Salim Daya

The routine use of gonadotropin-releasing hormone agonists prior to in vitro fertilization and gamete intrafallopian transfer: a meta-analysis of randomized controlled trials*

OBJECTIVE To assess the efficacy of gonadotropin-releasing hormone agonists (GnRH-a) used in ovulation induction for in vitro fertilization and embryo transfer (IVF-ET) and gamete intrafallopian transfer (GIFT). DESIGN Meta-analysis of 10 trials comparing treatment cycle outcomes after GnRH-a (n = 914) with other ovulation induction protocols (n = 722) and 7 trials comparing outcomes after short flare-up (n = 368) with longer suppression (n = 476) GnRH-a protocols. MAIN OUTCOME MEASURES The outcome of primary interest was clinical pregnancy rate (PR) per treatment cycle commenced. Data describing the amount of gonadotropin used, cycle cancellation rate, clinical pregnancy per ET, and multiple pregnancy and abortion rates were also analyzed. RESULTS Clinical PR per cycle commenced was significantly improved after GnRH-a use for IVF (common odds ratio [OR] 1.80, 95% confidence interval [CI] 1.33 to 2.44) and GIFT (common OR 2.37, 95% CI 1.24 to 4.51). Clinical PR per embryo transfer was also significantly improved with GnRH-a use (common OR 1.40, 95% CI 1.01 to 1.95). Cycle cancellation was decreased (common OR 0.33, 95% CI 0.25 to 0.44), whereas spontaneous abortion rate was similar with and without GnRH-a use. Cycle cancellation and PRs after short flare-up and longer suppression protocols were similar between groups. CONCLUSIONS This meta-analysis supports the routine use of GnRH-a for IVF and GIFT. Further research is needed, however, to assess the potential for increased rates of multiple pregnancy and ovarian hyperstimulation syndrome, which may be associated with this treatment.

Assisted reproductive technologies (ART) in Canada: 2003 results from the Canadian ART Register

OBJECTIVE To present a report on assisted reproductive technologies (ART) cycles performed in 2007 in Canada and show trends in outcomes over time. This is the seventh annual report from the Canadian ART Register (CARTR). DESIGN Prospective cohort study. SETTING Twenty-six of 26 ART centers in Canada. PATIENT(S) Couples undergoing ART treatment in Canada during 2007. INTERVENTION(S) ART treatments, including in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and frozen embryo transfer (FET). MAIN OUTCOME MEASURE(S) Clinical pregnancy, live-birth, and multiple-birth rates. RESULT(S) A total of 13,482 ART cycles was reported to CARTR. In 8,972 IVF/ICSI cycles using the womans own oocytes, per cycle started, the clinical pregnancy rate was 35.6% (41.0% per ET), and the live-birth rate was 28.6%; the multiple-birth rate per delivery was 30.2%, with a high-order multiple-birth rate of 1.1%. In 68% of cycles ICSI was performed. One or two embryos were transferred in 69% of cycles. In 404 IVF/ICSI cycles using donor oocytes, the clinical pregnancy rate was 44.6%, and the live-birth rate was 36.1%; the multiple-birth rate was 26.5%, with no triplet birth. In 3,224 FET cycles using the womans own oocytes, the clinical pregnancy rate was 23.7%, and the live-birth rate was 17.8%; the multiple-birth rate was 24.1%, with a triplet birth rate of 0.2%. Birth outcomes were unknown for 2.0% of ongoing pregnancies. CONCLUSION(S) For 2007, CARTR achieved 100% voluntary participation from Canadian ART centers for the fifth consecutive year. Clinical pregnancy and live-birth rates continued to increase in 2007 compared with previous years, with a decrease in high-order multiple births.

Follicle-stimulating hormone versus human menopausal gonadotropin for in vitro fertilization cycles: a meta-analysis

OBJECTIVE To conduct a systematic overview of available data comparing FSH with hMG in IVF treatment cycles. DESIGN A meta-analysis of randomized trials of FSH versus hMG use in ovarian stimulation protocols, with or without GnRH agonists, in IVF treatment cycles. Search strategies included on-line searching of the National Library of Medicine MEDLINE data base from 1975 to 1993 and hand searching of bibliographies of relevant publications and reviews and abstracts of scientific meetings. Common odds ratio (OR) and overall absolute treatment effect were calculated after demonstrating homogeneity of treatment effect across all trials. MAIN OUTCOME MEASURES Clinical pregnancy rates per cycle start, per cycle reaching oocyte retrieval, and per cycle reaching ET. RESULTS Eight trials met the inclusion criteria. The overall OR in favor of FSH for cycle start, oocyte retrieval, and ET were 1.71, 1.69 and 1.70, respectively, and represented an overall absolute treatment effect of 8.5%, 8.0% and 8.3%, respectively. CONCLUSIONS This meta-analysis demonstrates that in IVF cycles the use of FSH is associated with a significantly higher clinical pregnancy rate than hMG.

Elevated concentration and biologic activity of monocyte chemotactic protein-1 in the peritoneal fluid of patients with endometriosis * † ‡

OBJECTIVE To estimate the concentration and the biologic activity of monocyte chemotactic protein-1 (MCP-1) in the peritoneal fluid (PF) of women with and without endometriosis. DESIGN A case control study was conducted. SETTING Gynecology clinic and Laboratories of endocrinology of reproduction and immunology. PATIENTS Women presenting for infertility, pelvic pain, or tubal ligation in which endometriosis was diagnosed at laparoscopy (n = 36) and normal fertile controls presenting for tubal ligation (n = 21). INTERVENTIONS Collection of PF via laparoscopy. MAIN OUTCOME MEASURES Determination of PF concentrations of MCP-1 by an ELISA and evaluation of its monocyte chemotactic activity using a human hystiocytic cell line (U937). RESULTS. The concentration of MCP-1 (median, range of values) was increased in the PF of endometriosis patients (283, 0 to 1,930 pg/mL; conversion factor to SI unit, 0.155) compared with the control group (140, 0 to 435 pg/mL). The most significant elevation of MCP-1 levels was found in the stage II of the disease (371, 200 to 1,930 pg/mL). An increased chemotactic activity for monocytes (mean number of migrating cells/mm2 +/- SD) also was found in stages I (1,460 +/- 312) and II (1,541 +/- 336) of the disease when compared with fertile controls (393 +/- 56). Forty percent to 53% of this activity was inhibited in the presence of an antibody specific to MCP-1. CONCLUSIONS These observations are consistent with previous data indicating increased leukocyte chemotaxis in the PF of patients with endometriosis and suggest that MCP-1 may play a relevant role in the peritoneal inflammatory reaction associated with the disease.

Empirical evidence of bias in infertility research: overestimation of treatment effect in crossover trials using pregnancy as the outcome measure

OBJECTIVE To determine whether crossover trials with simple pooling of data over different study periods leads to a different estimate of treatment effect compared with parallel group trials in infertility research using pregnancy as the outcome measure. DESIGN An observational study using nine overviews that included trials with both crossover and parallel group designs. These overviews comprised 17 crossover and 17 parallel group trials. In total, there were 5,291 outcomes including 775 pregnancies. The association between study design and treatment effect estimate was analyzed using multiple logistic regression, controlling for differences in the therapeutic interventions and variations in the methodological quality of the trials. SETTING Infertile patients in an academic research environment. PATIENTS Infertile patients undergoing treatment efficacy evaluation in controlled trials. INTERVENTIONS Random allocation to a variety of treatments including clomiphene citrate, hCG, IUI, tamoxifen, and bromocriptine. MAIN OUTCOME MEASURE Estimate of bias between study designs, based on the interaction of study design and treatment in the logistic regression model. RESULTS Crossover trials produced a larger average estimate of treatment effect compared with trials with a parallel group design, overestimating the odds ratio by 74% (95% confidence interval, 2% to 197%). CONCLUSION The use of a crossover design for evaluating infertility treatments with outcomes that prevent patients from completing later phases of the trial should be avoided because it leads to exaggerated estimates of treatment effect and may result in erroneous inferences and clinical decisions. Furthermore, the type of study design should be taken into account when assessing the methodological quality of therapy trials in infertility.

Updated meta-analysis of recombinant follicle-stimulating hormone (FSH) versus urinary FSH for ovarian stimulation in assisted reproduction

OBJECTIVE To determine the relative efficacy of recombinant FSH (rFSH) and urinary FSH (uFSH) for ovarian stimulation in assisted reproductive techniques (ART). DESIGN Systematic review and meta-analysis of randomized, controlled trials comparing rFSH and uFSH. SETTING Infertility centers providing treatment with ART. PATIENT(S) Patients undergoing IVF with or without ICSI. INTERVENTION(S) Controlled ovarian stimulation using uFSH or rFSH (follitropin alpha or follitropin beta). MAIN OUTCOME MEASURE(S) Primary: rate of clinical pregnancy per cycle. Secondary: rates of spontaneous abortion, multiple pregnancy, and severe ovarian hyperstimulation syndrome (OHSS); total gonadotropin dose; serum E(2) level and number of follicles at hCG administration; number of oocytes retrieved. RESULT(S) Eighteen trials were included in the meta-analysis. Subgroup analyses demonstrated higher pregnancy rates with both follitropins compared with uFSH. However, statistical significance was reached only in the follitropin alpha versus uFSH comparison in IVF cycles, with an additional pregnancy for every 19 patients treated. Fewer units of rFSH than uFSH achieved the same E(2) level and oocyte yield. No differences were found between treatments in rates of spontaneous abortion, OHSS, and multiple gestation. CONCLUSION(S) rFSH produced higher pregnancy rates per cycle than uFSH when follitropin alpha was used in IVF, and the total gonadotropin dose required was lower.

Accuracy of gestational age estimation by means of fetal crown-rump length measurement.

OBJECTIVE The purpose of this study was to develop a gestational age table by means of crown-rump length measurements in the first trimester in pregnancies conceived through in vitro fertilization. STUDY DESIGN Ninety-four infertile women with singleton intrauterine pregnancies resulting from in vitro fertilization underwent ultrasonographic examinations in the first trimester. The relationship between gestational age (calculated with the day of oocyte retrieval used as day 14) and the crown-rump length was explored with regression analysis. RESULTS A quadratic model demonstrated the best fit to the data, indicating a curvilinear relationship between crown-rump length and gestational age. Estimates of gestational age with crown-rump length measurements between 40 and 60 mm were observed to be similar to published tables, but outside this range the tables either overestimate or underestimate the true gestational age. CONCLUSION A more accurate equation for gestational age estimation with crown-rump length measurements in early pregnancy has been developed with in vitro fertilization pregnancy data.

Preliminary characterization of two types of suppressor cells in the human uterus

Survival of the mammalian fetus in an immunologically hostile host has been shown to be determined by the properties of the tissue at the maternal-fetal interface. Suppressor cells have been found in the decidua in both murine and human systems. This study was carried out to further characterize these cells and to determine whether they were present in abnormal early pregnancies and in the endometrium at the time of implantation. Suppressor cells appear in the endometrium after ovulation, and their activity is present in the decidua of successful pregnancies but is absent in missed abortions. Two types of cells have been identified. An early phase large cell appears to be hormone dependent, and later phase small cell appears to be trophoblast dependent. This would suggest that suppressor cells may play a role in protecting the fetal allograft, from the time of implantation, against maternal immunity, thereby allowing a pregnancy to succeed.

The Effectiveness of Allogeneic Leukocyte Immunization in Unexplained Primary Recurrent Spontaneous Abortion

PROBLEM: Unexplained primary recurrent spontaneous abortion (RSA) can be viewed as a partner‐specific problem for which immunization with allogeneic leukocytes is being offered as therapy. Published data from randomized controlled trials have produced conflicting results regarding treatment effectiveness. The aim of this study was to perform a subgroup analysis of the data from a recent worldwide collaborative meta‐analysis using the raw data for patients with primary RSA entered into randomized controlled trials of immunotherapy.

A subset of patients with recurrent spontaneous abortion is deficient in transforming growth factor β-2-producing suppressor cells in uterine tissue near the placental attachment site

PROBLEM: To determine if patients with unexplained recurrent miscarriage have a deficiency of decidual immunosuppressor cells that produce transforming growth factor β type 2, as has been found in mice with abortion due to rejection and/or trophoblast failure.