MESTRADO INTEGRADO EM MEDICINA

Congenital uterine anomalies: the role of Maria Carolina Fernandes Lamouroux Barroso M 2021

Congenital uterine anomalies: the role of surgery

Dissertação de candidatura ao grau de Mestre em Medicina, submetida ao Instituto de Ciências Biomédicas Abel Salazar – Universidade do Porto

Maria Carolina Fernandes Lamouroux Barroso

Aluna do 6º ano profissionalizante de Mestrado Integrado em Medicina

Afiliação: Instituto de Ciências Biomédicas Abel Salazar – Universidade do Porto

Endereço: Rua de Jorge Viterbo Ferreira nº228, 4050-313 Porto

Endereço eletrónico: [email protected]; [email protected]

Orientador: Dra. Márcia Sofia Alves Caxide e Abreu Barreiro

Diretora do Centro de Procriação Medicamente Assistida e do Banco Público de Gâmetas do Centro Materno-Infantil do Norte

Assistente convidada, Instituto de Ciências Biomédicas Abel Salazar – Universidade do Porto.

Afiliação: Instituto de Ciências Biomédicas Abel Salazar – Universidade do Porto

Endereço: Largo da Maternidade de Júlio Dinis 45, 4050-651 Porto

Endereço eletrónico: [email protected]

Coorientador: Prof. Doutor Hélder Ferreira

Coordenador da Unidade de Cirurgia Minimamente Invasiva e Endometriose do Centro Materno- Infantil do Norte

Professor associado convidado, Instituto de Ciências Biomédicas Abel Salazar – Universidade do Porto.

Afiliação: Instituto de Ciências Biomédicas Abel Salazar – Universidade do Porto

Endereço: Rua Júlio Dinis 230, B-2, 9º Esq, Porto

Endereço eletrónico: [email protected]

Junho 2021

Porto, junho de 2021

______

(Assinatura da estudante)

______

(Assinatura da orientadora)

______

(Assinatura do coorientador)

ACKNOWLEDGEMENTS

À Dra. Márcia Barreiro, ao Dr. Luís Castro e ao Prof. Doutor Hélder Ferreira, por toda a disponibilidade e empenho dedicado à realização deste trabalho. Aos meus pais, irmão e avós, pela participação que desde sempre tiveram na minha formação, e pelo carinho e apoio incondicional.

i

ABSTRACT When disturbances occur in normal uterine embryogenesis, different uterine congenital malformations, defined as deviations from the normal anatomy of the , can occur. While a variety of etiological factors are related, among them: teratogenic agents, genetic, environmental, and multifactorial factors, there is still no concrete documentation on its influence or form of action. Although there is no universally accepted classification for congenital uterine anomalies, the ESHRE/ESGE classification is a recent and clear system, enabling physicians to organize any anomaly. Based on this classification system, protocols for an efficient diagnostic and treatment approach are developed for each type of malformation. These anomalies are often related to adverse reproductive outcomes, representing great relevance in clinical practice. They are usually only diagnosed when the woman reaches adulthood coinciding with the occurrence of these events. , repeated abortions (in the first or beginning of the second trimesters) and preterm births are common manifestations. This systematic review was carried out using the PubMed and Google Scholar databases, the research was based on the combination of the Medical Subject Headings (MeSH) terms defined. Scientific articles, written in English since 2010 were included, as well as older relevant articles by cross referencing. The Female Genital Tract Congenital Malformations: Classification, Diagnosis and Management, a 2015 published book, and the ESHRE/ESGE guidelines were also complementary research tools. Since it is currently accepted that the need for correction of uterine malformations varies from case to case, not being mandatory and depending on many variables such as: the clinical presentation, the degree of anomaly, the woman's history especially in terms of obstetric complications, her age, and her reproductive plans, the goal of this dissertation is to discuss in which situations surgery (restorage of the uterine architecture) plays an important role. It is also reviewed various surgical techniques and the post-surgery results for each class of anomaly, respectively, although it is notorious that large randomized controlled trials with consistent results are lacking, which may lead to contradictory bibliography.

Keywords: Uterine anomalies, malformations, congenital, classification, diagnosis, infertility, abortion, hysteroscopy, laparoscopy, surgery, dysmorphic, septate, bicorporeal, hemi-uterus, aplasia.

ii

RESUMO Quando ocorrem distúrbios na embriogénese uterina, diferentes malformações congénitas uterinas, definidas como desvios da anatomia normal do útero, surgem. Embora diversos fatores etiológicos estejam relacionados, nomeadamente: agentes teratogénicos, fatores genéticos, ambientais e multifatoriais, ainda não há documentação concreta sobre sua influência ou mecanismo de ação. Embora não haja uma classificação universalmente aceite para as anomalias uterinas congénitas, a classificação ESHRE/ESGE é um sistema recente e claro, permitindo aos médicos organizar qualquer anomalia. Com base nesse sistema de classificação, são desenvolvidos protocolos para uma abordagem diagnóstica e de tratamento eficiente para cada tipo de malformação. Muitas vezes, essas anomalias estão relacionadas a desfechos reprodutivos adversos, apresentando grande relevância na prática clínica. Geralmente, são diagnosticados apenas quando a mulher atinge a idade adulta coincidindo com a ocorrência desses eventos. Infertilidade, abortos repetidos (no primeiro ou início do segundo trimestre) e partos prematuros são manifestações comuns. Esta revisão sistemática foi realizada através das bases de dados PubMed e Google Scholar. A pesquisa foi baseada na combinação dos termos do Medical Subject Headings (MeSH) definidos. Artigos científicos, escritos em inglês desde 2010, foram incluídos, bem como artigos relevantes mais antigos por referências cruzadas. The Female Genital Tract Congenital Malformations: Classification, Diagnosis and Management, livro publicado em 2015, e as diretrizes ESHRE / ESGE também foram ferramentas complementares de pesquisa. Visto que atualmente é aceite que a necessidade de correção das malformações uterinas varia conforme a doente, não sendo obrigatória e dependendo de muitas variáveis como: a apresentação clínica, o grau de anomalia, a sua história médica passada principalmente em termos de complicações obstétricas, a sua idade, e os seus planos reprodutivos, o objetivo desta dissertação é discutir em quais situações a cirurgia de restauração da arquitetura uterina desempenha um papel importante. Também são revisadas várias técnicas cirúrgicas e os resultados pós-cirúrgicos para cada classe de anomalia, respetivamente, embora seja notório a falta de grandes ensaios clínicos randomizados com resultados consistentes, o que pode levar a bibliografia contraditória.

iii

Palavras-chave: Anomalias uterinas, malformações, congénitas, classificação, diagnóstico, infertilidade, abortamento, histeroscopia, laparoscopia, cirurgia, dismórfico, septado, bicorpóreo, hemi-útero, aplasia.

iv

ABBREVIATIONS

2D Two dimensional 3D Three dimensional AFS American Fertility Society AMH Anti-Müllerian hormone ASRM American Society of Reproductive Medicine CUA Congenital uterine anomaly DES ESGE European Society for Gynaecological Endoscopy ESHRE European Society of Human Reproduction and Embryology GnRH Gonadotropin-releasing hormone HSG IUA Intrauterine adhesions IUGR Intrauterine growth restriction IVF In-vitro fertilization MA Müllerian aplasia MRI Magnetic resonance imaging MRKH Mayer-Rokitansky-Kuster-Hauser syndrome RCT Randomized controlled trial TRUST The Randomised Uterine Septum Transsection Trial TVS Transvaginal scanning US Ultrasonography

v

LIST OF FIGURES Figure 1: Embryology of the female genito-urinary tract (frontal view)...... 27 Figure 2: ESHRE/ESGE classification of uterine anomalie ...... 28 Figure 3: Scheme for the classification of female genital tract anomalies according to the new ESHRE/ESGE classification system...... 29 Figure 4: Diagram of the incisions in dysmorphic uterus surgery...... 30 Figure 5: Surgical Technique of the Jones Procedure ...... 32 Figure 6: Surgical Technique of the Tompkins Procedure ...... 34 Figure 7: Surgical Technique of the Strassman Metroplasty...... 35

LIST OF TABLES Table I: Estimates of prevalence of different genital tract malformations using the new ESGE/ESHRE classification ...... 36 Table II: Variants of bicorporeal uterus and their surgical treatment ...... 36

vi

INDEX Acknowledgements ...... i Abstract ...... ii Resumo ...... iii Abbreviations ...... v List of Figures ...... vi List of Tables ...... vi Introduction ...... 1 Material and Methods ...... 2 Embryology ...... 3 Etiology ...... 5 Classification...... 7 Prevalence ...... 11 Clinical Presentation ...... 13 Diagnosis ...... 16 Surgical Management ...... 18 Class U1 (ESHRE/ESGE classification): Dysmorphic Uterus ...... 18 Class U2 (ESHRE/ESGE classification): Septate Uterus ...... 20 Class U3 (ESHRE/ESGE Classification): Bicorporeal Uterus ...... 23 Classes U4a and U5a (ESHRE/ESGE classification): Rudimentary Horns with Cavity ...... 24 Conclusion ...... 26 Appendix 1 ...... 27 Appendix 2 ...... 36 References ...... 37

vii

INTRODUCTION Disturbances of development, canalization, fusion or reabsorption of paired Müller channels and may lead to many congenital anomalies of the uterus, , , and fallopian tubes. The prevalence of these malformations in unselected population is approximately 5%, while women with reproductive issues are more commonly affected with prevalence of 8% in infertile women and 13% in women with past .1 Congenital uterine anomalies (CUA) may cause no symptoms or can implicate severe health consequences and diminish reproductive functions. It is described that morphologically identical defects have similar embryologic origin and may be related with similar clinical expression. 2 Several attempts have been made to label and organize these disorders of the Müller channels and establish definitions of specific types of malformations according to morphologic resemblance, embryologic origin, and suitable management. 3 During the past decade, classification systems and definitions of malformations have been established, altered, or clarified, although implications of these adjustments for patient management are not universally accepted and defined. 4 In this review, the recent European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) classification 5 is used as reference since it characterizes the uterine anomalies in a clear and objective way. Current non-invasive or minimally invasive diagnostic methods have become generally accessible and are now used for classification and surgical planning. These tools have replaced classic diagnostic tools such as hysterosalpingography, two-dimensional (2D) ultrasound, diagnostic hysteroscopy alone and hysteroscopy with laparoscopy. 4,6,7 Classically, corrective surgery of CUAs was performed in patients with specific clinical presentation: infertility, history of poor obstetrical outcomes, and recurrent miscarriages. It is now known the clinical implication of each type of anomaly and impact of surgery on fertility and obstetrical results are not the same for all defects. There have been many advances in the management of these patients including presurgical qualification, intraoperative imaging tools, surgical approaches, and postoperative care. 8

1

MATERIAL AND METHODS An online search was performed at Pubmed and Google Scholar, using the following Medical Subject Headings (MeSH) terms: uterine anomalies, congenital, Mullerian, abnormalities, malformations, etiology, classification, clinical presentation, diagnosis, surgery, hysteroscopy, laparoscopy, infertility, abortion, arcuate uterus, dysmorphic uterus, septate uterus, bicorporeal uterus, hemi-uterus, aplastic uterus, and the UpToDate database using congenital uterine anomalies as keywords. The selection took place between September and April 2021 and the following inclusion criteria were used: scientific articles, published since 2010, in English. After reading and critically analysing the abstracts and conclusions, the bibliographic review articles, systematic reviews, prospective studies, case reports, meta-analysis and clinical trials whose content was found to be relevant to the topics covered in this review were considered. At a later stage, cross references of relevant articles published prior to 2010 were also included, when information on the subject was limited in the recent bibliography. The Female Genital Tract Congenital Malformations: Classification, Diagnosis and Management, a 2015 published book, and the ESHRE/ESGE guidelines were also complementary research tools.

2

EMBRYOLOGY Up to the sixth week of embryogenesis, the urogenital system remains indifferent in both sexes. Two pairs of genital systems are present: the mesonephric (Wolffian duct) and paramesonephric (Müllerian duct). Further differentiation of the gonads is dependent on the presence or absence of the SRY gene on the Y chromosome, which stimulates differentiation of the testes in male individuals. In female individuals, the lack of anti-Müllerian hormone (AMH) allows differentiation of the paramesonephric ducts into the female internal organs, and estrogen drives the differentiation of female external genitalia (labia majora, labia minora and ). The testosterone insufficiency prevents the differentiation of the mesonephric ducts in female individuals. 9,10 At week 6, the mesonephric ducts will develop from the and span from the mesonephros (where the future gonad will be located) to the (which will originate the anorectal canal and the urogenital sinus). Until the eighth week, the paramesonephric ducts appear, through the longitudinal invagination of the celomic epithelium on the antero-external face of the mesonephros, parallel and externally to the mesonephric channels. During this week of embryogenesis, the Müller channels begin to move towards the midline, while the consequent degeneration of the male Wolff channels occurs. 10 The Müller channels eventually merge in the cranio-caudal direction, during week 10, forming the uterus-vaginal canal. However, its proximal portion remains separate as it will develop into the fallopian tubes, forming the fimbriae which derives from the tip of this structure, remaining open and acquiring a funnel shape. The fused caudal end gives origin to the left and right parts of what will ultimately become the uterus. This structure contains mesoderm that will form the and . It also remains divided by the inter-Müllerian septum, which is reabsorved during 11th week of gestation.11 If this midline septum is not completely reabsorbed by the twelfth week, it will persist and produce a septate uterus. A continuous differentiation of structures occurs up until week 40, namely differentiation of the uterine wall, cervix, and loss of the "V" shape of the uterus. From the fusion of the sinus-vaginal bulbs along with the caudal end of the two Mullerian ducts, the vaginal plaque is formed which, after bidirectional growth and central degeneration, allows cavitation, which is completed by the 20th week, constituting the lower third of the vagina. Thus, when disturbances in any of the steps in normal uterine embryogenesis occur, different uterine abnormalities will result. Therefore, 4 major developmental defects are considered:10

3

• Failure of one or both Müllerian ducts to form results in hemi-uterus without rudimentary cavity or aplastic uterus, respectively. Aplastic uterus is the most severe Müllerian defect. Cervical and vaginal aplasia frequently co-exist, and this is known as Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome or Müllerian aplasia (MA). • Abnormal canalization of the Müllerian ducts results in hemi-uterus with rudimentary cavity. • Fusion of both Müllerian ducts leads to formation of a uterus and upper vagina. o Horizontal fusion or unification (lower segments of paired müllerian duct fuse to form uterus, cervix and upper vagina)–defects, depending on the degree, lead to partial fusion or unification defect (bicorporeal uterus) or complete fusion or unification defect. o Vertical fusion (between the descending müllerian duct and ascending urogenital sinus to form vaginal canal)–defects cause an or a transverse . • Septal reabsorption involves the reabsorption of the horizontally fused Müllerian ducts leading to development of the uterine cavity. A failure of this mechanism results in a septate uterus. 12

All these malformations can be segmental, partial, or complete, related to the vagina, the cervix, the uterine fundus, the fallopian tubes, or can be associated. Therefore, congenital uterine anomalies may have characteristic features of various defects.11 Since the development of the genital and urinary systems are strongly associated, as both depend on the correct maturation of the mesonephric system, it should be noted that in case of interference of one of these systems, the other may also be affected. Therefore, it is imperative that, after the diagnosis of one of the two types of abnormalities, uterine or renal, the existence of the other is investigated. 13 This is widely documented in the literature, with studies indicating a coexistence of congenital uterine and renal abnormalities in about 30–50%. Heinonen et al.14 concluded that the unilateral renal agenesis was the most frequent renal tract malformation in women with Müllerian channel anomalies and renal malformations were more common in the main groups of uterine anomalies, especially in patients with concomitant cervical and vaginal obstructive anomaly. 14 If any factor causes disturbance at some point in the development of Müllerian channels, the malformations will correspond to the week in which there was exposure to this etiological factor. An exception is the exposure to Diethylstilbestrol (DES) in utero.

4

ETIOLOGY The occurrence of the malformations previously described are related to disturbances in normal embryogenesis however, the exact etiology remains unknown. There are several theories about possible causes and their form of action, namely teratogenic agents, genetic, chromosomal, environmental, and multifactorial factors, that together can create a favourable environment for the anomaly. 11,15 The karyotype is generally normal. However, some familiar cases are linked to a recessive autosomal gene and others to a dominant autosomal one. Currently, only a small number of genes (HNF1B, WNT4, WNT7A, HOXA13) have assembled a strong evidence of causality, mainly in syndromic presentations. The sequencing of candidate genes in series of individuals with isolated uterine abnormalities has been able to suggest an association for several genes, but confirmation of a strong causative effect is still missing for most of them. 16 According to Hammoud et al. 17 nearly 10% of patients with Müllerian anomalies seem to be accountable to a familiar association. They conclude that Müllerian anomalies have a strong familiar aggregation and follow a polygenic and multifactorial inheritance.17 Nevertheless, the familiar association is hard to research. Uterine ultrasounds have not usually been performed in extended family members with asymptomatic anomalies. Although in many families recurrences tend to repeat the same type of uterine malformation, recurrences with variable types of uterine maldevelopment have also been reported in several families suggesting that similar genetic background could still induce different types of uterine malformation with variable penetrance and expressivity. 16 It is implied that several cases of fetal genital tract defects are associated with a history of exposure, intra and extrauterine, to certain environmental factors. Apart from the DES syndrome, other teratogenic drugs, malnutrition, metabolic alterations, viral infections, and placental anomalies have been implied. Numerous reports of discordant phenotypes in monozygotic twins (e.g., MRKH syndrome vs. normal uterus) argue against strong heritability and suggest that post- zygotic somatic mutations or non-genetic mechanisms including epigenetic or microenvironmental factors regulate the occurrence of congenital uterine malformations. 18,19 The uterus exposed to DES in utero undergoes several changes in its development, having a characteristic aspect: uterus with "T" shaped cavity, usually hypoplastic, with widening of its lower segment, presence of median constricting bands and irregular endometrial edges.20 DES has been used by women for several years, since it was thought that it could reduce the risk of spontaneous abortions. However, it was discontinued in 1971, after perceived increased risk of developing clear cell adenocarcinoma of the lower genital tract (cervix and vagina) in women exposed in utero.21

5

Nevertheless, this dysmorphic T-shaped uterus can also be found in DES non-exposed patients, which is consistent with the idea that CUA are influenced by multifactorial, polygenic and familiar mechanisms that together can create a favourable environment for the anomaly, but in most patients there is no evident cause or association.

6

CLASSIFICATION Classifications are fundamental in medicine since they allow a systematization of medical knowledge and facilitate communication between physicians. Until today, there is no universally acknowledged classification system for CUAs, which is critical due to their prevalence and clinical relevance.22 The existing about an efficient classification emerge diagnostic and treatment difficulties. An ideal classification system includes a clear description of each class and subclass, allowing objective identification of each anatomical variation. It should also enable the inclusion of new classes, if new anomalies are detected. Finally, the correlation between the various classes and subclasses with the respective clinical presentations, treatment options and prognosis is crucial. Thus, it would allow the determination of obstetric and fertility impacts inherent to each anomaly and the therapeutic strategies that would improve them. 22 The first classifications for CUAs were carried out according to the descriptions of Cruveilher, Foerster and von Rokitansky in the mid-19th century. However, the first description to be widely recognised was published by Buttram and Gibbons in 1979, which was later revised and modified by the American Fertility Society (AFS), now known as the American Society of Reproductive Medicine (ASRM). This has been the most used classification over the past three decades. In 1988 the AFS published their classification scheme 23 for mechanical problems associated with poor reproductive outcomes. The Müllerian anomalies were classified as follows: (I) agenesis and hypoplasias; (II) unicornuate uterus; (III) didelphic uterus; (IV) ; (V) septate uterus; (VI) arcuate uterus; (VII) anomalies related to DES syndrome.

The goal of this classification was to provide an easy and reliable system to allow physicians to group cases, and for future patients to be counselled accurately and effectively. Nevertheless, this classification has several disadvantages, including the lack of strict morphometric criteria and the subjective description of the anomalies since there are no standardized diagnostic criteria. There was also no apparent definition of normal uterus. For these reasons, additional morphometric criteria were endorsed by ASRM in 2016 , which reported Class VI (arcuate uterus) as a normal variant, not clinically relevant. This leaves a grey zone between normal/arcuate and septate where some women will not meet the criteria for either diagnoses.

7

Another limitation is that the AFS classification only refers to Müllerian anomalies and is mainly focused on the uterus. Therefore, an embryologic-clinic classification was suggested by Acién et al. 3 which considers all female genitourinary malformations and their embryologic origin. Another group described the vagina, cervix, uterus, adnexa, and associated malformations (VCUAM) system influenced by the TNM oncology system.24 These two systems, although very understandable, are complex and not user friendly, for physicians. The ESHRE/ESGE developed in 2013 (figure 2) a “uterus-cervix-vagina” classification system5. Anatomy is the foundation for the systematic categorization of anomalies so deviations of uterine anatomy deriving from the same embryological origin are the basis for the design of the main classes. The sub-classes are based on the different degrees of uterine deformity, while cervical and vaginal anomalies are classified in independent supplementary sub-classes. Anomalies are sorted in the classes and sub-classes of the system according to increasing severity of the anatomical deviation. 5 All cases with normal uterus are classified in Class U0. A normal uterus is defined as any uterus having either straight or curved interostial line but with an internal indentation at the fundal midline not exceeding 50% of the uterine wall thickness. The arcuate uterus is now considered a normal variant, since it is the mildest form of uterine septum 5,25, resulting from anomalies at the end of resorption of the inter-Müllerian septum7,26. Patients are asymptomatic, have no compromise of fertility, and similar outcomes as those in the general obstetric population. In imaging it appears as a minimal myometrial prominence at the fundus, there is deviation less than 1 cm fundal indentation and an angle of indentation greater than 90º.6 Dysmorphic uterus (Class U1) refers to all cases with normal uterine outer configuration but with an abnormal shape of the uterine cavity excluding septa. It is subdivided into three categories: T-shaped uterus (Class U1a) represents a narrow uterine cavity due to thickened lateral walls with a ratio of 2/3 uterine corpus to 1/3 cervix. Uterus infantilis (Class U1b) characterized also by a narrow uterine cavity without lateral wall thickening and an inverse ratio of 1/3 uterine body and 2/3 cervix. Others (Class U1c) include minor deformities of the uterine cavity including those with an inner indentation at the fundal midline level of <50% of the uterine wall thickness. This clearly differentiates them from patients with septate uterus. The Septate uterus (Class U2) includes all cases with normal fusion of the Müller channels and abnormal absorption of the midline septum.27 The uterus presents with normal outline and an internal indentation at the fundal midline exceeding 50% of the uterine wall thickness.28 The septum is usually vascularized fibromuscular and it could divide partly or completely the uterine

8 cavity including in some cases cervix and/or vagina. The thickness and composition of the septum, the relative amounts of fibrous and muscular tissue, and the degree of vascularization from the adjacent uterine wall may also vary.27 No classification system standardizes all these variations. The anomalies are divided in two sub-class according to the degree of the uterine corpus deformity: Partial septate uterus (Class U2a) which has a septum dividing partly the uterine cavity above the level of the internal cervical ostium. Complete septate uterus (Class U2b) is characterized by the presence of a septum fully dividing the uterine cavity up to the level of the internal cervical ostium. Patients with complete septate uterus (ClassU2b) could have or not cervical (e.g. bicervical septate uterus) and/or vaginal defects. The Bicorporeal uterus (Class U3) occurs due to incomplete or partial fusion of both Müller channels.29 As bicorporeal is defined the uterus with an abnormal fundal outline, it is characterized by the presence of an external indentation at the fundal midline exceeding 50% of the uterine wall thickness. It also correlates with an inner indentation at the midline level that divides the cavity as the septate uterus. The degree of uterine corpus deformity divides this anomaly into three sub- classes: Partial bicorporeal uterus (Class U3a) when an external fundal indentation partly divides the uterine corpus above the cervix. Complete bicorporeal uterus (Class U3b) characterized by an external fundal indentation completely dividing the uterine corpus. These patients could have coexistent cervical defects, for instance double cervix (formerly didelphys uterus) and/or vaginal anomalies as an obstructive or non-obstructive septum. In some cases, duplication of other structures such as bladder, vagina or anus are present.(29) Bicorporeal septate uterus (Class U3c) characterized by the presence of an absorption defect combined with the main fusion defect. In patients with this anomaly, the width of the midline fundal indentation exceeds by 150% the uterine wall thickness. The Hemi-uterus (Class U4) is defined as a unilateral uterine development, while the contralateral part could be either incompletely formed or absent. The need to classify it in a different class than that of aplastic uterus (formation defect) is due to the existence of a fully developed functional uterine hemi-cavity. It is further divided into two sub-classes depending on the presence or not of a functional rudimentary cavity, since it changes the clinical presentation and treatment:

9

Hemi-uterus with a rudimentary cavity (Class U4a) which can be a communicating or noncommunicating functional contralateral horn. Hemi-uterus without rudimentary cavity (Class U4b) characterized either by the presence of non-functional contralateral uterine horn or by aplasia of the contralateral part. The Aplastic uterus (Class U5) means the absence of any fully or unilaterally developed uterine cavity due to defects during the initial development of the Müller channels. Some co- existent anomalies, as vaginal aplasia or MRKH Syndrome could be present. This class is further divided into two sub-classes depending on the presence or not of a functional cavity in an existent rudimentary horn: Class U5a or aplastic uterus with rudimentary (functional) cavity characterized by the presence of bi- or unilateral functional horn. Class U5b or aplastic uterus without rudimentary (functional) cavity characterized either by the presence of uterine remnants or by full uterine aplasia. Class U6 is kept for unclassified cases. Current imaging technology grants objective evaluations of uterine anatomy for the differential diagnosis among the six groups. However, infrequent anomalies, subtle changes or combined anomalies could not be allocated correctly to one of the group. The system is designed to include cases resulting from formation, fusion or absorption defects of normal embryological development. Duplication defects or ectopic Müllerian tissue anomalies, if existing, could not be described. These anomalies could be put in this class. This classification also has autonomous categories to classify vaginal and cervical defects that could be associated with the uterine defects. Figure 3 demonstrates the classification and description of the different types of vaginal and cervical anomalies.

10

PREVALENCE Malformations of the female genital tract are common but not always identified. CUA are the most frequent ones, being significant in the population with adverse reproductive history. The prevalence of female genital tract malformations in different populations of women has been exceedingly difficult to estimate in the past few decades owing to the lack of indispensable factors (a clear definition and selection of the populations examined; the use of a clear and consistent classification of the malformations; the use of accurate investigations to make the correct diagnosis of the malformations) explaining the notable difference of these values between them. 30–32 In an initial review by Grimbizis et al. 33 the prevalence of uterine anomalies was found to be around 4% in the general population, 4% in patients with infertility, and 12% in patients with recurrent abortions. This study has various limitations such as the retrospective design of the studies included, and diagnostic methods used in different studies included were not the same and of low accuracy. Recent systematic reviews 1,30 estimate the prevalence to be 5.5–6.7% for the general population, 7.3–8.0% for the infertile population and 13.3–16.7% for the recurrent and poor reproductive outcome population and 24.5 % in those with miscarriage and infertility. Overall, the prevalence of major congenital anomalies appears to be at least three times higher in women with poor reproductive outcome compared with the general population. 30 The commonest malformations appeared to be the Class U2 septate/subseptate uteri, followed by the class U3 bicorporeal uteri. Class U1 dysmorphic uteri, Class U4 hemi-uteri and Class U5 aplastic uteri all had a prevalence of less than 1%. 1,30 However, Class U2 uteri may be overrepresented since some arcuate uteri which will fall in the Class U2 septate/subseptate category may in fact be normal uterine variants according to the new ESGE/ESHRE classification. 5 Usually, the diagnosis is done after imaging tests in response to signs or symptoms presented by the patient. However, these can exist without clinical manifestations, with benign evolution and reproductive success, remaining asymptomatic. Thus, no clinical detection is ever made, or it is done unintentionally, so it is estimated that the prevalence of these anomalies is slightly higher than what has been reported. 34 On the other hand, in addition to hysterosalpingography (HSG), the increasing and everyday use of high-accuracy imaging techniques such as 3D ultrasound (3D US), magnetic resonance imaging (MRI) and the application of minimally invasive surgical procedures (hysteroscopy and laparoscopy) resulted in a more accurate diagnosis and in an observed increase in their prevalence. 30

11

With increased accessibility through imaging techniques, and therefore higher detection rates, an emerging question is: “What is clinically significant and requires intervention versus what may be ignored as a subtle and normal variant?” 15 This question acknowledges the issue of when intervention improves outcomes.

12

CLINICAL PRESENTATION Congenital uterine anomalies are frequently related to adverse reproductive outcomes with the leading clinical presentations being infertility, conflicting obstetric events (repetitive abortions especially during the first or beginning of the second trimester, preterm delivery, fetal malpresentation and intrauterine growth restriction [IUGR]), menstrual disorders and . 2,15,34 These women are also reported to have increased rates of pre-eclampsia and stillbirth. 35 Currently, it is established, the close association between the specific type of malformation and the respective clinical presentation, including reproductive results. 34 The factors that negatively influence fertility, include changes in morphology, volume, thickness, organization and function of the endometrium and myometrium, which may be associated with cervical incompetence or changes in uterine vascularization, according to each specific anomaly. Usually, the myometrium of congenitally abnormal uteri are thinner than normal and mural thickness diminishes as pregnancy advances, causing inconsistencies over different aspects of the uterus. 34 As cases of infertility are generally associated with other etiological factors, these must be excluded before proceeding to the treatment of uterine malformations. 15 While most cases are diagnosed during adulthood, certain groups of malformations are associated with primary without impuberism, making it possible to for the detection to be made at a younger age. The MRKH syndrome being an example. 15 Chan et al. 36 reviewed 3805 women with CUAs and reported that abortion rates resulting from all causes range between 21–50%, with a decrease in birth rates of about half in comparison to the general population. This author describes that those with septate and partial septate uteri, seem to have the worst reproductive performance, with a smaller conception rate (OR 0.86; 95% CI 0.77–0.96) and increased probability of first-trimester miscarriage (OR 2.89; 95% CI 2.02–4.14), (OR 2.14; 95% CI 1.48–3.11), and fetal malpresentation at delivery (OR 6.24; 95% CI 4.05–9.62). Compared with those with a partial septate uterus, women with a septate uterus have poorer outcomes throughout their . 35 Various hypothesis have been suggested, such as vascular abnormalities, since the septum is composed of fibroelastic tissue with inadequate vascularization and consequent imbalance in its relationship between the myometrium and the endometrium. This imbalance may cause disturbances in the implantation of the embryo and in the response of the septal endometrial mucosa to estrogen, with little proliferation and estrogenic maturation. Here an additional mechanism is identified, the inadequate growth of deciduous. Uncoordinated uterine contractions

13 or reduced uterine capacity are other factors that may contribute to the suboptimal reproductive performance. 36 The bicorporeal uterus and hemi-uterus do not appear to reduce fertility but are associated with increased risks of adverse outcomes during pregnancy. These patients have an increased risk of first trimester miscarriage (OR 3.4; 95% CI 1.18–9.76 and OR 2.15; 95% CI 1.03–4.47 respectively), preterm birth (OR 2.55; 95% CI 1.57–4.17 and OR 3.47; 95% CI 1.94–6.22 respectively) and fetal malpresentation (OR 5.38; 95% CI 3.15–9.19 and OR 2.74; 95% CI 1.3–5.77 respectively). 36 Vascularization may be deficient in some uterine malformations, due to its absence or the presence of abnormal uterine or ovarian vessels. This mechanism may explain possible IUGR or spontaneous abortions. There are also less endothelial growth factors, which are essential for the growth of the vascular network needed for embryo/fetus nutrition and development. In the hemi- uterus, the severe lack of volume and distorted morphology, which, throughout a pregnancy, will progressively cause a decrease in wall thickness the presence of a single uterine artery causes important lack in vascularization. While in the bicorporeal uterus, there is a poor vascularization of the medial endometrium, which is shared between the two semi-cavities. 34 The dysmorphic uterus is characterized by abnormal morphology (T-shaped or a infantilis uterus). Fernandez et al. 37 presented a retrospective study on 97 women with a T-shaped uterus; while 63 had a history of DES exposure, the remaining 35% had either a congenital malformation attributable to other causes or an acquired T-shaped malformation. On a total of 78 pregnancies before hysteroscopic metroplasty the miscarriage prevalence is 78.2 %, ectopic pregnancy 17.9 %, preterm delivery 3.8 % with all neonatal deaths and no live birth.37 Cervical insufficiency seems to be an important cause of poor reproductive results in cases of Müllerian anomalies, not due to the existence of malformations in the neck itself, but, according to several researchers, due to the imbalance between the amount of muscle fibres and connective tissue, which exists in less quantity. 38,39 In addition to this different composition, the forces exerted by the uterine content during pregnancy are also distinct, being asymmetrical and being increased in the presence of uterine malformations, which causes premature relaxation of the hypermuscular neck. Thus, a way to improve reproductive results in cases of uterine congenital anomalies may involve prophylactic , as has been successfully tested. 4011[NO_PRINTED_FORM] 15CUAs may also entail severe health conditions or have serious consequences that endanger the woman's life. 34 Regarding the obstructive anomalies, the uterus has a functioning endometrium with no communication (Classes U4 and U5) or is associated with aplasia or dysplasia of the cervix and/or vagina (Co-existing classes C1, C3, C4, V2, V3 and V4). These patients are asymptomatic until they reach puberty, then their main presenting symptom is amenorrhea (with normal secondary sexual characteristics) and cyclical abdominal pain (due to the retention of

14 menstruation and eventually leading to and hematocolpus) which may be followed by constant pain. These women are at increased risk for: due to retromenstruation; abnormal uterine or discharge; infections secondary to vaginal micro perforations; possible inability to establish a sexual life; reproductive difficulties (even under medically assisted procreation treatments).30 Considering pregnant patients, fertilization can occur in a functional non-communicating (rudimentary) uterine horn (Class U4a) by transmigration of sperm, however the exact incidence remains unknown. The eventual15 rupture and haemorrhage of this cavity corresponds almost15always to an emergency. 15 It 34is important to understand the negative psychological impact that these types of anomalies may have. The psychologic support of these adolescents will reduce the anxiety and depression they experience, will help them to adapt better to their congenital abnormality and help to prepare better for the appropriate surgical management. Finally, an idea to keep in mind is the possibility that the obstetric results presented are biased, and correspond to ‘worst-case scenarios’, due to the selection of symptomatic cases. It is estimated that there is an important number of undiagnosed cases, as they are asymptomatic and have reproductive success.

15

DIAGNOSIS The diagnostic work-up for female genital tract anomalies continues to represent a great challenge for the gynaecologist due to the presence of various techniques available for the diagnosis that differ in their invasiveness, availability, needs for training and, more importantly, diagnostic accuracy. It seems that, despite advances in ultrasound and new pelvic imaging techniques, late diagnosis of female genital tract anomalies remains frequent. Correct evaluation of the internal and external outlines of the uterus is essential for correct diagnosis and classification of CUAs. Formerly, the gold standard has been a combination of laparoscopy and hysteroscopy, since it also offers the advantage of concurrent treatment, as in the case of a uterine septum resection. However, imaging techniques that are non-invasive, easily accessible, and well-accepted from the patients such as ultrasonography (US), hysterosalpingography (HSG), sonohysterography and magnetic resonance imaging (MRI) are the choice to screen, diagnose and classify CUAs. 7 While conventional two-dimensional (2D) transvaginal US and HSG are suitable for screening for uterine anomalies, three-dimensional (3D) transvaginal US and MRI can accurately classify them. 41–43Clique ou toque aqui para introduzir texto. Conventional 2D transvaginal US is minimally invasive, available, and can give reliable, reproducible, and measurable information on uterine anatomy, leading to the exact diagnosis as well as the differential diagnosis between the different categories. However, it has a lower diagnostic accuracy in comparison with the other sonographic techniques. 6 Scanning in the second half of the menstrual cycle (the secretory phase) provides more accurate visualization of the endometrium and is therefore appropriate for assessment. Visualization of two endometrial cavities on a transverse plane indicates anomaly. 3D transvaginal US, by its unique feature of providing the coronal plane of the uterus, facilitates simultaneous visualization of both external (serosal surface) and internal (uterine cavity) outlines of the uterine fundus, being important for the correct classification of the partial bicorporeal, septate and partial septate uteri. 44 Complete bicorporeal, also demonstrates two endometrial cavities in the transverse plane of conventional 2D US, but 3D US, along with a clinical manifestation of two cervices or two on speculum examinations, can confirm the diagnosis. In cases of hemi-uterus, a normal long axis of the uterus is demonstrated on one side only of the . The parallel side is characterized by the lack of, or a rudimentary, uterine shadow. A banana- shaped uterine cavity and single interstitial portion of in the coronal plane is seen using 3D ultrasound. Saline infusion sonography has been suggested as a method for diagnosing

16 rudimentary horns, as saline can evidently be seen in the hemi-uterus, with absence of flow into the rudimentary horn, if it is non-communicating. 41

Currently, 3D transvaginal US is considered the gold standard for the assessment of CUAs as it is less invasive and can classify the varying types of uterine anomalies correctly. Criteria for the classification of uterine anomalies based on 3D ultrasound have been described in the Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies. 41 MRI of the pelvis is sensitive and specific for diagnosis of uterine malformations, as it outlines the endometrium and has the capacity to detect uterine horns. It also defines any abnormal gonadal location or renal anatomy.45 It is a less invasive modality than combined laparoscopy and hysteroscopy. While MRI is not routinely recommended in all women with a suspected CUA, it is useful for those women with unconfirmed diagnosis on 3D ultrasound, those with suspected complex anomalies, and for those who decline or are uncomfortable by internal examinations. 41 A urinary tract ultrasound scan, MRI or intravenous pyelogram is recommended in all women diagnosed with a uterine anomaly, choosing the most appropriate method accordingly. 14

17

SURGICAL MANAGEMENT

The purpose of CUA management relies on treating anatomical deformities associated with obstructive anomalies for symptomatic relief (therefore improving quality of life) and to avoid long- term health and reproductive adverse consequences. Relatively to non-obstructive anomalies, the goal is to improve reproductive outcomes in infertile women or women who have history of recurrent miscarriages. The fundamental intention is increasing live births at term, with an associated reduction in long term neonatal morbidity and mortality, therefore surgical application is dependent on its efficacy to reverse the reproductive consequences. 46,47 The need for treatment to correct uterine malformations varies from case to case, depending on the clinical presentation, the degree of change in the anatomy of the uterus, the woman's past medical history, especially in terms of obstetric complications, her age, and her reproductive plans. Intervention is not mandatory. The role of surgical treatment in incidentally diagnosed non-obstructive uterine anomalies to improve reproductive outcomes remains debatable. 15

CLASS U1 (ESHRE/ESGE CLASSIFICATION): DYSMORPHIC UTERUS There are no standardized criteria for reconstructive surgery of a T-shaped uterus (Class U1a), since many of these patients are asymptomatic and are able to carry a pregnancy to term 48, however some authors 37,49 are proposing hysteroscopic metroplasty as potential treatment, especially regarding repeated miscarriage, preterm deliveries, long-term infertility, implantation failures, or an upcoming IVF treatment (although prospective randomized controlled trials are lacking to give a firm recommendation). 47 This procedure can be performed in ambulatory setting, with the patient in conscient sedation. For patients with a dysmorphic uterus U1b (infantilis uterus), there is currently no indication for reconstructive surgery, according to Grimbizis et. al. 50 The aim of the metroplasty is the restorage of the normal triangular anatomy of the uterine cavity through incisions in the lateral walls of the dysmorphic uterus and, if necessary, in the fundus, as seen in Figure 4. 47 Hysteroscopic scissors, monopolar or bipolar resectoscope, mini- hysteroscopes with 5 Fr needles, or micro-scissors could be used for the enlargement of the endometrial cavity by successive incisions along an initial incision line from each tubal ostium to the isthmus uteri. Fundal incision should be made if there is a coexisting fundal indentation (especially if thickness greater than 11mm). A vaginoscopic approach is suggested to reduce the risk of unnecessary trauma or uterine perforations.

18

The complication rate during and after this hysteroscopic procedure is low. They include intraoperative (uterine perforation and haemorrhage) and postoperative complications (intrauterine adhesions [IUA], cervical insufficiency and abnormal placentation in a future pregnancy). In the literature there is only one case of uterine perforation and one case of haemorrhage after T-uterus surgery reported 37, while the postoperative complications are more common. Fernandez et al. using different surgical approaches reports an incidence of 5% of adhesions 37. To prevent IUA, a collagen gel barrier is advised to be inserted into the endometrial cavity. Use of estrogen as perioperative adjuvant therapy has been suggested for preventing recurrent IUA, based on its critical role in stimulating and enhancing endometrial growth via angiogenesis. However, according to the literature, 50 in case of normal endocrinological profile with regular menstrual cycles no adjuvant estrogen therapy is recommended. Although antibiotic is still used widely after hysteroscopic surgery recent randomised trials do not find evidence of benefit and recommend not to implement it, since it does not reduce the risk of infection. 51,52 The result of this surgery is usually assessed after two menstrual by hysteroscopy. Regarding abnormal placentation after surgical correction, three cases of placental retention described by Di Spiezio et al. 53 The depth of the myometrial incisions and altered vascularization in these patients could play a role in the pathophysiology. Cervical insufficiency is not as much established in the literature. Although Fernandez et al. 37 reported ten cases of cerclage after surgery in 97 women, five of them had previous history of cervical incompetence. Confounding factors are the use of cervical dilatation and the antecedent to DES-exposure that are related to cervical insufficiency. Fernandez et al. 37 noted ~50% of pregnancy rate after the hysteroscopic metroplasty with a mean time until the first conception of 10.5 months. Miscarriage rate was 36.8% and 8 pregnant women delivered before 30 weeks of gestation. Among those with secondary infertility, the first trimester miscarriage rate decreased from 78.2% to 26.9% and the live birth rate increased to 73% after the reconstructive surgery. Meier et al. 49 in a pool of 100 women without DES-exposure, reported 57% of pregnancy rates, with the median time to the first pregnancy of 4 months. Miscarriage rate was 16%, and no ectopic pregnancy was reported, while 36 deliveries were at term. Di Spiezio et al. 53 out of 214 patients with a dysmorphic uterus, metroplasty was completed in all cases, resulting in a significant increase of uterine cavity volume (100%) and optimization of uterine morphology in 211 of 214 women (98.6%). After 60 months, the overall clinical pregnancy rate was 72.9% and the live birth rate was 80.1%. Specifically, 74 of 156 women (47.4%) conceived spontaneously (with a median time to pregnancy of 5.5 months), of whom 32.4% had previously failed 1 or more attempts at in vitro fertilization/intracytoplasmic sperm injection.

19

It seems that the surgery improves or normalizes the reproductive results, although this evidence is mainly based on retrospective studies, none of which had a control group of untreated women for comparison. Nowadays, patients with dysmorphic uterus and history of recurrent pregnancy loss, preterm delivery or before entering an assisted reproductive programme could benefit from a hysteroscopic correction. For an experienced surgeon, using a small diameter hysteroscope and the micro scissors, excellent anatomical results are obtained in a simple ambulatory procedure with low complication rate. 50 Neto et. al 54, however states that the benefits of surgical treatment for this anomaly seem to be largely exaggerated and the current evidence available lack quality. They also emphasize that until randomized controlled trials (RCTs) demonstrate the benefit of this surgery, expectant management is the most appropriate choice in daily practice for women with a T-shaped uterus.

CLASS U2 (ESHRE/ESGE CLASSIFICATION): SEPTATE UTERUS The resection of the septum is a viable procedure which can be easily performed by hysteroscopy, currently considered the gold-standard. 15 Compared with a transabdominal approach (Jones or Tompkins metroplasty, demonstrated in figures 5 and 6, respectively), benefits include lower perioperative morbidity, avoidance of potential pregnancy complications related to transmyometrial incisions, and faster return to normal activity. The transcervical approach reduces the risk of pelvic infection and formation of intra-abdominal adhesions, which may cause future infertility or small bowel obstruction. Patients may attempt pregnancy sooner after a transcervical approach than a transabdominal approach, and future vaginal delivery is not contraindicated. 55 Transcervical resection of a septum is easier when the endometrium is thin since a thickened endometrium limits visualization. Therefore, typically the aim is to schedule the procedure in the early follicular phase, also decreasing the risk of undiagnosed pregnancy. Alternatively, a thinner endometrium can be accomplished by pre-treatment with a continuous estrogen/progestin contraceptive, progestin-only pill or a gonadotropin-releasing hormone (GnRH) agonist. Use of danazol is slightly preferable to use of a GnRH agonist because of lower cost and side effects. Furthermore, the use of a GnRH agonist may decrease the size of the uterine cavities, limiting the ability to perform the procedure. 47 When the preoperative imaging study clearly establishes the diagnosis and the septum is small, a hysteroscopic metroplasty is performed. However, when the imaging study does not clearly establish the diagnosis or the septum is large (extending from the fundus to the internal cervical os), a simultaneous laparoscopy is needed to evaluate the external uterus and observe the serosa during the procedure to help decrease the risk of perforation.

20

Various techniques and instruments can be used for incision or resection, including scissors, electrosurgical electrodes guided through the hysteroscope, resectoscopy, or fibre lasers. The resectoscope is widely used and its energy source can be monopolar or bipolar. When bipolar energy is used, the distention medium of the cavity is isotonic saline solution, and therefore, the risk of complications due to intravasation are low. Non-ionic low viscosity fluid such as Dextran or Glycin in case monopolar energy is used. 47 The goal of the procedure is reducing the septal surface area. A partial septum may require only incision of the septum, while a large septum requires resection, starting from the distal part of the septum. During surgery, the tubal ostia are the surgical landmarks for decent guidance. The septum incision is made equidistant from the anterior and posterior uterine wall and the procedure is completed when there is a good view of a restored triangular cavity, with free movement of the hysteroscope between the two ostia and exposure of the muscle fibres of the fundus. Using a graduated intrauterine palpator to objectively check the portion of septum resected, is an alternative that verifies completion of resection.56 It is of extreme importance to leave a safety thickness of 10 mm of the fundal wall, in order to avoid possible future uterine ruptures. 47 The small diameter hysteroscopes do not require general anaesthesia or even a local one. Several authors favour this “vaginoscopic” technique due to the accessible entry of the uterus, without cervical dilatation, use of saline solution as the distension medium and, according to their studies, low risk of uterine perforation and thermal trauma. Since the visualization of the cavity is not as broad as in the resectoscopic technique, two incisions, as landmarks, must be done at both sides of the septum before starting the incision. The incision can be done by cold scissors or electric devices. Potassium-titan-phosphate (KTP-532), Fibeoptic Nd:YAG or argon lasers are other viable techniques although their use has markedly decreased due to their cost and the simplification of electrosurgery using vaporizing and bipolar electrodes. 57 A cervical septum (class U2C1) or a double cervix (class U2C2) might also be present. Incision of a coexisting cervical septum can be performed, although potential after surgery must be considered. There are authors that defend the unification of the cavity should only be performed from the isthmus up to the fundus, while the repair of the cervical deformity should be avoided since it is too traumatic for the cervix and associated with cervical insufficiency in a subsequent pregnancy. In order to achieve this, a Foley balloon catheter is inserted into the uterus transcervically, slightly inflated, and pulled down against the internal ostium to prevent leakage of the distension media. Placing a flexible hysteroscope into the second cervix or instilling blue dye can be helpful for identifying when the hysteroscope has entered the second cavity. The

21 challenge in these cases is placing the first incision so it passes from one side of the septum to the other and does not compromise the internal cervical ostium of either cervix. A 2D or 3D ultrasound or a hysterosalpingogram can be performed two months postoperatively to assess results. Ideally, over 90% of the septum should have been removed. If there is a significant residual septum remaining, which happens occasionally, further resection of the septum is necessary. When the procedure is deemed adequate, a recent observational study 58, suggests that patients can begin attempting to conceive two months postoperatively. However, there not enough evidence to advocate a specific length of time before a woman should conceive after the procedure. Clinical results of hysteroscopic metroplasties are generally good and seem to be independent from the tools, the type of energy and the techniques used. In the past two systematic reviews 33,59 reported significant decrease in miscarriage rates (from 86.4 - 88% before to 16.4 - 14% after hysteroscopic incision) and an increase in term delivery rates (from 3 - 3.4% before to 76.2 - 80% after). A more recent review by Nouri et al. 60 analysed the accomplishment of pregnancy in infertile women after septum incision: they reported ~60% pregnancy rate and ~45% live birth rate. All studies indicating a positive effect of surgery although these are heterogeneous in population and in definition of uterine septum. Gergolet et al. 26 prospectively compared the reproductive outcome in patients with small (group A) and large (group B) septa who underwent metroplasty. Miscarriage rates dropped from 94.9% to 82.1% in groups A and B, respectively, before treatment to 11.1% and 14.0% after treatment. Delivery rates were 2.6% and 15.7%, respectively, before operation and 88.9% and 84.2% after surgery. It seems, therefore, that the length of the septum does not play a role in reproductive outcome, either before or after hysteroscopic metroplasty. Similar results were reported by Paradisi et al. 61 in women with small (<2.5 cm) and large partial uterine septum (>2.5 cm), and by Tomazevic et al. 62 who found that the clinical pot-surgery result of women with small septa is not different from that of women with large septa. A systematic review and meta-analysis of controlled studies 2 reported a decreased probability of spontaneous miscarriages (both first and second trimester) in women treated with hysteroscopic resection of septum compared with women who were not treated (RR 0.37, 95% CI 0.25–0.55). There was no difference in conception rates (RR 1.14, 95% CI 0.79–1.65) and preterm delivery rates (RR 0.66, 95% CI 0.29–1.49) among the hysteroscopic resection and control groups. RCTs are needed to confirm the beneficial effects of metroplasty reported by numerous publications. 63 The Randomised Uterine Septum Transsection Trial (TRUST)64 to assess whether hysteroscopic septum resection improves reproductive outcomes in women with a septate uterus

22 and a history of (recurrent) miscarriage, subfertility or preterm birth is a multicentre study in the Netherlands, Iran and USA. Recruitment has started since October 2009 and is ongoing, since the authors are experiencing difficulty in recruiting women and clinicians to participate. 64 Women are aware of all these of non-randomized publications which confirm the improvement of pregnancy and live birth rates after metroplasty. Also, the lack of uniformity in the distinction between a normal uterine cavity and a small septate uterus. The new ESHRE/ESGE classification 5 is a helpful tool to reach a greater homogeneity of studies and interpretation of uterine imaging procedures since the terminology “arcuate” uterus has been abandoned by this classification.

CLASS U3 (ESHRE/ESGE CLASSIFICATION): BICORPOREAL UTERUS The necessity of surgical repair for this anomaly is currently arguable, varying according to each subclass, as shown in table 2. 47 Since patients with a partial bicorporeal uterus (Class U3a) do not have an increased risk of adverse pregnancy outcomes, they do not benefit from surgical intervention. Traditionally, Strassman metroplasty by laparotomy was the gold standard for surgical correction of the complete bicorporeal uterus (Classes U3bC0 and U3bC2) 65. The technique, as shown in Figure 7, involves a single transverse incision across the uterine fundus from one cornua to the other so that both uterine cavities can be visualized. Then, eversion of each horn is made, and a single layer of interrupted figure-of-eight sutures is placed to form a single uterine cavity beginning from the posterior and continuing with the anterior wall. 65 However, whether surgical correction of bicorporeal uterus with Strassman metroplasty is necessary is highly controversial given that fertility rates are not significantly reduced and successful pregnancies without surgical correction intervention are common. 50 Thus, it should be avoided as a prophylactic procedure. Laparoscopic unification of bicorporeal uterus with normal (class U3bC0) or double cervix (class U3bC2) has been reported 13, but it is technically challenging. Laparoscopic subtotal hysterectomy in a woman with U3bC2 uterus due to abnormal uterine bleeding has been recently described as well. 66 The surgical steps of the procedure were similar to those of laparoscopic subtotal hysterectomy performed in morphologically normal uteri. 66 Counseling pregnant women with bicorporeal uterus, either surgically repaired or not, about the necessity of a cesarean section is crucial since the risk of uterine rupture is increased. 34 Cervical cerclage might be considered because cervical incompetence is an issue in these patients, however it is not clear at which week of pregnancy it should be performed.

23

Depending on the anatomical status of cervix and/or vagina, bicorporeal uterus could be presented in some uncommon variants. Surgical treatment is necessary and laparoscopic management feasible in these rare subclasses which present with obstructing symptoms. Patients with bicorporeal uterus, double cervix, and longitudinal obstructing vaginal septum (Class U3bC2V2) should be treated surgically by cutting or resecting the vaginal septum. This is necessary to alleviate vaginal and hemi-uterine obstruction by restoring continuity. 67 In cases of bicorporeal uterus with unilateral cervical aplasia (class U3bC3), removal of the obstructed hemi-uterus is indicated, since it might act as a rudimentary horn and has therefore similar clinical manifestation.13 Restoration of utero-vagina continuity of the obstructed hemi- uterus is an alternative technique either by laparoscopically assisted cervicoplasty in cases of cervical atresia or by isthmo-vagina anastomosis. In these types of malformation, the risk of complications such as ectopic pregnancy should be addressed to the patients before surgical management. 67 Finally, patients with a bicorporeal septate uterus (class U3c) represent a challenging management. A 2011 study 68 reported that hysteroscopic metroplasty (by incising the septate part of the indentation) improved reproductive outcome in 80% of the patients and also remarkably improved. 68 Larger number of patients and well-designed studies are essential to draw accurate conclusions. RCTs comparing the pregnancy outcomes between cases treated and not treated by metroplasty among patients with poor obstetric history are needed because it is not yet established whether surgery alone could improve live birth rate.

CLASSES U4A AND U5A (ESHRE/ESGE CLASSIFICATION): RUDIMENTARY HORNS WITH CAVITY While a hemi-uterus does not warrant surgical intervention, functioning rudimentary uterine horns, frequently attached, have strong surgical indications. They can be excised by laparotomy, but currently, laparoscopic removal is the usual gold-standard, along with excision of the ipsilateral fallopian tube. This technique has been reported for over a decade already. 69 Preoperative treatment with a GnRH-analogue or danazol has been suggested aiming to reduce the size of hematometra before surgery. The surgeon must avoid damage of the remaining unicorporeal uterus, especially in patients with large attachment between the unicorporeal body and the rudimentary horn. Scissors, electrosurgery ultracision energy, and endoscopic staplers have been reported as tools to remove the rudimentary horn, while the simultaneous use of hysteroscopy to separate the two horns is also described. 70

24

Regarding class U5a, prophylactic excision of the rudimentary horn is still controversial. It is certain that laparoscopic excision is the preferred management if the patient is symptomatic with cyclic and/or hematocavity in whom other underlying causes of pain have been excluded.71 In cases of MRKH patients with rudimentary functional uterine horns an different surgical approach can be offered: the uterovaginal anastomosis with restoration of menstrual function, which has been documented in the past.72 It involves neovagina creation, metroplasty (incision of the uterine bulbs, surgical consolidation of the uterine horns and creation of a large uterine cavity) and utero-neovaginal anastomosis can lead not only in the function of the horn but in successful reproductive outcome as well. A two-step surgery, combining a laparoscopic Davidov’s vaginoplasty with abdominal isthmo-neovagina anastomosis, has been reported recently.73 The anatomic restoration of the genital tract in these women appears to have good outcomes and leads to functional menstruation and restitution of the sexual life.73,74

25

CONCLUSION The new ESHRE/ESGE Classification, which has been recently published, seems to be a new, clear, and systematic categorization of CUA. Based on the best currently available evidence, it seems that surgical treatment is indicated in women presenting with symptoms related to specific uterine anomalies and it also improves or normalizes the reproductive results, although this evidence is mainly based on retrospective studies, being a relevant limitation. Many issues are still controversial among scientists, and prospective studies should be performed for a more reliable evaluation of outcomes of the proposed surgical techniques. Nowadays, patients with a dysmorphic (class U1 in ESHRE/ESGE Classification), septate (class U2 in ESHRE/ESGE Classification), or bicorporeal septate (class U3 in ESHRE/ESGE Classification) uterus presenting with infertility, poor reproductive outcomes, or before entering an assisted reproductive programme could benefit from a hysteroscopic correction. Excellent anatomical results are obtained in a simple ambulatory procedure with low complication rate. Surgical removal of the rudimentary horns with cavity (ESHRE/ESGE class U4a/U5a) appears to be the established method of treatment of rudimentary horns for symptoms relief and avoidance of complications. Another surgical treatment alternative in highly selected cases is restoration of continuity. The therapeutic objectives should always be pain relief and preservation of sexual and reproductive function, if possible.

26

APPENDIX 1

FIGURE 1: EMBRYOLOGY OF THE FEMALE GENITO-URINARY TRACT (FRONTAL VIEW). THE FORMATION OF THE UTERINE PRIMORDIUM AND THE OPENING OF THE MESONEPHRIC DUCTS INTO THE UROGENITAL SINUS ARE SHOWN. MÜLLERIAN TUBERCLE CAN BE SEEN BETWEEN BOTH WOLFFIAN DUCTS AND THE URETERAL BUDS SPROUTING FROM THE OPENING OF THE WOLFFIAN DUCT INTO THE UROGENITAL SINUS. MD, MÜLLERIAN DUCTS; WD, WOLFFIAN DUCTS; K, KIDNEY; MT, MÜLLERIAN TUBERCLE; US, UROGENITAL SINUS.75

27

FIGURE 2: ESHRE/ESGE CLASSIFICATION OF UTERINE ANOMALIES5

28

FIGURE 3: SCHEME FOR THE CLASSIFICATION OF FEMALE GENITAL TRACT ANOMALIES ACCORDING TO THE NEW ESHRE/ESGE CLASSIFICATION SYSTEM.5

29

A B

FIGURE 4: DIAGRAM OF THE INCISIONS IN DYSMORPHIC UTERUS SURGERY.50 (A) LATERAL INCISION IN SUBTYPE U1A; (B) LATERAL AND FUNDAL INCISIONS IN SUBTYPE U1C

30

31

E

FIGURE 5: SURGICAL TECHNIQUE OF THE JONES PROCEDURE ADAPTED FROM UPTODATE: (A) IN THE JONES PROCEDURE, THE COMMON CAVITY IS INITIALLY REACHED THROUGH A WEDGE RESECTION OF THE SEPTUM. (B) THE SEPTUM IS TOTALLY REMOVED AS THE TWO CAVITIES ARE UNROOFED. (C) UTERINE CLOSURE IS BEGUN IN THE LOWER PORTION OF THE CAVITY. THE ANTERIOR AND THEN THE POSTERIOR WALLS ARE CLOSED, INCLUDING THE ENDOMETRIUM AND A SMALL PORTION OF THE MYOMETRIUM. THE SUTURE MAY BE CONTINUOUS OR INTERRUPTED. (D) BEGINNING INFERIORLY, A ROW OF INTERRUPTED SUTURES IS THEN PLACED IN THE REMAINING THICKNESS OF THE UTERINE WALL. (E) USING THE LIGHTEST POSSIBLE SUTURE, THE THIRD LAYER APPROXIMATES THE SUPERFICIAL MYOMETRIUM AND SEROSA. THE ROUGH EDGES SHOULD BE IMBRICATED AS MUCH AS POSSIBLE TO PREVENT ADHESIONS ALONG THE SUTURE LINE.

32

33

FIGURE 6: SURGICAL TECHNIQUE OF THE TOMPKINS PROCEDURE ADAPTED FROM UPTODATE: (A) IN THE TOMPKINS PROCEDURE, THE SEPTUM IS INCISED, BUT NOT REMOVED. AN INITIAL INCISION IS MADE DOWN THE MIDDLE OF THE SEPTUM UNTIL THE COMMON CAVITY IS REACHED. (B) THE SEPTAL TISSUE IS INCISED BILATERALLY TO UNROOF THE TWO CAVITIES. (C) REPAIR THEN PROCEEDS AS IN THE JONES TECHNIQUE, WITH THE ANTERIOR AND THE POSTERIOR ASPECTS BEING APPROXIMATED WITH CONTINUOUS OR INTERRUPTED SUTURES. (D) THE DEEP MYOMETRIUM IS REPAIRED. (E) AFTER WHICH THE SUPERFICIAL MYOMETRIUM AND SEROSA ARE CLOSED WITH AN IMBRICATING SUTURE.

34

FIGURE 7: SURGICAL TECHNIQUE OF THE STRASSMAN METROPLASTY50 (A) BICORPOREAL UTERUS (B) INCISION FROM ONE CORNUA TO THE OTHER (C) POSTERIOR UTERINE WALL CLOSURE (D) ANTERIOR UTERINE WALL CLOSURE (E) SEROSAL CLOSURE

35

APPENDIX 2 TABLE I: ESTIMATES OF PREVALENCE OF DIFFERENT GENITAL TRACT MALFORMATIONS USING THE NEW ESGE/ESHRE CLASSIFICATION 1,30

TABLE II: VARIANTS OF BICORPOREAL UTERUS AND THEIR SURGICAL TREATMENT50

36

REFERENCES

1. Chan YY, Jayaprakasan K, Zamora J, Thornton JG, Raine-Fenning N, Coomarasamy A. The prevalence of congenital uterine anomalies in unselected and high-risk populations: A systematic review. Human Reproduction Update [Internet] 2011 [cited 2021 Jan 18];17(6):761–771. Available from: /pmc/articles/PMC3191936/?report=abstract 2. Venetis CA, Papadopoulos SP, Campo R, Gordts S, Tarlatzis BC, Grimbizis GF. Clinical implications of congenital uterine anomalies: A meta-analysis of comparative studies [Internet]. Reproductive BioMedicine Online. 2014 [cited 2021 Jan 18];29(6):665–683. Available from: http://dx.doi.org/10.1016/j.rbmo.2014.09.0061472-6483/ 3. Acién P, Acién MI. The history of female genital tract malformation classifications and proposal of an updated system†. Human Reproduction Update [Internet] 2011 [cited 2021 Jan 30];17(5):693–705. Available from: http://academic.oup.com/humupd/article/17/5/693/759275/The-history-of-female- genital-tract-malformation 4. Ludwin A, Ludwin I. Comparison of the ESHRE-ESGE and ASRM classifications of Mü llerian duct anomalies in everyday practice. Human Reproduction [Internet] 2015 [cited 2021 Jan 30];30(3):569–580. Available from: https://pubmed.ncbi.nlm.nih.gov/25534461/ 5. Grimbizis GF, Gordts S, Spiezio Sardo A di, et al. The ESHRE/ESGE consensus on the classification of female genital tract congenital anomalies. Human Reproduction 2013;28(8):2032–2044. 6. Ludwin A, Pityński K, Ludwin I, Banas T, Knafel A. Two- and Three-Dimensional Ultrasonography and Sonohysterography versus Hysteroscopy With Laparoscopy in the Differential Diagnosis of Septate, Bicornuate, and Arcuate Uteri. Journal of Minimally Invasive Gynecology [Internet] 2013 [cited 2021 Jan 31];20(1):90–99. Available from: https://pubmed.ncbi.nlm.nih.gov/23312248/ 7. Ludwin A, Ludwin I, Banas T, Knafel A, Miedzyblocki M, Basta A. Diagnostic accuracy of sonohysterography, hysterosalpingography and diagnostic hysteroscopy in diagnosis of arcuate, septate and bicornuate uterus. Journal of and Gynaecology Research [Internet] 2011 [cited 2021 Jan 31];37(3):178–186. Available from: https://pubmed.ncbi.nlm.nih.gov/21314802/ 8. Ludwin A, Pfeifer SM. Reproductive surgery for müllerian anomalies: a review of progress in the last decade. Fertility and Sterility 2019;112(3):408–416. 9. Lecture - Genital Development - Embryology [Internet]. [cited 2021 Jan 13];Available from: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_- _Genital_Development 10. Acien P, Acien M. Malformations of the Female Genital Tract and Embryological Bases. Current Women’s Health Reviews 2013;3(4):248–288. 11. Hassan M-AM, Lavery SA, Trew GH. Congenital uterine anomalies and their impact on fertility. Women’s Health [Internet] 2010 [cited 2021 Jan 13];6(3):443–461. Available from: www.futuremedicine.com 12. Akhtar MA, Saravelos SH, Li TC, Jayaprakasan K. Reproductive Implications and Management of Congenital Uterine Anomalies: Scientific Impact Paper No. 62 November 2019. BJOG: An International Journal of Obstetrics and Gynaecology 2020;127(5):e1–e13. 13. Nawfal AK, Blacker CM, Strickler RC, Eisenstein D. Laparoscopic Management of Pregnancy in a Patient with , Obstructed Hemivagina, and Ipsilateral Renal Agenesis. Journal of Minimally Invasive Gynecology [Internet] 2011 [cited 2021 Mar 23];18(3):381– 385. Available from: https://pubmed.ncbi.nlm.nih.gov/21545963/ 14. K. Heinonen P. Renal tract malformations associated with Müllerian duct anomalies. Clinical Obstetrics, Gynecology and Reproductive Medicine 2018;4(1).

37

15. Letterie GS. Management of congenital uterine abnormalities. In: Reproductive BioMedicine Online. 2011. p. 40–52. 16. Jacquinet A, Millar D, Lehman A. Etiologies of uterine malformations. American Journal of Medical Genetics Part A [Internet] 2016 [cited 2021 Jan 19];170(8):2141–2172. Available from: http://doi.wiley.com/10.1002/ajmg.a.37775 17. Hammoud AO, Gibson M, Peterson CM, Kerber RA, Mineau GP, Hatasaka H. Quantification of the familial contribution to müllerian anomalies. Obstetrics and Gynecology [Internet] 2008 [cited 2021 Jan 19];111(2):378–384. Available from: https://pubmed.ncbi.nlm.nih.gov/18238976/ 18. Milsom SR, Ogilvie CM, Jefferies C, Cree L. Discordant Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome in identical twins-a case report and implications for reproduction in MRKH women. Gynecological Endocrinology [Internet] 2015 [cited 2021 Jan 19];31(9):684– 687. Available from: https://www.tandfonline.com/doi/abs/10.3109/09513590.2015.1032928 19. Rall K, Eisenbeis S, Barresi G, et al. Mayer-Rokitansky-Küster-Hauser syndrome discordance in monozygotic twins: Matrix metalloproteinase 14, low-density lipoprotein receptor- related protein 10, extracellular matrix, and neoangiogenesis genes identified as candidate genes in a tissue-specific mosaicism. Fertility and Sterility [Internet] 2015 [cited 2021 Jan 19];103(2):494-502.e3. Available from: http://dx.doi.org/10.1016/j.fertnstert.2014.10.053 20. Herbst AL, Hubby MM, Azizi F, Makii MM. Reproductive and gynecologic surgical experience in diethylstilbestrol-exposed daughters. American Journal of Obstetrics and Gynecology [Internet] 1981 [cited 2021 Mar 19];141(8):1019–1028. Available from: https://pubmed.ncbi.nlm.nih.gov/7315913/ 21. Rosenfeld DL, Bronson RA. Reproductive problems in the DES-exposed female. Obstetrics and Gynecology 1980;55(4):453–456. 22. Grimbizis GF, Campo R. Congenital malformations of the female genital tract: the need for a new classification system. Fertility and Sterility [Internet] 2010 [cited 2021 Jan 22];94(2):401–407. Available from: https://pubmed.ncbi.nlm.nih.gov/20356581/ 23. Buttram VC, Gomel V, Siegler A, DeCherney A, Gibbons W, March C. The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, and intrauterine adhesions. Fertility and Sterility [Internet] 1988 [cited 2021 Jan 19];49(6):944–955. Available from: https://pubmed.ncbi.nlm.nih.gov/3371491/ 24. Oppelt P, Renner SP, Brucker S, et al. The VCUAM (Vagina Cervix Uterus Adnex-associated Malformation) classification: A new classification for genital malformations. Fertility and Sterility [Internet] 2005 [cited 2021 Jan 31];84(5):1493–1497. Available from: http://www.fertstert.org/article/S001502820502786X/fulltext 25. Knez J, Saridogan E, Bosch T van den, Mavrelos D, Ambler G, Jurkovic D. ESHRE/ESGE female genital tract anomalies classification system-the potential impact of discarding arcuate uterus on clinical practice. Human Reproduction [Internet] 2018 [cited 2021 Jan 31];33(4):600–606. Available from: https://pubmed.ncbi.nlm.nih.gov/29514262/ 26. Gergolet M, Campo R, Verdenik I, Šuster NK, Gordts S, Gianaroli L. No clinical relevance of the height of fundal indentation in subseptate or arcuate uterus: A prospective study. Reproductive BioMedicine Online [Internet] 2012 [cited 2021 Mar 15];24(5):576–582. Available from: https://pubmed.ncbi.nlm.nih.gov/22417666/ 27. Grimbizis G. The pathophysiology of septate uterus. BJOG: An International Journal of Obstetrics & Gynaecology [Internet] 2019 [cited 2021 Jan 19];126(10):1200–1200. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/1471-0528.15832 28. Rikken J, Leeuwis‐Fedorovich N, Letteboer S, et al. The pathophysiology of the septate uterus: a systematic review. BJOG: An International Journal of Obstetrics & Gynaecology [Internet] 2019 [cited 2021 Jan 19];126(10):1192–1199. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/1471-0528.15798

38

29. Theodoridis TD, Zepiridis L, Grimbizis GF. Bicorporeal uterus: Treatment options [Internet]. In: Female Genital Tract Congenital Malformations: Classification, Diagnosis and Management. Springer-Verlag London Ltd; 2015 [cited 2021 Apr 3]. p. 279–289.Available from: https://link.springer.com/chapter/10.1007/978-1-4471-5146-3_27 30. Saravelos SH, Cocksedge KA, Li TC. Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: A critical appraisal [Internet]. Human Reproduction Update. 2008 [cited 2021 Jan 18];14(5):415–429. Available from: https://pubmed.ncbi.nlm.nih.gov/18539641/ 31. Nahum G. Uterine anomalies. How common are they, and what is their distribution among subtypes? J Reprod Med 1998; 32. Acién P. Incidence of Mullerian defects in fertile and infertile women [Internet]. Human Reproduction. 1997 [cited 2021 Mar 19];12(7):1372–1376. Available from: https://pubmed.ncbi.nlm.nih.gov/9262259/ 33. Grimbizis GF, Camus M, Tarlatzis BC, Bontis JN, Devroey P. Clinical implications of uterine malformations and hysteroscopic treatment results [Internet]. Human Reproduction Update. 2001 [cited 2021 Jan 18];7(2):161–174. Available from: https://pubmed.ncbi.nlm.nih.gov/11284660/ 34. Reichman DE, Laufer MR. Congenital uterine anomalies affecting reproduction. Best Practice and Research: Clinical Obstetrics and Gynaecology. 2010;24(2):193–208. 35. Fox NS, Roman AS, Stern EM, Gerber RS, Saltzman DH, Rebarber A. Type of congenital uterine anomaly and adverse pregnancy outcomes. Journal of Maternal-Fetal and Neonatal Medicine [Internet] 2014 [cited 2021 Mar 19];27(9):949–953. Available from: https://pubmed.ncbi.nlm.nih.gov/24050215/ 36. Chan YY, Jayaprakasan K, Tan A, Thornton JG, Coomarasamy A, Raine-Fenning NJ. Reproductive outcomes in women with congenital uterine anomalies: A systematic review [Internet]. Ultrasound in Obstetrics and Gynecology. 2011 [cited 2021 Mar 19];38(4):371– 382. Available from: https://pubmed.ncbi.nlm.nih.gov/21830244/ 37. Fernandez H, Garbin O, Castaigne V, Gervaise A, Levaillant JM. Surgical approach to and reproductive outcome after surgical correction of a T-shaped uterus. Human Reproduction [Internet] 2011 [cited 2021 Apr 3];26(7):1730–1734. Available from: https://pubmed.ncbi.nlm.nih.gov/21398337/ 38. Mastrolia SA, Baumfeld Y, Hershkovitz R, Yohay D, Trojano G, Weintraub AY. Independent association between uterine malformations and cervical insufficiency: a retrospective population-based cohort study. Archives of Gynecology and Obstetrics [Internet] 2018 [cited 2021 Mar 19];297(4):919–926. Available from: https://pubmed.ncbi.nlm.nih.gov/29392437/ 39. Chifan M, Tîrnovanu M, Grigore M, Zanoschi C. Cervical incompetence associated with congenital uterine malformations. Revista medico-chirurgicalǎ̌ a Societǎţiǐ de Medici ş̧i Naturaliş̧ti din Iaş̧i 2012;116(4):1063–1068. 40. Yassaee F, Mostafaee L. The role of cervical cerclage in pregnancy outcome in women with uterine anomaly. Journal of Reproduction and Infertility [Internet] 2011 [cited 2021 Mar 19];12(4):277–279. Available from: /pmc/articles/PMC3719309/ 41. Grimbizis GF, Spiezio Sardo A di, Saravelos SH, et al. The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies. Gynecological Surgery [Internet] 2016 [cited 2021 Feb 4];13(1):1–16. Available from: /pmc/articles/PMC4753246/?report=abstract 42. Jayaprakasan K, Chan YY, Sur S, Deb S, Clewes JS, Raine-Fenning NJ. Prevalence of uterine anomalies and their impact on early pregnancy in women conceiving after assisted reproduction treatment. Ultrasound in Obstetrics and Gynecology [Internet] 2011 [cited 2021 Mar 19];37(6):727–732. Available from: https://pubmed.ncbi.nlm.nih.gov/21337662/

39

43. Marcal L, Nothaft MA, Coelho F, Volpato R, Iyer R. Mullerian duct anomalies: MR imaging [Internet]. Abdominal Imaging. 2011 [cited 2021 Mar 19];36(6):756–764. Available from: https://pubmed.ncbi.nlm.nih.gov/21207225/ 44. Salim R, Woelfer B, Backos M, Regan L, Jurkovic D. Reproducibility of three-dimensional ultrasound diagnosis of congenital uterine anomalies. Ultrasound in Obstetrics and Gynecology [Internet] 2003 [cited 2021 Mar 19];21(6):578–582. Available from: https://pubmed.ncbi.nlm.nih.gov/12808675/ 45. Maciel C, Bharwani N, Kubik-Huch RA, et al. MRI of female genital tract congenital anomalies: European Society of Urogenital Radiology (ESUR) guidelines. European Radiology [Internet] 2020 [cited 2021 Apr 2];30(8):4272–4283. Available from: https://pubmed.ncbi.nlm.nih.gov/32221681/ 46. Akhtar M, Saravelos S, Li T, Jayaprakasan K. Reproductive Implications and Management of Congenital Uterine Anomalies. BJOG: An International Journal of Obstetrics & Gynaecology [Internet] 2020 [cited 2021 Feb 5];127(5):e1–e13. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/1471-0528.15968 47. Theodoridis TD, Pappas PD, Grimbizis GF. Surgical management of congenital uterine anomalies (including indications and surgical techniques). Best Practice and Research: Clinical Obstetrics and Gynaecology. 2019;59:66–76. 48. Epelboin S. Utérus DES. Polémiques sur l’hystéroplastie d’agrandissement. Arguments contre. Gynecologie Obstetrique et Fertilite 2007;35(9):832–841. 49. Meier: Reproductive outcomes after hysteroscopic... - Google Académico [Internet]. [cited 2021 Apr 3];Available from: https://scholar.google.com/scholar_lookup?journal=Gynecol+Surg&title=Reproductive+ou tcomes+after+hysteroscopic+management+of+dysmorphic+uterus:+Report+of+100+cases &author=R+Meier&author=R+Campo&author=C+De+Bruin&author=G+Mestdagh&author= N+Dhont&volume=11&publication_year=2014&pages=154& 50. Grimbizis GF, Campo R, Tarlatzis BC, Gordts S. Female genital tract congenital malformations: Classification, diagnosis and management. Springer-Verlag London Ltd; 2015. 51. Deffieux X, Gauthier T, Menager N, Legendre G, Agostini A, Pierre F. Hysteroscopy: Guidelines for clinical practice from the French College of Gynaecologists and Obstetricians. European Journal of Obstetrics and Gynecology and Reproductive Biology [Internet] 2014 [cited 2021 Mar 6];178:114–122. Available from: https://pubmed.ncbi.nlm.nih.gov/24835861/ 52. Nappi L, Sardo ADS, Spinelli M, et al. A multicenter, double-blind, randomized, placebo- controlled study to assess whether antibiotic administration should be recommended during office operative hysteroscopy. Reproductive Sciences [Internet] 2013 [cited 2021 Mar 6];20(7):755–761. Available from: https://pubmed.ncbi.nlm.nih.gov/23232966/ 53. Spiezio Sardo A di, Campo R, Zizolfi B, et al. Long-Term Reproductive Outcomes after Hysteroscopic Treatment of Dysmorphic Uteri in Women with Reproductive Failure: An European Multicenter Study. Journal of Minimally Invasive Gynecology [Internet] 2020 [cited 2021 Mar 6];27(3):755–762. Available from: https://pubmed.ncbi.nlm.nih.gov/31146029/ 54. Neto MAC, Ludwin A, Petraglia F, Martins WP. Definition, prevalence, clinical relevance and treatment of T-shaped uterus: systematic review. Ultrasound Obstet Gynecol [Internet] 2021;57:366–377. Available from: https://www.bristol.ac.uk/ 55. Perino A, Forlani F, Casto A lo, et al. Septate uterus: Nosographic overview and endoscopic treatment [Internet]. Gynecological Surgery. 2014 [cited 2021 Apr 15];11(2):129–138. Available from: https://gynecolsurg.springeropen.com/articles/10.1007/s10397-014-0837- 5 56. Spiezio Sardo A di, Zizolfi B, Bettocchi S, et al. Accuracy of Hysteroscopic Metroplasty With the Combination of Presurgical 3-Dimensional Ultrasonography and a Novel Graduated

40

Intrauterine Palpator: A Randomized Controlled Trial. Journal of Minimally Invasive Gynecology [Internet] 2016 [cited 2021 Apr 22];23(4):557–566. Available from: https://pubmed.ncbi.nlm.nih.gov/26829218/ 57. Valle RF, Ekpo GE. Hysteroscopic Metroplasty for the Septate Uterus: Review and Meta- Analysis. Journal of Minimally Invasive Gynecology [Internet] 2013 [cited 2021 Apr 15];20(1):22–42. Available from: http://dx.doi.org/10.1016/j.jmig.2012.09.010 58. Yang JH, Chen MJ, Chen C der, Chen SU, Ho HN, Yang YS. Optimal waiting period for subsequent fertility treatment after various hysteroscopic . Fertility and Sterility [Internet] 2013 [cited 2021 Apr 22];99(7). Available from: https://tmu.pure.elsevier.com/zh/publications/optimal-waiting-period-for-subsequent- fertility-treatment-after-v 59. Homer HA, Li TC, Cooke ID. The septate uterus: A review of management and reproductive outcome [Internet]. Fertility and Sterility. 2000 [cited 2021 Apr 15];73(1):1–14. Available from: https://pubmed.ncbi.nlm.nih.gov/10632403/ 60. Nouri K, Ott J, Huber JC, Fischer E-M, Stögbauer L, Tempfer CB. Open Access REVIEW BioMed Central Reproductive outcome after hysteroscopic septoplasty in patients with septate uterus-a retrospective cohort study and systematic review of the literature [Internet]. 2010. Available from: http://www.rbej.com/content/8/ 61. Paradisi R, Barzanti R, Natali F, et al. Hysteroscopic metroplasty: Reproductive outcome in relation to septum size. Archives of Gynecology and Obstetrics [Internet] 2014 [cited 2021 Apr 15];289(3):671–676. Available from: https://pubmed.ncbi.nlm.nih.gov/24026089/ 62. Tomaževič T, Ban-Frangež H, Virant-Klun I, Verdenik I, Požlep B, Vrtačnik-Bokal E. Septate, subseptate and arcuate uterus decrease pregnancy and live birth rates in IVF/ICSI. Reproductive BioMedicine Online [Internet] 2010 [cited 2021 Apr 15];21(5):700–705. Available from: https://pubmed.ncbi.nlm.nih.gov/20864409/ 63. Rikken JFW, Kowalik CR, Emanuel MH, et al. Septum resection for women of reproductive age with a septate uterus [Internet]. Cochrane Database of Systematic Reviews. 2017 [cited 2021 Apr 22];2017(1). Available from: https://pubmed.ncbi.nlm.nih.gov/28093720/ 64. Rikken JFW, Kowalik CR, Emanuel MH, et al. The randomised uterine septum transsection trial (TRUST): Design and protocol. BMC Women’s Health [Internet] 2018 [cited 2021 Apr 22];18(1). Available from: https://pubmed.ncbi.nlm.nih.gov/30290803/ 65. Strassmann EO. Fertility and unification of double uterus. Fertility and sterility [Internet] 1966 [cited 2021 Apr 22];17(2):165–176. Available from: https://pubmed.ncbi.nlm.nih.gov/5907041/ 66. Erian J, Lee C, Watkinson S, Ali AA, Chaudhari L, Hill N. Laparoscopic subtotal hysterectomy in a case of uterine didelphys. Archives of Gynecology and Obstetrics [Internet] 2012 [cited 2021 Apr 22];285(1):139–141. Available from: https://pubmed.ncbi.nlm.nih.gov/21479807/ 67. Fedele L, Motta F, Frontino G, Restelli E, Bianchi S. Double uterus with obstructed hemivagina and ipsilateral renal agenesis: Pelvic anatomic variants in 87 cases. Human Reproduction [Internet] 2013 [cited 2021 Apr 23];28(6):1580–1583. Available from: https://pubmed.ncbi.nlm.nih.gov/23532323/ 68. Saman AM el, Shahin AY, Nasr A, et al. HHybrid septate uterus, coexistence of bicornuate and septate varieties: A genuine report. Journal of Obstetrics and Gynaecology Research [Internet] 2012 [cited 2021 Apr 23];38(11):1308–1314. Available from: https://pubmed.ncbi.nlm.nih.gov/22612567/ 69. Fedele L, Bianchi S, Zanconato G, Berlanda N, Bergamini V. Laparoscopic removal of the cavitated noncommunicating rudimentary uterine horn: Surgical aspects in 10 cases. Fertility and Sterility [Internet] 2005 [cited 2021 Apr 23];83(2):432–436. Available from: https://pubmed.ncbi.nlm.nih.gov/15705386/ 70. Hsiao SM, Chen WC, Lin HH, Tu JS. Robot-assisted laparoscopic removal of an unseparated non-communicating rudimentary uterine horn [Internet]. European Journal of Obstetrics

41

and Gynecology and Reproductive Biology. 2013 [cited 2021 Apr 23];168(2):237–238. Available from: https://pubmed.ncbi.nlm.nih.gov/23528824/ 71. Rall K, Barresi G, Wallwiener D, Brucker SY, Staebler A. Uterine rudiments in patients with Mayer-Rokitansky-Küster-Hauser syndrome consist of typical uterine tissue types with predominantly basalis-like endometrium. Fertility and Sterility [Internet] 2013 [cited 2021 Jan 2];99(5):1392–1399. Available from: https://pubmed.ncbi.nlm.nih.gov/23321321/ 72. Singh J, Devi YL. Pregnancy following surgical correction of nonfused mullerian bulbs and absent vagina. Obstetrics and Gynecology [Internet] 1983 [cited 2021 Jan 2];61(2):267– 269. Available from: https://europepmc.org/article/med/6823370 73. Fontoura Oliveira A, Ferreira H. Neovagina creation in congenital vaginal agenesis: New mini-laparoscopic approach applying intraoperative indocyanine green fluorescence. Surgical Innovation [Internet] 2021 [cited 2021 May 2];28(1):24–32. Available from: https://pubmed.ncbi.nlm.nih.gov/33124521/ 74. Grimbizis GF, Mikos T, Papanikolaou A, Theodoridis T, Tarlatzis BC. Successful isthmo- neovagina anastomosis after davydov’s colpopoiesis in Mayer-Rokitansky-Küster-Hauser syndrome patients with a functional rudimentary uterine horn. Journal of Minimally Invasive Gynecology [Internet] 2015 [cited 2021 Apr 8];22(1):142–150. Available from: http://www.jmig.org/article/S1553465014012886/fulltext 75. Acién P, Acién M. Congenital uterine abnormalities [Internet]. In: Encyclopedia of Reproduction. Elsevier; 2018 [cited 2021 Jan 19]. p. 113–120.Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780128012383645294

42