studies that did not present specific data on IVF and placenta accreta;\nstudies without a control arm; and articles written in languages other than\nEnglish or Portuguese.\nStudy selection was performed in three stages: identification, screening, and\ninclusion. In the identification stage, all titles and abstracts retrieved\nthrough the database search were reviewed by two independent reviewers, with the\nhelp of the Rayyan program. In the screening stage, the full texts of\npotentially relevant articles were assessed for inclusion and exclusion\ncriteria. Disagreements between reviewers were resolved by consensus ( Figure 1 ).\nFigure 1 Study Selection.\nStudy Selection.\nData were extracted in a standardized manner using a Microsoft Excel extraction\nform. The extracted information included: author, year of publication, country\nof study, study design, sample size, demographic characteristics of participants\n(such as maternal age, previous obstetric history), definition of placenta\naccreta used, main results (expressed as relative risk (RR) for cohort studies\nand odds ratio for case-control studies) and authors’ conclusions. In addition,\ndata were collected on potential confounders and statistical adjustments\nperformed.\nThe methodological quality of the included studies was assessed using the New\nCastle-Ottawa risk of bias assessment tool for cohort and case-control studies.\nEach study was classified as having low, moderate, or high risk of bias. Quality\nassessment was performed independently by two reviewers, with disagreements\nresolved by consensus.\nThe extracted data were qualitatively synthesized, with a detailed description of\nthe main findings of each study.\nSince this was a systematic literature review and did not involve direct patient\ninvolvement or primary data collection, it was not necessary to obtain approval\nfrom a research ethics committee. In line with good research practices, the\nanalysis followed the PRISMA (Preferred Reporting Items for Systematic Reviews\nand Meta-Analyses) guidelines to ensure transparency and quality of the\nreview.\n\nThirteen articles were included in the review ( Tables\n2  and  3 ), comprising 252,295\npregnancies conceived by assisted reproductive technology (in vitro fertilization or\nintracytoplasmic sperm injection) and 16,834,591 spontaneous pregnancies, used as a\ncontrol group. Few studies analyzed the difference in maternal outcomes between\nplacenta accreta after ART and spontaneous conception.\nComparison of the included studies.\nNewcastle-Ottawa classification of quality of non-randomized studies.\nThe articles included were published between 2011 and 2025. Most studies were\nconducted in China (46%), followed by the United States of America (23%) and Japan\n(23%). The studies were mostly retrospective cohort studies, with some being\ncase-control or prospective cohort studies. The criteria for diagnosing PAS were\nanatomopathological in 30% of the studies, clinical in 15% and unspecified in\n55%.\nZhu  et al.  (2016)  reported\nan increased risk of PAS in both nulliparous and multiparous patients and a 20-fold\nincrease in the risk of multiple pregnancies after IVF. He also observed that\nperforming ICSI did not increase the risk for those patients who underwent IVF. In\nthe retrospective cohort study conducted by  Tanaka\n et al.  (2020) , the relative risk of PAS after ART\nwas 7.35 (CI 3.2-16.6); however, 90% of the cases evaluated involved FET. Among the\nstudies that address this association,  Al-Khatib\n et al.  (2024)  stands out, which compared the\nprevalence of PAS after fresh-ET and FET, demonstrating that, although both\ncorrelate with a higher risk of PAS, when compared with spontaneous conception,\npregnancies resulting from FET had a higher RR than those from fresh-ET. This data\nwas also highlighted in the  Imafuku  et\nal.  (2021)  study.\nThe study conducted by  Zhang  et al. \n(2024)  identified a relative risk of 2.72 (CI 2.42-3.07) for the\ndevelopment of placenta accreta after the use of assisted reproductive technologies.\nIn this analysis, the relative risk was 1.46 (CI 1.19-1.79) for placenta accreta\nafter fresh embryo transfer and 3.89 (CI 3.39-4.46) after frozen embryo transfer. In\naddition, the study found an association between endometrial thickness less than 9\nmm and an increased risk of placenta accreta in patients undergoing frozen embryo\ntransfer ( Zhang  et al. ,\n2024 ).\nLin  et al . (2022)  compared\nthe incidence of PAS between IVF and spontaneous conceptions and conducted a\nspecific analysis among women with a previous cesarean section. Even in this group,\nthe study found that the risk of developing placenta accreta spectrum doubled if the\nmethod of conception was IVF. Furthermore, it was observed that 90% of patients with\na previous cesarean section, regardless of whether they conceived by ART or\nspontaneously, had a new cesarean section as an outcome in the subsequent pregnancy\n( Lin  et al. , 2022 ).\nThe study carried out by  Nagata  et\nal.  (2019) , was the first to evaluate maternal outcomes in\npatients with placenta accreta after assisted reproduction. The results showed a\nworse maternal outcome in pregnant women whose pregnancy was the result of assisted\nreproduction. A relative risk of 2.58 (CI 1.11-6.01) for intensive care unit(ICU)\nadmission was observed in IVF patients and 3.76 (CI 1.68-7.06) for ICSI patients.\nThe need for replacement of blood components after delivery was also higher in the\nIVF group, RR of 3.85 (CI 2.52-5.88), and ICSI, RR of 3.76 (CI 2.49 - 5.66). This\nanalysis was adjusted for potential confounding factors, reinforcing the association\nbetween assisted reproduction and adverse outcomes in cases of placenta accreta\n( Nagata  et al. ,\n2019 ).\nIn contrast, the cohort study conducted by  Modest\n et al.  (2021)  reported that pregnant women diagnosed\nwith placenta accreta after assisted reproduction treatments had lower rates of ICU\nadmission compared to pregnant women with placenta accreta resulting from\nspontaneous conception. However, those diagnosed with placenta accreta after IVF had\nfewer diagnoses performed in the prenatal period, since they often did not present\nthe risk factors traditionally associated with placenta accreta. In addition,\npatients undergoing IVF were less likely to develop placenta previa and had fewer\nprevious cesarean sections compared to the control group, showing that assisted\nreproduction technology is an independent risk factor for the emergence of PAS\n( Modest  et al. , 2021 ).\nThe studies by  Imafuku  et al. \n(2021) , as well as that by  Kong\n et al.  (2022) , also corroborate this association as\nan independent risk factor.\nIn  Jiang  et al.  (2021) , it\nwas observed that ART significantly increased the risk of developing gestational\ndiabetes mellitus (GDM), RR of 1.42, premature rupture of membranes, RR of 1.65, and\npostpartum hemorrhage, RR of 1.38, in twin pregnancies, whose controls were other\nmultiple pregnancies. Furthermore, an association was identified between IVF/ICSI\nand placenta accreta, with a relative risk of 2.12 (CI 1.42-3.17), which was also\nrelated to previous cesarean sections ( Jiang\n et al. , 2021 ). The study conducted by  Kong  et al.  (2022)  also\nobserved that pregnancies resulting from IVF were more likely to develop gestational\ncomplications, including gestational hypertension (RR 1.55 CI 1.51-1.59),\npreeclampsia (RR 1.54 CI 1.51-1.57), preterm birth (RR 1.48 CI 1.46-1.51), fetal\ndistress (RR 1.39 CI 1.37-1.42) and fetal growth restriction (RR 1.36 CI\n1.30-1.42).\nThe same study ( Jiang  et al. ,\n2021 ) revealed that 86.9% of monochorionic pregnancies were conceived\nspontaneously, while in dichorionic pregnancies 50% resulted from IVF and 50%\noccurred spontaneously. However, no significant association was found between\nassisted reproductive therapy and the occurrence of placenta previa, as in study by\n Esh-Broder  et al.  (2011) .\nIn contrast, the study carried out by  Violette\n et al.  (2023)  identified an increased risk of\nplacenta previa in pregnancies resulting from assisted reproductive therapy, with a\nrelative risk of 2.98 (CI 2.64-3.35), and an even higher risk, of 11.3 (CI\n5.86-21.8), for the occurrence of vasa previa, specifically in these pregnancies.\nThe same study indicated that the relative risk of association between placenta\nprevia and placenta accreta in the same patient after assisted reproduction therapy\nwas 2.8 (CI 1.32-5.92) ( Violette  et\nal. , 2023 ).\nWang  et al.  (2021)  analyzed\nthe etiology of infertility in relation to the risk of placenta accreta and found\nsignificance only in patients with tubal factor, presenting a relative risk of 1.61\n(CI 1.19-2.18), and with male factor, of 2.05 (CI 1.08-3.87). Endometriosis,\novulatory factor or the combination of multiple factors did not show a significant\nrelationship with the development of placenta accreta ( Wang  et al. , 2021 ).\n\nThe review of 13 articles and more than 17 million pregnancies reveals a significant\ngap in the analysis of specific maternal outcomes associated with placenta accreta\nafter ART, compared with spontaneous pregnancies. The predominance of retrospective\ncohort studies, together with a variety of diagnostic criteria for PAS, emphasizes\nthe complexity in directly comparing risks between the studied groups. The high\nrepresentation of Chinese studies is notable, given the one-child policy that was in\nforce for decades, influencing patient demographics and complicating the\ninterpretation of results regarding the impact of previous uterine scars on post-ART\npregnancies.\nThese results highlight the importance of rigorous and specialized monitoring during\npost-ART pregnancies, given the greater complexity and potential for complications,\nsuch as PAS. These are patients who require more rigorous prenatal monitoring, with\nultrasounds for placental investigation. Studies ( Birkmeyer  et al. , 2002 ;  Wright  et al. , 2010 ) have shown that prenatal diagnosis\nof PAS, with birth in reference centers, reduces morbidity and mortality at birth,\nas well as the need for blood component replacement.  Nieto-Calvache  et al.  (2022)  found a better detection\nrate of accreta in prenatal tests in reference centers.\nIn a study conducted by  Salmanian  et\nal.  (2020) , pregnancies resulting from ART had an 8.7 times\nhigher risk of PAS; however, in patients with one previous cesarean section, the RR\nwas 10.1 (CI 5.1-20.2) and with four or more cesarean sections, the RR was 49.1 (CI\n17-141.7). In this same study, it was observed that the diagnosis of placenta previa\nconstitutes an RR of 94.6 (CI 29.3-305.1) for the occurrence of PAS. Among the\n37,461 patients included, 5 had the three risk factors analyzed, with 100% of them\ndeveloping PAS. This demonstrates that, although IVF is an independent risk factor\nfor PAS, it presents a lower risk than the traditionally related risk factors, but\nit also adds significant risk when added to them ( Salmanian  et al. , 2020 ).\nThe exact pathophysiology of placenta accreta is not yet fully understood and remains\na topic of ongoing investigation. However, several risk factors for its occurrence\nare well established, including previous cesarean section, placenta previa, advanced\nmaternal age, multiparity, previous uterine curettage, and a history of uterine\nsurgeries that resulted in scarring of the uterus ( Esh-Broder  et al. , 2011 ). In IVF, uterine embryo\ntransfer occurs through the internal cervical canal using a catheter, which can\ninduce uterine contractions and the release of prostaglandins. This process can\nalter the interaction between the embryo and the endometrium, impacting the\nplacental implantation process ( Jauniaux  et\nal. , 2020 ).\nOne possible mechanism to explain the association between FET and placenta accreta is\nthat serum estradiol (E2) levels may modulate the degree of trophoblast invasion and\nthe extent of vascular remodeling during implantation. In both humans and nonhuman\nprimates, supraphysiological E2 concentrations may be related to abnormal\nplacentation and its sequelae, such as preeclampsia and fetal growth restriction. In\nFET cycles, E2 levels are typically lower than in fresh stimulation cycles, which\nmay allow the window for trophoblast invasion to be prolonged. After exposure to\nhigh peak E2, the endometrium becomes refractory to implantation within 24 hours\n( Salmanian  et al. ,\n2020 ).\nThe relationship between placenta accreta and maternal mortality is widely recognized\nand documented. As early as  O’Brien  et\nal.  (1996)  reported a 7% mortality rate associated with\nplacenta percreta, although they emphasized that this figure probably underestimates\nthe true risk. The main cause of maternal death associated with placenta accreta is\nmassive hemorrhage, often accompanied by coagulation disorders ( O’Brien  et al. , 1996 ). It is\nnoteworthy that maternal hemorrhage continues to be one of the main causes of\nmaternal mortality worldwide today ( PAHO - Pan\nAmerican Health Organization & WHO -World Health Organization, 2017 ).\nThese data reinforce the importance of early diagnosis of this condition during\nprenatal care, allowing detailed birth planning in tertiary care centers, with a\nmultidisciplinary team prepared to deal with possible complications ( American College of Obstetricians and Gynecologists\n& Society for Maternal-Fetal Medicine, 2018 ).\nBetran  et al.  (2021) , when\nanalyzing global data between 1990 and 2018, identified that more than half of\nbirths in Brazil are the result of cesarean sections. Worldwide, approximately 1 in\n5 children are born by cesarean section.  Betran\n et al.  (2021)  projection is that this number will\nincrease to 1 in 3 births by 2030. With the increasing number of cesarean sections\nand the increase in pregnancies through in vitro fertilization, the proportion of\npatients with multiple risk factors for placenta accreta spectrum will increase. In\nthis context, it will be crucial to differentiate and identify specific cases to be\nscreened during prenatal care, allowing for adequate planning, aiming for a\ngestational outcome with lower morbidity.\nIn summary, while ART offers a valuable opportunity for many couples to conceive, the\nchallenges associated with post-ART pregnancy, particularly in relation to placenta\naccreta, require an integrated and multidisciplinary approach to optimize maternal\nand perinatal outcomes. Further research is essential to fully elucidate the\nunderlying mechanisms and develop effective preventive strategies.\nIt is important to highlight that the study may be susceptible to the influence\nof confounding factors, since logistic regression was used to control for\npossible distorting variables. For example, patients undergoing IVF had a higher\nmean age than the control group, which in itself is already a known risk factor\nfor several obstetric complications, including placenta accreta. In addition,\nthe IVF group also showed a higher prevalence of other pathological conditions,\nsuch as metabolic disorders, which may contribute to an increased risk of\ncomplications, regardless of the reproductive method used. These factors, if not\nadequately controlled, may influence the results of the study and make it\ndifficult to interpret a direct causal relationship between IVF and placenta\naccreta. Thus, although logistic regression attempts to adjust for these\neffects, the possibility of confounding bias still persists, requiring caution\nin generalizing the findings.","source_license":"CC-BY-4.0","license_restricted":false}