Maier 2002

Methods	Double‐blind randomised controlled trial Study location: 14 centres in 4 European countries Study period: May 1998 to June 1999
Participants	219 ELBW infants were randomly assigned to early EPO, late EPO, or control on day 3 of life.
Interventions	74 infants in the early EPO group received EPO (NeoRecor‐mon, F. Hoffman‐La Roche, Basel, Switzerland) 250 IU/kg, IV or SC, 3 times a week (750 IU/kg/week, high dose), starting from day 3 of life, for 9 weeks. 74 infants in the late EPO group received EPO 250 IU/kg IV or SC, 3 times a week, starting from the fourth week of life, for 6 weeks. 71 infants in the control group received sham injections. Enteral iron 3 mg/kg was given to all infants from days 3 to 5 and was increased at days 12 to 14 to 6 mg/kg/d, and to 9 mg/kg/d at days 24 to 26 of life (high dose).
Outcomes	Use of 1 or more red blood cell transfusions Number of donors the infant was exposed to (median, quartiles) Number of transfusions per infant (mean) Mortality during hospital stay NEC IVH (grade not stated) PVL ROP (stage not stated) BPD (at 36 weeks' postmenstrual age) Growth Days in hospital (median, quartiles)
Notes	Sample size calculation was performed. 24 (32%) infants in the early EPO group and 22 (31%) in the control group were exposed to donor blood before study entry. Transfusion guidelines were followed. Study was industry funded (F. Hoffman‐La Roche, Basel Switzerland). One infant was excluded from all evaluations because parents withdrew consent a few hours after randomisation before the start of the treatment phase.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information provided
Allocation concealment (selection bias)	Low risk	Numbered sealed envelopes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Treating physicians determined whether infants could be enrolled or withdrawn from the study, and whether infants should receive transfusions, and monitored them without knowing their treatment group. Dosing investigators performed randomisation and administered rhEPO but were not involved in the infants’ care. When treatment was to be given, a dosing investigator carrying a “black box” containing appropriate equipment visited each infant, gave or simulated administration of study medication, and placed adhesive strips on both thighs (of rhEPO recipients and controls), which remained there until the next visit. During this procedure, staff and parents had to leave. A treating physician or a dosing investigator assigned to an infant served in that function as long as the infant was studied.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	See the information in the box above.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes; 1 of the 220 randomised infants (control group) was excluded from all evaluations because parents withdrew consent a few hours after randomisation before the start of the treatment phase.
Selective reporting (reporting bias)	Unclear risk	The protocol for the study was not available to us; therefore we cannot ascertain whether deviations from the protocol occurred.
Other bias	Low risk	Appears free of other bias