Methods

Parallel group study.

Number of women randomized: 152 (77 in intervention group; 75 in control group).

Number of withdrawals: 8 (1 in intervention group due to endometrioma; 7 in control group: 5 due to endometrioma or cysts and 2 chose not to proceed).

Number of women analyzed: 144.

Participants

Country of authors: UK.

Inclusion criteria: women planning to have an IVF cycle on the Southampton (UK) IVF programme.

Exclusion criteria: endometrioma or ovarian cyst seen on vaginal ultrasound scan on day 19 of the menstrual cycle (after recruitment).

Mean age ± SD: intervention group: 33.8 ± 4.1 years; control group: 33.5 ± 3.5 years.

Interventions

Intervention: medroxyprogesterone acetate (10 mg/day) on cycle days 19‐25 + GnRH agonist (buserelin acetate, nasal administration 200 μg 3 times daily) from cycle day 21 + hMG 4 ampoules/day (75 IU FSH and 75 IU LH per ampoule) from day 4 of ensuing menses.

Control: placebo on cycle days 19‐25 + GnRH agonist (buserelin acetate, 200 μg nasal administration, 3 times daily) from cycle day 21 + hMG 4 ampoules/day (75 IU FSH and 75 IU LH per ampoule) from day 4 of ensuing menses.

Both hMG and GnRH agonist continued until hCG injection (10,000 IU, IM), administered when leading 3 follicles reached diameter of ≥ 18 mm and serum oestradiol > 300 pmol/L for every follicle > 14 mm in diameter.

Outcomes

• Cyst development: intraovarian sonolucent structure with a mean diameter > 14 mm, measured after 12 days of pituitary suppression.

• Clinical pregnancy rates: not defined.

Notes

Power calculation performed: yes.

ITT analysis performed: no.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The hospital pharmacy randomized to contain placebo or progestogen."
Method of randomization not reported.

Allocation concealment (selection bias)

Low risk

Quote: "The hospital pharmacy provided a series of consecutively numbered bottles."

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double blind.
Women in control group received a placebo.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Proportions of withdrawals not balanced between the 2 treatment groups (1 in intervention group; 5 in control group) and data were not analyzed on ITT basis.

Selective reporting (reporting bias)

High risk

All planned outcomes not reported.

Other bias

Low risk

Quote: "No difference was seen between the study group and control group in the indication of IVF and age."

Methods

Academic centre, parallel group study.

Number of women randomized: 83 women undergoing 102 cycles (51 cycles in each group; number of women per group not reported).

Number of withdrawals: not reported.

Number of women analyzed: only number of cycles analyzed reported (102 cycles).

Participants

Country of authors: Canada.

Inclusion criteria: women who were receiving a long protocol of pituitary suppression in the early follicular phase as a part of IVF‐ET treatment.

Exclusion criteria: not reported.

Median age (range): intervention group: 35.2 years (32.5‐39.1); control group: 33.7 years (31.6‐38.3).

Interventions

Intervention: COCP on cycle days 1‐14 + GnRH agonist (buserelin acetate, long protocol 500 μg/day) started on cycle day 14 + hMG (75 IU FSH and 75 IU LH) or pure FSH (75 IU) started after achievement of pituitary suppression.

Control: GnRH agonist (buserelin acetate, long protocol 500 μg/day) started on cycle day 2 + hMG (75 IU FSH and 75 IU LH) or pure FSH (75 IU) started after achievement of pituitary suppression.

If no pituitary suppression (serum oestradiol < 40 pg/mL) achieved after 14 days of GnRH agonist administration, dosage of buserelin acetate increased to 500 μg twice daily + administration of an IM injection of progesterone 100 mg.

Both hMG/FSH and GnRH agonist continued until hCG injection, administered when ≥ 3 follicles reach a mean diameter of ≥ 18 mm.

Outcomes

• Clinical pregnancy rate per cycle started: presence of ≥ 1 foetal heart beats confirmed with ultrasound performed at least 4 weeks after embryo transfer.

• Number of women with a cyst: intraovarian sonolucent structure with a mean diameter of > 14 mm, measured after 7 days of pituitary suppression.

• Number of days of GnRHa treatment.

• Number of days of gonadotrophin treatment.

• Total quantity of gonadotrophin administered: measured in ampoules.

• Number of follicles.

• Number of oocytes collected/fertilised.

• Number of embryos replaced.

• Implantation rate.

Notes

Power calculation performed: yes.

ITT analysis performed: no.

No per‐woman data reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "They were randomized in two groups by drawing sealed envelopes that contained randomly generated numbers."

Allocation concealment (selection bias)

Low risk

Sealed envelopes.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Numbers and reasons for withdrawals not reported.

Selective reporting (reporting bias)

High risk

All planned outcomes not reported.

Other bias

Low risk

No significant difference in baseline characteristics between groups with regard to age, cause of infertility, number of previous attempts, and oestradiol, FSH or LH level.

Methods

Parallel group study.

Number of women randomized: 86 (44 in intervention group; 42 in control group).

Number of withdrawals: 14 (9 in intervention group due to cyst development, protocol violation, insufficient ovarian response, did not undergo treatment, did not receive embryo transfer; 5 in control group due to insufficient ovarian response, did not receive embryo transfer).

Number of women analyzed (for pregnancy outcome): 72 (35 in intervention group; 37 in control group).

Participants

Country: Belgium.

Inclusion criteria: women aged ≤ 36 years, BMI 18‐29 kg/m², underwent a first or second treatment cycle of IVF with ICSI, serum FSH on day 3 of the menstrual cycle < 12 IU/L, normal ultrasound scan regular ovulatory menstrual cycle of 21 to 35 days.

Exclusion criteria: oocyte donors, women with endometriosis ≥ grade 3, endocrine or metabolic abnormalities, PCOS or previous history of poor ovarian response (defined as development of < 4 follicles in previous IVF or ICSI cycle).

Mean age ± SD: intervention group: 29.2 ± 3.0 years; control group: 30.2 ± 3.0 years.

Setting: assisted reproduction programme in Belgium.

Interventions

Intervention: oestradiol valerate (2 × 2 mg/day) during 6‐10 consecutive days (from cycle day 25 onwards) prior to start of rFSH stimulation so that the first day of stimulation occurred between Friday and Sunday.

Control: no pretreatment; standard GnRH antagonist protocol.

Both groups received rFSH (150 IU) and on day 6 of stimulation GnRH antagonist protocol (ganirelix 0.25 mg/day).

Outcomes

Primary:

• Number of women undergoing oocyte retrieval during weekend days.

Secondary:

• Mean number of COCP in each treatment group.

• Number of oocytes.

• Duration of stimulation.

• Total cumulative dose of rFSH used.

• Pregnancy rate.

• Basal hormone serum values.

Notes

Power calculation: not reported.

ITT analysis: not reported.

Objective of the study was to assess the ability of oestradiol to control the oocyte retrieval of GnRH antagonist cycles prior to COS.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomization list.

Allocation concealment (selection bias)

Low risk

Consecutive sealed opaque envelopes.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Reasons for, and proportions of, withdrawals balanced between the 2 treatment groups and data were analyzed on the basis of ITT.

Selective reporting (reporting bias)

Low risk

All prespecified outcomes reported,

Other bias

Low risk

Groups comparable at baseline,

Methods

Multicentre (6 IVF centres), parallel group study.

Number of women randomized: 93 (21 in COCP group; 23 in progestogen group; 25 in oestrogen group; 24 in control group).

Number of withdrawals: 3 in oestrogen group (1 did not start any treatment, 1 due to an ovarian cyst and 1 due to major protocol violation).

Number of women analyzed: 90.

Duration of study: 10 months of recruitment.

Participants

Country of authors: France.

Inclusion criteria: regular normo‐ovulatory cycles (28‐35 days), aged < 38 years, BMI 18‐30.

Exclusion criteria: high levels of baseline serum FSH or oestradiol, < 5 follicles at the antral follicular count performed on day 3 of a spontaneous cycle, history of high (> 20 oocytes) or low (< 5 oocytes) ovarian response in a previous IVF attempt.

Mean age ± SD: COCP group: 30.8 ± 4.6 years; progestogen group: 32.9 ± 2.5 years; oestrogen group: 31.8 ± 3.2 years; control group: 31.2 ± 4.3 years.

Interventions

COCP group: COCP (ethinyl oestradiol 30 μg + desogestrel 150 μg daily), started cycle day 2 or 3 for 15‐21 days (stopped on a Sunday) + rFSH (recombinant follitropin beta 150‐300 IU/day), started post‐treatment day 5 + GnRH antagonist (ganirelix acetate 0.25 mg/day), started when leading follicle reached 14 mm in diameter.

Progestogen group: norethisterone 10 mg/day, started cycle day 15 for 10‐15 days (stopped on a Sunday) + rFSH (recombinant follitropin beta 150‐300 IU/day), started post‐treatment day 5 + GnRH antagonist (ganirelix acetate 0.25 mg/day), started when leading follicle reached 14 mm in diameter.

Oestrogen group: micronised 17‐βE₂ (2 mg twice daily), 10‐15 days, started 10 days before the presumed menses (stopped on a Sunday) + rFSH (recombinant follitropin beta 150‐300 IU/day), started post‐treatment day 5 + GnRH antagonist (ganirelix acetate 0.25 mg/day), started when leading follicle reached 14 mm in diameter.

Control group: rFSH (recombinant follitropin beta 150‐300 IU/day), started day 3 after spontaneous menses + GnRH antagonist (ganirelix acetate 0.25 mg/day), started when leading follicle reached 14 mm in diameter.

rFSH dose according to age, BMI and previous responses to stimulation; after 5 days of treatment dose adjustment according to ovarian response.

Both rFSH and GnRH antagonist were continued until hCG injection (10,000 IU), administered when ≥ 3 mature (of ≥ 17 mm diameter) follicles were obtained.

Outcomes

• Number of live births.

• Number of positive pregnancy tests.

• Clinical pregnancy rate: not defined.

• Ongoing pregnancy rate: pregnancy developing beyond 12 weeks.

• Multiple pregnancy rate: not defined.

• Hormonal profiles during the 5‐day washout period.

• Follicular growth.

• Antagonist duration.

• Pretreatment duration.

• Number of retrievals.

• FSH dose.

• Transferred embryos.

Notes

Power calculation performed: no.

ITT analysis performed: no (not for oestrogen group).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Random allocation sequence was generated from a table of random numbers... Randomization was stratified by centre..."

Allocation concealment (selection bias)

Low risk

Quote: "Random allocation sequence was concealed to each physician who enrolled and randomised patients."

Sealed envelopes.

Blinding (performance bias and detection bias)
All outcomes

High risk

Quote: "This study was not blind."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Reasons for withdrawals and proportions of withdrawals not clearly stated.

Selective reporting (reporting bias)

High risk

Some planned outcomes not reported.

Other bias

Low risk

No significant baseline imbalance with regard to age and BMI.

Methods

Parallel group study.

Number of women randomized: 472 (238 in intervention group; 234 in control group).

Number of withdrawals: 19 (5 in intervention group due to spontaneous pregnancy, discontinuation and no periods; 14 in control group due to spontaneous pregnancy, discontinuation, ovarian cyst and protocol change).

Number of women analyzed: 453 (233 in intervention group; 220 in control group).

Participants

Country France.

Inclusion criteria: regular normo‐ovulatory cycles (28‐35 days), aged < 38 years, BMI 18‐30 kg/m² and first or second IVF/ICSI attempt.

Exclusion criteria: high basal levels of serum FSH (> 12 IU/L) or oestradiol (> 80 pg/mL), < 5 follicles at the antral follicular count performed on day 3 of a spontaneous cycle or history of high (> 20 oocytes) or low (< 5 oocytes) ovarian response in earlier IVF attempt.

Mean age ± SD: intervention group: 31.1 ± 3.6 years; control group: 31.2 ± 3.7 years.

Setting: 10 private or university‐based centres in France.

Interventions

Intervention: oral 17 β‐oestradiol (4 mg; 2 mg x 2/day) started 7 days before the presumed onset of menses and administered up to the next Thursday after the occurrence of menstrual bleeding.

Control: no pretreatment.

Ovarian stimulation started on Friday in intervention group and on cycle day 2 after spontaneous menses in control group. Followed by GnRH antagonists on day 6, then hCG.

Outcomes

Primary:

• Number of retrieved oocytes.

Secondary:

• Consumption of gonadotropins.

• Duration of treatment.

• Implantation and pregnancy rates.

Notes

Power calculation for sample size (225 women per group).

ITT analysis not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Table of random numbers.

Allocation concealment (selection bias)

Low risk

Authors stated allocation concealed by sealed envelopes.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Reasons for withdrawals and proportions of withdrawals not balanced between groups and data not analyzed on the basis of ITT.

Selective reporting (reporting bias)

Low risk

All prespecified outcomes reported.

Other bias

Low risk

Groups balanced at baseline with respect to demographic characteristics.

Methods

Cross‐over study.

Number of women randomized: 25 (13 intervention group; 12 in control group).

Number of withdrawals: not reported.

Number of women analyzed: unclear.

Participants

Country of authors: USA.

Inclusion criteria: women, aged < 41 years, who were anticipated to have limited ovarian reserve based on transvaginal ultrasound showing limited follicles on cycle day 2‐3 or hormonal values (inhibin B, FSH, oestradiol).
Exclusion criteria: not reported.

Mean age: not reported.

Poor response: yes ("limited ovarian reserve").

Interventions

Intervention: COCP + GnRH agonist (leuprolide acetate, microdose) + hMG (300 IU FSH + 75 IU LH). Timing of administration of COCP, hMG and GnRH agonist not reported.

Control: oestradiol (2 mg) in the luteal phase of the preparation cycle + FSH (300 IU), started cycle day 2 + GnRH antagonist (ganirelix acetate) started in late follicular phase + hMG (375 IU FSH + 150 IU LH), timing not reported.

Outcomes

• Ongoing pregnancy: a viable pregnancy, method of assessment not reported.

• Clinical pregnancy: not defined.

• Number of mature oocytes.

• Number of good embryos.

• Implantation rate.

• Cancellation rate.

Notes

Power calculation performed: unclear.

ITT analysis performed: unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomized," method not reported.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding (performance bias and detection bias)
All outcomes

High risk

Unblinded.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Only abstract available. Numbers and reasons for withdrawals not reported.

Selective reporting (reporting bias)

High risk

Data on all planned outcomes reported. Pre‐cross‐over data on primary outcome reported, but on some secondary outcomes (implantation rate, mature oocytes, good embryos) only post‐cross‐over data reported.

Other bias

Unclear risk

No data on baseline characteristics reported.

Methods

Parallel group study.

Number of women randomized: 105 (47 in intervention group; 58 in control group).

Number of withdrawals: 0.

Number of women analyzed: 105.

Length of follow‐up: until end of treatment cycle.

Participants

Country: USA.

Inclusion criteria: day 3 FSH values < 15 mIU/mL.

Exclusion criteria: not reported.

Mean age ± SD: intervention: 36.7 ± 4.8 years; control: 35.8 ± 4.57 years.

Interventions

Intervention: norethindrone acetate (10 mg/day PO) on cycle days 1‐8 + GnRH agonist (leuprolide acetate, 1 mg/day, SC), started cycle day 1 + hMG (225 IU/day IM), started when serum oestradiol level was < 30 pg/mL.
2) GnRH agonist (leuprolide acetate 1 mg/day, SC), started cycle day 1 + hMG (225 IU/day, IM), started when serum oestradiol level was < 30 pg/mL.

Both hMG and GnRH agonist are continued until hCG injection (10,000 IU, IM), administered when the leading follicles reached a diameter of ≥ 18 mm.

Outcomes

• Number of deliveries/ongoing pregnancies; positive foetal heart activity on ultrasound.

• Number of clinical pregnancies; evidence of a clinical gestational sac.

• Days until suppression.

• Number of cysts cycles; intraovarian sonolucent structure with a mean diameter > 14 mm, measured after 8 days of pituitary suppression.

• Number of oocytes retrieved.

• Days of ovarian stimulation.

• Number of ampoules of hMG.

Notes

Power calculation performed: no.

ITT analysis performed: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly assigned by tossing a coin to one of two groups."

Allocation concealment (selection bias)

Low risk

Centralised randomization process.

Blinding (performance bias and detection bias)
All outcomes

High risk

No blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No withdrawals.

Selective reporting (reporting bias)

High risk

All planned outcomes not reported.

Other bias

Low risk

Quote: "The various infertility diagnoses were distributed equally between the control and study groups."

Methods

Parallel group study.

Number of women recruited: 123.

Number of women excluded: 6 (2 due to ovarian cysts ≥ 15 mm, 2 due to raised early follicular phase serum FSH, 2 did not undergo IVF).

Number of women randomized: 117 (63 in intervention group; 54 in control group).

Number of withdrawals: 1 (in intervention group, due to violation of the study protocol).

Number of women analyzed: 116.

Duration of study: 1 year of recruitment.

Source of funding: Schering Health Care Limited, West Sussex, UK, supplied the norethindrone.

Participants

Country of authors: UK and Canada.

Inclusion criteria: aged 18‐44 years at time of screening, duration of infertility ≥ 1 year, early follicular phase serum FSH ≤ 11.0 IU/L, good physical and mental health, suitability for the long‐term buserelin protocol for desensitisation.

Exclusion criteria: endometrioma of the ovary, ovarian cysts (≥ 15 mm) in the early follicular phase, known contraindications to the use of progestogen, GnRH agonists or hMG.

Mean age ± SD: intervention group: 35.3 ± 4.3 years; control group: 33.8 ± 5.5 years.

Interventions

Intervention: norethindrone (10 mg on cycle day 1 and 5 mg twice daily on cycle day 2‐5) + GnRH agonist (buserelin acetate 500 μg/day, SC, long protocol), started on cycle day 2 (dose adjustment after pituitary suppression to 200 μg/day) + hMG (Normegon, 75 IU FSH 2‐5 ampoules/day) or rFSH, started when serum oestradiol ≤ 150 pmol/L.

Control: GnRH agonist (buserelin acetate 500 μg/day, SC, long protocol) started on cycle day 2 (dose adjustment after pituitary suppression to 200 μg/day) + hMG (Normegon, 75 IU FSH 2‐5 ampoules/day) or rFSH, started when serum oestradiol ≤ 150 pmol/L.

Pituitary suppression achieved when there was an absence of follicular activity and endometrial thickness < 5 mm.

hMG or rFSH dose according to woman's age, previous response, basal serum FSH levels and PCOS.

Both hMG/rFSH and GnRH agonist continued until hCG injection (10,000 IU, IM), administered when 2 or 3 leading follicles ≥ 18 mm in diameter.

Outcomes

• Incidence of functional ovarian cysts (≥ 10 mm, measured after 1 week of GnRH agonist).

• Number of days required to achieve pituitary desensitisation.

• Number of hospital visits before ovarian stimulation.

• Number of preovulatory follicles and mature oocytes.

• Fertilisation rate.

• Number of good‐quality embryos produced and transferred.

• Implantation rate.

• Clinical pregnancy rate: positive pregnancy test with evidence of a gestational sac.

• Amount of gonadotrophins administered: measured in ampoules.

• Pregnancy loss.

Notes

Power calculation performed: yes.

ITT analysis performed: no.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Eligible patients were randomly assigned in a ratio of 1:1 by means of computer‐generated random numbers. To ensure similar distributions of age in the two groups, separate randomization schedules were drawn up for women < 40 years old and women ≥ 40 years old by use of stratified randomised blocks."

Allocation concealment (selection bias)

Low risk

Quote: "Selection into the groups (and of administration of the appropriate treatment protocol) was performed by the clinic nurses by using a series of consecutively numbered sealed envelopes (one for each age group)."

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Quote: "Although the patient could guess her treatment status, treatment allocation was not recorded in the clinical notes, and all clinicians were blinded to the status of study participants until the trial was over."

However, no information on outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Proportions of withdrawals fairly balanced between the 2 groups.

Selective reporting (reporting bias)

Low risk

Data on all planned outcomes reported.

Other bias

Low risk

No significant baseline imbalance between groups with regard to age, duration of infertility, previous attempts, baseline serum FSH, polycystic ovaries and cause of infertility.

Methods

Parallel group study.

Number of women randomized: 100 (number of women per group not reported).

Number of withdrawals: 10 (4 due to personal reasons and 6 due to major protocol violation).

Number of women analyzed: 90 (47 in intervention group; 43 in control group).

Duration of study: 1 IVF‐ET cycle, from day 20 of the previous cycle to day of hCG administration (information obtained from contact person).

Participants

Country of authors: France.

Inclusion criteria: aged ≤ 38 years; regular, ovulatory menstrual cycles every 25‐35 days; both ovaries present; no current or past diseases affecting ovaries or gonadotrophin or sex steroid secretion, clearance or excretion; BMI 18‐27 kg/m²; no hormone therapy during the past 6 weeks; adequate visualisation of both ovaries in transvaginal ultrasound scans.

Exclusion criteria: not reported.

Median age (range): intervention group: 33 (26‐38) years; control group: 33 (25‐38) years.

Interventions

Intervention: micronised 17β‐E₂ (4 mg/day, PO), started cycle day 20 until day 2 of the next cycle + rFSH (225 IU/day, SC) on cycle days 3‐7 + GnRH antagonist (cetrorelix acetate 3 mg single dose, SC) when ≥ 1 follicle > 13 mm in diameter.

Control: rFSH (225 IU/day SC) on cycle days 3‐7 + GnRH antagonist (cetrorelix acetate 3 mg single dose, SC) when ≥ 1 follicle > 13 mm in diameter.

rFSH dose adjustments according to follicle growth determined by serum oestradiol levels and ultrasound monitoring.

Outcomes

• Days of GnRH antagonist administration.

• Day of hCG administration.

• Dose of gonadotrophins.

• Number of mature follicles.

• Number of embryos transferred.

• Clinical pregnancy rates per cycle (cycles equivalent to number of participants); presence of a gestational sac with foetal heart activity at 6 weeks on ultrasound scan.

Notes

Power calculation performed: yes.

ITT analysis performed: no

Our data analysis in this review includes 90 women with full follow‐up. We did not include all randomized women because it is unclear how many women were randomized to each group before dropouts.

The study publication reports very low measures of variability which can be to be assumed SEs and which we have converted to SDs

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Women randomly received...", "...according to a computer‐generated, blocked randomization list."

Allocation concealment (selection bias)

Low risk

Quote: "Treatment allocation was decided by an independent person."

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No blinding, information obtained from contact person.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Unclear how many withdrew in each group and data not analyzed on the basis of ITT.

Selective reporting (reporting bias)

High risk

All planned outcomes not reported.

Other bias

Low risk

No difference in baseline characteristics with regard to age, indication for IVF‐ET, duration of infertility, rank of the current IVF‐ET attempt, menstrual cycle length, day 3 serum FSH and oestradiol.

Methods

Parallel group study.

Number of women recruited: 22.

Number of women randomized: 22 (16 in intervention group; 6 in control group).

Number of withdrawals: 1 (both in intervention group, due to spontaneous pregnancies).

Number of women analyzed: 20.

Participants

Country of authors: Brazil.

Inclusion criteria: women without specific ovulatory dysfunction, aged ≤ 37 years, who would be submitted to ovarian stimulation.

Exclusion criteria: not reported.

Mean age ± SD: intervention group: 32.2 ± 2.1 years; control group: 31.8 ± 1.9 years.

Interventions

Intervention: oestradiol valerate (4 mg/day) for 14 days, started cycle day 21 + rFSH (150‐300 IU) (fixed dose for 5 days), started post‐treatment day 1 + GnRH antagonist (ganirelix acetate 0.25 mg/day), started when follicular diameter ≥ 15 mm.

Control: GnRH agonist (nafarelin acetate 200 μg twice daily, nasal), started cycle day 21 + rFSH (150‐300 IU) (fixed dose for 5 days), started stimulation day 14.

Both rFSH and GnRH analogues continued until hCG injection (5000‐10,000 IU), administered when ≥ 2 follicles were ≥ 17 mm in diameter.

Outcomes

• Clinical pregnancy rate: ≥ 1 foetal heart beats confirmed with ultrasound, performed at least 4 weeks after embryo transfer.

• Ovarian cyst: intraovarian sonolucent structure with mean diameter of > 14 mm, time of measurement not reported.

• OHSS: not defined.

• Values of LH, oestradiol, progesterone.

• Dose of FSH.

• Number of collected oocytes.

• Number of oocytes in metaphase II.

• Fertilisation rate.

• Number of transferred embryos.

• Embryo implantation rate.

• Gestation rate per embryo transfer.

Notes

Power calculation performed: no.

ITT analysis performed: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation by drawing lots after constructing a table of distribution.
2:1 randomization (intervention:control).

Allocation concealment (selection bias)

High risk

After drawing lots, clinicians and participants could see in the table to which treatment they were assigned to.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Insufficient information to make a conclusive judgement.

Incomplete outcome data (attrition bias)
All outcomes

High risk

There was imbalance in the proportions of withdrawals between the 2 groups and data analyzed on the basis of ITT.

Selective reporting (reporting bias)

High risk

All planned outcomes not reported.

Other bias

Low risk

No significant difference in baseline characteristics with regard to age.

Methods

2‐arm parallel RCT.

Number of women randomized: 228 (115 in intervention; 113 in control).

Withdrawals: not reported.

Number of women analyzed: not reported.

Participants

Country: Spain.

Inclusion criteria: regular cycle women under 39 years, < 3 previous IVF attempts.

Exclusion criteria: previous low response to COH, ovarian surgery or PCOS.

Mean age: intervention group: 34.1 years; control group: 33.7 years.

Setting: not reported.

Interventions

Intervention: COCP (ethinyl oestradiol 30 μg + desogestrel 150 μg) for 12‐16 days and COH started on day 5 post COCP using GnRH antagonist.

Control: GnRH agonist long protocol from days 20‐22 of the previous cycle.

Outcomes

• Duration of stimulation.

• FSH used.

• Number of oocyte retrieved.

• Miscarriage rate.

• Multiple pregnancy rate.

• Ongoing pregnancy.

Notes

Duration of stimulation, FSH used and number of oocyte retrieved were continuous variables.

Power calculation was not reported.

ITT analysis: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated list with consecutive inclusion.

Allocation concealment (selection bias)

Low risk

Opaque consecutively numbered envelopes with assignment under nurse control.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Proportions of withdrawals and reasons for withdrawals not reported.

Selective reporting (reporting bias)

Low risk

All prespecified outcomes reported.

Other bias

Low risk

Groups comparable at baseline with regard to demographic characteristics.

Methods

Parallel group study.

Number of women randomized: 100 (50 in each group).

Number of withdrawals: 16 (7 in intervention group; 9 in control group).

Number of women analyzed: 100 (ITT analysis).

Participants

Country: Spain.

Inclusion criteria: aged 18‐38 years, regular normo‐ovulatory menstrual cycles (26‐35 days), BMI < 30 kg/m², normal cycle day 3 basal serum hormone levels (FSH < 10 IU/L and oestradiol < 60 pg/mL) and < 3 previous IVF/ICSI attempts.

Exclusion criteria: previous ovarian surgery, low ovarian response (cancellation of cycle due to poor follicular development after ≥ 7 days of gonadotropin stimulation or < 5 oocytes retrieved) in previous IVF/ICSI cycle and PCOS.

Mean age ± SD: intervention group: 33.9 ± 3.4 years; control group: 34.5 ± 3.1 years.

Setting: single hospital clinic in Madrid, Spain.

Interventions

Intervention: COCP: (ethinyl oestradiol 30 μg + levonorgestrel 150 μg) on day 1 or 2 of cycle prior to IVF/ICSI and continued for 12‐16 days, with stimulation starting 5 days after stopping pretreatment.

Control: (oestradiol valerate 4 mg/day (2 mg × 2)) from day 20 of menstrual cycle for 5‐12 days until the day before starting stimulation.

In both groups, GnRH antagonist (ganirelix 0.25 mg/day) started when the leading follicle reached 13 mm in diameter and ovarian triggering performed with rhCG (250 μg) (when 2 leading follicles reached ≥ 17 mm mean diameter).

Outcomes

Primary:

• Ongoing pregnancy rate.

Secondary:

• Implantation rate.

• Clinical pregnancy rate.

• Miscarriage rate.

• Live birth rate.

Notes

Power calculation for sample size: yes but not achieved because this was a single‐centre study.

ITT analysis: yes.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random number list.

Allocation concealment (selection bias)

Low risk

Consecutively numbered opaque envelopes.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Although personnel involved in data collection and data analysis blinded it was not reported whether other personnel and participants were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Reasons for withdrawals and proportions of withdrawals were fairly balanced between groups and data were analyzed on the basis of ITT.

Selective reporting (reporting bias)

Low risk

All prespecified outcomes reported.

Other bias

Low risk

Groups balanced at baseline with respect to demographic characteristics.

Methods

Parallel group study.

Number of women randomized: 45 (20 in intervention group; 25 in control group).

Number of withdrawals: not reported.

Number of women analyzed: not reported.

Participants

Country of authors: France.

Inclusion criteria: not reported.

Exclusion criteria: not reported.

Mean age: not reported.

Interventions

Intervention: norethisterone (10 mg/day) for 10‐15 days + GnRH agonist (DTRP6‐LHRH 100 μg/day).

Control: GnRH agonist (DTRP6‐LHRH 100 μg/day).

Timing of treatments not reported.

Outcomes

• Oestradiol and progestogen levels.

Notes

Power calculation performed: unclear.

ITT analysis performed: unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomised," method not reported.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Numbers and reasons of withdrawals not reported.

Selective reporting (reporting bias)

High risk

All planned outcomes not reported. No data on pregnancy rates.

Other bias

Unclear risk

Baseline demographic characteristics not reported.

Methods

Academic, multicentre, parallel group study.

Number of women randomized: 64 (32 in each group).

Number of withdrawals: 1 (in intervention group, due to unwillingness to take OCP).

Number of women analyzed: 63.

Source of funding: Serono Geneva supplied the antide.

Participants

Country: the Netherlands and Belgium.

Inclusion criteria: regular IVF or ICSI indication (i.e. idiopathic infertility after 6 unsuccessful IUIs, infertility based on a male or tubal factor); spontaneous, regular ovulatory menstrual cycle; 2 ovaries and a normal uterine cavity; aged 18‐38 years.

Exclusion criteria: FSH ≥ 12 IU/L on cycle day 2‐4; BMI > 30 kg/m²; abnormal gynaecological bleeding; extrauterine pregnancy within the last 3 months; previous ART cycles with < 3 oocytes or severe OHSS; any contraindication to receive gonadotrophins or OCP; PCOS.

Mean age ± SD: intervention group: 32.3 ± 4.0 years; control group: 33.3 ± 3.8 years.

Interventions

Intervention: COCP (ethinyl oestradiol 30 μg + levonorgestrel 150 μg) for 14‐28 days, started cycle day 2 or 3 + rFSH (150‐300 IU), started post‐treatment day 2 or 3 (= stimulation day 1) + GnRH antagonist (antide 0.5 mg/mL daily), started stimulation day 6.

Control: rFSH (150‐300 IU), started on cycle days 2 or 3 (= stimulation day 1) + GnRH antagonist (antide 0.5 mg/mL daily), started on stimulation day 6.

rFSH dose adjustments after 5 days of stimulation (up to a maximum of 450 IU), according to number and size of oocytes and risk for OHSS.

Both rFSH and GnRH antagonist were continued until hCG injection (6500 IU), administered when ≥ 1 follicle reached a diameter ≥ 18 mm + ≥ 2 follicles reached a diameter ≥ 16 mm.

Outcomes

• Ongoing pregnancy rate: positive heart activity at gestational age of 12 weeks.

• Clinical pregnancy rate: presence of ≥ 1 intrauterine sac confirmed with ultrasound at gestational age of 6 weeks.

• Number of oocytes retrieved.

• Ovarian cysts: not defined.

• Number and size of follicles.

• Cumulative dose of rFSH.

• Duration of r‐FSH treatment.

• Implantation rates.

• Serum hormone concentrations.

• Endometrial thickness.

• Bleeding pattern.

Notes

Power calculation performed: yes.

ITT analysis performed: no.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "64 patients were randomly allocated according to a computer‐generated, blocked randomization list. The randomization was stratified by centre."

Allocation concealment (selection bias)

Low risk

Quote: "Treatment allocation was decided by an independent person from an independent monitoring company..."

Blinding (performance bias and detection bias)
All outcomes

High risk

Open‐label study.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Proportions of withdrawals were fairly balanced between groups (3% in intervention group vs 0% in control group).

Selective reporting (reporting bias)

Low risk

Data on all planned outcomes reported.

Other bias

Low risk

No significant differences in baseline characteristics with regard to age, BMI, cycle length, primary infertility, smoking habits, duration of infertility, type of infertility and antral follicle count.

Methods

Multicentre (8 IVF centres), parallel group study.

Number of women recruited: 216.

Number of women excluded: 34 (reasons not reported).

Number of women randomized: 182 (91 in each group).

Number of withdrawals: 22 (10 in intervention group: 1 due to hepatitis B, 1 due to non‐compliance, 1 due to personal reasons, 2 due to insufficient follicular response, 1 due to conversion to IUI, 1 due to absence of mature oocytes, 3 due to absence of viable embryos; 12 in control group: 2 due to spontaneous pregnancy, 3 due to failure of desensitisation, 1 due to personal reasons, 1 due to stimulation failure, 3 due to absence of 'mature' oocytes, 2 due to failure of fertilisation).

Number of women analyzed: 182.

Participants

Country of authors: the Netherlands, Belgium, France and Austria.

Inclusion criteria: regular IVF/ICSI indication, male partner with viable sperm in the ejaculate, aged 18‐39 years.

Exclusion criteria: any previous ART cycles with < 3 oocytes or ≥ 3 consecutive ART cycles without a clinical pregnancy, any contraindication to ART, gonadotrophins or OCPs, significant systemic disease.

Mean age ± SD: intervention group: 32.8 ± 3.8 years; control group: 32.2 ± 4.2 years.

Interventions

Intervention: COCP (ethinyl oestradiol 30 μg + levonorgestrel 150 μg daily), started within 5 days of onset of menses for 21‐28 days (stop on a Sunday) + r‐hFSH (150‐225 IU/day), started post‐treatment day 5 (= stimulation day 1) + GnRH antagonist (cetrorelix acetate 0.25 mg/day, SC), started stimulation day 6.

Control: GnRH agonist (buserelin acetate 500 μg/day, SC), started cycle day 18‐22 (reducing dose to 200 μg/day when downregulation was achieved) + r‐hFSH (150‐225 IU/day), started when downregulation was achieved.

After 5 days of r‐hFSH treatment, the dose could be adjusted by steps of 75 IU (maximal dose 450 IU/day), according to the ovarian response.

Both rhFSH and GnRH analogues were continued until hCG injection, administered when the largest follicle reached a mean diameter ≥ 18 mm and ≥ 2 other follicles had a mean diameter ≥ 16 mm.

Outcomes

• Ongoing pregnancy rate: positive heart activity at a gestational age of 12 weeks.

• Clinical pregnancy rate: presence of ≥ 1 foetal sacs with or without heart activity confirmed with ultrasound, performed at least 4 weeks after embryo transfer.

• Numbers of oocytes retrieved per woman.

• Multiple clinical pregnancies.

• Total number of oocyte retrievals performed on weekends or public holidays.

• Cancellation rate.

• Drug requirements.

• Total number of (good quality) embryos.

• Implantation rate.

Notes

Power calculation performed: yes.

ITT analysis performed: no.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "182 were randomly allocated to...", "The treatment assigned to each patient was determined according to a computer‐generated concealed randomization list. Randomization was performed by centre."

Allocation concealment (selection bias)

Unclear risk

"Concealed randomization list," method not reported.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All women randomized were included in final analysis.

Selective reporting (reporting bias)

Low risk

Data on all planned outcomes reported.

Other bias

Low risk

No significant difference in baseline characteristics with regard to age, race, duration of infertility, cause of infertility, smoking habits, primary infertility, number of previous ART attempts, number of follicles, endometrial thickness, FSH levels and oestradiol levels.

P value of BMI was 0.04.

Methods

Single‐centre, parallel group study.

Number of women recruited: 60.

Number of women excluded: 4 (2 refused to participate, 2 did not meet inclusion criteria).

Number of women randomized: 56 (27 in intervention group; 29 in control group).

Number of withdrawals: 7 (2 in intervention group: 1 due to poor ovarian response, 1 due to personal reasons; 5 in control group: 2 due to inadequate ovarian response, 3 due to risk of severe OHSS).

Number of women analyzed: 49.

Participants

Country: Taiwan.

Inclusion criteria: PCOS.

Exclusion criteria: diagnosis of congenital adrenal hyperplasia, Cushing's syndrome, androgen‐producing tumours, hyperprolactinaemia or thyroid dysfunction; aged > 38 years; serum FSH levels > 12 mIU/mL.

Mean age ± SD: intervention group: 31.4 ± 3.5 years; control group: 31.7 ± 3.7 years

Interventions

Intervention: COCP (Diane‐35, oral) on cycle days 5‐25 for 3 consecutive cycles + GnRH antagonist (cetrorelix acetate 0.25 mg single dose, SC on post‐treatment day 3; 0.125 mg/day on post‐treatment days 4‐9; and 0.25 mg/day started post‐treatment day 10 + hMG 150 IU/day), started post‐treatment day 4.

Control: GnRH agonist (buserelin acetate 500 μg/day, long protocol) started day 3 of induced or spontaneous menstruation, and 250 μg/day started day of ensuing pituitary downregulation + hMG (150 IU/day) for 6 days started when pituitary downregulation was achieved.

hMG dose can be adjusted according to woman's follicular response.

Pituitary downregulation achieved when serum oestradiol levels < 50 pg/mL and there was an absence of ovarian cysts > 10 mm in diameter.

Both GnRH analogues and hMG were continued until hCG injection (10,000 IU, IM), administered when ≥ 2 follicles reached 18 mm in diameter with adequate oestradiol response.

Outcomes

• Fertilisation.

• Clinical pregnancy: presence of ≥ 1 foetal heart beat confirmed with ultrasound, performed 7 weeks after embryo transfer.

• Implantation rates.

• Serum LH and testosterone status upon starting and during hMG administration.

• Total days and amount of gonadotrophins administered: measured in ampoules.

• Pregnancy loss.

• Multiple pregnancy rate: ongoing or live born.

• OHSS: not defined.

Notes

Power calculation performed: yes.

ITT analysis performed: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was done by opening sealed envelopes containing computer‐generated block randomization numbers with a block size of 10."

Allocation concealment (selection bias)

Low risk

Sealed envelopes.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Quote: "The laboratory staff were blinded to the stimulation protocol."

Unclear if treating physicians were blinded.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Reasons for withdrawals and proportions of withdrawals were not balanced between groups and data were not analyzed on the basis of ITT.

Selective reporting (reporting bias)

Low risk

Data on all planned outcomes were reported.

Other bias

Low risk

No significant difference in baseline characteristics with regard to age, duration of infertility, BMI and hormonal levels.

Methods

Parallel group study.

Number of women randomized: 120.

Number of withdrawals: 0.

Number of women analyzed: 120.

Duration of study: 1 cycle.

Participants

Country of authors: South Korea.

120 poor responders (repeated day 3 levels of FSH > 8.5 mIU/mL or antral follicle count ≤ 5, or both). 40 in each group.

Inclusion criteria: not clearly stated.

Exclusion criteria: PCOS (Rotterdam criteria).

Mean age ± SD: group 1: 36.7 ± 3.1 years; group 2: 35.9 ± 2.8 years; group 3: 36.4 ± 3.3 years.

Setting: university‐based infertility clinic, Seoul. Korea.

Interventions

Pretreatment was ethinyl oestradiol 0.03 mg and levonorgestrel 0,15 mg for 21 days in the cycle preceding COS.

Group 1: GnRH antagonist multiple dose protocol after OCP pretreatment. Ovarian stimulation started 5 days after OCP discontinued using rFSH (225 IU/day, dose adjusted every 3‐4 days). Cerotide (0.25 mg) started when lead follicle was 14 mm diameter and continued until day of hCG injection.

Group 2 GnRH antagonist multiple dose protocol without OCP pretreatment. Ovarian stimulation started on cycle day 3 using rFSH (225 IU/day, dose adjusted every 3‐4 days). Cerotide (0.25 mg) started when lead follicle was 14 mm diameter and continued until day of hCG injection.

Group 3: GnRH agonist luteal low‐dose long protocol without OCP pretreatment. Daily injection of decapeptyl (0.1 mg) started from mid‐luteal phase and continued until menses followed by a dose reduction to 0.05 mg daily and continued until day of hCG injection.

Outcomes

Primary:

• Number of mature oocytes retrieved.

Secondary:

• Total amount and days of rFSH.

• Number of fertilised oocytes and grade I and II embryos.

• Implantation rate ongoing pregnancy rate.

• Clinical pregnancy rate per cycle and live birth rate per cycle.

• Miscarriage rate.

Notes

Power calculation: yes.

ITT analysis: yes.

Earlier publications were Kim 2005 and Kim 2009.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Computer generated lists."

Allocation concealment (selection bias)

Unclear risk

Quote: "The sequence of allocation to the three groups was provided to the investigating physicians."

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

In groups 1 and 3 there were no losses, withdrawals or cancellations. In group 2, 1 cycle was cancelled before embryo transfer; all women randomized were included in data analysis.

Selective reporting (reporting bias)

Low risk

All outcomes listed were reported although multiple pregnancy was reported it is not listed a priori.

Other bias

Low risk

Groups similar at baseline with respect to demographic characteristics.

Methods

Academic, single centre, parallel group study.

Number of women randomized: 504 (250 in intervention group; 254 in control group).

Number of withdrawals: 79 (36 in intervention group: 28 due to personal reasons, 6 due to abnormal steroid levels, 2 due to spontaneous pregnancy; 43 in control group: 31 due to personal reasons, 10 due to abnormal steroid levels, 2 due to spontaneous pregnancy).

Number of women analyzed: 425.

Duration of study: 3 years of recruitment.

Source of funding: the Fund for Scientific Research Flanders.

Participants

Country: Belgium.

Inclusion criteria: aged < 39 years, ≤ 3 previous ART attempts, BMI 18‐29 kg/m², FSH < 10 IU/L, LH < 10 IU/L.

Exclusion criteria: polycystic ovaries, endometriosis > stage II, poor response to ovarian stimulation

Mean age ± SD: intervention group: 31.2 ± 0.3 years; control group: 31.5 ± 0.3 years.

Interventions

Intervention: COCP (ethinyl oestradiol 30 μg + desogestrel 150 μg) for 14 days, started cycle day 1 + rFSH (200 IU/day) (fixed dose), started post‐treatment day 5 + GnRH antagonist (ganirelix acetate).

Control: rFSH (200 IU/day) (fixed dose), started cycle day 2 + GnRH antagonist (ganirelix acetate).

Timing of GnRH antagonist not reported.

Both rFSH and GnRH antagonist continued until hCG injection (10,000 IU), administered when ≥ 3 follicles ≥ 17 mm in diameter.

Outcomes

• Ongoing pregnancies per started cycles equivalent to number of participants): developing beyond 12 weeks.

• Stimulation length.

• Gonadotrophin consumption.

• Early pregnancy loss: proportion of women with initially positive hCG in whom pregnancy failed to develop before 12 weeks of gestation.

Notes

Power calculation performed: yes.

ITT analysis performed: no.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomized on the basis of a computer‐generated list."

Allocation concealment (selection bias)

High risk

Quote: "... randomized at the outpatient clinic by the treating physician." "The sequence of allocation was not concealed and thus it was possible for the treating physician to be aware of the next treatment to be allocated."

Blinding (performance bias and detection bias)
All outcomes

High risk

Treating physician not blinded as this was the person to allocate the participants.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Reasons for withdrawals and proportions of withdrawals fairly balanced between groups.

Selective reporting (reporting bias)

Low risk

Data on all planned outcomes reported.

Other bias

Low risk

No significant differences in baseline characteristics with regard to age, BMI, primary/secondary infertility, duration of infertility, number of previous IVF trials, indication for treatment.

Methods

2‐arm parallel multicentre RCT.

Number of women randomized: 298 (154 in intervention group; 144 in control group).

Withdrawals: not reported.

Number of women analyzed: not reported.

Participants

Country: Poland.

Inclusion criteria: women aged < 40 years, AMH > 0.6 ng/mL, BMI 18‐29 kg/m², and undergoing a first or second treatment cycle of IVF with ICSI.

Exclusion criteria: presence of endometriosis and pre‐implantation diagnosis cycles.

Mean age ± SD: intervention group: 32.5 ± 3.97; control group: 32.5 ± 2.96 years.

BMI (mean ± SD): intervention group: 22.2 ± 1.3 kg/m²; control group: 22.4 ± 1.1 kg/m².

Setting: infertility clinics, 2 centres.

Interventions

Intervention: OCP pretreatment: pretreated with COCP (Ovulastan, Adamed, Pabianice, Poland) from day 2‐4 of the cycle. Beginning from the day 14 of cycle, pituitary was suppressed by administering triptorelin (0.1 mg) every 2 days; treatment continued for 2 weeks. Ovarian stimulation started with gonadotropin injections (150‐225 IU/day) starting from days 2‐4 of cycle and continued with a daily dose of triptorelin (0.1 mg) until hCG injection was administered 36 hours before retrieval.

Control: oestradiol pretreatment: pretreated with oral oestradiol (2 mg twice daily) from day 20 of natural cycle until the day 1‐4 of the new cycle. Ovarian stimulation started with hMG injections (150‐225 IU/day) starting from days 2‐4 of cycle, 2 days after discontinuation of oestradiol administration, and continued with a daily dose of triptorelin (0.1 mg) until the hCG injection 5000 IU was administered 36 hours before retrieval.

Outcomes

• Clinical pregnancy.

• Number of oocyte retrieved.

• Multiple pregnancy.

• Duration of stimulation days.

Notes

All outcomes were measured in denominators other than "per woman randomized."

Power calculation was performed.

No, outcome measured in denominators other than "per woman randomized."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation using "block randomization software."

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Only doctors who retrieved oocytes and embryologists were blinded to treatment groups.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No information reported on reasons for withdrawals and proportion of withdrawals.

Selective reporting (reporting bias)

Low risk

Important outcome measures were prespecified in the methods section and data were reported.

Other bias

Low risk

Demographic and infertility characteristics similar between the two groups.

Methods

Parallel group multicentre study.

Number of women randomized: 442 (223 in intervention group; 219 in control group).

Number of withdrawals: 34 (14 in intervention group; 20 in the control group due to adverse events, withdrawal of consent, spontaneous pregnancy and "other" reasons).

Number of women analyzed: 408 (209 in intervention group; 199 in control group).

Participants

Country: multicentre (USA, Europe).

Inclusion criteria: aged 18‐39 years, BMI ≤ 32 kg/m², menstrual cycle length 24‐35 days, access to ejaculatory sperm, indication for COS and IVF or ICSI or IVF plus ICSI and scheduled for first COS cycle.

Exclusion criteria: history of endocrine abnormality, < 2 ovaries or any other ovarian abnormality, presence of unilateral or bilateral hydrosalpinx, clinically relevant pathology affecting the uterine cavity, fibroids ≥ 5 cm, history of recurrent miscarriage (≥ 3), with or without FSH or LH levels > 12 IU/L in the early follicular phase.

Mean age ± SD: intervention group: 31.8 ± 3.7 years; control group: 31.6 ± 4.1 years.

Setting: 8 centres in USA, 6 centres in Europe (Denmark, Germany, Spain and Turkey).

Interventions

Intervention: COCP pretreatment: Marvelon (ethinyl oestradiol 30 μg + desogestrel 150 μg) for 14‐21 days. Women started daily rFSH 5 days after stopping COCP pretreatment provided a withdrawal bleed occurred.

Control: no pretreatment: daily rFSH on day 2 or 3 of the next menstrual cycle.

In both groups, a single SC injection of rFSH (200 IU) started on stimulation day 1 and continued daily up to and including day of triggering of final oocyte maturation by urinary hCG. Maximum total duration of stimulation 19 days. Starting on day 5 of stimulation, all women received ganirelix (0.25 mg/day).

Outcomes

Primary:

• Number of oocytes obtained.

Secondary:

• Number of follicles ≥ 11 mm at day 8.

• Number of follicles ≥ 11 mm at day of hCG.

Other:

• Duration of stimulation.

• Total rFSH dose.

• Number of embryos.

• Number of embryos transferred.

• Implantation rate.

• Clinical pregnancy rate.

• Ongoing pregnancy rate.

Notes

Power calculation for sample size: yes (200 women per group with an additional 20 to compensate for discontinuation).

ITT analysis: modified: all randomized women who received at least 1 dose of rFSH.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding (performance bias and detection bias)
All outcomes

High risk

Study reported as open label.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Minimal (< 10%) discontinuations and balanced between groups with similar reasons given.

Selective reporting (reporting bias)

Low risk

All prespecified outcomes reported.

Other bias

Low risk

Groups appeared balanced at baseline with respect to age, BMI, age at menarche, duration of infertility, cycle length, alcohol use and smoking.

Methods

Parallel group study.

Number of women randomized: 150 (75 in each group).

Number of withdrawals: not reported.

Number of women analyzed: unclear.

Participants

Country of authors: Austria.

Inclusion criteria: women undergoing COS and IVF.

Exclusion criteria: not reported.

Mean age: not reported.

Interventions

Intervention: COCP (ethinyl oestradiol 30 μg + desogestrel 150 μg daily), started cycle day 1 for 18‐28 days (stopped on a Sunday) + rFSH (150 IU/day), started post‐treatment day 5 (= stimulation day 1) + GnRH antagonist (cetrorelix acetate 0.25 mg/day), started stimulation day 6.

Control: rFSH 150 IU/day, started cycle day 3 (= stimulation day 1) + GnRH antagonist (cetrorelix acetate 0.25 mg/day), started stimulation day 6.

Both rFSH and GnRH antagonist continued until final follicular maturation.

Outcomes

• Number of cancelled cycles.

• Number of oocytes.

• Number of transferred embryos.

• Clinical pregnancy rate; not defined.

• Number of weekend oocyte retrievals.

Notes

Power calculation performed: unclear.

ITT analysis performed: unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomized," method not reported.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Number and reasons for withdrawals not reported.

Selective reporting (reporting bias)

High risk

All planned outcomes not reported.

Other bias

Unclear risk

No data on baseline characteristics reported.

Methods

2‐arm parallel group study.

Number of women randomized: 150 women (75 in each group).

Number of withdrawals: 4 women in intervention group; 3 in control group did not have embryo transfer.

Number of women analyzed: 71 in intervention group; 72 in control group.

Duration of study: 1 year of recruitment.

Source of funding: Yazd IVF Centre, Yazd, Iran.

Participants

Country of authors: Argentina.

Inclusion criteria: aged < 39 years, first IVF attempt, baseline FSH < 12 mlU/mL.

Exclusion criteria: PCOS, prior ovarian surgery and TESE needing.

Mean age: not reported.

Interventions

Intervention: COCP group: April® (ethinyl oestradiol 20 μg + levonorgestrel 100 μg) for 21 days in preceding cycle and follicular development induced using rFSH (200 IU/day) from menstrual cycle day 2‐3.

Control: rFSH (200 IU/day) from menstrual cycle day 2‐3.

Both groups received GnRH antagonist (cetrorelix 0.25 mg, SC) in flexible protocol starting when the leading follicle reached 14 mm continuing daily until the day of hCG administration.

Outcomes

• Dose of gonadotrophin administered.

• Days of gonadotrophin treatment.

• Clinical pregnancy.

Notes

Power calculation not reported.

ITT: no.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Proportions of exclusion and reason for exclusion similar between groups.

Selective reporting (reporting bias)

Low risk

All reported outcomes pre‐specified in the methods section.

Other bias

Unclear risk

Insufficient information to make a conclusive judgement.

Methods

Academic, single‐centre, parallel group study.

Number of women randomized: 54 women (number of women per group not reported).

Number of withdrawals: 3 women excluded due to incomplete data.

Number of women analyzed: 51.

Duration of study: 1 year of recruitment.

Source of funding: Yazd IVF Centre, Yazd, Iran.

Participants

Country: Iran.

Inclusion criteria: women undergoing IVF and ICSI.

Exclusion criteria: not reported.

Mean age ± SD: intervention: 31.48 ± 5.82 years; control: 35.27 ± 4.13 years.

Interventions

Intervention: COCP (ethinyl oestradiol 30 μg + desogestrel 150 μg), on cycle days 1‐14 + GnRH agonist (triptorelin acetate depot 3.75 mg, IM) single dose on post‐treatment day 1 + hMG (FSH 75 IU + LH 75 IU), started post‐treatment day 2.

Control: GnRH agonist (triptorelin acetate depot 3.75 mg, IM) single dose on cycle day 1 + hMG (FSH 75 IU + LH 75 IU), started cycle day 1.

Outcomes

• Cyst formation > 28 mm: measured 7 and 14 days after pituitary suppression.

• Number of follicles.

• Number of oocytes retrieved.

• Implantation rate.

• Clinical pregnancy rate: presence of ≥ 1 foetal heart beats confirmed with ultrasound performed ≥ 4 weeks after embryo transfer.

Notes

Power calculation performed: no.

ITT analysis performed: unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomized allocation method," method not reported.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No information on reasons for withdrawals and proportions of withdrawals per treatment group.

Selective reporting (reporting bias)

Unclear risk

All planned outcomes not reported.

Other bias

Unclear risk

Number of women per group not reported.

Quote: "The etiology and duration of infertility were equally distributed among the groups." No table of demographic characteristics available.

Methods

Multicentre (10 IVF centres), parallel group study.

Number of women randomized: 351 (117 in each group).

Number of withdrawals: 19 (5 due to spontaneous pregnancy: 2 in COCP group; 3 in GnRH antagonist group). Other reasons not reported.

Number of women analyzed: 332 (111 in COCP group; 110 in GnRH antagonist group; 111 in GnRH agonist group).

Participants

Country: Australia, Denmark, Jordan and Norway.
Inclusion criteria: healthy women of infertile couples, aged 18‐39 years, BMI 18‐29 kg/m², bodyweight ≤ 90 kg, normal menstrual cycle with a range of 24‐35 days and intra‐individual variation of ± 3 days.

Exclusion criteria: contraindications for the use of gonadotrophins, endocrine abnormalities (e.g. PCOS), > 3 unsuccessful COS cycles, history of low or no ovarian response during FSH/hMG treatment, clinically relevant abnormal laboratory values (including hormones) or medical examination findings.

Mean age ± SD: COCP group: 32.7 ± 3.9 years; GnRH antagonist group: 32.1 ± 3.7 years; GnRH agonist group: 32.2 ± 4.0 years.

Interventions

COCP group: COCP (ethinyl oestradiol 30 μg + desogestrel 150 μg daily), started cycle day 1 for 14‐28 days (depending on the planned started of rFSH treatment) + rFSH (follitropin beta 200 IU/day, SC), started post‐treatment day 2 (= stimulation day 1) + GnRH antagonist (ganirelix acetate 0.25 mg/day, SC), started stimulation day 5 or 6.

GnRH antagonist: rFSH (follitropin beta 200 IU/day, SC), started cycle day 2 or 3 (= stimulation day 1) + GnRH antagonist (ganirelix acetate 0.25 mg/day, SC), started stimulation day 5 or 6.

GnRH agonist: nafarelin acetate (0.8 mg/day, intranasal), started cycle day 21‐24 + rFSH (follitropin beta 200 IU/day, SC), started when downregulation (i.e. serum oestradiol ≤ 50 pg/mL) achieved after 2‐4 weeks of GnRH agonist treatment).

After 5‐6 days of rFSH treatment, dose could be adjusted depending on the ovarian response as assessed by ultrasound.

rFSH and GnRH analogues are both continued until hCG injection (10,000 IU, SC or IM), administered when ≥ 3 follicles ≥ 17 mm in diameter, or ≥ 1 follicle ≥ 20 mm in diameter.

Outcomes

• Ongoing pregnancy rate: assessed by ultrasound at ≥ 12‐16 weeks.

• Number of cumulus‐oocyte complexes.

• Number of grade 1 or 2 embryos.

• Number and size of follicles.

• Serum hormone values.

• Duration of rFSH treatment.

• Total rFSH dose.

• Number of good‐quality embryos.

• Implantation rate.

• Incidences of LH rises.

• Pregnancy loss.

• OHSS: according to WHO classification.

Notes

Power calculation performed: yes.

ITT analysis performed: no.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The subjects were randomly assigned..." "To improve balance, the randomization of subjects to treatment was stratified for type of infertility (primary or secondary), IVF or ICSI, centre, and age."

Method not reported.

Allocation concealment (selection bias)

Low risk

Quote: "...by central remote allocation."

Blinding (performance bias and detection bias)
All outcomes

High risk

Open‐label study.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Proportions of withdrawals fairly balanced between groups although reasons for withdrawals were not completely reported.

Selective reporting (reporting bias)

Low risk

Data on all planned outcomes reported.

Other bias

Low risk

No differences in baseline characteristics with regard to age, BMI, height and weight.

Methods

Parallel group study.

4 study arms (A1+A2 and B1+B2), of which we can only include 2 study arms (A2 and B2).

Number of women randomized: 42 (21 in intervention group (A2); 21 in control group (B2)).

Number of withdrawals: 13 (8 in intervention group (A2): 3 due to poorly followed treatment, 1 due to inadequate response, 2 due to spontaneous ovulation, 2 due to other reasons; 5 in control group (B2): 1 due to ovarian cyst, 4 due to inadequate response).

Number of women analyzed: 29.

Duration of study: 7 months of recruitment.

Participants

Country of authors: France.

Inclusion criteria: infertile women scheduled for IVF treatment, aged < 38 years.

Exclusion criteria: not reported.

Mean age ± SD: intervention group (A1+A2): 32.8 ± 0.7 years; control group (B1+B2): 31.7 ± 0.5 years.

Interventions

Intervention (A2): progestogen (ethynodiol acetate 2 mg twice daily) for 11‐17 days, started cycle day 15 + pure FSH 4 ampoules on post‐treatment days 6‐7 and 2 ampoules on post‐treatment days 8‐9 + hMG (FSH 75 IU + LH 75 IU) 2 ampoules on post‐treatment days 10‐11.

Control (B2): pure FSH 4 ampoules on cycle days 2‐3 and 2 ampoules on cycle days 4‐5 + hMG (FSH 75 IU + LH 75 IU) when needed.

FSH and GnRH agonist both continued until hCG injection (10,000 IU), administration depending on follicular maturity.

Outcomes

• Clinical pregnancy rate: not defined.

• Pregnancy loss.

• Day of hCG.

• Values of oestradiol and P on day of hCG.

• Number of oocytes recovered, cleaved or replaced.

Notes

Power calculation performed: no.

ITT analysis performed: no.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomized," method not reported.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Proportions of, and reasons for, withdrawals not balanced between groups and data not analyzed on the basis of ITT.

Selective reporting (reporting bias)

High risk

All planned outcomes not reported.

Other bias

Low risk

Baseline demographic characteristics balanced between groups.

Methods

Parallel group study.

Number of women randomized: 49 (number per group not reported; 22 cycles in intervention group; 29 cycles in control group) but total number of cycles not the same as total number of women randomized.

Number of withdrawals: 11 cycles (3 in intervention group: 2 due to poor response, 1 due to failure of embryo cleavage; 8 in control group: 3 due to conversion to IUI, 1 due to poor response, 2 due to failed fertilisation, 2 due to risk of OHSS).

Number of women analyzed: unclear.

Duration of study: 8 months of recruitment.

Participants

Country of authors: UK.

Inclusion criteria: women who underwent IVF treatment cycles and had an ovarian cyst > 15 mm in diameter or an endometrial thickness > 5 mm and serum oestradiol concentration > 100 pmol/L after 14 days of GnRH agonist (buserelin acetate) treatment

Exclusion criteria: relevant uterine or ovarian pathology.

Mean age ± SEM: intervention group: 36.0 ± 0.86 years; control group: 35.72 ± 0.69 years.

Interventions

Intervention: GnRH agonist (buserelin acetate 500 μg/day) started cycle day 2 or 3 + progestogen (100 mg IM single dose) on cycle day 16 or 17 + hMG, started when serum oestradiol concentration ≤ 100 pmol/L.

Control: GnRH agonist (buserelin acetate 500 μg/day), started cycle day 2 or 3 + hMG, started when serum oestradiol concentration ≤ 100 pmol/L.

hMG start dose according to women's age, baseline serum FSH level, response to stimulation in previous treatment cycles.

hMG and GnRH agonist both continued until hCG injection (10,000 IU), administered when 3 follicles ≥ 18 mm in diameter.

Outcomes

• Clinical pregnancy rate: not defined.

• Serum oestradiol levels on day of recruitment.

• Number of days of hMG administration.

• Number of days of GnRH agonist.

• Endometrial thickness.

• Mean diameter of ovarian cyst on day of recruitment and 6 days later.

• Total number of hMG ampoules.

• Number of follicles.

• Number of oocytes retrieved.

• Number of embryos transferred.

Notes

Power calculation performed: no.

ITT analysis performed: unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was done by drawing sequentially labelled sealed envelops, each containing a number obtained from a table of random numbers."

Allocation concealment (selection bias)

Low risk

Sealed envelopes.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Reasons for withdrawals and proportions of participants who withdrew not reported per treatment group.

Selective reporting (reporting bias)

Low risk

Data on all planned outcomes reported.

Other bias

Low risk

No significant differences in baseline characteristics between groups with regard to age, length of infertility, number of previous IVF cycles and cause of infertility.

Methods

Parallel group study.

Number of women randomized: 117 (number per group not reported).

Number of withdrawals: not reported.

Number of women analyzed: unclear.

Participants

Country of authors: Canada.

Inclusion criteria: not reported.

Exclusion criteria: not reported.

Mean age: not reported.

Interventions

Intervention: progestogen (norethindrone) for 5 days, started cycle day 1 + GnRH agonist, start cycle day 2.

Control: GnRH agonist. Timing of treatment not reported.

Outcomes

• Cyst formation.

• Time required to achieve pituitary suppression.

• Implantation rate.

• Pregnancy rate.

Notes

Power calculation performed: unclear.

ITT analysis used: unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not reported.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No data reported.

Selective reporting (reporting bias)

High risk

All prespecified outcomes not reported.

Other bias

Unclear risk

Insufficient information to make a conclusive judgement.

Methods

Parallel group study.

Number of women randomized: 210 (105 to each group).

Number of withdrawals: 5 (4 in intervention group; 1 in control group).

Number of women analyzed: not clear; assumed 205.

Participants

Country: Argentina.

Inclusion criteria: aged ≤ 39 years, first IVF attempt, basal FSH ≤ 12 mIU/mL.

Exclusion criteria: PCOS, prior ovarian surgery, "TESE needing."

Mean age: not reported.

Setting: assume single fertility centre in Buenos Aires, Argentina.

Interventions

Intervention: COCP (ethinyl oestradiol 0.02 mg + levonorgestrel 0.1 mg) for 14/25 days in the preceding cycle.

Control: no pretreatment.

All women stimulated with rFSH (200 IU/day) from menstrual cycle day 2 or 3, hMG (225 UI/day) from day 4 and GnRH antagonist (cetrorelix 0.25 mg) in a flexible protocol starting with 14 mm leading follicle continuing both daily until the day of hCG. Oocyte maturation was triggered by rhCG (250 μg). Embryo transfer performed 3 days later.

Outcomes

Primary:

• Clinical pregnancy rate.

Other:

• Total gonadotropin stimulation days.

• Fertilisation rate.

• Implantation rate.

• Number of oocytes retrieved.

• Total number of embryos achieved.

• Embryo quality rate.

Notes

Abstract with minimal data reported.

Power calculation for sample size: not reported.

ITT analysis: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Proportions of withdrawals fairly balanced between groups although reasons for withdrawals not reported.

Selective reporting (reporting bias)

Unclear risk

Outcome data not clearly reported.

Other bias

Unclear risk

Not clear whether groups were comparable at baseline with respect to demographic characteristics.

Methods

Parallel group study.

Number of women randomized: 220 (109 in intervention group; 111 in control group).

Number of withdrawals: none reported.

Number of women analyzed: 208 cycles (103 in intervention group; 105 in control group) and numbers of cycles were equivalent to numbers of participants.

Participants

Country: China.

Inclusion criteria: aged 25‐35 years; BMI 18‐25 kg/m²; number of previous IVF cycles < 3, and no previous poor response to ovarian stimulation (poor ovarian response characterised by cancellation of the cycle due to either poor follicular development or ≤ 4 cumulus‐oocyte‐complexes collected at oocyte retrieval); normal ovulatory cycles (25‐35 days); both ovaries present and normal uterus; no hormone therapy within the past 3 months; no current or past diseases affecting ovaries, gonadotrophin, sex steroid secretion, clearance or excretion.

Exclusion criteria: not explicitly reported.

Age range: 25‐35 years.

Setting: IVF centre, China.

Interventions

Intervention: oral oestradiol valerate (4 mg/day) preceding the IVF cycle from day 21 until day 2 of next cycle before GnRH antagonist protocol.

Control: standard long GnRH agonist protocol.

Outcomes

• Number of oocytes collected.

• MII oocytes.

• Fertilisation.

• Implantation.

• Live birth.

• Early pregnancy rate.

• Clinical pregnancy rate.

• OHSS rate.

• Hormone profiles.

Notes

Outcomes measured as per 'embryo transfer cycle' but numbers of cycles transferred were equivalent to numbers of women randomized.

Power calculation for sample size: not reported.

ITT analysis: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomization allocation sequence was generated from a table of computer‐generated random numbers."

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding (performance bias and detection bias)
All outcomes

High risk

"This study was not blind."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No withdrawals reported, cycle cancellation (number of cycles were equivalent to numbers of women randomized) similar between groups.

Selective reporting (reporting bias)

Low risk

All prespecified outcomes reported.

Other bias

Low risk

Groups comparable at baseline with respect to demographic characteristics.