Annefloor W Pouwer, Cindy Farquhar, Jan AM Kremer

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, eight studies; I² statistic = 44%) or OHSS (RR 1.00, 95% CI 0.74 to 1.37; 3753 participants, nine studies; I² statistic = 0%). We compared subgroups by dose of long-acting FSH. There was evidence of 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). 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.