Risks and complications associated with ovarian stimulation for fertility treatment

Almost all fertility treatment involves ovarian stimulation. This can be in the form of ovulation induction in women with anovulation or controlled ovarian stimulation for in vitro fertilisation treatment. The stepwise approach to fertility treatment in most cases it will be safe and successful. In certain cases, it might be however ineffective or related with adverse health outcomes for the woman causing significant distress for the couple and the treating clinicians. Fertility treatment could be perceived as a paradox, as healthy women undergo treatment ‘willingly’, with often no cause identified of their failed conceptions. Exposure to assisted reproduction can therefore result in these healthy women being admitted to hospital suffering from complications of fertility treatment. In this thesis of the genetic make-up of women, who had ovulation induction with or without success, is evaluated. Aiming for potential prediction of response for future patients. In order to gain more insight in the pathophysiology of ovarian overresponse, the ovarian renin angiotensin system was assessed during stimulation for IVF. The use of a dopamine agonist to alleviate or prevent OHSS was studied. And any assisted reproductive treatment adverse outcome rates after a salpingectomy prior to treatment were investigated. The studies presented in this thesis utilized various research modalities, including systematic literature reviews, three-dimensional ultrasound, single nucleotide polymorphism analysis and polymerase chain reactions. When OHSS develops dopamine agonists provide limited symptomatic relieve, but causes no harm. Salpingectomy prior to ovarian stimulation with potential harm to the ovarian blood supply does not influence the overall treatment outcome. Serum renin levels during ovarian stimulation might be able to differentiate which women become symptomatic of OHSS, but is a difficult test to implement in daily practice. For ovulation induction the use of genotyping of CYP450 might allow adjusting the dose needed to prevent unwanted response. We need to remain critical of our practise. Registration and evaluation of complications will allow achievement of safer and better fertility treatment in the future. The overall conclusion is that the next trial should focus on the patient group found to be at risk of overresponse and randomise them to an antagonist protocol with agonist trigger and modified luteal support. Controlled ovarian stimulation should be in conjunction with a national complication registration to have a real picture of the risks associated with fertility treatment

O comportamento "borderline" e as noções espaço-temporais e causais : um estudo de caso

30

Efficacy of dehydroepiandrosterone (DHEA) to overcome the effect of ovarian ageing (DITTO): a proof of principle double blinded randomized placebo controlled trial

Objective: To evaluate the effect of DHEA supplementation on In-Vitro Fertilisation (IVF) outcome as assessed by ovarian response, oocyte developmental competence and live birth rates in women predicted to have poor ovarian reserve (OR). The feasibility of conducting a large trial is also assessed by evaluating the recruitment rates and compliance of the recruited participants with DHEA/placebo intake and follow-up rates. Study design: A single centre, double blinded, placebo controlled, randomized trial was performed over two years with 60 women undergoing in-vitro fertilisation (IVF). Subjects were randomized, based on a computer-generated pseudo-random code to receive either DHEA or placebo with both capsules having similar colour, size and appearance. 60 women with poor OR based on antral follicle count or anti-Mullerian hormone thresholds undergoing IVF were recruited. They were randomised to receive DHEA 75 mg/day or placebo for at-least 12 weeks before starting ovarian stimulation. They had long protocol using hMG 300 IU/day. Data analysed by “intention to treat”. Ovarian response, live birth rates and molecular markers of oocyte quality were compared between the study and control groups. Results: The recruitment rate was 39% (60/154). A total of 52 participants (27 versus 25 in the study and placebo groups) were included in the final analysis after excluding eight. While the mean (standard deviation) DHEA levels were similar at recruitment (9.4 (5) versus 7.5 (2.4) ng/ml; P = 0.1), the DHEA levels at pre-stimulation were higher in the study group than in the controls (16.3 (5.8) versus 11.1 (4.5) ng/ml; P < 0.01). The number (median, range) of oocytes retrieved (4, 0–18 versus 4, 0–15 respectively; P = 0.54) and live birth rates (7/27, 26% versus 8/25, 32% respectively; RR (95% CI): 0.74 (0.22-2.48) and mRNA expression of developmental biomarkers in granulosa and cumulus cells were similar between the groups. Conclusion: Pre-treatment DHEA supplementation, albeit statistical power in this study is low, did not improve the response to controlled ovarian hyperstimulation or oocyte quality or live birth rates during IVF treatment with long protocol in women predicted to have poor OR

Deregulation of the endometrial stromal cell secretome precedes embryo implantation failure

STUDY QUESTION Is implantation failure following ART associated with a perturbed decidual response in endometrial stromal cells (EnSCs)? SUMMARY ANSWER Dynamic changes in the secretome of decidualizing EnSCs underpin the transition of a hostile to a supportive endometrial microenvironment for embryo implantation; perturbation in this transitional pathway prior to ART is associated with implantation failure. WHAT IS KNOWN ALREADY Implantation is the rate-limiting step in ART, although the contribution of an aberrant endometrial microenvironment in IVF failure remains ill defined. STUDY DESIGN, SIZE, DURATION In vitro characterization of the temporal changes in the decidual response of primary EnSCs isolated prior to a successful or failed ART cycle. An analysis of embryo responses to secreted cues from undifferentiated and decidualizing EnSCs was performed. The primary clinical outcome of the study was a positive urinary pregnancy test 14 days after embryo transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS Primary EnSCs were isolated from endometrial biopsies obtained prior to IVF treatment and cryopreserved. EnSCs from 10 pregnant and 10 non-pregnant patients were then thawed, expanded in culture, subjected to clonogenic assays, and decidualized for either 2 or 8 days. Transcript levels of decidual marker gene [prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP1) and 11β-hydroxysteroid dehydrogenase (HSD11B1)] were analysed using real-time quantitative PCR and temporal secretome changes of 45 cytokines, chemokines and growth factors were measured by multiplex suspension bead immunoassay. The impact of the EnSC secretome on human blastocyst development was scored morphologically; and embryo secretions in response to EnSC cues analyzed by multiplex suspension bead immunoassay. MAIN RESULTS AND THE ROLE OF CHANCE Clonogenicity and induction of decidual marker genes were comparable between EnSC cultures from pregnant and non-pregnant group groups (P > 0.05). Analysis of 23 secreted factors revealed that successful implantation was associated with co-ordinated secretome changes in decidualizing EnSCs, which were most pronounced on Day 2 of differentiation: 17 differentially secreted proteins on Day 2 of decidualization relative to undifferentiated (Day 0) EnSCs (P 0.05)

Risks and complications associated with ovarian stimulation for fertility treatment

Almost all fertility treatment involves ovarian stimulation. This can be in the form of ovulation induction in women with anovulation or controlled ovarian stimulation for in vitro fertilisation treatment. The stepwise approach to fertility treatment in most cases it will be safe and successful. In certain cases, it might be however ineffective or related with adverse health outcomes for the woman causing significant distress for the couple and the treating clinicians. Fertility treatment could be perceived as a paradox, as healthy women undergo treatment ‘willingly’, with often no cause identified of their failed conceptions. Exposure to assisted reproduction can therefore result in these healthy women being admitted to hospital suffering from complications of fertility treatment. In this thesis of the genetic make-up of women, who had ovulation induction with or without success, is evaluated. Aiming for potential prediction of response for future patients. In order to gain more insight in the pathophysiology of ovarian overresponse, the ovarian renin angiotensin system was assessed during stimulation for IVF. The use of a dopamine agonist to alleviate or prevent OHSS was studied. And any assisted reproductive treatment adverse outcome rates after a salpingectomy prior to treatment were investigated. The studies presented in this thesis utilized various research modalities, including systematic literature reviews, three-dimensional ultrasound, single nucleotide polymorphism analysis and polymerase chain reactions. When OHSS develops dopamine agonists provide limited symptomatic relieve, but causes no harm. Salpingectomy prior to ovarian stimulation with potential harm to the ovarian blood supply does not influence the overall treatment outcome. Serum renin levels during ovarian stimulation might be able to differentiate which women become symptomatic of OHSS, but is a difficult test to implement in daily practice. For ovulation induction the use of genotyping of CYP450 might allow adjusting the dose needed to prevent unwanted response. We need to remain critical of our practise. Registration and evaluation of complications will allow achievement of safer and better fertility treatment in the future. The overall conclusion is that the next trial should focus on the patient group found to be at risk of overresponse and randomise them to an antagonist protocol with agonist trigger and modified luteal support. Controlled ovarian stimulation should be in conjunction with a national complication registration to have a real picture of the risks associated with fertility treatment

Patologias limites na infância : prós e contras para um diagnóstico precoce

20

Acesso ao mundo simbólico : e as crianças que não sabem o que é uma história?

27

Acesso ao mundo simbólico : e as crianças que não sabem o que é uma história?

27