Rose 2020.

Study characteristics
Methods	Study design: single‐centre randomised controlled trial (RCT). The study was cross‐over in design, but only data from the first phase of the study, prior to cross‐over, are included in the review. Country: Australia Setting: fertility clinic, Adelaide Sponsorship source: EmbryoGen/BlastGen media was supplied by ORIGIO, a Cooper Surgical company. A grant from Cooper Surgical also funded MLH and EJK for statistical support. Fertility SA and The Robinson Institute, University of Adelaide provided in kind support from staff and affiliates providing time and expertise. Trials registry number: NCT02305420 (prospectively registered)
Participants	Inclusion criteria: the inclusion criteria selected for a poor‐prognosis patient population. Patients must have previously had consecutive transfer of 2 or more embryos without a positive pregnancy outcome OR have had a history of at least 1 previous pregnancy loss OR a previous history of poor embryo development (< 20% of embryos developing on the time at day 3 or no blastocysts above grade 2 on day 5). Other additional inclusion parameters included a maternal age between 25 and 41 years, the use of a standard gonadotrophin‐releasing hormone (GnRH) agonist or antagonist protocol, and 3 or more follicles of > 14 mm as seen by transvaginal ultrasound before the day of human chorionic gonadotropin administration. Exclusion criteria: exclusion criteria included a need for surgical sperm retrieval (except in cases of previous vasectomy), the use of another investigational drug within 30 days of oocyte retrieval, and/or the presence of a severe chronic disease that could impact the in‐vitro fertilisation (IVF) cycle or reproductive outcomes. Number of participants randomised to each arm of the study: 50 to intervention arm, 50 to control arm. Dropouts: none Group differences: participants were matched for age, body mass index (BMI), and smoking status. A greater number of participants in the intervention group underwent intracytoplasmic sperm injection (ICSI) opposed to IVF versus the control group (37/50 versus 29/50). Fresh or frozen cycle?: fresh cycle IVF or ICSI?: IVF and ICSI Length of time exposed to intervention medium: 5 days Trade name and concentration of granulocyte macrophage colony‐stimulating factor (GM‐CSF) in intervention medium: EmbryoGen days 0 to 3 followed by BlastGen days 3 to 5 Trade name of control medium: "Standard embryo culture medium" Day of embryo transfer: day 5 (apart from 1 in the control group and 2 in the intervention group who transferred 1 embryo on day 3 due to delayed embryo development) Number of embryos transferred: single‐embryo transfer. "Couples who insisted on transferring two embryos, once embryo quality was known, were included in the study but were recorded as having a trial variation (four in the standard group and six in the intervention group).”
Interventions	Intervention: GM‐CSF‐supplemented culture medium Control: Sydney IVF medium
Outcomes	Live‐birth rate Miscarriage rate Clinical pregnancy rate Multiple gestation rate Preterm birth rate Birth defect rate Aneuploidy rate Stillbirth rate
Notes	Email correspondence with all additional data outlined in Appendix 13.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"50 cards with control and 50 with BlastGen written on them were placed in opaque sealed envelopes by a person unrelated to the trial. They were shuffled several times and the envelopes were marked from 1‐100 in consecutive order."
Allocation concealment (selection bias)	Low risk	"When the eligible patient was scheduled for an egg retrieval the embryologist took the next envelope by sequence and the random assignment was made."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Clinicians, sonographers, statisticians, and patients were completely blinded"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Sonographers were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All dropouts accounted for.
Selective reporting (reporting bias)	Low risk	"We reported all outcomes as per our prospective clinical trials registration (ClinicalTrials.gov Identifier: NCT02305420)."
Other bias	High risk	There is a potential conflict of interest regarding the funding and administration of this study, as it was granted by the manufacturer of the intervention culture medium. However, the study authors have been very forthcoming with information regarding the trial, and there has been transparency. We assessed the study as at high risk of other bias due to the small sample size of 100 participants.