Review question
The aim of this Cochrane review was to compare the effectiveness and safety of weekly (long-acting) follicle stimulating hormone (FSH) compared to daily FSH in women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles.
Background
When assisted reproduction techniques such as IVF and ICSI are performed, the fertilisation of the egg takes place outside the woman's body. Multiple eggs are needed to increase the availability of fertilised eggs. The growth of multiple eggs is achieved by stimulation of the ovary with FSH. There is a risk of overstimulation (ovarian hyperstimulation syndrome or OHSS). OHSS is a serious adverse effect which can cause illness or death.
Current treatment regimens to stimulate the growth of multiple eggs prescribe daily injections of FSH during the first seven days of treatment. A new treatment is now available which replaces these injections with just a single injection. This new treatment can be more patient friendly, as daily injections may cause discomfort and be a physical burden to the women.
Study characteristics
We included six randomised controlled trials comparing weekly versus daily FSH in 3753 women undertaking controlled ovarian stimulation as part of an IVF/ICSI cycle. Their age ranged from 18 to 41 years. The studies used different dosages of weekly FSH ranging from 60 to 240 μg. Five studies reported live birth rate and all six studies reported OHSS rate (our primary outcomes). The evidence is current to June 2015.
Key results
There was no evidence of a difference in live birth rates between medium dose (150 to 180 μg) weekly FSH and daily FSH. There was evidence of a reduced live birth rate in women who received lower doses (60 to 120 μg) of weekly FSH when compared to daily FSH. Only one study used a high dose of weekly FSH, so we cannot make conclusions about this dosage group.There was no evidence of a difference between the groups in OHSS rate. We concluded that medium dose (150 to 180 μg) weekly FSH is a safe treatment option and is as effective in terms of life birth rate as daily FSH injections.
Quality of the evidence
The quality of the evidence was graded as moderate. Five out of six studies were funded by the same drug manufacturer.
The use of a medium dose (150 to 180 μg) of long-acting FSH is a safe treatment option and equally effective compared to daily FSH in women with unexplained subfertility. There was evidence of reduced live birth rate in women receiving a low dose (60 to 120 μg) of long-acting FSH compared to daily FSH. Further research is needed to determine whether long-acting FSH is safe and effective for use in hyper- or poor responders and in women with all causes of subfertility.
Assisted reproduction techniques (ART), such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), can help subfertile couples to create a family. It is necessary to induce multiple follicles, which is achieved by follicle stimulating hormone (FSH) injections. Current treatment regimens prescribe daily injections of FSH (urinary FSH either with or without luteinizing hormone (LH) injections or recombinant FSH (rFSH)).
Recombinant DNA technologies have produced a new recombinant molecule which is a long-acting FSH, named corifollitropin alfa (Elonva) or FSH-CTP. A single dose of long-acting FSH is able to keep the circulating FSH level above the threshold necessary to support multi-follicular growth for an entire week. The optimal dose of long-acting FSH is still being determined. A single injection of long-acting FSH can replace seven daily FSH injections during the first week of controlled ovarian stimulation (COS) and can make assisted reproduction more patient friendly.
To compare the effectiveness of long-acting FSH versus daily FSH in terms of pregnancy and safety outcomes in women undergoing IVF or ICSI treatment cycles.
We searched the following electronic databases, trial registers and websites from inception to June 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialized Register, MEDLINE, EMBASE, PsycINFO, CINAHL, electronic trial registers for ongoing and registered trials, citation indexes, conference abstracts in the ISI Web of Knowledge, LILACS, Clinical Study Results (for clinical trial results of marketed pharmaceuticals), PubMed and OpenSIGLE. We also carried out handsearches.
We included all randomised controlled trials (RCTs) comparing long-acting FSH versus daily FSH in women who were part of a couple with subfertility and undertaking IVF or ICSI treatment cycles with a GnRH antagonist or agonist protocol.
Two review authors independently performed study selection, data extraction and assessment of risk of bias. We contacted trial authors in cases of missing data. We calculated risk ratios for each outcome, and our primary outcomes were live birth rate and ovarian hyperstimulation syndrome (OHSS) rate. Our secondary outcomes were ongoing pregnancy rate, clinical pregnancy rate, multiple pregnancy rate, miscarriage rate, any other adverse event (including ectopic pregnancy, congenital malformations, drug side effects and infection) and patient satisfaction with the treatment. Trials reported all outcomes, except patient satisfaction with the treatment.
We included six RCTs with a total of 3753 participants and we graded the quality of the included studies as moderate. All studies included women with an indication for COS as part of an IVF/ICSI cycle with age ranging from 18 to 41 years. A comparison of long-acting FSH versus daily FSH did not show evidence of difference in effect on overall live birth rate (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.84 to 1.07; 2363 participants, five studies; I² statistic = 44%) or OHSS (RR 1.00, 95% CI 0.74 to 1.37; 3753 participants, six studies; I² statistic = 0%). We compared subgroups by dose of long-acting FSH. There was evidence of a reduced live birth rate in women who received lower doses (60 to 120 μg) of long-acting FSH compared to daily FSH (RR 0.70, 95% CI 0.52 to 0.93; 645 participants, three studies; I² statistic = 0%). There was no evidence a difference between the groups in live births in the medium dose (150 to 180 μg) subgroup (RR 1.03, 95% CI 0.90 to 1.18; 1685 participants, four studies; I² statistic = 6%). There was no evidence of a difference between the groups in the clinical pregnancy rate (any dose), ongoing pregnancy rate (any dose), multiple pregnancy rate (any dose), miscarriage rate (low or medium dose), ectopic pregnancy rate (any dose), congenital malformation rate, congenital malformation rate; major or minor (low or medium dose).