Placental bed research: I. The placental bed: from spiral arteries remodeling to the great obstetrical syndromes.

The term placental bed was coined to describe the maternal-fetal interface (ie, the area in which the placenta attaches itself to the uterus). Appropriate vascularization of this area is of vital importance for the development of the fetus; this is why systematic investigations of this area have now been carried out. Initially, the challenge was the identification and classification of the various successive branching of uterine arteries in this area. These vessels have a unique importance because failure of their physiological transformation is considered to be the anatomical basis for reduced perfusion to the intervillous space in women with preeclampsia, fetal growth restriction, preterm labor, preterm premature rupture of membranes, abruptio placentae, and fetal death. To investigate in depth the pathophysiology of the placental bed, some 60 years ago, a large number of placental bed biopsies, as well as of cesarean hysterectomy specimens with placenta in situ, from both early and late normotensive and hypertensive pregnancies, were carefully dissected and analyzed. Thanks to the presence of a series of specific physiological changes, characterized by the invasion and substitution of the arterial intima by trophoblast, this material allowed the identification in the placental bed of normal pregnancies of the main vessels, the uteroplacental arteries. It was then discovered that preeclampsia is associated with defective or absent transformation of the myometrial segment of the uteroplacental arteries. In addition, in severe hypertensive disease, atherosclerotic lesions were also found in the defective myometrial segment. Finally, in the basal decidua, a unique vascular lesion, coined acute atherosis, was also identified This disorder of deep placentation, coined defective deep placentation, has been associated with the great obstetrical syndromes, grouping together preeclampsia, intrauterine growth restriction, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and abruptio placentae. More recently, simplified techniques of tissue sampling have been also introduced: decidual suction allows to obtain a large number of decidual arteries, although their origin in the placental bed cannot be determined. Biopsies parallel to the surface of the basal plate have been more interesting, making possible to identify the vessels' region (central, paracentral, or peripheral) of origin in the placental bed and providing decidual material for immunohistochemical studies. Finally, histochemical and electron microscopy investigations have now clarified the pathology and pathogenetic mechanisms underlying the impairment of the physiological vascular changes.

Preeclampsia: the role of persistent endothelial cells in uteroplacental arteries.

We explore the potential role of the endothelial lining of uteroplacental arteries in the pathogenesis of preeclampsia, a severe pregnancy disorder characterized by incomplete invasion of the uterine vasculature by extravillous trophoblast and angiogenic imbalance. In normal pregnancy, the endothelium disappears progressively from the uteroplacental arteries and is replaced by trophoblast and deposition of fibrofibrinoid structure, underpinning the so-called physiological transformation of uterine spiral arteries. We hypothesize that partial persistence of the endothelium, albeit injured, initiates a chain of events leading to the emergence of preeclampsia in 3 sequential stages. The first stage results in retention of the endothelium in uteroplacental arteries secondary to incomplete physiological transformation of the vessels. Consequently, the uteroplacental vessels are reactive to pathological cues, which drives local arteriopathy. The second stage starts with progressive reduction in uteroplacental blood flow, generating oxidative stress in the whole placenta, and heightened maternal inflammation in response to circulating trophoblastic debris. In the third stage, generalized endotheliosis causes systemic angiogenic imbalance, hypertension, and other clinical manifestation of preeclampsia.

The placental bed vascular pathology revisited: a risk indicator for cardiovascular disease.

AIM: The present paper intends in the first place to clarify the confusing terminology for describing the vascular pathology of the placental bed in relation to long-term risk of cardiovascular disease. METHODS: Systematic review of relevant topics. RESULTS: The maternal blood supply to the placenta is achieved by some 100 utero-placental spiral arteries with an outside diameter varying between 200 and 600 microns. Defective physiological changes of the myometrial segment of utero-placental spiral arteries and, particularly in preeclampsia associated to hypertensive disease, the presence of atherosclerosis in their proximal segment are a cause of obstructive vascular pathology. On the other hand, basal arteries which supply the inner myometrium and basal decidua are not affected by physiological change and maintain their musculoelastic structure. They can be identified by their external diameter of less than 120 microns. Acute atherosis is an aspecific vascular lesion that occurs in basal as well as spiral arteries inside, as well as outside, the placental bed in association with a variety of obstetrical conditions. CONCLUSIONS: An increased risk of future cardiovascular disease, should be linked to atherosis or, at a later stage, atherosclerosis of utero-placental spiral arteries, rather than to that of decidual basal arteries.

Adolescent Preeclampsia: Pathological Drivers and Clinical Prevention.

Preeclampsia is an important cause of maternal and perinatal morbidity, especially in first-time pregnant adolescent women. Although prevention of preeclampsia has been attempted for many decades, effective intervention can only be achieved upon the full elucidation of the risk factors and mechanisms of disease. As the pathogenesis of preeclampsia during adolescence may differ from that in older women, preventive interventions should be tailored accordingly. During adolescence, 4 putative drivers of preeclampsia can be identified. First, uterine immaturity in very young teenagers is likely a major cause of defective deep placentation and adverse reproductive outcome, underscoring the importance of educational programs and public health initiatives focused on teen pregnancy prevention. Second, the association between adolescent obesity and preeclampsia merits further studies on the benefits of weight loss and dietary interventions to improve pregnancy outcome. Third, there is a need for greater awareness of the link between cardiovascular risk factors in young women and early-onset preeclampsia associated with atherosclerosis of the uteroplacental arteries. Finally, infrequent menstruations may prolong uterine immaturity because of lack of "menstrual preconditioning." This risk factor may be amenable to pharmacological/hormonal preconditioning prior to conception.

Progress in the diagnosis and management of adolescent endometriosis: an opinion.

Increasing evidence indicates that early onset endometriosis (EOE), starting around menarche or early adolescence, may have an origin different from the adult variant, originating from neonatal uterine bleeding (NUB). This implies seeding of naïve endometrial progenitor cells into the pelvic cavity with NUB; these can then activate around thelarche. It has its own pathophysiology, symptomatology and risk factors, warranting critical management re-evaluation. It can also be progressive, endangering future reproductive capacity. This variant seems to be characterized by the presence of ovarian endometrioma. Today, the diagnosis of endometriosis in young patients is often delayed for years; if rapidly progressive, it can severely affect pelvic organs, even in the absence of serious symptoms. Given the predicament, great attention must be paid to symptomatology that is often non-specific, justifying a search for new, simple, non-invasive markers of increased risk. Better use of modern imaging techniques will aid considerably in screening for the presence of EOE. Traditional laparoscopy should be limited to cases in which imaging gives rise to suspicion of severity and a stepwise, minimally invasive approach should be used, followed by medical treatment to prevent recurrence. In conclusion, EOE represents a condition necessitating early diagnosis and stepwise management, including medical treatment.

The impact of uterine immaturity on obstetrical syndromes during adolescence.

Pregnant nulliparous adolescents are at increased risk, inversely proportional to their age, of major obstetric syndromes, including preeclampsia, fetal growth restriction, and preterm birth. Emerging evidence indicates that biological immaturity of the uterus accounts for the increased incidence of obstetrical disorders in very young mothers, possibly compounded by sociodemographic factors associated with teenage pregnancy. The endometrium in most newborns is intrinsically resistant to progesterone signaling, and the rate of transition to a fully responsive tissue likely determines pregnancy outcome during adolescence. In addition to ontogenetic progesterone resistance, other factors appear important for the transition of the immature uterus to a functional organ, including estrogen-dependent growth and tissue-specific conditioning of uterine natural killer cells, which plays a critical role in vascular adaptation during pregnancy. The perivascular space around the spiral arteries is rich in endometrial mesenchymal stem-like cells, and dynamic changes in this niche are essential to accommodate endovascular trophoblast invasion and deep placentation. Here we evaluate the intrinsic (uterine-specific) mechanisms that predispose adolescent mothers to the great obstetrical syndromes and discuss the convergence of extrinsic risk factors that may be amenable to intervention.

Transvaginal laparoscopy: A minimally invasive approach to obtain brush cytology of the Fallopian tube.

OBJECTIVE: To evaluate in a prospective pilot study the feasibility of cytobrushing of the fimbrial end using a transvaginal endoscopic access. STUDY DESIGN: Prospective feasibility study. The procedure was performed in a consecutive series of 15 infertile women referred for a transvaginal laparoscopy as part of their fertility investigation. Tubal cells were collected using a 5Fr cytobrush. Cytology and immunocytochemistry was done. RESULTS: In all patients enough cell material was obtained for analysis, without traumatizing the fimbrial end. Specimens showed the presence of a sufficient amount of cells enabling standard cytologic examinations and immunocytochemistry (Ki 67, p53). CONCLUSION: Fimbrial cytobrushing using the transvaginal approach is an easy and minimally invasive procedure. The easy accessibility of the fimbrial end and the distal ampullary part at TVL allows an accurate collection of tubal epithelial cells. In view of the recent data reporting the Fallopian tube and more specifically the fimbrial end as a possible origin of ovarian carcinoma, further research is needed to evaluate the potential of this technique as a possible screening method for patients at risk for ovarian cancer.

Neonatal uterine bleeding as a biomarker for reproductive disorders during adolescence: a worldwide call for systematic registration by nurse midwife.

Neonatal uterine bleeding (NUB) occurs in approximately 5% of newborns and is generally considered to be of little clinical significance. However, the real clinical importance of this condition and its long-term implications remain to be determined. The reason why NUB is rare despite high circulating levels of progesterone can be attributed to a progesterone resistance present in a majority of neonates. Recent work indicates that NUB represents a significant biomarker for events that can occur later-on during adolescence. Indeed, clinical studies have shown that "neonatal menstruation" constitutes a sign of fetal distress during late pregnancy, reflecting a stage of endometrium development that may subsequently have an impact on the reproductive life of the adolescent and the young adult. Via retrograde flow, NUB can cause endometrial stem/progenitor cells to arrive into the pelvic cavity and survive there, dormant underneath the peritoneal surface, until menarche activates them. Indeed, there is both clinical and epidemiological evidence of a link between NUB and adolescent endometriosis. In addition, if progesterone resistance persists till the onset of menarche, in case of an early teen pregnancy, it can result in a disorder of deep placentation. Therefore, we propose that NUB should be carefully recorded so that prospective studies can examine its links with reproductive disorders in adolescence and beyond.

Pharmacologic treatment of the ovarian endometrioma.

INTRODUCTION: Treatment of ovarian endometriomas is commonly achieved through laparoscopic surgery and this can be effective in eliminating the disease, although a majority of recent trials documented an adverse effect of surgery on ovarian reserve markers. With the advancement in imaging techniques, ovarian endometriomas are increasingly diagnosed at an earlier stage when the endometrioma may be smaller, less fibrotic and more responsive to medical treatment, making an evaluation of medical options critically important. AREAS COVERED: The review focuses on currently utilized pharmacologic therapies for endometrioma (oral contraceptives, the levonorgestrel-releasing IUS, the hormone-releasing subdermal implant, Implanon); experimental and future treatments are also mentioned (GnRH antagonists, progesterone receptor modulators, antioestrogens, newer subdermal implants and intracystic administration of pharmacologic agents). Finally, the usefulness of post-operative adjuvant medical treatments is discussed Expert opinion: Today, reliable, non-invasive diagnostic procedures of an ovarian endometrioma are available and should be utilized to identify its presence and type of pathology. In a young patient, classic medical therapies such as oral contraceptives and synthetic progestins should be tried first to alleviate symptoms. Only when these regimens fail, should a minimally invasive surgery be envisaged. Following endoscopic surgery, adjuvant medical treatment may reduce recurrence of both symptoms and the lesion.

Origins and Progression of Adolescent Endometriosis.

Accumulating evidence indicates that adolescent endometriosis is common and often severe. Here we explore the possibility that seeding of naive endometrial progenitor cells into the pelvic cavity early in life, that is, at the time of neonatal uterine bleeding or soon after the menarche, results in more florid and progressive disease, characterized by highly angiogenic implants, recurrent ectopic bleeding, and endometrioma formation. We discuss the potential intergenerational risk factors associated with early-onset endometriosis and explore the molecular drivers of disease progression. Taken together, the available data suggest that an increased focus on early-life events may help to identify young women at risk of severe, progressive endometriosis.

Ovarian endometrioma in the adolescent: a plea for early-stage diagnosis and full surgical treatment.

The incidence and severity of endometriosis in adolescent are comparable with the incidence in adult women. The mean delay between the onset of symptoms and the final diagnosis varies between 6.4 and 11.7 years. The longer the diagnosis is delayed, the more the endometriosis can progress to a more severe stage certainly in the group of patients with pelvic pain. The evolution of endometriosis and its progressivity are not predictable, and the severity of the disease is not directly related to the degree of pain. Endometriotic cysts have a detrimental effect on the ovarian reserve by the evolution in time and the surgical excision technique. Already, in small endometriotic cysts (<4 cm), loss of follicular reserve is present together with the formation of fibrosis in the cortex of the ovary. Early diagnosis of endometriosis in the adolescent deserves our full attention. Non-invasive imaging techniques like 2-D and 3-D ultrasound are helpful in the early diagnosis. Early ablative surgery is recommendable. Although laparoscopy is traditionally recommended, transvaginal laparoscopy has been shown to be most effective in ablating endometriomas with a maximum diameter of 3 cm. Early detection and intervention will contribute to a better quality of life in these adolescents and also to a lower damage of the ovarian tissue by a less invasive ablative surgery.

Survival, re-expansion and cell survival of human blastocysts following vitrification and warming using two vitrification systems.

PURPOSE: This study evaluated and compared survival, re-expansion, and percentage of live cells of individual Days 5 and 6 human blastocysts that were vitrified and warmed with the Vit Kit Freeze/Thaw (Irvine Scientific, CA), or with two protocols using the Global Fast Freeze/Thaw Kits (LifeGlobal, Canada). METHODS: Frozen/thawed Day 2-3 or discarded embryos were cultured to blastocyst (culture day 5-6). Group 1 blastocysts were vitrified with the Vit Kit (n = 29) and High Security Vitrification (HSV) devices. Group 2 (n = 47) and Group 3 (n = 48) blastocysts were cryopreserved with the Global Fast Freeze Kit and 0.25 ml straws, using a direct plunge or a -100 °C holding step, respectively. Group 4 (Controls, n = 30) were not vitrified. Blastocysts were subsequently cultured for 24 h, assessed for survival and expansion, and then stained individually with propidium iodide and Hoechst. Live and total cell number was assessed with ImageJ (NIH), and the percentage of live cells calculated for each blastocyst. RESULTS: The percentage of live cells was not different between vitrified and control (non-vitrified) blastocysts, thus vitrification did not affect cell survival. Survival (following thawing and after 24 h culture), re-expansion, and percentage of live cells were not different for blastocysts vitrified and warmed between the two vitrification/warming kits, or between the two protocols for the Global Fast Freeze/Thaw Kits. CONCLUSIONS: Blastocyst vitrification can be achieved with equal success using simplified protocols and cheaper and easy to load freezing straws, providing simultaneously increased safety, and efficiency with lower cost, when compared with vitrification using specialized embryo vitrification devices.

Pathophysiology proposed as the basis for modern management of the ovarian endometrioma.

Present management of the ovarian endometrioma focuses on the size of the cyst and dictates that surgery should not be performed unless this exceeds 3 cm, which neglects the complex pathology of this condition. Studies of ovaries with the endometrioma in situ show progressive smooth muscle cell metaplasia and fibrosis of the cortical layer as the main ovarian lesion. There is no correlation between the size of the endometrial cyst and the degree of ovarian pathology: it is the mere presence of an ovarian endometrioma that has a detrimental impact on the cortical layer's follicle reserve. Cystectomy in young patients with an endometrioma may be particularly detrimental to follicle reserve, with the ovarian parenchyma loss at the time of surgery being related to the cyst's diameter. An underutilized diagnostic procedure, transvaginal hydrolaparoscopy with in-situ inspection of the cyst wall by ovarioscopy, allows careful diagnosis of ovarian pathology and selection of appropriate surgery with minimal invasiveness. Thus, available evidence shows that expectant management may not be the best choice when an endometrioma is suspected. On the contrary, early diagnosis through a minimally invasive technique, followed by early ablative surgery whenever indicated, represents the management of choice to preserve normal ovarian function. Present management of ovarian endometriomata is based on the size of the cyst and dictates that surgery should not be performed unless this exceeds 3cm. We argue that this approach neglects the true pathology of the ovary, since pioneers have studied ovaries with the endometrioma in situ and demonstrated that progressive smooth muscle cell metaplasia and fibrosis in the cortical layer constitute the main features of an endometrioma. There is no correlation between the size of the endometrial cyst and the degree of ovarian pathology: it is in the first place the mere presence of an ovarian endometrioma that has a detrimental impact on follicle reserve. It has been shown that cyst ablation in young patients with an endometrioma may be particularly detrimental to follicle reserve. An underutilized diagnostic procedure, transvaginal needle endoscopy with in-situ inspection after injection of saline suspension into the peritoneal cavity (hydrolaparoscopy) allows careful diagnosis of ovarian cortical pathology by colour changes from pearl-white to dark fibrotic. Thus, available evidence shows that expectant management may not be the best choice when an endometrioma is suspected: the delay in diagnosis causes delay in treatment and progression of the process leading to loss of follicles. On the contrary, early diagnosis through a minimally invasive technique, followed by early ablative surgery whenever indicated, represents the management of choice to preserve normal ovarian function.

Endometriosis: a life cycle approach?

To improve the still fragmented understanding of endometriosis, a life cycle approach was adopted that revealed unexpected aspects of the natural history of the disease throughout a woman's life. Three age-related stages of endometriosis are distinguished. In premenarcheal and adolescent endometriosis, 2 types can be distinguished: a classic form that can occur before menarche, and a congenital obstructive form that is caused by uterine anomaly and outflow obstruction. The lesions include superficial peritoneal implants, but adhesions and endometrioma can also occur. It is suggested that premenarcheal and possibly adolescent endometriosis develop by activation of resting stem cells shed at the time of neonatal retrograde uterine bleeding. In the adult, endometriosis can be related to uterine preconditioning by cyclic menstruations acting as a priming mechanism for deep placentation. In adult life, the typical lesions are peritoneal, ovarian, and deep or adenomyotic endometriosis. More recently, endometriosis has been associated with endometrial dysfunction and myometrial junctional zone hyperplasia. These uterine changes can be linked with some major obstetrical syndromes. In postmenopause, endometriosis can develop or be reactivated both in the presence or absence of exogenous estrogens and can spread to a variety of organs and structures causing constrictive lesions.

The effectiveness of hysteroscopy in improving pregnancy rates in subfertile women without other gynaecological symptoms: a systematic review.

BACKGROUND: Although hysteroscopy is frequently used in the management of subfertile women, a systematic review of the evidence on this subject is lacking. METHODS: We summarized and appraised the evidence for the benefit yielded by this procedure. Our systematic search was limited to randomized and controlled studies. The QUOROM and MOOSE guidelines were followed. Language restrictions were not applied. RESULTS: We identified 30 relevant publications. Hysteroscopic removal of endometrial polyps with a mean diameter of 16 mm detected by ultrasound doubles the pregnancy rate when compared with diagnostic hysteroscopy and polyp biopsy in patients undergoing intrauterine insemination, starting 3 months after the surgical intervention [relative risk (RR) = 2.3; 95% confidence interval (CI): 1.6-3.2]. In patients with one fibroid structure smaller than 4 cm, there was a marginally significant benefit from myomectomy when compared with expectant management (RR = 1.9; 95% CI: 1.0-3.7). Hysteroscopic metroplasty for septate uterus resulted in fewer pregnancies in patients with subfertility when compared with those with recurrent pregnancy loss (RR = 0.7; 95% CI: 0.5-0.9). Randomized controlled studies on hysteroscopic treatment of intrauterine adhesions are lacking. Hysteroscopy in the cycle preceding a subsequent IVF attempt nearly doubles the pregnancy rate in patients with at least two failed IVF attempts compared with starting IVF immediately (RR = 1.7; 95% CI: 1.5-2.0). CONCLUSIONS: Scarce evidence on the effectiveness of hysteroscopic surgery in subfertile women with polyps, fibroids, septate uterus or intrauterine adhesions indicates a potential benefit. More randomized controlled trials are needed before widespread use of hysteroscopic surgery in the general subfertile population can be justified.

Transvaginal hydrolaparoscopy in the treatment of polycystic ovary syndrome.

OBJECTIVE: To evaluate the efficacy of transvaginal endoscopic ovarian capsule drilling. DESIGN: Retrospective efficacy study. SETTING: Private tertiary care center. PATIENT(S): Thirty-nine PCOS patients with previously failed ovulation induction; mean duration of infertility 26.5 months (SD +/-2.6); mean age 30.38 years (SD +/-3.8); mean body mass index of 29.4 (SD +/-9.7). INTERVENTION(S): Through transvaginal hydrolaparoscopy in a 1-day clinic setting, drilling of the ovarian capsule is performed with a 5-Fr bipolar needle (Karl Storz, Tüttlingen, Germany) creating 10-15 holes of +/-0.20 mm in each ovary. MAIN OUTCOME MEASURE(S): Evaluation of feasibility, spontaneous resumption of ovulatory cycles and pregnancy rates. RESULT(S): Ovarian capsule drilling was performed in 39 patients. Six patients were lost of follow-up. In total, 25 out of 33 patients (76%) became pregnant with a mean duration between procedure and onset of pregnancy of 7.2 months (SD +/-5.4). Natural conception with or without controlled ovarian hyperstimulation and/or intrauterine insemination occurred in 13 of the 16 patients (81%). Of the 17 patients referred to our IVF program, 12 became pregnant. There were no multiple pregnancies or complications. CONCLUSION(S): The transvaginal approach for ovarian capsule drilling offers a valuable alternative to the standard laparoscopic procedure.

Clinical factors determining pregnancy outcome after microsurgical tubal reanastomosis.

OBJECTIVE: To evaluate pregnancy rates after tubal microsurgical anastomosis. DESIGN: Retrospective study. SETTING: Private tertiary care center. PATIENT(S): Two hundred sixty-one women undergoing tubal microsurgical anastomosis. INTERVENTION(S): Tubal anastomoses were performed by minilaparotomy using microsurgical principles and approximating proximal and distal tubal ends in a two-layer technique with 8-0 ethylon. MAIN OUTCOME MEASURE(S): Pregnancy outcome was analyzed for the technique of sterilization, location of anastomosis, tubal length, age, and semen parameters. RESULT(S): After exclusion of 89 patients lost to follow-up (34%) and 8 who did not attempt to conceive, 164 of the 261 patients were analyzed.The overall intrauterine pregnancy rate was 72.5%, with a miscarriage rate of 18% and a tubal pregnancy rate of 7.7%. Related to age, the cumulative intrauterine pregnancy rate was, respectively, 81%, 67%, 50%, and 12.5% for patients <36, 36-40, 40-43, and >43 years. Mean time to pregnancy was respectively 6.9, 6.2, and 12.7 months, respectively, for patients aged <36, 36-39, and 40-43 years According to the type of sterilization, intrauterine pregnancies occurred in 72% after ring sterilization, 78% after clip sterilization, 68% after coagulation, and 67% after Pomeroy sterilization. Intrauterine pregnancies and ectopic pregnancies, respectively, occurred in 80% and 3.4% in the isthmo-isthmic, 63% and 18% in the isthmo-ampullar, 75% and 8.3% in the isthmo-cornual, 100% and 0% in the ampullo-ampullar, and 60% and 0% in the ampullo-cornual anastomosis groups. Tubal length after anastomosis did not influence the pregnancy rate. In case of fertile sperm, the pregnancy rate was found to be 80%, and it decreased to 50% in case of subfertile semen. CONCLUSION(S): Our results clearly demonstrate the validity of tubal microsurgical anastomosis, establishing a quasinormalization of the fertility potential and offering the opportunity for a spontaneous conception.