Title: Recurrent pregnancy losses, a lasting cause of infertility
Abstract: Recurrent pregnancy loss (RPL), defined as two to three spontaneous pregnancy terminations occurring before 12 weeks of gestation, affects approximately 1% of the general population. The causes may include congenital factors that originate with the quality of the gametes (sperm or oocyte) or the resulting embryo, or factors that originate within the uterus. Alterations of endometrial receptivity from endometriosis and/or endometritis, which are associated with impaired action of progesterone, have also been implicated in RPL. Finally, immunologic factors and thrombophilia, congenital and acquired, have also been suspected to cause RPL. Recurrent pregnancy loss (RPL), defined as two to three spontaneous pregnancy terminations occurring before 12 weeks of gestation, affects approximately 1% of the general population. The causes may include congenital factors that originate with the quality of the gametes (sperm or oocyte) or the resulting embryo, or factors that originate within the uterus. Alterations of endometrial receptivity from endometriosis and/or endometritis, which are associated with impaired action of progesterone, have also been implicated in RPL. Finally, immunologic factors and thrombophilia, congenital and acquired, have also been suspected to cause RPL. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/31950 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/31950 Spontaneous terminations of pregnancy that occur before 20 weeks of gestation are generally considered to be miscarriages (pregnancy losses that take place later are referred to as premature births, and they generally have different etiologies). However, in practical terms, the designation of miscarriage is often reserved for spontaneous terminations of pregnancy that occur before the 12th week of gestation. Miscarriages are possibly the most common pathology encountered in medicine: 12% to 15% of all pregnancies spontaneously terminate through an early miscarriage, and the incidence is markedly influenced by the woman's age. The frequency with which miscarriages occur has been extraordinarily stable over time. In past decades, pregnancies conceived both spontaneously and through assisted reproductive technology had a similar incidence of miscarriage. However, as assisted reproduction has early measurements of β-human chorionic gonadotropin it has permitted identifying biochemical pregnancies before any clinical manifestation, and these losses have been counted as very early pregnancy arrests. In contexts other than assisted reproduction, this latter parameter is generally not recognized. On certain occasions, miscarriages occur repetitively. Recurrent pregnancy loss (RPL), defined as three episodes of miscarriage, affects approximately 1% of cases in the general population. At present, investigations into potential causes of RPL are commonly initiated after two miscarriages. Among infertile women, the incidence of RPL is higher. Several causes of RPL have been identified, and practical measures to overcome recurrence have been developed, as reviewed in the present series of articles. Klimczak et al. (1Klimczak A.M. Patel D.P. Hotaling J.M. Scott Jr., R.T. Role of the sperm, oocyte, and embryo in recurrent pregnancy loss.Fertil Steril. 2021; 115: 533-537Abstract Full Text Full Text PDF Scopus (1) Google Scholar) review the causes of RPL stemming from disorders affecting sperm, oocytes, or embryos. These authors emphasize that sperm anomalies likely contribute to a fraction of the high incidence of genetic disorders encountered in products of conception ending in miscarriage. They review the various methods of assessing sperm reproductive potential, with an emphasis on sperm DNA integrity assessment and chromosomal aberrations. They also review the options that have been tested or are in development for sperm sorting. Oocyte abnormalities—intrinsic functional disorders that likely are present in all of an individual's cohort of oocytes—may be lethal to the developing conceptus. Structural rearrangements of the chromosome may be present in 12% of couples with RPL; 40% of these rearrangements are identifiable by traditional karyotypes. Preimplantation genetic testing for monogenic disorders may help in selecting disease-free embryos. Balanced translocations are found in 4% to 8% of couples with RPL, including in those who may have had one or more healthy children. Finally, asymmetric inactivation of the X chromosome has been found to be more common in women with RPL, but no specific treatment is currently available. The uterine causes of miscarriages and RPL can be divided into congenital (malformations) and acquired disorders. The former category comprises various degrees of nonresorption of the septum separating the two müllerian ducts at the time of their fusion in utero. As described by Carbonnel et al. (2Carbonnel M. Pirtea P. de Ziegler D. Ayoubi J.M. Uterine factors in recurrent pregnancy losses.Fertil Steril. 2021; 115: 538-545Abstract Full Text Full Text PDF Scopus (1) Google Scholar), the anomaly most frequently associated with miscarriages and RPL is the septated uterus, defined by a septum protruding >10 mm in the uterine cavity. Conversely, anomalies of nonresorption of the septum—double uteri and arcuated uterus (septum <10 mm)—are less prone to cause miscarriages. A near consensus of opinion recommends surgical metroplasty in cases of septate uteri with RPL whereas no surgery is generally recommended for other nonresorption malformations, including double uteri and arcuated uterus (2Carbonnel M. Pirtea P. de Ziegler D. Ayoubi J.M. Uterine factors in recurrent pregnancy losses.Fertil Steril. 2021; 115: 538-545Abstract Full Text Full Text PDF Scopus (1) Google Scholar). Uterine fibromas and endometrial polyps constitute the bulk of the acquired anatomic anomalies, together with intrauterine adhesions. Uterine fibroids are classified according to their anatomic position in relation to the uterine cavity and uterine wall. Today, the classification system of the International Federation of Gynecologists (FIGO) is preferred over the descriptive localizations that had been used previously. For example, fibroids classified as FIGO 0-2 protrude inside the uterine cavity. Common sense and widely accepted medical practice recommend the surgical removal of such fibroids, even if guidelines such as those proposed by the European Society of Human Reproduction and Embryology remain elusive for such indications. However, as underscored by Carbonnel et al. (2Carbonnel M. Pirtea P. de Ziegler D. Ayoubi J.M. Uterine factors in recurrent pregnancy losses.Fertil Steril. 2021; 115: 538-545Abstract Full Text Full Text PDF Scopus (1) Google Scholar), there is no clear evidence of benefit to removing endometrial polyps, despite the general practice of endoscopically removing such protruding structures. Intrauterine adhesions and scar tissue are lingering problems encountered in women who have had uterine procedures and/or infections. As discussed by Carbonnel et al. (2Carbonnel M. Pirtea P. de Ziegler D. Ayoubi J.M. Uterine factors in recurrent pregnancy losses.Fertil Steril. 2021; 115: 538-545Abstract Full Text Full Text PDF Scopus (1) Google Scholar), the management of these problems continues to be a matter of debate. In unmanageable cases—where the alterations are beyond the hope of repair—some have proposed using stem cells or potentially even uterine transplantation or gestational surrogacy. Embryo implantation, the necessary first step to pregnancy, requires proper development of the embryo and adequate receptivity of the endometrium. Embryo quality—namely, its euploidy status—stems from the quality of the oocyte and sperm, as discussed by Klimczak et al. (1Klimczak A.M. Patel D.P. Hotaling J.M. Scott Jr., R.T. Role of the sperm, oocyte, and embryo in recurrent pregnancy loss.Fertil Steril. 2021; 115: 533-537Abstract Full Text Full Text PDF Scopus (1) Google Scholar). An impairment in endometrial quality may affect implantation and placentation, which in turn may impair proper embryo development and result in miscarriage—and, in certain circumstances, in RPL, as reviewed by Pirtea et al. (3Pirtea P. Cicinelli E. De Nola R. de Ziegler D. Ayoubi J.M. Endometrial causes to KPL: endometriosis, adenomyosis and chronic endometritis.Fertil Steril. 2021; 115: 546-560Abstract Full Text Full Text PDF Scopus (3) Google Scholar). Endometriosis has been demonstrated to also affect the eutopic endometrium. Inflammation caused by endometriosis ultimately impairs the normal endometrial response to progesterone. As addressed by Pirtea et al. (3Pirtea P. Cicinelli E. De Nola R. de Ziegler D. Ayoubi J.M. Endometrial causes to KPL: endometriosis, adenomyosis and chronic endometritis.Fertil Steril. 2021; 115: 546-560Abstract Full Text Full Text PDF Scopus (3) Google Scholar) in a dedicated article of this series, endometriosis-led changes alter the endometrial response to progesterone and, notably, the proper predecidual transformation of the endometrium. Endometriosis has indeed been associated with an increased miscarriage risk, possibly leading to RPL. The mechanisms causing endometrial alterations in cases of endometriosis are linked to a prevailing inflammation in the eutopic endometrium. Adenomyosis, a variant of endometriosis, is also susceptible to inducing the same consequences and may result in RPL. This is primarily the case for internal adenomyosis. Still another circumstance associated with endometrial inflammation is chronic endometritis (CE), which is found in 10% to 15% of infertile women and 40% of women with endometriosis. Pirtea and colleauges conduct a systematic review of the incidence of miscarriages and RPL in cases of CE also reported in the same article of this series (3Pirtea P. Cicinelli E. De Nola R. de Ziegler D. Ayoubi J.M. Endometrial causes to KPL: endometriosis, adenomyosis and chronic endometritis.Fertil Steril. 2021; 115: 546-560Abstract Full Text Full Text PDF Scopus (3) Google Scholar), also assessing the beneficial effects of specific treatments. These authors emphasize the difficulty in making the diagnosis of CE, thereby explaining the some of the discrepancies in results, and underscore the need to perform both endometrial biopsies and hysteroscopy. The core message on the role of CE on RPL as conveyed by Pirtea and colleagues is that it can be diagnosed and effectively treated, thereby reducing if not preventing the risk of recurrence. The development of pregnancy implies an immune tolerance for the development of the "nonself" embryo. In their discussion of this issue, Alecsandru et al. (4Alecsandru D. Klimczak A.M. Garcia Velasco J.A. Pirtea P. Franasiak J.M. Immunological causes and thrombophilia in recurrent pregnancy losses (RPL).Fertil Steril. 2021; 115: 561-566Abstract Full Text Full Text PDF Scopus (1) Google Scholar) review the immunological mechanisms that permit the normal development of an embryo and the possible impairments that may lead to miscarriages and RPL. Likewise, they review metabolic disorders (including diabetes mellitus) and autoimmune disorders that may be associated with RPL (4Alecsandru D. Klimczak A.M. Garcia Velasco J.A. Pirtea P. Franasiak J.M. Immunological causes and thrombophilia in recurrent pregnancy losses (RPL).Fertil Steril. 2021; 115: 561-566Abstract Full Text Full Text PDF Scopus (1) Google Scholar). In a sub-section of the same article, Alecsandru et al. review the alterations of hemostasis—thrombophilias—that may lead to miscarriages and RPLs (4Alecsandru D. Klimczak A.M. Garcia Velasco J.A. Pirtea P. Franasiak J.M. Immunological causes and thrombophilia in recurrent pregnancy losses (RPL).Fertil Steril. 2021; 115: 561-566Abstract Full Text Full Text PDF Scopus (1) Google Scholar). Reminding us that pregnancy itself is a prothrombotic state, these authors explain that thrombophilias may increase the risk of complications. It is debated whether inherited thrombophilias are associated with RPLs, with a majority of studies indicating that this is not the case (4Alecsandru D. Klimczak A.M. Garcia Velasco J.A. Pirtea P. Franasiak J.M. Immunological causes and thrombophilia in recurrent pregnancy losses (RPL).Fertil Steril. 2021; 115: 561-566Abstract Full Text Full Text PDF Scopus (1) Google Scholar). Conversely, acquired thrombophilias may cause RPLs; for example, antiphospholipid antibody syndrome is encountered in 5% to 20% of cases of RPL (4Alecsandru D. Klimczak A.M. Garcia Velasco J.A. Pirtea P. Franasiak J.M. Immunological causes and thrombophilia in recurrent pregnancy losses (RPL).Fertil Steril. 2021; 115: 561-566Abstract Full Text Full Text PDF Scopus (1) Google Scholar).