Giovanni Battista La Sala

Cancer and fertility preservation: International recommendations from an expert meeting

In the last years, thanks to the improvement in the prognosis of cancer patients, a growing attention has been given to the fertility issues. International guidelines on fertility preservation in cancer patients recommend that physicians discuss, as early as possible, with all patients of reproductive age their risk of infertility from the disease and/or treatment and their interest in having children after cancer, and help with informed fertility preservation decisions. As recommended by the American Society of Clinical Oncology and the European Society for Medical Oncology, sperm cryopreservation and embryo/oocyte cryopreservation are standard strategies for fertility preservations in male and female patients, respectively; other strategies (e.g. pharmacological protection of the gonads and gonadal tissue cryopreservation) are considered experimental techniques. However, since then, new data have become available, and several issues in this field are still controversial and should be addressed by both patients and their treating physicians.In April 2015, physicians with expertise in the field of fertility preservation in cancer patients from several European countries were invited in Genova (Italy) to participate in a workshop on the topic of “cancer and fertility preservation”. A total of ten controversial issues were discussed at the conference. Experts were asked to present an up-to-date review of the literature published on these topics and the presentation of own unpublished data was encouraged. On the basis of the data presented, as well as the expertise of the invited speakers, a total of ten recommendations were discussed and prepared with the aim to help physicians in counseling their young patients interested in fertility preservation.Although there is a great interest in this field, due to the lack of large prospective cohort studies and randomized trials on these topics, the level of evidence is not higher than 3 for most of the recommendations highlighting the need of further research efforts in many areas of this field. The participation to the ongoing registries and prospective studies is crucial to acquire more robust information in order to provide evidence-based recommendations.

Pregnancy complications in women with polycystic ovary syndrome

BACKGROUND The great majority of studies performed so far concerning women diagnosed with polycystic ovary syndrome (PCOS) have focused on diagnosis, menstrual cycle abnormalities, hirsutism and infertility. Although progress has been made in developing methods for achieving a pregnancy and reducing multiple gestations in women with PCOS, little attention has been paid to pregnancy complications and subsequent child outcomes. This review aims to summarize current knowledge regarding the clinical and pathophysiological features of pregnancy and children in women with PCOS. METHODS A literature search up to April 2015 was performed in PubMed, Medline, the Cochrane Library and Web of Science without language restriction. All articles were initially screened for title and abstract and full texts of eligible articles were subsequently selected. Systematic reviews with meta-analysis were initially included for each specific subject. Recent randomised controlled trials (RCTs), which were not included in the systematic reviews, were also included. In addition to evidence from meta-analyses or RCTs, we used non-randomized prospective, uncontrolled prospective, retrospective and experimental studies. When specific data for patients with PCOS were lacking, results from general population studies were reported. RESULTS Women with PCOS exhibit a clinically significant increased risk of pregnancy complications compared with controls. Data which were not adjusted for BMI or other confounders demonstrated in PCOS a 3-4-fold increased risk of pregnancy-induced hypertension and pre-eclampsia, a 3-fold increased risk of gestational diabetes and 2-fold higher chance for premature delivery. Features characteristic of PCOS, such as hyperandrogenism, obesity, insulin resistance and metabolic abnormalities, may contribute to the increased risk of obstetric and neonatal complications. Limited available data suggest that offspring of women with PCOS have an increased risk for future metabolic and reproductive dysfunction. Underlying pathophysiological mechanisms of pregnancy complications along with its association with health of offspring remain uncertain. To date, the strategies for prevention and management of pregnancy complications in women with PCOS, and whether long-term health of these women is influenced, and to what extent, by pregnancy and/or pregnancy complications, remain to be elucidated. CONCLUSIONS Women with PCOS show an increased risk of pregnancy complications. Heterogeneous aetiological factors involved in PCOS and associated co-morbidities may all be involved in compromised pregnancy and child outcomes. In women with PCOS, a possible relationship with genetic, environmental, clinical and biochemical factors involved in this complex condition, as well as with pregnancy complications and long-term health for both mother and child, remains to be established.

Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial

To assess whether antithrombotic prophylaxis with low-molecular-weight heparin effectively prevents recurrence of late pregnancy complications, 135 women with previous history of preeclampsia, hemolytic anemia, elevated liver enzymes and low platelet count syndrome, intrauterine fetal death, fetal growth restriction, or placental abruption who had been referred within the 12th gestational week were randomized to medical surveillance alone (n = 68) or combined to open-label nadroparin (3800 IU daily subcutaneous injections) treatment (n = 67) in the setting of a randomized, parallel-group, superiority trial, run in Italy from April 2007 to April 2010. Primary outcome was a composite end point of late-pregnancy complications. Analysis was by intention to treat. The study was stopped for futility at the time of the first planned interim analysis. Among the 128 women eventually available for final analyses, 13 of the 63 (21%) randomized to nadroparin compared with 12 of the 65 (18%) on medical surveillance alone progressed to the primary end point. The absolute event risk difference between treatment arms (2.2; -1.6 to 16.0) was not statistically significant (P = .76). Thus, nadroparin did not prevent late-pregnancy complications in women at risk of recurrence. This finding challenges the role of antithrombotic prophylaxis with low-molecular-weight heparin in the prevention of recurrent late pregnancy complications The trial was registered at http://ricerca-clinica.agenziafarmaco.it as EudraCT 2006-004205-26.

The role of diagnostic hysteroscopy and endometrial biopsy in assisted reproductive technologies

OBJECTIVE To study the incidence of unsuspected endouterine abnormalities in patients for whom IVF-ET repeatedly fails. DESIGN Prospective study. SETTING Infertility Unit of the Department of Obstetrics and Gynecology, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. PATIENT(S) One hundred patients for whom two IVF-ET cycles failed in which > or =2 good-quality embryos were transferred. INTERVENTION(S) In-office diagnostic hysteroscopy and endometrial biopsy. MAIN OUTCOME MEASURE(S) Relation between IVF-ET failure and unsuspected endouterine abnormalities. RESULT(S) In 18 patients, hysteroscopy showed an important unsuspected endouterine abnormality. Fifteen of these patients did not become pregnant after IVF-ET, and 3 became pregnant but had a spontaneous abortion. Histologic examination of the endometrium revealed chronic endometritis in 1 patient and tuberculous endometritis in another. CONCLUSION(S) Previous studies have reported that the incidence of endouterine abnormalities is high in patients undergoing IVF-ET. Our data confirm the previous reports and lead us to conclude that diagnostic hysteroscopy should be performed on all patients before they undergo IVF-ET.

Multicenter observational study on slow-cooling oocyte cryopreservation: clinical outcome

OBJECTIVE To evaluate the efficacy of oocyte cryopreservation by a single slow-cooling protocol involving sucrose (0.2 mol/L) in the freezing solution. DESIGN Observational comparison of the clinical outcome in fresh and frozen thawed cycles. SETTING Public and private IVF centers. PATIENT(S) Infertile couples undergoing IVF treatment. INTERVENTION(S) Use of a maximum three oocytes in fresh cycles, as established by local law, and cryopreservation and later use of surplus oocytes. Likewise fresh cycles, maximum three thawed oocytes were used per cycle. All thawed oocytes were microinjected. MAIN OUTCOME MEASURE(S) Embryologic and clinical parameters of fresh and thawed cycles. RESULT(S) Two thousand forty-six patients underwent 2,209 oocyte retrievals involving oocyte cryopreservation. Overall, the survival rate of thawed oocytes was 55.8%. In 940 thaw cycles, the mean numbers of inseminated oocytes and fertilization rates were significantly decreased vs. fresh cycles outcomes (2.6 ± 0.7 vs. 2.9 ± 0.2 and 72.5% vs. 78.3%, respectively), as were the rates of implantation (10.1% vs. 15.4%), pregnancy rates per transfer (17.0% vs. 27.9%), and pregnancy rates per cycle (13.7% vs. 26.2%). Differences in clinical outcome were found among centers. A pregnancy rate per thawing cycle above 14% was achieved by most clinics. Fifty-seven retrievals involving oocyte cryopreservation achieved a pregnancy after fresh embryo replacement. Implantation and pregnancy rates per embryo transfer and per thawing cycles were 17.5%, 28.6%, and 24.6%, respectively. CONCLUSION(S) Under the conditions tested, the clinical outcome of oocyte slow-cooling cryopreservation is reduced compared with fresh cycles. Nevertheless, in cases of inapplicability of embryo cryopreservation, oocyte cryopreservation should be offered to patients with surplus oocytes.

Pervasive developmental disorders in children of hyperandrogenic women with polycystic ovary syndrome: a longitudinal case-control study.

Foetal exposure to high testosterone concentrations seems to be involved in the development of mammalian brain and related to pervasive developmental disorders (PDDs). The aim of the current study was to test the hypothesis that children born from hyperandrogenic women with polycystic ovary syndrome (PCOS) are at higher risk of PDDs.

Depressive symptoms during late pregnancy and early parenthood following assisted reproductive technology

OBJECTIVE To evaluate the relationship between assisted reproduction technology (ART) and depressive symptoms during late pregnancy and early parenthood. DESIGN Case-control longitudinal study. SETTING The Center of Reproductive Medicine, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. PATIENT(S) Women who conceived by ART compared with men and compared with women following spontaneous conceptions. INTERVENTION(S) The sample of 87 subjects, 48 ART (25 mothers, 23 fathers; response rate of 30%) and 39 non-ART mothers were evaluated by the Edinburgh Postnatal Depression Scale (EPDS) at 30-32 weeks of gestation, and at 1 week and 3 months after delivery. MAIN OUTCOME MEASURE(S) Mean scores and prevalence of low scores. RESULT(S) The main sociodemographic and obstetric characteristics were similar between groups. Edinburgh Postnatal Depression Scale scores were higher in ART women compared with non-ART women during all assessments and higher during the third trimester of pregnancy and at 1 week postpartum compared with ART men. The prevalence of depressed subjects was significantly higher in ART women compared with non-ART women during the antenatal assessment. CONCLUSION(S) Assisted reproductive technology pregnancies are more frequently associated with depressive symptoms that may persist after delivery, suggesting a greater emotional vulnerability of these women. The risk of depression during and following ART pregnancies needs monitoring to avoid adverse effects of postpartum depression on the mother-infant relationship and infants psychologic development.

Decidual Endovascular Trophoblast Invasion in Women with Polycystic Ovary Syndrome: An Experimental Case-Control Study

CONTEXT Previous experimental and clinical data suggest impaired decidual trophoblast invasion in patients with polycystic ovarian syndrome (PCOS). OBJECTIVE The objective of the study was to test the hypothesis that decidual endovascular trophoblast invasion in pregnant patients with PCOS is impaired and to clarify the potential mechanisms involved. DESIGN This was an experimental case-control study. SETTING The study was conducted at the academic Departments of Obstetrics and Gynecology and the Unit of Pathology (Italy). PATIENTS Forty-five pregnant subjects screened from a wide population of women waiting for legal pregnancy termination were included in the final analysis. Specifically, 15 pregnant patients with PCOS were enrolled as cases and another 30 age- and body mass index (BMI)-matched healthy pregnant women without any feature of PCOS were enrolled as the controls. INTERVENTION Interventions included the collection of trophoblastic and decidual tissue at the 12th week of gestation. MAIN OUTCOME MEASURES Clinical, ultrasonographic, and biochemical data as well as the histological analysis of decidual endovascular trophoblast invasion. RESULTS The rate of implantation site vessels with endovascular trophoblast invasion (ratio between total number of implantation site vessels and total number of vessels with endovascular trophoblast invasion) and the extent of endovascular trophoblast invasion (proportion between immunoreactive areas to cytokeratin 7 and to CD34) were significantly lower in patients with PCOS compared with healthy non-PCOS controls. Endovascular trophoblast invasion data were significantly and indirectly related to the markers of insulin resistance and testosterone concentrations in PCOS patients. CONCLUSIONS Pregnant patients with PCOS patients have impaired decidual trophoblast invasion. Further studies are needed to evaluate the exact mechanisms through which insulin resistance and hyperandrogenemia exert this effect.

Human amniotic fluid-derived and dental pulp-derived stem cells seeded into collagen scaffold repair critical-size bone defects promoting vascularization

IntroductionThe main aim of this study is to evaluate potential human stem cells, such as dental pulp stem cells and amniotic fluid stem cells, combined with collagen scaffold to reconstruct critical-size cranial bone defects in an animal model.MethodsWe performed two symmetric full-thickness cranial defects on each parietal region of rats and we replenished them with collagen scaffolds with or without stem cells already seeded into and addressed towards osteogenic lineage in vitro. After 4 and 8 weeks, cranial tissue samples were taken for histological and immunofluorescence analysis.ResultsWe observed a new bone formation in all of the samples but the most relevant differences in defect correction were shown by stem cell–collagen samples 4 weeks after implant, suggesting a faster regeneration ability of the combined constructs. The presence of human cells in the newly formed bone was confirmed by confocal analysis with an antibody directed to a human mitochondrial protein. Furthermore, human cells were found to be an essential part of new vessel formation in the scaffold.ConclusionThese data confirmed the strong potential of bioengineered constructs of stem cell–collagen scaffold for correcting large cranial defects in an animal model and highlighting the role of stem cells in neovascularization during skeletal defect reconstruction.

Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotropin-stimulated in vitro fertilization cycles: a randomized, controlled trial

OBJECTIVE To test whether metformin administration reduces the incidence of ovarian hyperstimulation syndrome (OHSS) in infertile high-risk patients with polycystic ovary syndrome (PCOS) who have been treated with gonadotropins for IVF. DESIGN Parallel, randomized, double-blind, placebo-controlled clinical trial. SETTING Academic departments, general hospital, and IVF centers. PATIENT(S) One hundred twenty patients with PCOS at high risk for OHSS. INTERVENTION(S) Gonadotropins ovarian stimulation for IVF and metformin (500 mg three times daily) or placebo tablets (three times daily). MAIN OUTCOME MEASURE(S) The primary end point of the current clinical trial was the rate of OHSS. Anthropometric and reproductive data were evaluated. RESULT(S) The total OHSS and cancellation rates were significantly reduced in patients treated with metformin. The relative risk for OHSS was of 0.28 (95% confidence interval, 0.11-0.67). With metformin the stimulation length and the total amount of gonadotropins used were significantly increased, whereas the peak E(2) levels were significantly reduced. CONCLUSION(S) In patients with PCOS who are at high risk for OHSS and who have been stimulated with gonadotropins for IVF cycles, metformin reduces the risk of OHSS by modulating the ovarian response to the stimulation. REGISTRATION ID NUMBER FROM CLINICALTRIALS.GOV: NCT01233206.