Dimitra Kyrou

How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis

OBJECTIVE To systematically review the literature to identify randomized controlled trials, which evaluate interventions aiming to improve the probability of pregnancy in poor responders undergoing in vitro fertilization (IVF). DESIGN Systematic review and meta-analysis. SETTING University-based hospital. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Pregnancy rate. RESULT(S) Twenty-two eligible randomized controlled trials were identified that evaluated in total 15 interventions to increase pregnancy rates in poor responders. Based on limited evidence, the only interventions that appear to increase the probability of pregnancy were the addition of GH to ovarian stimulation (odds ratio for live birth: 5.22, confidence interval: 95% 1.09-24.99) and the performance of embryo transfer on day 2 compared with day 3 (ongoing pregnancy rate: 27.7% vs. 16.3%, respectively; difference: +11.4, 95% confidence interval: +1.6 to +21.0). CONCLUSION(S) Insufficient evidence exists to recommend most of the treatments proposed to improve pregnancy rates in poor responders. Currently, there is some evidence to suggest that addition of GH, as well as performing embryo transfer on day 2 versus day 3, appear to improve the probability of pregnancy.

Elevated progesterone during ovarian stimulation for IVF

There is an ongoing debate regarding the impact of premature progesterone rise on the IVF outcome. The objective of this review is to assess evidence of poorer ongoing pregnancy rate in IVF cycles with elevated serum progesterone at the end of follicular phase in ovarian stimulation. It also explores the origin of the progesterone rise, potential modifying factors and possible methods to prevent its rise during ovarian stimulation. This review draws on information already published from monitoring progesterone concentrations at the end of follicular phase in ovarian stimulation. The databases of Medline and PubMed were searched to identify relevant publications. Good-quality evidence supports the negative impact on endometrial receptivity of elevated progesterone concentrations at the end of the follicular phase in ovarian stimulation. Future trials should document the cause and origin of premature progesterone in stimulated IVF cycles. There is an ongoing debate regarding the impact of premature progesterone rise on the IVF outcome. The objective of this review is to assess evidence of poorer ongoing pregnancy rate in IVF cycles with elevated serum progesterone at the end of follicular phase in ovarian stimulation. It also explores the origin of the progesterone rise, potential modifying factors and possible methods to prevent its rise during ovarian stimulation. This review draws on information already published from monitoring progesterone concentrations at the end of follicular phase in ovarian stimulation. The databases of Medline and PubMed were searched to identify relevant publications. Good-quality evidence supports the negative impact on endometrial receptivity of elevated progesterone concentrations at the end of follicular phase in ovarian stimulation. Future trials should document the cause and origin of premature progesterone in stimulated IVF cycles.

Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin-induced natural cycle.

OBJECTIVE To assess whether there is a difference in the ongoing pregnancy rate after transferring frozen-thawed embryos in natural cycles with spontaneous LH-P rise compared with natural cycles controlled by hCG for final oocyte maturation and ovulation. DESIGN Randomized controlled trial. SETTING Tertiary referral center. PATIENT(S) A total of 168 patients were assigned randomly to undergo frozen ET on day 3 from October 2007 until November 2008. Finally, analysis was performed in 124 patients; 61 belonged to the spontaneous LH group and 63 to the hCG group. INTERVENTION(S) In the spontaneous LH group the transfer was planned 5 days after the LH surge. In the hCG group, the cryopreserve ET was planned 5 days after the administration of 5000 IU of hCG, when an endometrial thickness of ≥7 mm and a follicle of ≥17 mm were present on ultrasound examination. MAIN OUTCOME MEASURE(S) Ongoing pregnancy rate. RESULT(S) The study was terminated early, when a prespecified interim analysis found a significantly higher ongoing pregnancy rate in the spontaneous LH group as compared with the hCG group (31.1% vs. 14.3%; difference 16.9%, 95% confidence interval 4.4%-28.8%). CONCLUSION(S) The results suggest the superiority of the natural cycle as compared with the natural cycle controlled by hCG administration in cryothawed ET cycles.

The relationship of premature progesterone rise with serum estradiol levels and number of follicles in GnRH antagonist/recombinant FSH-stimulated cycles

OBJECTIVE(S) To investigate the relationship between premature progesterone (P) rise and serum estradiol (E(2)) levels and the number of follicles in GnRH antagonist/rec-FSH stimulated cycles. STUDY DESIGN Two hundred and seven patients treated by IVF/ICSI at the Centre for Reproductive Medicine of the Dutch-Speaking Brussels Free University were included in this observational study. They received 200 IU/day rec-FSH from day 2 of the cycle and daily GnRH antagonist starting on day 6 of stimulation. The criteria for hCG administration included the presence of ≥3 follicles of ≥17 mm diameter. Serum P, E(2) and LH were determined on the day of hCG administration. The outcome measure was to identify a threshold of E(2) and number of follicles on the day of hCG administration which would define a progesterone rise on the day of hCG administration (cut-off value of 1.5 ng/ml). RESULT(S) Patients with a P >1.5 ng/ml had significantly higher concentrations of E(2) and increased number of follicles on the day of hCG administration compared to those with P ≤1.5 ng/ml. However, patients with a P >1.5 ng/ml the day of hCG showed lower pregnancy rates than those with P <1.5 ng/ml (17.8 vs. 32.7%, respectively; p<0.05). A ROC curve was employed in order to estimate a cut-off for E(2) on day of hCG >1790.5 pg/ml and more than 9.5 follicles of ≥11 mm in diameter for progesterone rise over 1.5 ng/ml. CONCLUSION(S) A significant impact is shown on progesterone rise by E(2) and number of follicles on the day of hCG administration in GnRH antagonist/rec-FSH-stimulated cycles. With this knowledge, an upcoming progesterone rise during follicular phase can be anticipated and prevented.

The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives

In stimulated IVF/intracytoplasmic sperm injection cycles, the luteal phase is disrupted, necessitating luteal-phase supplementation. The most plausible reason behind this is the ovarian multifollicular development obtained after ovarian stimulation, resulting in supraphysiological steroid concentrations and consecutive inhibition of LH secretion by the pituitary via negative feedback at the level of the hypothalamic-pituitary axis. With the introduction of the gonadotrophin-releasing hormone-(GnRH) antagonist, an alternative to human chorionic gonadotrophin triggering of final oocyte maturation is the use of GnRH agonist (GnRHa) which reduces or even prevents ovarian hyperstimulation syndrome (OHSS). Interestingly, the current regimens of luteal support after HCG triggering are not sufficient to secure the early implanting embryo after GnRHa triggering. This review discusses the luteal-phase insufficiency seen after GnRHa triggering and the various trials that have been performed to assess the most optimal luteal support in relation to GnRHa triggering. Although more research is needed, GnRHa triggering is now an alternative to HCG triggering, combining a significant reduction in OHSS with high ongoing pregnancy rates.

Is earlier administration of human chorionic gonadotropin (hCG) associated with the probability of pregnancy in cycles stimulated with recombinant follicle-stimulating hormone and gonadotropin-releasing hormone (GnRH) antagonists? A prospective randomized trial

OBJECTIVE To evaluate the association of timing of hCG administration and probability of pregnancy in patients stimulated with recombinant FSH/GnRH antagonists for IVF. DESIGN Prospective randomized controlled clinical trial. SETTING Dutch-speaking Free University of Brussels. PATIENT(S) One hundred twenty patients, aged <40 years, treated by IVF or intracytoplasmic sperm injection. INTERVENTION(S) Ovarian stimulation was achieved using recombinant FSH starting on day 2 of the menstrual cycle at a fixed dose. To inhibit premature LH surge, daily GnRH antagonist was used from day 6 of stimulation. Triggering of final oocyte maturation was performed using 10,000 IU of hCG. Patients were randomized to receive hCG either as soon as three or more follicles of size ≥16 mm were present on ultrasonography (early-hCG group) or 1 day after the above criterion was met (late-hCG group). MAIN OUTCOME MEASURE(S) Ongoing pregnancy rate. RESULT(S) Significant differences were observed between the early-hCG and the late-hCG group regarding E(2) (1,388 ± 931 [mean ± SD] vs. 2,040 ± 1,231 pg/mL, respectively) and P (0.8 ± 0.3 vs. 1.1 ± 0.5 ng/mL, respectively) levels on the day of hCG administration and the number of metaphase II oocytes (9.2 ± 7.1 vs. 6.1 ± 4.9, respectively). No significant differences were observed between the early-hCG and the late-hCG group regarding positive hCG (46.2% vs. 50%, respectively) and ongoing pregnancy rates (34.6% vs. 40.7%, respectively). CONCLUSION(S) The current study provides evidence that earlier administration of hCG is not associated with the probability of pregnancy in cycles stimulated with recombinant FSH and GnRH antagonists.

Increased live birth rates with GnRH agonist addition for luteal support in ICSI/IVF cycles: a systematic review and meta-analysis

BACKGROUND The aim of this systematic review and meta-analysis was to evaluate whether the addition of GnRH agonist for luteal support in ICSI/IVF cycles enhances the probability of live birth. METHODS Systematic literature search (MEDLINE, EMBASE, CENTRAL and RCT registries) was conducted to identify relevant randomized controlled trials published as full manuscripts. Meta-analysis of data yielded pooled risk differences (RDs) and 95% confidence intervals (CIs). A random effects model was applied for pooling the studies. RESULTS Six relevant RCTs were identified including a total of 2012 patients. The probability of live birth rate (RD: +16%, 95% CI: +10 to +22%) was significantly higher in patients who received GnRH agonist support compared with those who did not. The subgroup analysis according to the type of GnRH analogue used for LH suppression did not change the effect observed (studies in which GnRH agonist was used during ovarian stimulation, RD: +15%, 95% CI: +5 to +23%); (studies in which GnRH antagonist was used during ovarian stimulation, RD: +19%, 95% CI: +11 to +27%). CONCLUSIONS The best available evidence suggests that GnRH agonist addition during the luteal phase significantly increases the probability of live birth rates.

Is the use of donor sperm associated with a higher incidence of preeclampsia in women who achieve pregnancy after intrauterine insemination

OBJECTIVE To evaluate the incidence of preeclampsia after intrauterine insemination (IUI) with either donors or partners sperm in women with primary infertility. DESIGN Retrospective cohort study. SETTING Tertiary referral center. PATIENTS Between January 1999 and December 2006, 823 women who achieved pregnancy after IUI and delivered at > or =24 weeks of gestation were reviewed. Only women with primary infertility and no known medical disorders were included. On the basis of the available outcome data, the final analysis was performed in 713 pregnancies (438 pregnancies using donors sperm and 275 pregnancies using partners sperm). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The incidence of preeclampsia. RESULT(S) The incidence of preeclampsia in pregnancies resulting from donor sperm was higher than in the partner insemination group: 10.9% (48/438) versus 7.2% (20/275), respectively (difference, 3.7; 95% confidence interval -0.8 to +7.8). Logistic regression was performed controlling for the following parameters: type of sperm, number of previous cycles, and number of babies. In the final model, the variables that significantly predicted the risk of preeclampsia were the type of sperm used for insemination and the number of previous IUI cycles performed. The fewer cycles that were performed, the higher the incidence of preeclampsia that was observed. CONCLUSION(S) IUI with donor sperm appears to increase the incidence of preeclampsia when pregnancy is achieved. A protective effect of multiple cycles appears also to be present in this respect.

High exposure to progesterone between the end of menstruation and the day of triggering final oocyte maturation is associated with a decreased probability of pregnancy in patients treated by in vitro fertilization and intracytoplasmic sperm injection

OBJECTIVE To investigate the association between the probability of pregnancy and hormone exposure between the end of menstruation and the day of triggering final oocyte maturation (menstruation-free interval). DESIGN Prospective study. SETTING University. PATIENT(S) One hundred women (aged ≤ 39 years) stimulated with a fixed dose of recombinant follicle-stimulating hormone (200 IU). INTERVENTION(S) Daily gonadotropin-releasing hormone antagonist (GnRH, 0.25 mg) used from day 6 of stimulation onward, final oocyte maturation triggered by administration of 10,000 IU of human chorionic gonadotropin (hCG) as soon as ≥ 3 follicles ≥ 17 mm were present, and hormone assessment performed at initiation of stimulation, on the first day after menstruation had stopped, on the day of antagonist initiation, and on the day of hCG administration. MAIN OUTCOME MEASURE(S) The association between hormone exposure during the menstruation-free interval and the probability of ongoing pregnancy. RESULT(S) The exposure to progesterone during the menstruation-free interval was statistically significantly higher in patients who did not become pregnant compared with those who did (4.20 ± 2.54 vs. 3.13 ± 1.14, respectively). Binary logistic regression confirmed the adverse effect of the increased exposure to progesterone for the achievement of pregnancy. CONCLUSION(S) In recombinant follicle-stimulating hormone/gonadotropin-releasing hormone antagonist in vitro fertilization/intracytoplasmic sperm injection cycles, a lower probability of pregnancy is associated with a higher exposure to progesterone during the menstruation-free interval.

Does cessation of progesterone supplementation during early pregnancy in patients treated with recFSH/GnRH antagonist affect ongoing pregnancy rates? A randomized controlled trial

BACKGROUND The aim of this study was to assess whether the cessation of progesterone (P) supplementation during early pregnancy after GnRH antagonist cycles is not inferior to its continuation in terms of pregnancy rates beyond 12 weeks of gestation METHODS There were 200 patients, with a positive β-hCG test (followed by a doubling in β-hCG levels 48 h later) after a fixed recombinant FSH (recFSH)/GnRH antagonist protocol for IVF/ICSI and a Day-3 fresh embryo transfer (ET), participated in this randomized controlled study. All patients received luteal support, with 200 mg vaginal P being administered three times daily for 14 days, beginning on the day of ET until the second β-hCG test, 16 days post-ET. In the control group (n = 100) the administration of P was continued until 7 weeks of gestation. In the study group (n = 100), vaginal P was discontinued on the 16th day post-ET RESULTS: The ongoing pregnancy rate beyond 12 weeks, the primary outcome measure, did not differ between the study and control groups (82 versus 73%, P = 0.175; difference 9%, 95% CI: -2.6 to 20.3). There were also no significant differences observed between the study and control group in terms of abortion before or after 7 weeks of gestation [(9 versus 12%, P = 0.645) and (8 versus 10%, P = 0.806), respectively]. The same was true for bleeding episodes (14 versus 19%, P = 0.446). CONCLUSIONS After recFSH/GnRH antagonist cycles, the withdrawal of P supplementation in early pregnancy, with normally increasing β-hCG levels on the 16th day post-ET, had no significant clinical impact in terms of ongoing pregnancy rates beyond 12 weeks.