FSH replaced by low-dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques
ABSTRACT During controlled ovarian hyperstimulation (COH) follicle-stimulating hormone (FSH) is frequently used for several days to achieve follicular development. FSH is a relatively expensive drug, substantially contributing to the total expenses of assisted reproductive techniques (ART). When follicles achieve a diameter greater than 10 mm they start expressing luteinising hormone (LH) receptors. At this point, FSH might be replaced by low-dose human chorionic gonadotropin (hCG), which is less expensive. In addition to cost reduction, replacing FSH by low-dose hCG has a theoretical potential to reduce the incidence of ovarian hyperstimulation syndrome (OHSS).
To evaluate the effectiveness and safety of using low-dose hCG to replace FSH during the late follicular phase in women undergoing COH for assisted reproduction, compared to the use of a conventional COH protocol.
We searched for randomised controlled trials (RCT) in electronic databases (Menstrual Disorders and Subfertility Group Specialized Register, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), trials registers (ClinicalTrials.gov, Current Controlled Trials, World Health Organization International Clinical Trials Registry Platform), conference abstracts (ISI Web of knowledge), and grey literature (OpenGrey); additionally we handsearched the reference list of included studies and similar reviews. The last electronic search was performed in February 2013..
Only true RCTs comparing the replacement of FSH by low-dose hCG during late follicular phase of COH were considered eligible; quasi or pseudo-randomised trials were not included. Cross-over trials would be included only if data regarding the first treatment of each participant were available; trials that included the same participant more than once would be included only if each participant was always allocated to the same intervention and follow-up periods were the same in both/all arms, or if data regarding the first treatment of each participant were available. We excluded trials that sustained FSH after starting low-dose hCG and those that started FSH and low-dose hCG at the same time.
Study eligibility, data extraction, and assessment of the risk of bias were performed independently by two review authors, and disagreements were solved by consulting a third review author. We corresponded with study investigators in order to solve any query, as required. The overall quality of the evidence was assessed in a GRADE summary of findings table.
The search retrieved 1585 records; from those five studies were eligible, including 351 women (intervention = 166; control = 185). All studies were judged to be at high risk of bias. All reported per-woman rather than per-cycle data.When use of low-dose hCG to replace FSH was compared with conventional COH for the outcome of live birth, confidence intervals were very wide and findings were compatible with appreciable benefit, no effect or appreciable harm for the intervention (RR 1.56, 95% CI 0.75 to 3.25, 2 studies, 130 women, I² = 0%, very-low-quality evidence). This suggests that for women with a 14% chance of achieving live birth using conventional COH, the chance of achieving live birth using low-dose hCG would be between 10% and 45%.Similarly confidence intervals were very wide for the outcome of OHSS and findings were compatible with benefit, no effect or harm for the intervention (OR 0.30, 95% CI 0.06 to 1.59, 5 studies, 351 women, I² = 59%, very-low-quality evidence). This suggests that for women with a 3% risk of OHSS using conventional COH, the risk using low-dose hCG would be between 0% and 4%.The confidence intervals were wide for the outcome of ongoing pregnancy and findings were compatible with benefit or no effect for the intervention (RR 1.14, 95% CI 0.81 to 1.60, 3 studies, 252 women, I² = 0%, low-quality evidence). This suggests that for women with a 32% chance of achieving ongoing pregnancy using conventional COH, the chance using low-dose hCG would be between 27% and 53%.The confidence intervals were wide for the outcome of clinical pregnancy and findings were compatible with benefit or no effect for the intervention (RR 1.19, 95% CI 0.92 to 1.55, 5 studies, 351 women, I² = 0%, low-quality evidence). This suggests that for women with a 35% chance of achieving clinical pregnancy using conventional COH, the chance using low-dose hCG would be between 32% and 54%.The confidence intervals were very wide for the outcome of miscarriage and findings were compatible with benefit, no effect or harm for the intervention (RR 1.08, 95% CI 0.50 to 2.31, 3 studies, 127 pregnant women, I² = 0%, very-low-quality evidence). This suggests that for pregnant women with a 16% risk of miscarriage using conventional COH, the risk using low-dose hCG would be between 8% and 36%.The findings for the outcome of FSH consumption were compatible with benefit for the intervention (MD -639 IU, 95% CI -893 to -385, 5 studies, 333 women, I² = 88%, moderate-quality evidence).The findings for the outcome of number of oocytes retrieved were compatible with no effect for the intervention (MD -0.12 oocytes, 95% CI -1.0 to 0.8 oocytes, 5 studies, 351 women, I² = 0%, moderate-quality evidence).
We are very uncertain of the effect on live birth, OHSS and miscarriage of using low-dose hCG to replace FSH during the late follicular phase of COH in women undergoing ART, compared to the use of conventional COH. The current evidence suggests that this intervention does not reduce the chance of ongoing and clinical pregnancy; and that it is likely to result in an equivalent number of oocytes retrieved expending less FSH. More studies are needed to strengthen the evidence regarding the effect of this intervention on important reproductive outcomes.
SourceAvailable from: Wellington P Martins[Show abstract] [Hide abstract]
ABSTRACT: To evaluate the efficacy and safety of using cabergoline for reducing the risk of ovarian hyperstimulation syndrome (OHSS). Systematic review and meta-analysis of randomized clinical trials (RCTs). Women submitted to controlled ovarian stimulation (COS) for assisted reproduction. Cabergoline. Fertility centers. Moderate-severe OHSS, live birth, clinical pregnancy, number of retrieved oocytes, miscarriage, congenital abnormalities. Comparisons were performed with the use of risk ratios (RRs) or mean differences (MDs) and their respective 95% confidence intervals (CIs). Eight RCTs were considered to be eligible; data from seven studies could be extracted and included in the meta-analysis. Cabergoline reduces the risk of moderate-severe OHSS (RR 0.38, 95% CI 0.29-0.51, 7 studies, 858 women) and probably has no clinically relevant negative impact on clinical pregnancy (RR 1.02, 95% CI 0.78-1.34, 4 studies, 561 women) or on the number of retrieved oocytes (MD 1.15, 95% CI -0.76 to 3.07, 5 studies, 628 women). However, our estimates were imprecise for distinguishing between substantial harm, no effect, and substantial benefit considering live birth (RR 1.03, 95% CI 0.71-1.48, 1 study, 200 women), and miscarriage (RR 0.69, 95% CI 0.27 to 1.76, 3 studies, 194 pregnant women). No studies reported congenital abnormalities. Cabergoline reduces the occurrence of moderate-severe OHSS. Cabergoline is unlikely to have a clinically relevant negative impact on clinical pregnancy or on the number of retrieved oocytes. However, we are still uncertain of its impact on live birth, miscarriage, and congenital abnormalities.Fertility and sterility 12/2013; 101(3). DOI:10.1016/j.fertnstert.2013.11.005 · 4.30 Impact Factor
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ABSTRACT: Objective To identify, appraise and summarize the existing evidence available regarding the effectiveness and safety of time-lapse embryo monitoring on the main outcomes of assisted reproductive techniques (ART).Methods In this systematic review and meta-analysis, we only included randomized clinical trials (RCT) comparing time-lapse embryo imaging versus standard embryo monitoring. Our primary outcomes were live birth (efficacy) and congenital abnormality (safety). The secondary outcomes were clinical pregnancy, ongoing pregnancy and miscarriage.ResultsTwo RCT were considered eligible, and their data were extracted and included in a meta-analysis. Both studies transferred the embryos at blastocyst stage. No studies reported live birth or congenital abnormalities. Our estimates were not sufficiently precise to identify whether time-lapse caused a small benefit, no effect or small harm considering clinical pregnancy (RR, 1.05; 95% confidence interval [CI], 0.80-1.38, two studies, 138 women, moderate quality-evidence) and ongoing pregnancy rates (RR, 1.05; 95% CI, 0.76-1.45, two studies, 138 women, moderate quality-evidence). Considering the available data, we were unable to distinguish if the intervention poses substantial benefit, no effect or substantial harm in the risk of miscarriage (RR, 0.95; 95% CI, 0.30-2.99, two studies, 76 clinical pregnancies, low quality-evidence).Conclusions Time-lapse embryo imaging is unlikely to have a large effect on the chance of achieving clinical and/or ongoing pregnancy when transferring embryos at blastocyst stage. More studies are still required to improve the quality of the current evidence and also to examine whether this intervention is useful when transferring embryos at cleavage-stage.Ultrasound in Obstetrics and Gynecology 10/2014; 44(4). DOI:10.1002/uog.13428 · 3.14 Impact Factor
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ABSTRACT: Objective: To determine whether different ratios of administered LH-to-FSH influence the risk of clinically relevant late follicular P elevations and whether there is an optimal range of LH-to-FSH to mitigate this risk. Design: Retrospective cohort. Setting: Private academic center. Patient(s): A total of 10,280 patients undergoing their first IVF cycle. Intervention(s): None. Main Outcome Measure(s): The ratio of exogenous LH-to-FSH throughout stimulation and association with absolute serum P level >= 1.5 ng/mL on the day of hCG administration. Result(s): Stimulations using no administered LH (N = 718) had the highest risk of P elevation >= 1.5 ng/mL (relative risk [RR] = 2.0; 95% confidence interval [CI] 1.8-2.2). The lowest risk of P increase occurred with an LH-to-FSH ratio of 0.30: 0.60 (20%; N = 4,732). In contrast, ratios < 0.30, reflecting proportionally less administered LH (N = 4,847) were at increased risk for premature P elevation (32%, RR = 1.6; 95% CI 1.5-1.7) as were ratios >0.60 (23%, RR 1.1; 95% CI 1.0-1.3). This pattern of lowest risk in the 0.30-0.60 range held true for cycles characterized by low, normal, and high response. When performing a logistic regression to control for multiple confounding variables this relationship persisted. Conclusion(s): Absent or inadequate LH dosing is associated with a risk for a late follicular elevation in P sufficient to induce suboptimal outcomes. A total LH-to-FSH ratio of 0.30: 0.60 was associated with the lowest risk of P elevation. Optimization of this parameter should be considered when making gonadotropin dosing decisions. (C) 2014 by American Society for Reproductive Medicine.Fertility and Sterility 08/2014; 102(5). DOI:10.1016/j.fertnstert.2014.07.766 · 4.30 Impact Factor