Hazlett 2008

Methods	Parallel randomised controlled trial Prospective participant recruitment Participant sampling in consecutive order but stated as non‐consecutive in Hazlett 2005 Single‐centre trial performed at the Department of Embryology of Karande and Associates in Hoffman Estates, Illinois, USA Patients who were excluded were diagnosed as having a low success rate, which meant having a diminished ovarian reserve (FSH of at least 10 IU/ml), being older than 40 years of age or having a hydrosalpinx Participants were selected for a day five embryo transfer if a minimum of five embryos with little fragmentation were present on day three and/or if they had eight or more fertilised zygotes A power calculation was performed, which estimated that a 20% difference in clinical pregnancy rate would be found, with 5% significance and 80% power if at least 107 participants were included in each arm of the study Length of follow‐up per participant was 11 weeks No intention‐to‐treat analysis was performed Participants were able to enrol in the study with multiple treatment cycles in case of treatment failure
Participants	Mean age (SD): Participants were divided into day three and day five transfer subgroups. Treatment groups: day three, 33.4 (4.4), day five, 31.4 (4.2) years; control groups: day three, 33.4 (5.0), day five, 33.1 (4.8) years Causes and duration of subfertility not reported. Nor was it reported whether study concerned primary or secondary subfertility. Yet text states that there were no differences between treatment and control groups regarding cause and duration Included participants underwent IVF or ICSI. Unclear whether they underwent previous treatments No age analysis 233 participants appear to be recruited, even though only 224 were stated in the text. Of 233 participants, 223 were randomly assigned to a treatment group of 116 or a control group of 107 Five participants were part of a preliminary study and were not randomly assigned. Five others were withdrawn for protocol violations. The treatment group was divided into 84 participants who had a day three transfer and 32 who had a day five transfer. The control group comprised 78 day three transfers and 29 day five transfers The total number of transferred embryos was 519: 266 in the treatment group and 253 in the control group
Interventions	Embryo transfer on day three or day five of development in EmbryoGlue (0.5 mg/ml HA) versus transfer in IVC‐1 or IVC‐2 + 0.5% HSA (human serum albumin) on day three or G2.3 (0.125 mg/ml HA) + 0.5% HSA on day five. Therefore, for data analysis, this trial is divided into day three transfers, which compare HA versus no HA, and day five transfers, which compare HA versus low concentrations of HA Embryos were cultured in IVC‐1 or IVC‐2 until day three and in G2.3 for the additional two days Timing of randomisation was unclear. It appears that it occurred on the day before embryo transfer, for it is stated this was in the trial Hazlett 2005, which comprises data on the same participants Exposure time to EmbryoGlue in the treatment group was 10 to 60 minutes before embryo transfer No frozen‐thaw protocol was followed No donor oocytes were included Transfer and culture media were manufactured by two different manufacturers: In Vitro Care and Vitrolife Mean number of transferred embryos: treatment group day three: 2.5 ± 0.9, day five: 2.1 ± 0.5; control group day three: 2.4 ± 0.8, day five: 2.1 ± 0.9 Pregnancy was determined via pregnancy tests and demonstration of gestational sac and fetal heartbeat on ultrasound scan
Outcomes	Primary outcomes Live birth rate: data received after contact with author regarding other publication of the same data (Hazlett 2005); reported for the whole study population and for day three and day five transfers separately. Defined as number of live births divided by number of participants Secondary outcomes Clinical pregnancy rate: defined as number of participants with at least one intrauterine gestational sac on ultrasound two weeks after positive hCG pregnancy test divided by total number of participants Additional outcomes Implantation rate: defined as total number of intrauterine gestational sacs divided by total number of embryos transferred Other outcomes Viable pregnancy rate: defined as ongoing pregnancy demonstrated by fetal cardiac activity at seven weeks of gestation divided by group size
Notes	This study comprises data from previous publications (Hazlett 2004 and Hazlett 2005), but only outcome data have been extracted from it Additional data were retrieved by contacting study authors
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned to treatment or control groups by a computer‐generated random numbers sequence
Allocation concealment (selection bias)	Low risk	Randomisation was performed by computer‐generated random numbers sequence using sealed envelopes to allocate to the treatment arm
Blinding (performance bias and detection bias) All outcomes	Low risk	Participant and clinician/nurse were blinded. Embryologist was not
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Live births were reported after contact with study author. No intention‐to‐treat analysis was performed. Loss to follow‐up was accounted for. Actual length of follow‐up per participant in published study was 11 weeks; live birth data were retrieved later on
Selective reporting (reporting bias)	Low risk	Clinical pregnancy rate and implantation rate were reported in a prespecified way
Other bias	High risk	Free from commercial funding. Different media brands were used, therefore not comparable. No multiple pregnancy rate was reported, although multiple embryos were transferred per cycle