Congenital uterine anomalies result from the abnormal differentiation, migration, fusion, and subsequent canalization of Mullerian ducts during embryogenesis [1]. They have been reported to be implicated as a potential cause of reduced fertility and miscarriages [2, 3, 4]. Basing on anomalies in the embryological development process, the uterine malformations can be divided in unification defects of the Mullerian ducts (unicornuate, bicornuate or didelphys uterus), canalization defects for incomplete resorption of the midline septum (sub-septate or septate uterus), Mullerian agenesis and arcuate uterus [5]. Data from literature, demonstrated that the aforementioned anomalies are present in 1-10% of unselected population, 2-8% of infertile women and 5-30% of women with a history of miscarriage [6]; however, the prevalence rate is uncertain due to the application of several diagnostic methods such as hysterosalpingography, hysteroscopy, laparoscopy, magnetic resonance imaging and three-dimensional sonography. In the same view, the use of three different classification systems developed by the American Society of Reproductive Medicine (ASRM, 2006) [7], the European Society of Human Reproduction and Embryology (ESHRE, 2013) and the European Society for Gynecological Endoscopy (ESGE, 2013) does not permit to establish a unique consensus about the prevalence of these malformations [2]. Moreover, uterine anomalies are often asymptomatic and accidentally diagnosed during ultrasounds for other gynecological pathologies, assessment of tubal patency or pregnancy [8, 9]. Moreover, they may also be recognized at delivery during spontaneous or cesarean section [10]. The presence of congenital uterine alterations represents a potential cause of infertility, recurrent pregnancy loss, preterm delivery, fetal malpresentation as well as small-for-gestational age infants, with greater effects being evident in women with more profound defects [11]. The presented study focused on the assessment of the perinatal outcomes in women affected by congenital uterine anomalies.

Continuous data (age and gestational week) were presented as median (interquartile range) or mean $\pm$ standard deviation. Categorical data (multiparity, preterm birth, fetal malpresentation and SGA) were analyzed using the Pearson’s chi square test. The association congenital anomalies with preterm birth, after adjusting for potential confounders, was examined by multivariate linear regression. All covariates (women age, gestational week, BMI and ethnicity) were simultaneously entered to the multivariate linear regression model. The assumptions for the final model were successfully tested. All statistical tests used a two-tailed $\alpha$ of 0.05. All data were calculated using SPSS 17 software (SPSS Inc., Chicago, IL, USA).

The results of our retrospective study demonstrated that uterine congenital anomalies had a significant negative effect on perinatal outcomes including preterm birth, fetal malpresentation at the end of the gestation and SGA. In particular, women with canalization defects, such as the complete and incomplete septate uterus, showed the worst reproductive outcomes, with a higher incidence of preterm birth and SGA [14], while patients with bicornuate uterus reported the highest rate of fetal malpresentation. Our results support previous series [15, 16, 17] and confirmed that the different types of Mullerian anomalies were individually associated with different obstetrics outcomes at varying severity degrees, with higher incidence of the worst outcomes in patients with more severe malformations [18]. Although the association between defects of canalization and the poor reproductive outcomes seems to be widely supported by scientific evidence, its pathophysiological process deserves future confirmations.

In this context, scientific background described that uterine septum consisted of a fibrous muscle tissue with poor vascularization. This uterine cavity alteration determines local uterine contractions, leading to preterm premature rupture of membranes and preterm birth [19, 20, 21] or difficult decidualization and implantation, with smaller uterine cavity and, thus, increased risks of SGA and miscarriages [22, 23, 24, 25]. In this view, it would be interesting to investigate the association between septate uterus and miscarriage. Indeed, septate uterus is the only congenital uterine anomaly which, if surgically corrected with minimally invasive intervention such as hysteroscopic septum removal, may determine an improvement in reproductive outcomes. According to this, the largest series reported so far, showed a significant decrease in the early miscarriage rate from 89.6% to 12.4% after hysteroscopic septum removal, as well as an increase in term of delivery rate from 1.4% to 74.4% [26]. With regards to unification defects, such as bicornuate, unicornuate and didelfis uterus, their effects on perinatal outcomes depend on the type of anomaly. Our results reported that women with bicornuate and unicornuate uterus had an elevated risk of fetal malpresentation and SGA, while patients with the didelphys uterus showed high risk of preterm birth and SGA. Given this, our results are partially in accord with those of previous studies which reported that uterine unification negatively influenced pregnancy in particular, bicornuate and unicornuate uterus were associated with an increased risk of preterm birth and fetal malpresentation, whereas didelphys uterus showed a mild increased risk of preterm birth [27, 28]. The strength of our study relies on the accurate selection process of patients with uterine anomalies. However, limitations do exist and should be considered when interpreting the results, indeed, uterine abnormalities may be underestimated especially during pregnancy and, in general, the diagnosis of arcuate uterus may be overlooked for its minimally altered uterine cavity.

Congenital uterine anomalies, related to Mullerian development defects, are not so rare as supposed. Our study highlighted that congenital uterine anomalies are associated with poor perinatal outcomes. Complete and incomplete septate uterus malformations are associated with the worst perinatal outcomes. In this context, due to the consistent improving in minimally invasive and resolutive surgical techniques during the last two decades [29], it is reasonable to auspicate for this approach, in order to ameliorate reproductive and perinatal outcomes.

Ethics approval was not required due to the observational/retrospective nature of the study. Written informed consent has been obtained by all the patients included in the study.

EZ and RA designed the study and wrote the manuscript. RA is responsible for data collection. EZ and LMDG provide the statistical analysis. FDG, GCM, FAG, SC, MCC and MP critically commented and substantially revised the manuscript. All authors participated in drafting the manuscript and approved the final version.

The authors thank the ultrasound ambulatory doctors for recruiting patients of the control group.

This work was not supported by any grant or other form of funding.

The Authors declare that they have no conflict of interest.