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Meta-Analysis
. 2013 Mar 28;2013(3):CD010042.
doi: 10.1002/14651858.CD010042.pub2.

FSH replaced by low-dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques

Wellington P Martins  1 , Andrea D D Vieira, Jaqueline B P Figueiredo, Carolina O Nastri
Affiliations
Meta-Analysis

FSH replaced by low-dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques

Wellington P Martins et al. Cochrane Database Syst Rev. .

Abstract

Background: 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).

Objectives: 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.

Search methods: 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..

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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).

Authors' conclusions: 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.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 FSH replaced by low‐dose hCG versus FSH throughout the COH, outcome: 1.1 Live birth.
5
5
Forest plot of comparison: 1 FSH replaced by low‐dose hCG versus FSH throughout the COH, outcome: 1.2 OHSS.
6
6
Forest plot of comparison: 1 FSH replaced by low‐dose hCG versus FSH throughout the COH, outcome: 1.3 Ongoing pregnancy.
7
7
Forest plot of comparison: 1 FSH replaced by low‐dose hCG versus FSH throughout the COH, outcome: 1.4 Clinical pregnancy.
8
8
Forest plot of comparison: 1 FSH replaced by low‐dose hCG versus FSH throughout the COH, outcome: 1.5 Miscarriage.
9
9
Forest plot of comparison: 1 FSH replaced by low‐dose hCG versus FSH throughout the COH, outcome: 1.6 Total dose of FSH (IU).
10
10
Forest plot of comparison: 1 FSH replaced by low‐dose hCG versus FSH throughout the COH, outcome: 1.7 Oocytes retrieved.
1.1
1.1. Analysis
Comparison 1 FSH replaced by low‐dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 1 Live birth.
1.2
1.2. Analysis
Comparison 1 FSH replaced by low‐dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 2 OHSS.
1.3
1.3. Analysis
Comparison 1 FSH replaced by low‐dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 3 Ongoing pregnancy.
1.4
1.4. Analysis
Comparison 1 FSH replaced by low‐dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 4 Clinical pregnancy.
1.5
1.5. Analysis
Comparison 1 FSH replaced by low‐dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 5 Miscarriage.
1.6
1.6. Analysis
Comparison 1 FSH replaced by low‐dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 6 Total dose of FSH (IU).
1.7
1.7. Analysis
Comparison 1 FSH replaced by low‐dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 7 Oocytes retrieved.
2.1
2.1. Analysis
Comparison 2 Analysis grouped by participant characteristics, Outcome 1 OHSS.
3.1
3.1. Analysis
Comparison 3 Analysis grouped by the drug used to prevent premature LH surge (GnRH agonist or antagonist), Outcome 1 OHSS.
3.2
3.2. Analysis
Comparison 3 Analysis grouped by the drug used to prevent premature LH surge (GnRH agonist or antagonist), Outcome 2 Total dose of FSH.
4.1
4.1. Analysis
Comparison 4 Analysis grouped by the daily dose of FSH (≤ 150 IU/day or > 150 IU/day), Outcome 1 OHSS.
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