Salvadora Civico

Assisted Reproductive Technologies Are Associated With Cardiovascular Remodeling In Utero That Persists Postnatally

Background— Assisted reproductive technologies (ARTs) have been shown to be associated with general vascular dysfunction in late childhood. However, it is unknown whether cardiac remodeling is also present and if these changes already manifest in prenatal life. Our aim was to assess fetal and infant (6 months of age) cardiovascular function in ART pregnancies. Methods and Results— This prospective cohort study included 100 fetuses conceived by ART and 100 control pregnancies. ART fetuses showed signs of cardiovascular remodeling, including a more globular heart with thicker myocardial walls, decreased longitudinal function (tricuspid ring displacement in controls: median, 6.5 mm [interquartile range, 6.1–7.1 mm]; tricuspid ring displacement in ART: 5.5 mm [interquartile range, 5.1–6.1]; P<0.001), impaired relaxation, and dilated atria (atrial area in controls, 1.46 cm2 [interquartile range, 1.2–1.5 cm2]; atrial area in ART, 1.6 cm2 [interquartile range, 1.3–1.8 cm2]; P<0.001). Additionally, ART infants showed persistence of most cardiac changes and a significant increase in blood pressure and aortic intima-media thickness (systolic blood pressure in controls, 74 mm Hg [interquartile range, 67–83 mm Hg]; systolic blood pressure in ART, 83 mm Hg [interquartile range, 75–94 mm Hg]; P<0.001; aortic intima-media thickness in controls, 0.52 mm [interquartile range, 0.45–0.56 mm]; aortic intima-media thickness in ART, 0.64 mm [interquartile range, 0.62–0.67]; P<0.001). We could not demonstrate that our findings were directly caused by ART because of their association with various confounding factors, including intrauterine growth restriction or factors related to the cause of infertility. Conclusions— Children conceived by ART manifest cardiac and vascular remodeling that is present in fetal life and persists in postnatal life, suggesting opportunities for early detection and potential intervention. The underlying mechanisms and the effect of potential confounders such as growth restriction or prematurity remain to be elucidated.

The effect of exogenous luteinizing hormone (LH) on oocyte viability: evidence from a comparative study using recombinant human follicle-stimulating hormone (FSH) alone or in combination with recombinant LH for ovarian stimulation in pituitary-suppressed women undergoing assisted reproduction.

Purpose: The purpose of this prospective, randomized study was to compare ovarian response and oocyte and embryo yields in women undergoing ovulation induction for IVF/ICSI using recombinant human FSH (rhFSH) alone or in combination with recombinant human LH (rhLH).Methods: Patients were randomized to receive rhFSH alone (group F; n = 13) or rhFSH + rhLH (group L; n = 15). rhFSH was administered according to a step-down protocol; patients assigned to group L received rhLH at a fixed dose of 75 IU (1 ampoule) throughout the treatment period.Results: The total dose of rhFSH, number of growing follicles, and serum concentrations of estradiol (E2) on the day of hCG administration were similar in both treatment groups. However, the percentage of metaphase II oocytes and fertilization rate were significantly higher in group F than in group L. The lower fertilization rates associated with rhLH were also seen in a subgroup of patients from group L who had undergone a previous ART cycle stimulated with FSH only and thus acted as their own controls. However, when in vitro fertilization (IVF) and intracytoplasmic sperm injection cycles were considered separately, differences in fertilization rates were statistically significant only for oocytes treated by conventional IVF.Conclusions: This study shows that the addition of recombinant LH to recombinant FSH in pituitary-suppressed women undergoing ART does not improve the ovarian response and even may have a negative impact on oocyte maturation and fertilization.

The comparison of two gonadotropin-releasing hormone agonists in an in vitro fertilization program

OBJECTIVE To compare two gonadotropin-releasing hormone agonists (GnRH-a), buserelin acetate and leuprolide acetate [LA], used in combination with gonadotropins in ovarian stimulation for in vitro fertilization (IVF). DESIGN Randomized prospective study. SETTING Assisted Reproduction Unit of the Hospital Clínic i Provincial in Barcelona. PATIENTS Thirty-five pairs of IVF patients who were matched on age, indication, and number of attempts. These women were randomized to receive either buserelin acetate plus gonadotropins (group B) or LA plus gonadotropins (group L). MAIN OUTCOME MEASURES Luteolysis, ovarian response, and IVF outcome. RESULTS The mean time for total ovarian arrest and the total dose of gonadotropins and estradiol levels on the day of human chorionic gonadotropin administration were similar in the two groups of patients. The number of follicles punctured, the number of oocytes retrieved, and the percentage of mature oocytes in group L were significantly higher. The number of embryos suitable for replacement and cryopreservation was higher in group L compared with group B approaching statistical significance. CONCLUSION Our results warrant further studies to compare different GnRH-a as therapeutic tools in IVF.

Long-term down-regulation does not improve pregnancy rates in an in vitro fertilization program

OBJECTIVE To investigate the effects of long-term down-regulation (4 months) used in combination with gonadotropin ovarian stimulation for IVF-ET. DESIGN Prospective randomized study. SETTING Assisted Reproduction Unit of the Hospital Clinic i Provincial in Barcelona, a tertiary care setting. PATIENT(S) Thirty pairs of IVF patients who were matched for age, indication for IVF, and number of attempts. INTERVENTION(S) Women were randomized to receive a standard long protocol of SC leuprolide acetate (n = 30, group L) or a monthly injection of leuprolide acetate depot for 4 months (n = 30, group D) before gonadotropin stimulation. MAIN OUTCOME MEASURE(S) Ovarian response and IVF outcome. RESULT(S) Days of ovarian stimulation, follicular recruitment and growth during gonadotropin treatment, and the endometrial thickness on the day of hCG administration were similar for the 2 groups of IVF patients. However, the serum concentration of E2 was significantly higher in group L even though group D received a higher total dose of gonadotropins. The number of follicles punctured, the number of oocytes retrieved, the number of oocytes fertilized, the number of embryos suitable for replacement and cryopreservation, the number of patients with ET, and implantation and clinical pregnancy rates were similar for groups L and D. However, the percentage of metaphase II oocytes was significantly higher in group L than in group D. CONCLUSION(S) Long-term down-regulation does not improve pregnancy rates in a general IVF program.

Early Hormonal Markers of Pregnancy Outcome After In Vitro Fertilization and Embryo Transfer

AbstractPurpose: To investigate the relative power of HCG, estradiol, and progesterone determinations in the prediction of pregnancy outcome after IVF. These prognostic hormonal factors were studied as single and combined predictors. Methods: Serum concentrations of β-HCG, progesterone, and estradiol were measured 12–13 days after embryo transfer (study point 1) and 7 days later (study point 2) in a series of 20 consecutive infertile patients having a first-trimester spontaneous clinical abortion after an IVF-embryo transfer cycle. As a control group (n=60), the next three IVF-embryo transfer cycles resulting in an ongoing pregnancy after each miscarried IVF cycle in our assisted reproduction program was used. The discrimination attained between the two study groups (ongoing pregnancies and miscarriages) was evaluated by logistic regression and receiver operating characteristic (ROC) curve analysis. Results: Mean hormone concentrations at study points 1 and 2 were higher in the ongoing pregnancy than in the abortion group. Regarding pregnancy outcome the percentage increment of HCG serum levels (≥1321%), with an accuracy (predictive value of pregnancy outcome) of 81.2% (sensitivity 98%, specificity 50%), had the best prognostic reliability but no significant differences were found when this parameter was compared with the predictive value of HCG concentration (≥72 IU/l) at study point 1 (diagnostic accuracy 80.5%; sensitivity 70%; specificity 80%). When ROC analysis was used, the best predictor of ongoing pregnancy according to the AUCROC was HCG concentration at study point 2 but again no significant differences were found when this parameter was compared with the predictive value of HCG serum levels at study point 1. A multiple marker strategy did not help distinguish viable from nonviable pregnancies. Conclusion: A single, early (days 12–13 after embryo transfer) HCG quantitative serum measurement in IVF cycles not only is diagnostic but also has good predictive value for pregnancy outcome.

Reduced plasma fibrinolytic potential in patients with recurrent implantation failure after IVF and embryo transfer

BACKGROUND Recurrent implantation failure (RIF) following embryo transfer (ET) is a major continuing problem in IVF. Women with haemostatic defects may be at increased risk of miscarriage and preclinical pregnancy loss. The fibrinolytic system is considered, at present, the key to new thrombotic pathogenic mechanisms. Patients with unexplained recurrent miscarriage have an impairment of fibrinolysis, as demonstrated by prolonged clot lysis time (CLT) in association with increased plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI). In this study, we investigated fibrinolytic potential in patients with RIF. METHODS Three groups of patients were studied: 30 women with RIF (RIF group), 60 patients undergoing a first successful IVF-ET cycle (IVF group) and 60 healthy fertile women (FER group). Plasma CLT was measured using a global fibrinolysis assay. TAFI antigen plasma levels and polymorphisms in the TAFI gene (+505A/G and +1542C/G) were analysed using enzyme-linked immunosorbent assay and allele-specific PCR, respectively. RESULTS CLT was significantly longer (P < 0.0001 and P < 0.0009, respectively) and TAFI antigen levels were significantly higher (both P < 0.0001) in the RIF versus the IVF and FER groups. A direct relationship between CLT and TAFI antigen levels (r = 0.40; P = 0.001) was detected in the whole study population. There were no differences in distribution of TAFI polymorphisms between groups. CONCLUSIONS Patients with RIF have reduced plasma fibrinolytic potential, as shown by a prolonged CLT, and this may be explained, at least in part, by increased TAFI antigen levels.

THE ROLE OF LUTEINIZING HORMONE IN HUMAN FOLLICLE DEVELOPMENT AND OOCYTE FERTILITY : EVIDENCE FROM IN VITRO FERTILIZATION IN A WOMAN WITH LONG-STANDIN G HYPOGONADOTROPIC HYPOGONADISM AND USING RECOMBINANT HUMAN FOLLICLE-STIMUL ATING HORMONE

To evaluate the relative importance of follicle stimulating hormone (FSH) and luteinizing hormone (LH) in follicular development and oocyte fertility in the human species, the use of recombinant human FSH, human menopausal gonadotrophin (HMG), and very highly purified urinary human FSH (FSH-HP) plus oestradiol valerate for ovarian stimulation and in-vitro fertilization (IVF) were compared in three cycles in a woman with isolated congenital gonadotrophin deficiency who had never been treated with ovarian stimulating agents. The total number of ampoules of gonadotrophins used was lower in the HMG treatment cycle. Ovarian response and IVF outcome in the three treatment cycles were as follows: (i) HMG cycle: normal follicular growth, normal pattern of oestradiol and inhibin through the menstrual cycle, high fertilization rate (93%); (ii) recombinant FSH cycle: normal follicular growth, low oestradiol and abnormal inhibin, finally poor rate of fertilization (28%); (iii) FSH-HP plus oestradiol valerate cycle: normal follicular growth, normal pattern of inhibin and poor fertilization rate (27%). Luteal plasma progesterone concentrations were much higher in the HMG treatment cycle. This case shows that FSH is the only factor required in order to induce follicular growth in the human, although LH or a product derived from its action may assist in order to achieve full follicular maturity and oocytes capable of fertilization. Though oestradiol might have a mediatory role in the process of follicular maturation, our results favour a direct primary role of LH in complete maturation of the follicle.

Materno-fetal Immunogenetic Disparity: The Biological Basis for In vitro Fertilization Treatment in Patients with Unexplained Recurrent Abortion?

Problem: The majority of women with recurrent miscarriage have no discernible cause but it has been postulated that immunologic aberrations may be the cause in most of such cases. Also, it has been stressed that deliberate modification of the maternal host defense system can improve the chances of success. We tested the hypothesis that it is possible to potentiate maternal immune functions so as to improve reproductive performance by replacing several embryos into the uterus, thus favoring the recognition of fetal antigens.

Increased circulating cell-derived microparticle count is associated with recurrent implantation failure after IVF and embryo transfer

Cell-derived microparticles (cMPs) are small membrane vesicles that are released from many different cell types in response to cellular activation or apoptosis. Elevated cMP counts have been found in almost all thrombotic diseases and pregnancy wastage, such as recurrent spontaneous abortion and in a number of conditions associated with inflammation, cellular activation and angiogenesis. cMP count was investigated in patients experiencing unexplained recurrent implantation failure (RIF). The study group was composed of 30 women diagnosed with RIF (RIF group). The first control group (IVF group) (n = 30) comprised patients undergoing a first successful IVF cycle. The second control group (FER group) included 30 healthy women who had at least one child born at term and no history of infertility or obstetric complications. cMP count was significantly higher in the RIF group compared with the IVF and FER groups (P < 0.05 and P < 0.01, respectively) (RIF group: 15.8 ± 6.2 nM phosphatidylserine equivalent [PS eq]; IVF group: 10.9 ± 5.3 nM PS eq; FER group: 9.6 ± 4.0 nM PS eq). No statistical difference was found in cMP count between the IVF and FER groups. Increased cMP count is, therefore, associated with RIF after IVF and embryo transfer.

Increased messenger ribonucleic acid expression of the cyclin-dependent kinase inhibitor p27Kip1 in cleavage-stage human embryos exhibiting developmental arrest

OBJECTIVE To quantify p27 messenger RNA (mRNA) levels in human arrested and normally developing embryos and nonfertilized oocytes to determine whether the p27 protein abundance, reported in cleavage-stage embryos exhibiting developmental arrest, is regulated at the mRNA expression level. DESIGN Real-time reverse transcription quantitative polymerase chain reaction was used to quantify the expression of p27 in three samples: arrested embryos (group A, n = 29), normally developing embryos (group D, n = 34), and nonfertilized oocytes (group O, n = 20). SETTING Research laboratory working closely with a clinical IVF practice. PATIENT(S) Oocytes and embryos were obtained from patients undergoing assisted fertilization. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Quantification of mRNA transcripts. RESULT(S) The amount of p27 mRNA was statistically significantly higher in group A (mean +/- SEM, 86,143 +/- 42,496 relative units [RU]) compared with groups D (10,680 +/- 3,850 RU) and O (3,555 +/- 1,458 RU). Furthermore, in a group of 13 two- to four-cell arrested embryos, high levels of p27 mRNA (51,481 +/- 31,120 RU) were found in comparison with the nonfertilized oocyte group (3,555 +/- 1,458 RU). CONCLUSION(S) Cleavage-stage human embryos exhibiting developmental arrest show increased p27 mRNA expression. This probably is due to increased transcriptional activity.