Palomba 2011

Methods	Generation of the allocation sequence: computer randomisation system Allocation concealment method: random allocation sequence was concealed in the central pharmacy of the University of Catanzaro Blinding method: yes Number and reasons for withdrawals: no participants dropped out ITT analysis: yes Prospective, randomised, double‐blind, placebo‐controlled trial Metformin versus placebo
Participants	Number of eligible cycles: 120 infertile women with PCOS who had a history of 1 previous cancelled cycle due to a high risk of OHSS or history of a moderate or severe case of OHSS during their previous IVF cycle Diagnosis of PCOS followed the Rotterdam criteria (ESHRE/ASRM) 120 PCOS participants were screened and underwent 120 consecutive IVF/ICSI cycles 60 participants were randomised to each group (metformin and placebo) No participants dropped out Age: younger than 35 years Did not report the causes of infertility Both groups were matched for age, median duration of infertility, BMI and hirsutism according to modified Ferriman‐Gallwey score Inclusion criteria ‐ only participants who had received in the previous cycle: a) mid‐luteal long GnRH agonist and a gonadotropin step‐down stimulation protocol with a starting dose of 225 IU daily Exclusion criteria: a) age > 35 years b) FSH level of > 10 c) BMI > 30 kg/m2 d) neoplastic, metabolic, hepatic or cardiovascular disorders or other concurrent medical illness e) hypothyroidism f) hyperprolactinaemia h) Cushing's syndrome i) nonclassic congenital adrenal hyperplasia j) alcohol abuse k) current or previous: a wash‐out period of at least 6 months without use of any antidiabetic, obesity or hormonal drugs except those used during the previous IVF cycle l) male factor infertility
Interventions	Metformin 500 mg tid and placebo tablets were started on the same day that down‐regulation with GnRH‐agonist began and continued until a positive pregnancy test was obtained or menstrual bleeding appeared Protocol for controlled ovarian hyperstimulation: long luteal phase pituitary down‐regulation using the GnRH analogue Enantone 1mg® (0.5 mg twice daily, SC) and reduced to 0.5 mg (0.25 mg twice daily) after pituitary suppression with step‐down rec‐FSH (Gonal F® ‐ starting dose 150 IU). hCG (Profasi® 10000 IU) was administered when at least 3 follicles were larger than 18 mm. Oocyte retrieval was performed within 36 hrs after hCG injection Assisted reproductive technology (ART): IVF or ICSI Embryo transfer: maximum of 2 embryos were transferred per participant on day 2, 3 or 5 after oocyte retrieval without ultrasonographic guidance Catheter used for transfer: not reported Luteal phase support: intramuscular progesterone (Prontogest® ‐ 50 mg/day)
Outcomes	Primary outcomes: a) OHSS rate per woman Secondary outcomes: a) live birth rate per woman b) clinical pregnancy rate c) number of collected oocytes d) number of good‐quality embryos g) total dose of FSH given during stimulation h) number of days of gonadotrophins
Notes	Country of the study: Italy
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Adequate ‐ computer randomisation system
Allocation concealment (selection bias)	Low risk	Random allocation sequence was concealed in the central pharmacy
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	There were no withdrawals
Selective reporting (reporting bias)	Low risk	All main outcomes were reported
Other bias	High risk	There is a discrepancy in the data in the published study: in both the Metformin group and the placebo group the clinical pregnancy rate is lower than the live birth rate (pregnancy 26/60, 24/60; live birth 29/60, 27/60). We have attempted to contact the first author (emailed 8/19/14) but have not received a response. There were no significant differences in the baseline characteristics of the participants between the 2 groups