Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

OS

• Female age: 28.83 ± 4.76 years (mean ± SD)

• Duration of infertility: 4.93 ± 3.27 years (mean ± SD)

OS‐IUI

• Female age: 29.52 ± 3.65 years (mean ± SD)

• Duration of infertility: 4.91 ± 2.72 years (mean ± SD)

Sample size: OS (n = 69); OS‐IUI (n = 44)

Included criteria: couples with unexplained infertility: biphasic basal body temperature charts; in‐phase late luteal endometrial biopsy; normal serum levels of thyroid, prolactin, luteinising hormone, and follicle‐stimulating hormone; hysterosalpingogram indicating normal uterine contour and laparoscopy indicating bilateral tubal patency; absence of pelvic adhesions; and endometriosis. All men had normal values on at least 2 standard semen analyses (sperm concentration > 20 million/mL, > 50% motile, and > 50% morphologically normal spermatozoa) and a positive post‐coital test. Tests for immunological causes of infertility for both partners revealed negative results (antisperm antibodies)

Excluded criteria: NA

Pretreatment: NA

Interventions

Intervention characteristics

OS

• Description: clomiphene citrate 50 to 150 mg orally from day 3 to 7 of menstrual cycle depending on response. Follicular monitoring was done by serial vaginal ultrasonography beginning day 10 until demonstration of ovulation. Human chorionic gonadotropin (hCG) 10,000 IU intramuscular was administered when not more than 4 leading follicles > 16 mm were seen. Couples were advised to have intercourse 36 to 40 hours after administration of hCG

OS‐IUI

• Description: clomiphene citrate 50 to 150 mg orally from day 3 to 7 of menstrual cycle depending on response. Follicular monitoring was done by serial vaginal ultrasonography beginning day 10 until demonstration of ovulation. hCG 10,000 IU intramuscular was administered when not more than 4 leading follicles > 16 mm were seen. IUI was performed 36 to 40 hours later. Sperm cells present in 90% fraction were used after 2 washes to remove the Percoll. Culture media used were Ham’s F10 (SIGMA, USA) enriched with 7.5% patient’s serum or 1% human serum albumin. A volume of 0.3 to 0.4 mL of the preparation was taken for IUI with an IUI cannula used for the procedure. The woman was instructed to lie in supine/lateral position for 30 minutes after the procedure

Outcomes

Clinical pregnancy

Identification

Sponsorship source: Council of Scientific and Industrial Research, New Delhi, India

Country: India

Setting: Gynecological Outpatients of All India Institute of Medical Sciences (AIIMS), New Delhi

Author's name: Sonika Agarwal

Institution: Department of Obstetrics Gynaecology, All India Institute of Medical Sciences, New Delhi, India

Email: [email protected]

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The 140 couples were divided into two groups using random number table, 70 in each group and followed over three years"

Judgement comment: random numbers table used

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details of allocation concealment not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding not possible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blind not likely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "Twenty six women in group B and one in group A did not have complete follow up and were thus excluded from the analysis"

Judgement comment: 26/70 in OS‐IUI group and 1/70 in OS group lost to follow‐up

Selective reporting (reporting bias)

High risk

Judgement comment: outcomes for the 2 groups (live birth, miscarriage, and multiple pregnancy) not reported separately

Other bias

Low risk

Judgement comment: no other sources of bias detected

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

OS

• Female age: 33.4 ± 4.7 years (mean ± SD)

• Duration of infertility: 47 (28 ± SD) months

OS‐IUI

• Female age: 34.6 (4.9 ± SD) years

• Duration of infertility: 50 (19 ± SD) months

Sample size: OS (n = 32); OS‐IUI (n = 36)

Included criteria: unexplained infertility diagnosed after normal results were obtained from the following tests: basal body temperature measurements and endometrial biopsy in the luteal phase, hysterosalpingography, post‐coital test, and at least 2 semen analyses for the partner. Laparoscopy showed a normal pelvis in all patients

Excluded criteria: NA

Pretreatment: NA

Interventions

Intervention characteristics

OS

• Description: CC 100 mg/d from day 3 to 7 of the cycle and hMG 1 to 3 ampoules/d from day 8 of the cycle until development of 2 or more follicles (maximum 6) with diameter > 17 mm. hCG 10,000 IU was administered when 17beta E2 levels were > 200 pg/mL/follicle but not over a total of 2000 pg/mL, and when the lead follicles had diameter > 17 mm. Intercourse was recommended 24 and 48 hours after hCG administration. Three to five cycles of treatment, preferably consecutive, were planned

OS‐IUI

• Description: CC 100 mg/d from day 3 to 7 of the cycle and hMG 1 to 3 ampoules/d from day 8 of the cycle until development of 2 or more follicles (maximum 6) with diameter > 17 mm. hCG 10,000 IU was administered when 17beta E2 levels were > 200 pg/mL/follicle but not over a total of 2000 pg/mL, and when the lead follicles had diameter > 17 mm. IUI was performed 24 and 48 hours after hCG administration. Three to five cycles of treatment, preferably consecutive, were planned

Outcomes

Clinical pregnancy

Identification

Sponsorship source: NA

Country: Italy

Setting: Infertility Unit of the Modern Medical Center, Milan, Italy

Authors name: Luisa Arcaini, Luigi Fedele*

Institution: Department of Obstetrics and Gynecology, L. Mangiagalli, University of Milan, Milan, Italy

Email: NA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: details of sequence generation not reported

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details of allocation concealment not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding not possible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding not likely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

High risk

Judgement comment: 14/68 (20.5%) lost to follow‐up

Selective reporting (reporting bias)

High risk

Judgement comment: outcomes for the 2 groups (live birth/ongoing pregnancy, miscarriage, and multiple pregnancy) not reported separately

Other bias

Low risk

Judgement comment: no sources of bias detected

Methods

Study design: randomised controlled trial

Study grouping: cross‐over

Only data for the first cycle (before cross‐over) were extracted

Participants

Baseline characteristics

Overall

• Female age: 32.3 years (mean)

• Duration of infertility: 3.5 years (mean)

Sample size: IUI (n = 16); OS‐IUI (n = 10)

Included criteria: for unexplained infertility, all couples exhibited normal semen analysis, negative antisperm antibodies, normal hysterosalpingogram, regular ovulatory cycles (by luteal phase P levels and/or in‐phase endometrial biopsy), and normal laparoscopic findings. Five patients with surgically treated minimal endometriosis without pelvic adhesive disease were included in this diagnostic group

Excluded criteria: all patients positive for sperm antibodies by immunobead testing were excluded. Couples unwilling to be randomised were also excluded from the study

Pretreatment: NA

Interventions

Intervention characteristics

IUI

• Description: the natural cycle group underwent urinary LH timed lUI during an unstimulated natural cycle. Urine samples were collected twice daily, in the evening and as the second voided morning sample, and quantitative urinary LH measurements were performed using an immunofluorometric assay (Delphia; LKB‐WAUAC Pharmacia, Turku, Finland). Intrauterine insemination was performed on the day of the LH peak and the next day when possible

OS‐IUI

• Description: 50 mg CC/d between days 5 and 9 of the menstrual cycle. An injection of 10,000 U 1 M hCG was administered when 1 or more follicles reached 18 mm mean diameter as determined by US. A single lUI was performed 32 hours after hCG injection

Outcomes

Clinical pregnancy

Identification

Sponsorship source: NA

Country: USA

Setting: tertiary academic medical centre

Author's name: Aydin Arici

Institution: Department of Obstetrics and Gynecology, Yale University School of Medicine

Email: NA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "couples were randomized using a computer‐generated random numbers table to one of the two study groups"

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding not possible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding not likely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Judgement comment: original report included 2 subgroups of participants: male infertility and unexplained infertility. Data for participants lost to follow‐up not reported separately

Selective reporting (reporting bias)

Unclear risk

Judgement comment: live birth and multiple pregnancy not reported

Other bias

Unclear risk

Judgement comment: no sufficient information to judge baseline characteristics

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

OS‐IUI

• Female age: 34 ± 3.67 years (mean ± SD)

• Duration of infertility: 2.30 (1.82 to 3.13) years (median, IQR)

IVF/ICSI

• Female age: 33 ± 3.39 years (mean ± SD)

• Duration of infertility: 2.13 (1.73 to 3.01) years (median, IQR)

Sample size: OS‐IUI (n = 207); IVF/ICSI (n = 201)

Included criteria: couples seeking fertility treatment after at least 12 months of unprotected intercourse were eligible. All couples underwent basic fertility investigations, which included semen analysis, evaluation of ovulation, and tubal patency testing (Chlamydia antibody test, hysterosalpingography, or laparoscopy). Inclusion criteria were age of female partner between 18 and 38 years, unfavourable prognosis for natural conception, and diagnosis of unexplained or mild male subfertility. We classified couples as having unexplained subfertility when fertility investigations showed at least 1 patent fallopian tube, an ovulatory menstrual cycle, and a normal semen analysis (pre‐wash total motile sperm count > 10 million). We considered couples who qualified for intrauterine insemination with donor sperm after at least 6 cycles of artificial intracervical insemination with donor sperm to have unexplained subfertility for the purpose of this study. Mild male subfertility was diagnosed when semen analysis showed a pre‐wash total motile sperm count between 3 and 10 million (according to Dutch guidelines). We defined an unfavourable prognosis for natural conception as a probability of natural conception within the next 12 months of < 30%, as calculated through the validated synthesis model of Hunault. This model encompasses female age, duration of subfertility, whether subfertility is primary or secondary, percentage of motile progressive sperm, and referral status. It is readily available for the use of all clinicians (www.freya.nl/web_bereken/bereken.php)

Excluded criteria: anovulation, double‐sided tubal disease, severe endometriosis, premature ovarian failure, known endocrine disorders (such as Cushing’s syndrome or adrenal hyperplasia)

Pretreatment: none

Interventions

Intervention characteristics

OS‐IUI

• Description: intrauterine insemination with controlled ovarian hyperstimulation: (1) hyperstimulation from cycle day 3 or 4; start with 100 mg clomiphene citrate or subcutaneous injections of 75 IU FSH; (2) monitoring of follicular growth by transvaginal ultrasound; (3) induction of final oocyte maturation with 5000 IU of hCG when ≥ 1 follicle has diameter of 17 or 18 mm; (4) IUI 36 hours thereafter

• Cancel criteria: hCG administration and IUI withheld with > 3 follicles with diameter of 16 mm or > 5 follicles with diameter of 12 mm

IVF/ICSI

• Description: in vitro fertilisation with single embryo transfer: (1) downregulation with GnRH agonist in long/short protocol or fixed start antagonist protocol; stimulation start dose 150 IU FSH; (2) ultrasound monitoring according to local protocol; (3) ovulation induction with 10,000 IU hCG until ≥ 2 follicles > 18 mm; (4) oocyte retrieval 36 hours thereafter; (5) embryo transfer day 2, 3, or 4; (6) cryopreservation of non‐transferred good quality embryos (1 embryo will be transferred per freeze‐thaw cycle if it is of good quality)

• Cancel criteria: ovarian hyperstimulation syndrome, non‐response

Outcomes

Clinical pregnancy

Live birth

Multiple pregnancy

OHSS

Identification

Sponsorship source: the study was supported by a grant from ZonMW, the Dutch Organization for Health Research and Development (120620027), and a grant from Zorgverzekeraars Nederland, the Dutch Association of Healthcare Insurers (09‐003)

Country: Netherlands

Setting: 17 fertility clinics in Netherlands

Authors' names: A.J. Bensdorp, M. van Wely*

Institution: Centre for Reproductive Medicine, Academic Medical Centre, University of Amsterdam, 1100DD Amsterdam, Netherlands

Email: [email protected]

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation was performed with an online randomisation program, using biased coin minimisation, stratified for study centre"

Allocation concealment (selection bias)

Low risk

Quote: "minimisation, stratified for study centre. A web based program generated a unique number with allocation code after entry of the patient’s initials and date of birth. Neither the recruiters nor the trial project group could access the randomisation sequence. "

Judgement comment: a web‐based programme generated a unique number with allocation code after entry of the patient’s initials and date of birth. Neither the recruiters nor the trial project group could access the randomisation sequence

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "blinding was not possible owing to the nature of the interventions"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding not likely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: IVF (SET): 2/201 lost to follow‐up; IVF (NC): 3/194 lost to follow‐up; OS‐IUI: 1/207 lost to follow‐up

Selective reporting (reporting bias)

Low risk

Judgement comment: all relevant outcomes reported

Other bias

Low risk

Judgement comment: no other sources of bias detected

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

EM

• Female age: 32 ± 3.4 years (mean ± SD)

• Duration of subfertility (months): 30 (25 to 38) months (median, IQR)

OS

• Female age: 32 ± 3.5 years (mean ± SD)

• Duration of subfertility (months): 30 (24 to 38) months (median, IQR)

IUI

• Female age: 32 ± 3.7 years (mean ± SD)

• Duration of subfertility (months): 30 (25 to 40) months (median, IQR)

Sample size: EM (n = 193); OS (n = 194); IUI (n = 193)

Included criteria: at least 2 years of infertility, bilateral tubal patency (demonstrated by laparoscopy or hysterosalpingography), ovulation demonstrated by appropriately timed mid‐luteal progesterone, and normal semen variables (according to World Health Organization criteria). Also couples with minimum sperm motility of 20% or minimal endometriosis (rAFS stage 1)

Excluded criteria: NA

Pretreatment: none

Interventions

Intervention characteristics

EM

• Description: 6 months during which no clinic visits or medical interventions were scheduled. Couples were given general advice regarding the need for regular intercourse, but no specific measures such as basal temperature charts or luteinising hormone kits were recommended

OS

• Description: 50 mg (starting dose) CC from day 2 to 6 of each treatment cycle. Couples were advised to have intercourse on days 12 to 18 of the cycle. If 3 or more ovarian follicles were detected by scan in the first cycle, the cycle was cancelled and the couple was advised to avoid intercourse. In the next cycle, women who were overstimulated on the first cycle started on a reduced dose of clomiphene (25 mg) and were monitored in the same way as they would be for a first cycle (i.e. scan on day 12 and blood test for progesterone on day 21) with a further reduction to alternate days of 25 mg offered in the next cycle if necessary

IUI

• Description: monitor urinary luteinising hormone concentrations from day 12 of the cycle. A single insemination was performed 20 to 30 hours after an endogenous surge was detected

Outcomes

Live birth

Clinical pregnancy

Multiple pregnancy

OHSS

Identification

Sponsorship source: Chief Scientist Office, Scotland

Country: UK

Setting: 4 teaching hospitals and a district general hospital in Scotland

Author's name: S. Bhattacharya

Institution: Department of Obstetrics and Gynaecology, University of Aberdeen

Email: [email protected]

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Judgement comment: central telephone randomisation system used

Allocation concealment (selection bias)

Low risk

Quote: "research nurses enrolled participants at each centre and assigned them to their groups using a central telephone randomisation system based in Aberdeen (the coordinating centre)"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Blinding not possible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Non‐blinding not likely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: lost to follow‐up (EM: 0, OS: 2, IUI: 2)

Selective reporting (reporting bias)

Low risk

Judgement comment: all outcomes prespecified and adequately reported

Other bias

Low risk

Judgement comment: no other bias detected

Methods

Study design: randomised controlled trial

Study grouping: cross‐over (after the first cycle)

Participants

Baseline characteristics

Overall

• Female age: NA

• Duration of infertility: NA

Sample size: OS (n = 73); OS‐IUI (n = 64); IVF/ICSI (n = 30)

Included criteria: (a) women were to be < 38 years of age and must have experienced > 36 months of infertility before study entry; (b) only women with at least 1 macroscopically normal tubo‐ovarian unit, as identified by a recent diagnostic laparoscopy, were included; (c) there must have been evidence of the occurrence of spontaneous ovulation in 2 recent cycles, as judged by plasma progesterone levels in the luteal phase; (d) it was necessary for semen to be classed as 'normal' by WHO criteria; (e) it was mandatory for patients to refrain from sexual activity for 6 days before and 3 days after treatments; (f) there must have been a period of at least 2 months without treatment for infertility before study entry

Excluded criteria: NA

Pretreatment: no

Interventions

Intervention characteristics

OS

• Description: NA

OS‐IUI

• Description: NA

IVF/ICSI

• Description: NA

Outcomes

Clinical pregnancy

Identification

Sponsorship source: Ares‐Serono (Geneva)

Country: France, Greece, Italy, Germany, Belgium, Sweden, Norway, Finland, Austria, and Netherlands

Setting: 19 fertility centres in Europe

Authors' names: P.G. Crosignani, D.E. Walters*

Institution: Department of Obstetrics and Gynaecology, University of Milan, Milan, Italy

Email: NA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: details of sequence generation at each centre not reported

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details of allocation concealment at each centre not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding impossible because of the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Judgement comment: details not reported

Selective reporting (reporting bias)

Unclear risk

Judgement comment: live birth and multiple pregnancy not reported

Other bias

Unclear risk

Judgement comment: insufficient information to judge

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

OS‐IUI

• Female age: 34.0 (2.9) years

• Duration of infertility: 2.2 (1.8) years

IVF/ICSI

• Female age: 33.6 (3.0) years

• Duration of infertility: 2.3 (1.9) years

Sample size: OS‐IUI (n = 58); IVF/ICSI (n = 58)

Included criteria: couples were invited to participate if they were diagnosed with unexplained or mild male subfertility. Couples had to have poor fertility prospects as calculated by the validated model of Hunault. Poor fertility prospects were defined as a chance of natural conception of 30% within 12 months. All couples had undergone a basic fertility workup according to the guidelines of the Dutch Society of Obstetrics and Gynecology. This workup included medical history, cycle monitoring, post‐coital test, semen analysis, and assessment of tubal patency. Mild male subfertility was defined as a total motile count (TMC) of 3 to 10 × 10⁶ spermatozoa/mL. Unexplained subfertility was defined as TMC > 10 × 10⁶ spermatozoa/mL and exclusion of a cervical factor

Excluded criteria: other causes of subfertility, including severe male subfertility, cervical factor, and polycystic ovary syndrome; female age > 38 years; prior treatment within this subfertility episode. Age limit was based on concerns that IUI‐COS may compromise pregnancy rates in older women

Pretreatment: none detected

Interventions

Intervention characteristics

OS‐IUI

• Description: in couples allocated to receive IUI‐COS, women underwent ovarian stimulation with 50 to 75 IU rFSH (Puregon; Organon) in a low‐dose step‐up protocol to achieve the growth of 1 to (maximally) 3 dominant follicles. In case the cycle was monofollicular, the amount of rFSH was raised in the subsequent cycle. Cycles with 1 dominant follicle (R15 mm) and at least 1 more follicle > 10 mm at the time of hCG administration were considered multi‐follicular. In case more than 3 dominant follicles were present, the cycle was cancelled. Ovulation was induced with 5000 or 10,000 IU of hCG (Pregnyl). Semen samples were processed within 1 hour of ejaculation by density‐gradient centrifugation followed by washing with culture medium. The volume of semen that was inseminated varied between 0.2 mL and 1.0 mL. Women were inseminated 36 to 40 hours after hCG administration

IVF/ICSI

• Description: patients allocated to receive IVF‐eSET underwent controlled ovarian hyperstimulation after downregulation with the GnRH agonist triptorelin (Ferring) in a long protocol with a midluteal start. Controlled ovarian hyperstimulation was started with 100 to 150 U recombinant FSH (rFSH). Treatment was continued until at least 3 follicles > 18 mm had developed. Ovulation was induced by 10,000 IU hCG (Pregnyl; Organon), and cumulus–oocyte complexes were recovered by transvaginal ultrasound–guided retrieval 36 hours thereafter. Embryos were scored with the use of validated morphological scoring criteria at the time of fertilisation (pronuclear morphology) and daily until the time of transfer. Embryos were assessed for their morphology daily by an embryologist/IVF technician using an Olympus IX71 inverted microscope equipped with Relief Contrast optics at a magnification of 320, or a similar kind of microscope. On day 3, 1 embryo was selected for transfer if 1 or more embryos of good quality were available. In case no good‐quality embryos were available, 2 embryos were transferred. Non‐transferred good‐quality embryos were cryopreserved on the fourth day (conventional slow freezing). When implantation was not successful or early miscarriage occurred, the frozen embryos were thawed and transferred. Again, only 1 embryo was transferred per freeze–thaw cycle if it was of good quality

Outcomes

Clinical pregnancy

Live birth

Multiple pregnancy

Identification

Sponsorship source: Organon, Oss, Netherlands.

Country: Netherlands

Setting: 3 academic and 6 teaching hospitals in Netherlands

Author's name: Inge M. Custers

Institution: Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Center, Room H4‐213, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands

Email: [email protected]

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "couples who gave informed consent were randomized by a central Internet‐based randomization stratified for center"

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding impossible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: zero lost to follow‐up

Selective reporting (reporting bias)

Low risk

Judgement comment: all relevant outcomes reported

Other bias

Low risk

Judgement comment: no other sources of bias detected

Methods

Study design: randomised controlled trial

Study grouping: cross‐over

Participants

Baseline characteristics

Overall

• Female age: 33 (4.0) years

• Duration of infertility: 3.5 (1.7) years

Sample size: EM (n = 28); OS‐IUI (n = 23)

Included criteria: couples with unexplained infertility or surgically corrected endometriosis

Excluded criteria: women with tubal disease

Pretreatment: NA

Interventions

Intervention characteristics

EM

• Description: during the 4 control cycles, the couple was instructed to have intercourse during the periovulatory period. The BBT chart or luteinising hormone (LH) kit was analysed after each cycle to ensure that intercourse was appropriately timed. No other adjuvant therapy was used during the control cycles. Women exhibiting an anovulatory cycle at any time during the study were excluded from the analysis

OS‐IUI

• Description: treatment cycles: treatment consisted of CC 50 mg orally on cycle days 5 through 9. If a subject's cycle length was 27 days, then the CC was given on days 4 through 8. Morning ultrasound for folliculogenesis was performed during the first cycle on or about day 12. Timing of the ultrasound in future cycles was planned based on the response in the first cycle. Assuming follicular growth of 2 mm/d, an intramuscular injection of human chorionic gonadotropin (hCG) 10,000 U was administered on the evening when the lead follicle was estimated to be at least 18 mm. Thirty‐six hours after hCG injection, a semen sample for lUI was obtained. After liquefaction, the ejaculate was placed in 10 cc warmed (38℃) Ham's F‐10 (GIBCO, Grand Island, NY) and centrifuged at 1000 × g for 5 minutes. The supernatant was then discarded, and the pellet was resuspended in roughly 200 µL. Sperm suspension was introduced into the uterine cavity via a no. 5 paediatric feeding tube

Outcomes

Clinical pregnancy

Multiple pregnancy

OHSS

Ongoing pregnancy

Identification

Sponsorship source: American College of Obstetricians and Gynecologists, Washington, DC; Mead Johnson Laboratories, Evansville, IN

Country: USA

Setting: University of Vermont College of Medicine

Authors' names: Jeffrey L. Deaton, John R. Brumsted

Institution: Department of Obstetrics and Gynecology, University of Vermont, Given C‐252, Burlington, VT 05405

Email: NA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: details not reported

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding not possible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

High risk

Judgement comment: 16/67 participants excluded from analysis due to anovulation, poor semen quality, or inability to follow the treatment protocol. Of the remaining 51 participants, 6 couples did not complete treatment because of illness or relocation. 4/51 dropped out before cross‐over

Selective reporting (reporting bias)

Unclear risk

Judgement comment: live birth not reported

Other bias

Unclear risk

Judgement comment: insufficient data to make a judgement

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

IVF/ICSI

• Female age: 34 (3.5) years

• Duration of infertility: 3.1 (1.3) years

OS‐IUI

• Female age: 33 (4.2) years

• Duration of infertility: 3.2 (2.5) years

Sample size: IVF/ICSI (n = 11); OS‐IUI (n = 33)

Included criteria: eligible participants were adults, had primary or secondary infertility of at least 1 year's duration, with evidence of ovulation and tubal patency, and were 18 to 42 years of age if female and 18 to 60 years of age if male

Excluded criteria: IUI or IVF treatment in previous 12 months, coital disorder, untreated ovulatory disorders, or endometriosis (American Fertility Society criteria grade 2 to 4), tubal obstruction, abnormal semen analyses (concentration 20*10⁶/mL, progressive motility 25%, abnormal morphology > 95% or positive sperm antibodies), or any contraindication for multiple pregnancy

Pretreatment: NA

Interventions

Intervention Characteristics

IVF/ICSI

• Description: all female participants received the same ovarian stimulation protocol using recombinant FSH 112.5 IU/d (Gonal‐F; Serono East Frenchs Forest, Australia) starting from cycle day 3. Transvaginal ultrasound was performed on day 8 of the cycle and was repeated every 2 to 3 days if necessary. When ultrasound revealed follicles reaching a mean diameter of 14 mm, 250 g per day of GnRH antagonist Cetrorelix (Serono, East Frenchs Forest, Australia) was given to prevent premature ovulation and was repeated if necessary to avoid weekend oocyte retrieval. To minimise complications of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy, only women who had an ultrasound scan indicating that there would be either 2 or 3 preovulatory follicles (> 16 mm) at the time of hCG injection were randomised 3 to 1 to IUI or IVF. Final oocyte maturation was induced with 250 g of recombinant hCG (Ovidrel, Serono, East Frenchs Forest, Australia) when follicles had reached 18 mm in mean diameter, and IUI or IVF was scheduled 36 hours later. For IVF, oocyte retrieval was performed 36 hours after hCG administration under light sedation using transvaginal ultrasound, and groups of 2 or 3 oocytes were cultured with 0.29 10⁶/mL motile sperm in 0.5 mL of Quinn’s Advantage Sequential Medium. Embryo transfer of 1 or 2 embryos at cleavage stage, according to patient preference, was performed using a soft catheter (Cook Ireland Ltd, Limerick, Ireland). Embryos were selected for transfer on cell number and morphological grade. Supernumerary embryos were cryopreserved for subsequent transfer

OS‐IUI

• Description: all female participants received the same ovarian stimulation protocol using recombinant FSH 112.5 IU/d (Gonal‐F; Serono East Frenchs Forest, Australia) starting from cycle day 3. Transvaginal ultrasound was performed on day 8 of the cycle and was repeated every 2 to 3 days if necessary. When ultrasound revealed follicles reaching a mean diameter of 14 mm, 250 g per day of GnRH antagonist Cetrorelix (Serono, East Frenchs Forest, Australia) was given to prevent premature ovulation and was repeated if necessary to avoid weekend oocyte retrieval. To minimise complications of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy, only women who had an ultrasound scan indicating that there would be either 2 or 3 preovulatory follicles (> 16 mm) at the time of hCG injection were randomised 3 to 1 to IUI or IVF. Final oocyte maturation was induced with 250 g of recombinant hCG (Ovidrel, Serono, East Frenchs Forest, Australia) when follicles had reached 18 mm in mean diameter and IUI or IVF was scheduled 36 hours later. For IUI, fresh semen was collected after 2 days’ abstinence and when liquefied was prepared using colloidal silica density gradient and made up to a final volume of 0.6 mL. An aliquot of 0.1 mL was used for analysis to determine motile sperm concentration, and 0.5 mL was used for insemination. Insemination was performed using an intrauterine insemination catheter (Cook Ireland Ltd., Limerick, Ireland)

Outcomes

Clinical pregnancy

Live birth

Multiple pregnancy

OHSS

Identification

Sponsorship source: Serono (Geneva, Switzerland) and Melbourne IVF (Melbourne, AUSTRALIA) supported this trial financially

Country: Australia

Setting: a tertiary level fertility centre at the Royal Women’s Hospital in Melbourne

Author's name: Hossam ELZEINY

Institution: Reproductive Services, Royal Women’s Hospital, Carlton; Melbourne IVF, 320 Victoria Parade, East Melbourne, Vic 3002, Australia

Email: [email protected]

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "computer‐generated, adaptive‐biased coin randomisation schedule"

Allocation concealment (selection bias)

Low risk

Quote: "allocation was concealed through the use of sequentially numbered opaque sealed envelopes and was held by the research trial manager and opened after the clinician indicated two or three follicles"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding impossible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Judgement comment: 1/44 not included in the analysis

Selective reporting (reporting bias)

Low risk

Judgement comment: all relevant outcomes reported

Other bias

Low risk

Judgement comment: no other sources of bias detected

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

EM

• Female age: 33.6 (3.7) years

• Duration of infertility: median IQR 46.0 (27.8 to 60.0) months

OS‐IUI

• Female age: 34.4 (3.5) years

• Duration of infertility: 41.0 (31.0 to 60.0) months

Sample size: EM (n = 100); OS‐IUI (n = 101)

Included criteria: we included women younger than 42 years with body mass index < 35 kg/m² and unexplained infertility, which was defined as normal ovulation (or normal with ovarian stimulation), bilateral patent fallopian tubes as determined by laparoscopy or hysterosalpingography, normal semen analysis (progressive motility ≥ 32% and concentration ≥ 15 million per mL), and a prediction score of natural conception leading to live birth in the next year < 30%. We used the validated Hunault prediction model for natural conception, which includes age, length of infertility, any previous pregnancies, source of referral, and sperm motility. We included women with mild endometriosis (diagnosed by laparoscopy), polycystic ovarian syndrome according to the Rotterdam criteria (providing ovulation was confirmed with or without ovarian stimulation for at least six cycles), and previous IUI or IVF cycles

Excluded criteria: couples requiring donor sperm

Pretreatment: NA

Interventions

Intervention characteristics

EM

• Description: couples assigned to EM were followed up for 3 cycles. They were advised to be sexually active around the likely time of ovulation and were provided with a diary to record the first day of each menstrual cycle and dates of sexual activity. Women in the EM group who had anovulatory polycystic ovary syndrome continued with their ovulation induction

OS‐IUI

• Description: in the IUI with ovarian stimulation group, women received oral clomiphene citrate (Merck Serono; 50 to 150 mg, days 2 to 6) or oral letrozole (Douglas Pharmaceuticals; 2.5 to 7.5 mg, days 2 to 6) for ovarian stimulation according to patient response. Choice of ovarian stimulation was made by the clinic. When 1 to 3 follicles were present, IUI was performed by injecting the prepared sample of 0.5 mL sperm into the uterus. Oestradiol and luteinising hormone were measured on day 7. Serial ultrasound started when oestradiol was higher than 400 pmol/L in the first cycle and if clinically indicated on subsequent cycles. Daily luteinising hormone tracking started when the leading follicle was 14 mm or larger in diameter, or when oestradiol reached 400 pmol/L. When 1 to 3 follicles were present, IUI was performed approximately 24 hours after the luteinising hormone surge or 36 hours after a human chorionic gonadotropin trigger injection. Ultrasound generally was not used in the second or third cycle unless the oestradiol level was ≥ 2000 pmol/L. Letrozole cycles were monitored with both oestradiol levels and ultrasound. The semen sample was prepared using density gradients of 45% and 90%, and following centrifugation, the sample was washed in 3 mL of culture media and was resuspended in 0.5 mL of culture media. A TomCat catheter (Santesel, Turkey) was used for a single insemination. The prepared sperm sample of 0.5 mL was injected into the uterus. Luteal support was not routinely given. If 7 days after insemination, the progesterone level was < 20 pmol/L, utrogestan vaginal pessaries 200 mg 3 times a day were started. Cycles were cancelled if there was no response (no rise in oestradiol or development of follicles) or if there were more than 3 follicles (in which case women were requested to avoid unprotected intercourse). The cancelled cycle was replaced by a further cycle with appropriate dose adjustment

Outcomes

Clinical pregnancy

Live birth

Multiple pregnancy

Identification

Sponsorship source: Auckland Medical Research Foundation, Evelyn Bond Fund of Auckland District Health Board, Mercia Barnes Trust of Royal Australian, and New Zealand College of Obstetricians and Gynaecologists, Maurice and Phyllis Paykel Trust, and The Nurture Foundation for Reproductive Research

Country: New Zealand

Setting: 2 fertility clinics in New Zealand

Author's name: Cynthia M. Farquhar

Institution: Department of Obstetrics and Gynaecology, University of Auckland, Auckland 1101, New Zealand

Email: [email protected]

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "we used a computer‐generated randomisation sequence, prepared by an independent statistician, to randomly assign women (1:1) to three cycles of IUI with ovarian stimulation or three cycles of EM in blocks of four, six, and ten, without stratification"

Allocation concealment (selection bias)

Low risk

Quote: "allocations were concealed in sequentially numbered, sealed, opaque envelopes, which were opened by the study coordinator at the University of Auckland research department after verification of the inclusion criteria and obtaining written informed consent from each participant"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "the participating couple and the clinicians were informed of treatment allocation"

Judgement comment: blinding not possible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "no data were missing for any of the pregnancy, livebirth, or neonatal outcomes"

Judgement comment: zero lost to follow‐up

Selective reporting (reporting bias)

Low risk

Judgement comment: all relevant outcomes reported

Other bias

Low risk

Judgement comment: no other sources of bias detected

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

Overall

• Female age: 30.3 (3) years

• Duration of infertility: 4.3 (1.4) years

Sample size: OS (n = 76); EM (n = 72)

Included criteria: unexplained infertility; primary infertility of 2 or more years' duration; normal history and physical examination; proven ovulation by regular cycles and biphasic basal body temperature charts, serum progesterone (P) > 10 ng/mL in the midluteal phase, or an in‐phase, secretory endometrial biopsy in the late luteal phase; normal hysterosalpingogram; normal laparoscopy done within the last 2 years confirming bilateral tubal patency and no other pelvic pathology; normal serum prolactin; ≥ 2 normal semen analyses fitting the following criteria: volume > 1 cc, count ˜20 × 10⁶ sperm/cc, morphology > 60% normal, motility > 50%

Excluded criteria: NA

Pretreatment: NA

Interventions

Intervention characteristics

OS

• Description: group 3 patients were given CC tablets (Serophene, Serono, Randolph, MA) 100 mg (2 tablets) on cycle day 5 to 9 with saline injections as in group 1. Group 4 patients were given CC and hCG injections with dosage and schedule as noted previously

EM

• Description: group 1 patients were given a placebo (2 tablets) taken by mouth on cycle day 5 to 9 followed by saline injections given intramuscularly (IM) on cycle days 19, 22, 25, and 28. Group 2 patients were given placebo tablets as described above with hCG injections (APL; Ayerst Pharmaceuticals, Montreal, Quebec, Canada) 5000 IU given IM on cycle days 19, 22, 25, and 28

Outcomes

Clinical pregnancy

Identification

Sponsorship source: Medical Research Council of Canada, Ayerst Pharmaceutical Company, Pharmascience, Montreal, Quebec, Canada

Country: Canada

Setting: 5 Canadian university centres

Authors' names: Patricia Fisch, Robert F. Casper*

Institution: 6‐240 EN, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada, M5G 2C4

Email: NA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"using a computer‐generated random number table"

Allocation concealment (selection bias)

Low risk

"assignment of code numbers and distribution of drugs was coordinated by one center"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo‐controlled trial

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Unclear whether outcome assessors were blinded, but this was unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

22 of 177 couples excluded from analysis for the following reasons: 11 had incomplete data or missed tablets or injections, 7 dropped out, 2 had endometriosis found on review of their records, and 2 were found to have secondary infertility

Selective reporting (reporting bias)

Unclear risk

Live births in the 2 groups not reported separately

Other bias

Unclear risk

Insufficient information to make a judgement

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

Overall

• Female age: no difference between groups

• Duration of infertility: NA

Sample size: OS (n = 70); EM (n = 70)

Included criteria: women with a diagnosis of unexplained infertility

Excluded criteria: NA

Pretreatment: no statistical difference between the 2 groups in terms of age, presence of medical complications, or side effects of the medication received

Interventions

Intervention characteristics

OS

• Description: women were instructed to take 2 tablets (100 mg CC) daily from the 2nd to the 6th day of the cycle and to present for a transvaginal ultrasound examination on day 12. If follicular development was adequate as determined by size > 18 mm, hCG 5000 units was administered in the morning and the couple was advised to have intercourse 34 to 36 hours later. If follicular growth was not adequate, ultrasound examination was carried out on an appropriate day, estimating a follicular growth pattern of 2 mm/d. Women so treated were instructed to start the next course of treatment on the 2nd day of the next cycle, if pregnancy did not occur. If a period was missed, they were asked to report for a pregnancy test and subsequently for a transvaginal ultrasound for confirmation of clinical pregnancy at 7 weeks' gestation. Three treatment cycles were planned and carried out, and women were followed up for a further 3 months

EM

• Description: women were instructed to take 2 tablets (placebo) daily from the 2nd to the 6th day of the cycle and to present for a transvaginal ultrasound examination on day 12. If follicular development was adequate as determined by size > 18 mm, hCG 5000 units was administered in the morning and the couple was advised to have intercourse 34 to 36 hours later. If follicular growth was not adequate, ultrasound examination was carried out on an appropriate day, estimating a follicular growth pattern of 2 mm/d. Women so treated were instructed to start the next course of treatment on the 2nd day of the next cycle, if pregnancy did not occur. If a period was missed, they were asked to report for a pregnancy test and subsequently for a transvaginal ultrasound for confirmation of clinical pregnancy at 7 weeks' gestation. Three treatment cycles were planned and carried out, and women were followed up for a further 3 months

Outcomes

Clinical pregnancy

Live birth

Multiple pregnancy

Identification

Sponsorship source: no funding

Country: India

Setting: single centre

Author's name: K. George

Institution: Christian Medical Coll, Vellore, India

Email: NA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "(computer generated in blocks of 5)"

Allocation concealment (selection bias)

Low risk

Quote: "opening consecutively numbered opaque envelopes"

Judgement comment: concealed envelopes

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "neither the physician [nor] the patients were aware of the contents of the treatment packets"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: not sure whether outcomes assessors were blinded, but this was unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Judgement comment: not reported in the abstract

Selective reporting (reporting bias)

Low risk

Judgement comment: all relevant outcomes reported

Other bias

Unclear risk

Judgement comment: insufficient information to make a judgement

Methods

Study design: randomised controlled trial

Study grouping: cross‐over

Participants

Baseline characteristics

Overall

• Female age: median 28 years (range 19 to 44)

• Duration of infertility: median 28 months (12 to 102)

Sample size: OS (n = 109); EM (n = 105)

Included criteria: at least 1 year's infertility, with the following provisions. All women had normal menstrual cycles (21 to 35 days), normal serum prolactin and thyroid hormone levels, normal coital frequency (at least twice weekly), and normal post‐coital sperm‐mucus penetration. Those who failed to conceive within a few months had a laparoscopy to exclude pelvic disease and tubal damage. A blood sample was taken at the midluteal phase in 3 cycles for serum progesterone measurement (timing checked retrospectively as occurring 5 to 10 days before the next menstrual period)

Excluded criteria: NA

Pretreatment: NA

Interventions

Intervention characteristics

OS

• Description: clomiphene (Clomid, Merrell) 100 mg on days 2 to 6 of the menstrual cycle for 3 cycles, crossing over to the alternative treatment for a further 3 cycles. Only the first 3 cycles were included

EM

• Description: matched placebos were given on days 2 to 6 of the menstrual cycle for 3 cycles, crossing over to the alternative treatment for a further 3 cycles

Outcomes

Clinical pregnancy

Multiple pregnancy

Identification

Sponsorship source: South Western Regional Health Authority Medical Research Committee for support for Dr. Glazener; Dr. H.C. Masheter of Merrell Pharmaceuticals Ltd., for the supply of clomiphene and matching placebo

Country: UK

Setting: single centre

Author's name: C.M.A. Glazener

Institution: Health Services Research Unit, University of Aberdeen

Email: NA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: details not reported

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement comment: placebo controlled

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: double‐blind study but unclear whether outcome assessors were blinded; unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: outcome of 1 participant of 109 in CC group not reported

Selective reporting (reporting bias)

Unclear risk

Judgement comment: live birth not reported

Other bias

High risk

Judgement comment: in methods, it was reported that 118 patients were recruited. However, in results, it was reported that 105 patients were treated with placebo and 109 with clomiphene

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

OS‐IUI

• Female age: 40.3 (1.3) years

• Duration of infertility: NA

IVF/ICSI

• Female age: 39.9 (1.4) years

• Duration of infertility: NA

Sample size: OS‐IUI (n = 103); IVF/ICSI (n = 51)

Included criteria: couples in which the woman was 38 to 42 years of age and sought care for unexplained infertility from August 2004 to November 2009 at Boston IVF and from November 2008 to November 2009 at Brigham and Women's Hospital were screened. Eligibility criteria included 6 months of attempted conception; at least 1 ovary and ipsilateral patent fallopian tube confirmed by hysterosalpingogram or laparoscopy; regular menstrual cycles of 21 to 45 days; and no pelvic pathology, ectopic pregnancy, or previous infertility treatment (except up to 3 cycles of clomiphene without IUI). Acceptable ovarian reserve was demonstrated by a clomiphene challenge test (100 mg clomiphene on cycle days 5 to 9; FSH value 15 mIU/mL on cycle days 3 and 10; and oestradiol value 100 pg/mL on cycle day 3). Normal prolactin and thyroid‐stimulating hormone levels and body mass index (BMI) ≤ 38 in the woman, and sperm concentration ≥ 15 million total motile sperm or ≥ 5 million total motile sperm at reflex IUI preparation in partner required. Only the first 2 cycles were included

Excluded criteria: NA

Pretreatment: no previous infertility treatment (except up to three cycles of clomiphene without IUI)

Interventions

Intervention characteristics

OS‐IUI

• Description: treatment with CC was 100 mg orally daily for 5 days starting between cycle days 3 and 5, with serial ultrasound monitoring beginning between cycle days 10 and 12 and luteinising hormone (LH) home monitoring beginning on cycle day 11. One IUI was performed either the day after the LH surge was detected or 36 to 40 hours after subcutaneous/intramuscular (SC/IM) administration of 10,000 IU of human chorionic gonadotropin (hCG) when the lead follicle was R18 mm, whichever came first. If pregnancy was not achieved after 2 treatment cycles, patients proceeded to IVF

IVF/ICSI

• Description: patients randomised to the immediate IVF arm initiated therapy with an IVF protocol consisting of 21 days of an oral contraceptive followed by a microdose leuprolide acetate protocol (40 mg SC twice/d until hCG injection) with a starting dose of twice‐daily gonadotropins (300 IU FSH in the morning and 150 IU human menopausal gonadotropin (hMG) in the afternoon) for 3 days beginning on day 3 or 4 of leuprolide acetate. Adjustments to gonadotropin dosage were determined by oestradiol monitoring and ultrasound; 10,000 IU hCG was given SC or IM when the lead follicle was R17 mm and at least 3 follicles were R15 mm in size. Oocyte retrieval was performed 36 hours after hCG administration, and embryos were routinely transferred on day 3. The number of embryos transferred was based on American Society for Reproductive Medicine (ASRM) guidelines for day 3 embryo transfers (6). Standardised cancellation criteria and low response protocols were used. Intracytoplasmic sperm injection (ICSI) was used only after failed fertilisation or when10 million total motile sperm were available at IVF. Preimplantation genetic diagnosis (3.6% of cycles) and assisted embryo hatching (one‐third of cycles) were performed when considered necessary. Patients in all arms who did not become clinically pregnant after 2 treatment cycles continued with the IVF protocol up to a maximum of 6 IVF cycles, usually 4 fresh and 2 thaw cycles, if available

Outcomes

Clinical pregnancy

Live birth

Multiple pregnancy

OHSS

Identification

Sponsorship source: supported by the National Institutes of Health Eunice Kennedy Shriver, National Institute of Child Health and Human Development (grant R01‐HD44547)

Country: USA

Setting: academic medical centres and private infertility centre in a state with mandated insurance coverage (Boston IVF and Brigham and Women's Hospital)

Author's name: Marlene B. Goldman

Institution: Department of Obstetrics and Gynecology and Community and Family Medicine, Geisel School of Medicine at Dartmouth and Dartmouth‐Hitchcock Medical Center, Lebanon, New Hampshire

Email: [email protected]

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "randomization was performed using permuted blocks of varying sizes, stratified by the woman's age"

Judgement comment: but details of sequence generation were not reported

Allocation concealment (selection bias)

Low risk

Quote: "the allocation sequence was generated by an independent biostatistician and was implemented by an epidemiologist"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "neither the patients nor their providers were blind to their treatment assignment"

Judgement comment: blinding not possible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "all clinical investigators were blinded to the outcome determinations"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: 6/154 with incomplete outcome data

Selective reporting (reporting bias)

Low risk

Judgement comment: all relevant outcomes reported

Other bias

Low risk

Judgement comment: no other sources of bias detected

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

IUI

• Female age: 31.61 (3.73) years

• Duration of infertility: 3.88 (1.71) years

OS‐IUI

• Female age: 31.73 (3.92) years

• Duration of infertility: 4.20 (1.87) years

IVF/ICSI

• Female age: 32.06 (4.20) years

• Duration of infertility: 4.45 (2.82) years

Sample size: IUI (n = 86); OS‐IUI (n = 85); IVF/ICSI (n = 87)

Included criteria: couples who had been affected by idiopathic subfertility for at least 3 years, or by male subfertility for at least 1 year, were eligible for the study

Excluded criteria: if woman had cycle disorders, untreated endometriosis (American Fertility Society criteria grade 2 to 4), or bilateral occluded tubes, or if a semen sample yielded fewer than 1 million progressively motile spermatozoa after processing by Percoll 40/80 gradient centrifugation; if more than 20% of spermatozoa carried antibodies as tested with an immunobead test after Percoll processing, or if more than 50% of spermatozoa had no acrosome. Patients had undergone extensive investigation of infertility including a basal body temperature chart, a late luteal‐phase endometrial biopsy, a post‐coital test, a hysterosalpingogram, a diagnostic laparoscopy, and ≥ 2 semen analyses. Couples were diagnosed as having idiopathic subfertility if no abnormality was found during the full infertility investigation. Male subfertility was diagnosed if ≥ 3 of 5 semen analyses showed a total motile sperm count of fewer than 20 million progressively motile spermatozoa in the ejaculate, and if the remainder of the infertility investigation revealed no additional abnormalities. In both groups of patients, semen processing by Percoll 40/80 gradient centrifugation yielded a minimum of 1 million progressively motile spermatozoa at least once

Pretreatment: none detected

Interventions

Intervention characteristics

IUI

• Description: for IUI in a spontaneous cycle, a single IUI was done 20 to 30 hours after the endogenous luteinising‐hormone surge was detected with a urinary semi‐quantitative monoclonal‐antibody‐based kit with a detection level of 40 IU (OvuQuick, Quidel, San Diego, CA, USA). Patients tested their urine samples twice daily (second morning void and between 1800 hours and 1900 hours) starting on an individually calculated cycle day. A maximum of 0.5 mL suspension of processed spermatozoa was introduced into the uterine cavity with a catheter 10 cm in length (International Medical, Zutphen, Netherlands). Patients were tested for pregnancy if menstruation had not started on the 15th day after insemination

OS‐IUI

• Description: for IUI in a mildly hyperstimulated cycle, a low dose of follicle‐stimulating hormone was given to achieve the growth of 2 to 3 dominant follicles before administration of human chorionic gonadotropin (to optimise the pregnancy rate while preventing a high multiple pregnancy rate). Multi‐follicular growth was defined as growth of more than 1 follicle with a diameter ≥ 14 mm on the day of administration of human chorionic gonadotropin. Baseline pelvic ultrasonography was done at cycle day 3 to exclude ovarian cysts larger than 20 mm. When this point had been established, patients injected themselves intramuscularly with 1 ampoule (75 IU) follicle‐stimulating hormone (Metrodin, Ares Serono, Geneva, Switzerland) daily until transvaginal ultrasonography showed ≥ 1 follicle with diameter 18 mm. Patients tested their urine twice daily (morning and evening void) for the occurrence of a luteinising‐hormone surge. In the event of such a surge, 10,000 IU human chorionic gonadotropin (Profasi, Ares Serono) was given as soon as possible, and a single IUI was done 20 to 30 hours after detection of the surge. When no luteinising‐hormone surge was detected in the presence of at least 1 follicle with diameter of 18 mm or more, 10,000 IU human chorionic gonadotropin was given intramuscularly, and a single IUI was done 40 to 42 hours later. Administration of human chorionic gonadotropin was withheld and IUI was not done when more than 3 follicles with diameter of at least 18 mm, or more than 6 follicles with diameter of at least 14 mm, were present. The daily dose of follicle‐stimulating hormone was increased by 0.5 ampoules in every subsequent cycle when the dose of the previous cycle had resulted in monofollicular growth. Patients were tested for pregnancy if menstruation had not started on the 15th day after insemination

IVF/ICSI

• Description: a standard IVF procedure was carried out as described by Roseboom and colleagues. Women aged 38 years or younger underwent controlled ovarian hyperstimulation with a “long” protocol with gonadotropin‐releasing hormone agonist (Decapeptyl, Ferring, Copenhagen, Denmark). Gonadotropins were given at a daily dose of 2 to 3 ampoules (150 to 225 IU) of human menopausal gonadotropin (Pergonal, Ares Serono) or follicle‐stimulating hormone, depending on patient age or previous response to gonadotropins. In women older than 38 years, a “short” stimulation protocol was applied. In both protocols, gonadotropin‐releasing hormone agonists and gonadotropins were discontinued if transvaginal ultrasonography showed the presence of at least 1 follicle with diameter of at least 18 mm and a minimum of 3 follicles of at least 16 mm in diameter. 35 hours before follicle aspiration, 10,000 IU human chorionic gonadotropin was given unless the serum oestradiol concentration exceeded 20,000 nmol/L. Follicular aspiration guided by transvaginal ultrasonography was done under systemic analgesia (7.5 mg diazepam orally and 50 mg pethidine hydrochloride intramuscularly), and all follicles present were aspirated. Retrieved oocytes were cultured in Earls' + medium (Sigma, St. Louis, MO, USA), and was inseminated with Percoll‐processed spermatozoa 42 hours after the human chorionic gonadotropin injection. We transferred a maximum of 2 pre‐embryos in women 35 years of age or younger, and 3 pre‐embryos in women older than 35 years, 48 to 72 hours after oocyte retrieval. The luteal phase was supported by 3 doses of progesterone (200 mg; Progestan, Nourypharma, Oss, Netherlands) intravaginally daily from the day of oocyte retrieval, or, in the case of breakthrough bleeding, before the 13th day of the luteal phase under progesterone treatment, by 1500 IU human chorionic gonadotropin (Pregnyl, Organon, Oss, Netherlands) intramuscularly every 48 hours, starting from the second day after oocyte retrieval until a pregnancy test was done at the 15th day after oocyte retrieval

Outcomes

Live birth

OHSS

Multiple pregnancy

Identification

Sponsorship source: this work was financially supported by the Health Insurance Executive Board, Amstelveen, Netherlands

Country: Netherlands

Setting: single centre

Author's name: Angelique J. Goverde

Institution: Department of Obstetrics and Gynaecology, University Hospital Vrije Universiteit

Email: [email protected]

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "computer‐generated randomisation schedule"

Allocation concealment (selection bias)

Low risk

Quote: "administered by numbered masked and sealed envelopes"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding impossible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Judgement comment: 13/86, 14/85, and 37/87 participants withdrew during the study in IUI, OS‐IUI, and IVF groups, respectively. Breakdown data unclear in unexplained infertility

Selective reporting (reporting bias)

Low risk

Judgement comment: all relevant outcomes reported

Other bias

Low risk

Judgement comment: no other sources of bias detected

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

IUI

• Female age: 32 (4) years

• Duration of infertility: 46 (31) months

OS‐IUI

• Female age: 32 (4) years

• Duration of infertility: 42 (26) months

Sample size: IUI (n = 234); OS‐IUI (n = 231)

Included criteria: females younger than 40 years of age; negative pregnancy test; normal pelvis and uterine cavity*; “in‐phase” endometrial biopsy; negative serum antisperm antibody test; normal serum follicle‐stimulating hormone and thyrotropin values on days 1 to 5 of cycle; length of 2 of the 3 most recent menstrual cycles between 24 and 40 days; history of infertility for > 1 year. Males younger than 55 years of age; negative serum antisperm antibody test; presence of any motile sperm on screening semen analysis; history of infertility for > 1 year

Excluded criteria: females with previous use of in vitro fertilisation or other assisted reproductive technology; previous treatment with gonadotropins; previous intrauterine insemination with current partner; history of chronic disease; history of chemotherapy or radiation to the abdomen or pelvis; history of tubal surgery; extensive tubal adhesions; endometriosis of more than stage II; history of myomectomy, ovarian cystectomy, or unilateral oophorectomy. Males with previous use of in vitro fertilisation or other assisted reproductive technology; previous intrauterine insemination; history of vasovasostomy; varicocelectomy within 6 months before study; history of pelvic node dissection

Pretreatment: no pretreatment

Interventions

Intervention characteristics

IUI

• Description: women who were not assigned to superovulation underwent insemination timed to spontaneous ovulation. Four days before the expected time of ovulation, women began daily testing of their second morning urine specimen for luteinising hormone, using a qualitative kit (OvuQuick, Quidel, San Diego, CA)

OS‐IUI

• Description: 150 IU follicle‐stimulating hormone was administered intramuscularly daily from day 3 through day 7. On day 8, ultrasonography was repeated and serum oestradiol measured. Daily administration of follicle‐stimulating hormone was continued, with the dose adjusted if necessary, until ≥ 2 follicles reached > 18 mm (average 2 dimensions) and the serum oestradiol concentration ranged from 500 to 3000 pg/mL (1835 to 11,010 pmol/L). Once these criteria were met, treatment with follicle‐stimulating hormone was discontinued and 10,000 IU human chorionic gonadotropin (Profasi, Serono Laboratories) was administered intramuscularly. A single insemination was performed 36 to 40 hours later

Outcomes

Clinical pregnancy

Live birth

Identification

Sponsorship source: supported in part by Cooperative Agreements with the National Institute of Child Health and Human Development (U10 HD26975, U10HD26981, U10 HD27006, U10 HD27009, U10 HD27001, U10HD27049, U10 HD33172, and U10 HD33173) and by Serono Laboratories

Country: USA

Setting: 10 clinical sites

Authors' names: David S. Guzick, Sandra Ann Carson*

Institution: Dr. Carson at Baylor College of Medicine, Department of Obstetrics and Gynecology, 6550 Fannin #801, Houston, TX 77030

Email: [email protected]

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: "randomisation was carried out with use of a permuted block procedure, stratified according to center", but details of random sequence generation not reported

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding mentioned and seemed impossible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: although there were 22 (9%) in the IUI group and 50 (22%) in the OS‐ IUI group, withdrawal from the study led to numbers of participants with unknown pregnancy outcomes of 1 and 2 in IUI and OS‐IUI groups, respectively

Selective reporting (reporting bias)

Unclear risk

Judgement comment: data for multiple pregnancy in each group not available

Other bias

Low risk

Judgement comment: no other sources of bias detected

Methods

Study design: randomised controlled trial

Study grouping: cross‐over

Participants

Baseline characteristics

Overall

• Female age: 29.3 (26 to 41) years

• Duration of infertility: 5.4 (2 to 14) years

• Primary infertility (%): 20/30

• Previous treatments: initially, clomiphene citrate was given at a dosage of 100 mg daily for 4 days from day 3 of the cycle to all patients for 3 cycles

Sample size: EM (n = 15); OS (n = 15)

Included criteria: unexplained infertility: semen analysis, post‐coital test, hysterosalpingogram, laparoscopy, immunological tests, and plasma hormone profile (FSH, LH, oestradiol, prolactin, and progesterone) had been found normal. All women had 3 cycles of CC before randomisation

Excluded criteria: NA

Pretreatment: NA

Interventions

Intervention characteristics

EM

• Description: 15 were scheduled to take Clomid 100 mg daily for 4 days from day 3 of the cycle plus self‐administered 5000 IU hCG IM on day 12 of the cycle for 6 cycles. This was to be followed by 6 cycles of placebo, identically dosed as the clomid, with again 5000 IU hCG IM on day 12

OS

• Description: the other 15 patients were given the same regimen but in reverse order

Outcomes

Clinical pregnancy

Identification

Sponsorship source: Merrell U.K., Ltd.

Country: Ireland

Setting: Rotunda or St. James’s Infertility Clinics

Author's name: Robert F. Harrison

Institution: Rotunda Hospital, Dublin

Email: NA

Address: Rotunda Hospital, Dublin

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: details not reported

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement comment: placebo‐controlled study

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: placebo‐controlled study; objective outcomes used

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcome data presented

Selective reporting (reporting bias)

Unclear risk

Judgement comment: live birth and multiple pregnancy not reported

Other bias

Unclear risk

Judgement comment: insufficient information to judge

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

Overall

• Female age: NA

• Duration of infertility: NA

Sample size: OS (n = 45); OS‐IUI (n = 45)

Included criteria: couples presenting with subfertility due to subnormal semen or unexplained infertility

Excluded criteria: NA

Pretreatment: unclear

Interventions

Intervention characteristics

OS

• Description: women were treated with 3 cycles of ovarian stimulation with human menopausal gonadotropin (hMG) alone. Couples were asked to have vaginal intercourse after administration of human chorionic gonadotropin (hCG)

OS‐IUI

• Description: women were treated with 3 cycles of IUI after the same regimen of ovarian stimulation with hMG

Outcomes

Clinical pregnancy

OHSS

Multiple pregnancy

Identification

Sponsorship source: NA

Country: Hong Kong, China

Setting: single centre

Author's name: P.C. Ho

Institution: Department of Obstetrics and Gynecology, University of Hong Kong, Hong Kong, China

Email: NA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: details not reported

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding impossible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding not likely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to make a judgement

Selective reporting (reporting bias)

Unclear risk

Judgement comment: live birth not reported

Other bias

Unclear risk

Judgement comment: insufficient information to make a judgement

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

EM

• Female age: 33.1 (3.7) years

• Duration of infertility: 58 (33) months

IVF/ICSI

• Female age: 32.9 (3.2) years

• Duration of infertility: 54 (24) months

Sample size: EM (n = 27); IVF/ICSI (n = 24)

Included criteria: duration of subfertility > 2 years, defined as no live birth during that time; no previous IVF treatment; female age 18 ± 39 years; willingness to commence either IVF within 6 weeks of allocation or a 3‐month period of observation without intervention; day 3 serum FSH level > 15 IU/L or standard level for inclusion in an individual centre's IVF programme, whichever level was lower; semen analysis available within last 6 months showing an adequate number of sperm to perform ICSI; evidence of Fallopian tube patency, based on a hysterosalpingogram (HSG) or laparoscopy (only data for unexplained infertility were included)

Excluded criteria: women with bilateral Fallopian tube occlusion confirmed by HSG or laparoscopy; use of donor sperm; need for sperm recovery procedures; concurrent serious medical illnesses that could be a relative contraindication to IVF

Pretreatment: All couples had exhausted appropriate lower intensity treatment options, such as ovulation induction and intrauterine insemination.

Interventions

Intervention characteristics

EM

• Description: 90 days of observation with no treatment: no medications that might reduce spontaneous conception were allowed, such as commencement of GnRH analogue pretreatment for subsequent IVF

IVF/ICSI

• Description: patient's first ever cycle of IVF treatment: similar IVF techniques were used across centres. All programmes used "long protocol" GnRH analogue suppression followed by recombinant FSH as a prelude to oocyte retrieval and IVF. Drugs and dosages used for each patient's stimulation were recorded, along with the numbers of oocytes retrieved and embryos produced, quality of individual embryos, day of transfer, and number and quality of embryos transferred and frozen. Oocyte retrieval was carried out under vaginal ultrasound guidance, and no centre transferred more than 4 embryos per cycle. The day of embryo transfer was not standardised and ranged between day 3 and day 5 post retrieval. Medication was begun within 42 days of randomisation to ensure that all embryo transfers occurred within 90 days ‐ the same period of observation used in the control group

Outcomes

Live birth

Clinical pregnancy

Identification

Sponsorship source: NA

Country: Canada

Setting: 5 Canadian fertility clinics

Author's name: E.G. Hughes

Institution: Department of Obstetrics and Gynecology, McMaster University Medical Centre, 1200 Main Street West, Room 4D14, Hamilton, ON L8N 3Z5, Canada

Email: [email protected]

Address: Department of Obstetrics and Gynecology, McMaster University Medical Centre, 1200 Main Street West, Room 4D14, Hamilton, ON L8N 3Z5, Canada

Notes

Breakdown outcome data of unexplained infertility were extracted from a Cochrane Review (Pandian 2015)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Random allocation was based on a blocked schedule using numbered, sealed, opaque envelopes. Randomization was stratified by centre"

Judgement comment: but details of random sequence generation not available

Allocation concealment (selection bias)

Low risk

Judgement comment: numbered sealed opaque envelopes used

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding impossible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: outcome data of all participants reported

Selective reporting (reporting bias)

Low risk

Judgement comment: all relevant outcomes reported

Other bias

Low risk

Judgement comment: no other sources of bias detected

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

OS

• Female age: NA

• Duration of infertility: NA

OS‐IUI

• Female age: NA

• Duration of infertility: NA

Sample size: OS (n = 36); OS‐IUI (n = 36)

Included criteria: couples with a history of more than 3 years of unexplained subfertility

Excluded criteria: NA

Pretreatment: NA

Interventions

Intervention characteristics

OS

• Description: stimulation of follicular growth + timed intercourse. OS with 10 ampoules Pergonal or Humegon and timing with hCG Pregnyl 10,000 IU for up to 3 cycles

OS‐IUI

• Description: stimulation of follicular growth + IUI. OS with 10 ampoules Pergonal or Humegon and timing with hCG Pregnyl 10,000 IU for up to 3 cycles

Outcomes

Clinical pregnancy

Identification

Sponsorship source: NA

Country: Slovakia

Setting: not reported

Author's name: P. Janko

Institution: Department of Gynaecology and Obstetrics, Postgraduate Medidcal School, Limbovn 5, Bratislava 883 07, Slovakia

Email: NA

Address: Limbova 5, Bratislava 833 07, Slovakia

Notes

Noor Danhof on 4 June 2018, 19:25
Outcomes
A 19.5% per patient, B 29.4% per patient

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: details not reported

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: not reported; blinding impossible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: unblinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Judgement comment: details not available

Selective reporting (reporting bias)

Unclear risk

Judgement comment: live birth and multiple pregnancy not reported

Other bias

Unclear risk

Judgement comment: insufficient information to judge

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

Overall

• Female age: 21 to 38 years

• Duration of infertility: 2 to 14 years

Sample size: OS (n = 47); OS‐IUI (n = 32)

Included criteria: couples with unexplained infertility including cases with minimal or mild endometriosis according to the American Fertility Society score: (1) duration of the infertility should be at least 2 years; (2) no previous treatment with hMG and/or insemination; (3) woman should be 39 years of age and should have regular ovulatory menstrual cycles with maximum length of 35 days; (4) normal sperm sample according to the World Health Organization criteria and a swim‐up test in hyaluronic acid (Sperm Select; Kabi Pharmacia, Uppsala, Sweden; Select Medical Systems, Williston, VT) using 1‐mL aliquot of semen should result in at least 0.5 × 10⁶/mL progressive motile sperm; (5) laparoscopy and HSG should reveal patent tubes without any adhesions; (6) normal PCT (> 3 progressive motile sperm per high power field)

Excluded criteria: NA

Pretreatment: NA

Interventions

Intervention characteristics

OS

• Description: CC or hMG: CC (Pergotime; Serono, Jerusalem, Israel) at a daily dosage of 100 mg was given orally for 5 days starting on days 3 to 5 of the cycle; hMG (Pergonal; Serono, Aubonne, Switzerland) was started at 2 ampoules (150 IU) on days 2 to 4 of the menstrual cycle. Couples were instructed to have intercourse at night the day of the LH surge and the next day. When ovulation occurred during weekends, couples were instructed to have intercourse and in the analysis were transferred to the group treated with CC only. In the group treated with hMG only, couples were instructed to have intercourse the 2 following nights after hCG injection. When ovulation occurred during weekends, couples were instructed to have intercourse, and in the analysis, they were transferred to the group treated with hMG only

OS‐IUI

• Description: CC or hMG: CC (Pergotime; Serono, Jerusalem, Israel) at a daily dosage of 100 mg was given orally for 5 days starting on days 3 to 5 of the cycle; hMG (Pergonal; Serono, Aubonne, Switzerland) was started at 2 ampoules (150 IU) on days 2 to 4 of the menstrual cycle. Daily administration of hMG continued until the leading follicle reached an average diameter ≥ 17 mm or until detection of a luteinising hormone (LH) surge in serum or urine. Ovulation was induced by an injection of 10,000 IU of human chorionic gonadotropin (hCG, Profasi; Serono) the day after the last hMG injection. lUI was performed 36 to 41 hours after hCG administration. In cases with endogenous LH surge, hCG was given the same day and insemination was performed the day after. In the group treated with hMG only, couples were instructed to have intercourse the 2 following nights after hCG injection. When ovulation occurred during weekends, couples were instructed to have intercourse, and in the analysis, they were transferred to the group treated with hMG only

Outcomes

Clinical pregnancy

Identification

Sponsorship source: supported by grant no. B91‐17X‐03495‐20A from The Swedish Medical Research Council, Stockholm, Sweden

Country: Sweden

Setting: Departments of Obstetrics and Gynecology, Central Hospital, Vasteras and Aka‐demiska Hospital, Uppsala University, Uppsala, Sweden

Author's name: Per‐Olof Karlstrom

Institution: Department of Obstetrics and Gynecology, Central Hospital, S‐721 89 Viis‐teras, Sweden

Email: NA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: details not reported

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding impossible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Judgement comment: this is a factorial design; study authors reported only withdrawals in CC and hMG groups, respectively. Unclear how many in OS and OS‐IUI groups withdrew from the study

Selective reporting (reporting bias)

Unclear risk

Judgement comment: live birth not reported

Other bias

Unclear risk

Judgement comment: insufficient information to judge

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

EM

• Female age: NA

• Duration of infertility: NA

IUI

• Female age: NA

• Duration of infertility: NA

Sample size: EM (n = 53); IUI (n = 69)

Included criteria: couples included in this trial had at least 2 years of infertility and gave informed consent to participate in the trial. All males except those in the semen defect groups had normal spermiograms on at least 2 occasions. A normal spermiogram consisted of > 40 × 10⁶ sperm/mL, > 45% progressive motility, and > 40% normal morphology. This corresponds to the 15th percentile of a reference population of all men who approached our clinic as potential semen donors. Tubal patency was assessed by laparoscopic tubal dye insufflation, whereas ovulation and cycle endocrinology were assessed in tracking cycles before treatment. Couples selected for the trial had no identifiable cause of infertility (unexplained group) or a single identified cause. The latter categories included cervical mucus hostility, moderate semen defect, and severe semen defect

Excluded criteria: NA

Pretreatment: NA

Interventions

Intervention characteristics

EM

• Description: patients were requested to have intercourse approximately 40 hours after the start of the endogenous LH rise

IUI

• Description: inseminations were performed in the periovular period. Serum LH, oestradiol, and progesterone were assessed during this period, and inseminations were timed for 40 hours after the start of the endogenous LH rise

Outcomes

Clinical pregnancy

Identification

Sponsorship source: supported in part by grant 850294 from the National Health and Medical Research Council of Australia, Canberra, Australia

Country: Australia

Setting: clinical infertility service

Authors' names: Christine A. Kirby; Colin D. Matthews*

Institution: Department of Obstetrics and Gynaecology, The University of Adelaide, The Queen Elizabeth Hospital

Email: NA

Address: Department of Obstetrics and Gynaecology, The University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia 5011, Australia

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: details not reported

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding impossible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Judgement comment: details not reported

Selective reporting (reporting bias)

Unclear risk

Judgement comment: protocol not available; live birth and multiple pregnancy not reported

Other bias

Unclear risk

Judgement comment: insufficient information to judge

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

Overall

• Female age: 25 to 45 years

• Duration of infertility: > 3 years

Sample size: IUI (n = 34); OS‐IUI (n = 34)

Included criteria: sterility for longer than 3 years, no severe male factors, no tubal damage, moderate oligoasthenospermia, minimal endometriosis, cervical factor, luteal phase defect

Excluded criteria: chronic vaginal infection, liver disease, ovarian cyst, 45 years old, uterine malformation, chronic disease

Pretreatment: NA

Interventions

Intervention characteristics

IUI

• Description: CC: 50 mg per day from day 3 to day 8 of cycle. Once the leading follicle reached 19 to 20 mm, a slot of hCG was done, after 36 to 40 hours, IUI was carried out

OS‐IUI

• Description: assumed placebo (multi‐vitamin) from day 3 to day 8 of cycle. Once the leading follicle reached 19 to 20 mm, a slot of hCG was done, after 36 to 40 hours, IUI was carried out

Outcomes

Clinical pregnancy

Identification

Sponsorship source: NA

Country: Italy

Setting: University of Catania

Authors' names: V. Leanza, F. Grasso

Institution: Department of Surgery, Obstetrics and Gynecology, University of Catania

Email: [email protected]

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: details not reported

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement comment: placebo‐controlled study

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Judgement comment: 9 couples excluded from the analysis

Selective reporting (reporting bias)

Unclear risk

Judgement comment: protocol not available; live birth not reported

Other bias

Unclear risk

Judgement comment: Insufficient information to make a judgement

Methods

Study design: randomised controlled trial

Study grouping: cross‐over

Participants

Baseline characteristics

Overall

• Female age: 32.1 ± 4.1 years

• Duration of infertility: 6.5 ± 3.1 years

Sample size: EM (n = 10); OS (n = 10); IUI (n = 10); OS‐IUI (n = 10)

Included criteria: male or idiopathic factor infertility

Excluded criteria: NA

Pretreatment: NA

Interventions

Intervention characteristics

EM

• Description: timed intercourse was advised between 16 and 28 hours after detection of the first positive LH colour test

OS

• Description: 100 mg of CC for a period of 5 days starting on cycle day 3. Timed intercourse was advised between 16 and 28 hours after detection of the first positive LH colour test

IUI

• Description: intrauterine insemination was performed between 16 and 28 hours after detection of the first positive LH colour test. Only 1 single lUI per treatment cycle was performed

OS‐IUI

• Description: 100 mg of CC for a period of 5 days starting on cycle day 3. Timed intercourse was advised between 16 and 28 hours after detection of the first positive LH colour test. Intrauterine insemination was performed between 16 and 28 hours after detection of the first positive LH colour test. Only 1 single lUI per treatment cycle was performed

Outcomes

Clinical pregnancy

Identification

Sponsorship source: Organon International, Oss, Netherlands

Country: Netherlands

Setting: single centre

Author's name: Antonio R. Martinez

Institution: Department of Obstetrics and Gynecology, Free University Hospital

Email: NA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: details of random sequence generation not reported

Allocation concealment (selection bias)

Unclear risk

Judgement comment: details of allocation concealment not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding not possible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: no withdrawal in the first cycle

Selective reporting (reporting bias)

Unclear risk

Judgement comment: live birth and multiple pregnancy not reported

Other bias

Unclear risk

Judgement comment: insufficient information to judge

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

OS

• Age: 34.8 (5.3) years

• Duration of infertility: 50.6 (13.8) months

OS‐IUI

• Age: 33.3 (4.5) years

• Duration of infertility: 52.1 (11.2) months

Sample size: OS (n = 93); OS‐IUI (n = 91)

Included criteria: unexplained and mild male factor‐related infertility. All couples underwent evaluation that included at least 2 semen analyses with andrological evaluation, female endocrine profile (FSH, LH, PRL, and T assay during the very early follicular phase), ovulation assessment (P and PRL assays during luteal phase), endometrial biopsy, transvaginal ultrasonography, post‐coital test, hysterosalpingogram, and diagnostic laparoscopy. All couples had undergone 3 cycles of induction of ovulation with clomiphene citrate (CC) associated with timed vaginal intercourse and 3 cycles of induction of ovulation with CC associated with lUI without conceiving before being enrolled in this trial

Excluded criteria: couples with severe male factor‐related infertility (sperm concentration 10*10^6/mL, progressive motility 15%, total motility 30%, and normal morphology 30%), tubal damage, anovulatory cycle, polycystic ovary disease, hyperprolactinaemia, uterine fibroids, and endometriosis were treated according to their pathology and were not considered eligible for the study

Pretreatment: no significant difference was present between baseline characteristics

Interventions

Intervention characteristics

OS

• Description: ovulation induction with gonadotropins was obtained by administering purified FSH (Metrodin; Serono, Rome, Italy), starting with a daily dose of 3 ampoules from the 3rd day of the cycle. During treatment with exogenous gonadotropins, pelvic ultrasonography, to determine the number and diameter of ovarian follicles, and blood samples for E2 rapid assay (Medical System, Genova, Italy) were obtained every other day until the mean diameter of the dominant follicles reached 12 mm and E2 plasma levels reached 300 pg/mL (conversion factor to SI unit, 3.671). Thereafter, both examinations were performed daily. The dose of FSH was adjusted according to ultrasonic and endocrine monitoring. Treatment was discontinued when E2 plasma levels reached 800 to 1500 pg/mL and there were at least 2 follicles with a mean diameter of 16 mm. Cycles were cancelled if E2 plasma level was > 1500 pg/mL. Human chorionic gonadotropin (10,000 IU Profasi; Serono) was administered 36 hours after the last injection of FSH. First timed intercourse was suggested 12 hours after hCG administration, whereas lUI was performed 30 to 36 hours after hCG administration. In both timed vaginal intercourse and lUI groups, patients were requested to avoid intercourse from 4 days before the expected time of ovulation until either timed intercourse or lUI was indicated

OS‐IUI

• Description: OS protocol was the same as that in the OS group. Intrauterine insemination was performed using a Frydman catheter. The cervix was exposed with a bivalve speculum and the tip of the catheter was passed into the uterus until it lay about 0.5 cm from the top of the uterine cavity in the fundal region. The in vitro‐prepared sperm was expelled gently and the catheter subsequently was withdrawn

Outcomes

Clinical pregnancy

Live birth

Multiple pregnancy

OHSS

Identification

Sponsorship source: NA

Country: Italy

Setting: single centre: Infertility Centre of Department of Obstetrics and Gynecology of the University of Cagliari, Cagliari, Italy

Author's name: Gian Benedetto Melis

Institution: Department of Obstetrics and Gynecology, University of Cagliari, Cagliari, Italy

Email: NA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: details not reported

Allocation concealment (selection bias)

Low risk

Quote: "numbered sealed envelopes"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding not possible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: 16/184 lost to follow‐up

Selective reporting (reporting bias)

Low risk

Judgement comment: all relevant outcomes reported

Other bias

Unclear risk

Judgement comment: insufficient information to judge

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

OS‐IUI

• Female age: 32 (30 to 35) years

• Duration of infertility: 23.7 (3.4) months

IVF/ICSI

• Female age: 32.5 (30‐35) years

• Duration of infertility: 23.5 (2.9) months

Sample size: OS‐IUI (n = 101); IVF/ICSI (n = 106)

Included criteria: eligible participants were couples with primary or secondary subfertility of minimum 1 year's duration, where the female partner was between 23 and 37 years of age, body mass index (BMI) was 19 to 30, with a regular menstrual cycle of 21 to 35 days, day 2 FSH 10 IU/L, and confirmed bilateral patent tubes. A midluteal serum P level was used to confirm ovulation. The male partner with normal semen parameters (i.e. sperm density > 15 million/mL, progressive motility > 40%, and normal forms > 4% (World Health Organization criteria), or total progressive motile sperm count > 5 million) was included in the trial

Excluded criteria: couples not fulfilling the inclusion criteria, with known uterine anomaly or physical disability, or having difficulty in achieving vaginal intercourse, and couples using donor sperm or previous fertility treatment like IUI or IVF. Those with confirmed endometriosis of grade II to IV were also excluded from the trial. However, routine laparoscopy was not performed in all cases to diagnose endometriosis. Self‐funded patients were excluded from the trial due to lack of research funding

Pretreatment: No pretreatment

Interventions

Intervention characteristics

OS‐IUI

• Description: COH was performed with daily SC injections of 75 IU FSH (Fostimon, a highly purified urofollitropin, Pharmasure) starting from days 2 to 5 of the menstrual cycle onward. When at least 2 follicles with diameter of 17 to 18 mm were present, final oocyte maturation was induced by SC administration of 250 mg hCG (Ovitrelle, Merck Serono), and 24 hours later, IUI was performed. IfR3 follicles of R14 mm developed, then the cycle was cancelled by withholding hCG and IUI and recommending avoiding sexual intercourse due to risk of multiple pregnancies. Semen samples were processed within 1 hour of ejaculation using density gradient centrifugation followed by washing with culture medium. Single insemination was done by the nurse or an on‐duty doctor

IVF/ICSI

• Description: in the IVF group, women underwent downregulation with GnRH agonist in a long protocol, starting on day 21 of the previous cycle. COH was started with FSH (either hMGs or recombinant FSH) with a dose ranging from 150 to 450 IU depending on the woman's ovarian reserve (as tested by anti‐mullerian hormone level, basal antral follicle count, and day 2FSH level) and decided by the attending clinician. When most follicles were R18 mm, ovulation was triggered with 250 mg recombinant hCG (Ovitrelle, Merck Serono), and cumulus‐oocyte complexes were retrieved by transvaginal ultrasound‐guided oocyte retrieval 36 hours later. Women who were deemed high risk for ovarian hyperstimulation syndrome (OHSS) (anti‐mullerian hormone > 25 pmol/L, antral follicle count > 20) underwent a GnRH antagonist protocol for stimulation when COH was achieved with low‐dose FSH (150 IU) and starting GnRH antagonist on day 6 of stimulation. Ovulation was induced by GnRH agonist (Buserelin 0.5 mg SC), and oocyte retrieval was performed after 36 hours. If > 20 oocytes were collected, embryos were frozen and transferred at a later date in a frozen embryo replacement cycle. In that case, the first frozen ET cycle was considered as the first cycle and was included in the analysis. We did not collect data for additional frozen ET cycles, as this was not in our study design. For the frozen ET cycle, downregulation was achieved with GnRH agonist starting from day 21 of the previous cycle followed by endometrial preparation with daily E2 valerate of 8 mg for 10 to 14 days, or until endometrial thickness > 8 mm was achieved. If at least 1 top‐grade embryo was available, then only 1 embryo was transferred on day 3 or day 5. If no top‐grade embryos were available, couples were given the option to transfer up to 2 embryos. Luteal phase support was provided with P vaginal pessaries (Cyclogest 400 mg twice daily, Actavis UK, Ltd.). For frozen ET cycle or GnRH agonist trigger cycle where a fresh embryo was transferred daily, E2 valerate of 8 mg and P gel (Crinone gel, Allergan) were given in addition to P vaginal pessaries for luteal support

Outcomes

Clinical pregnancy

Live birth

Multiple pregnancy

OHSS

Identification

Sponsorship source: this trial had no funding

Country: UK

Setting: single centre

Author's name: Anupa Nandi

Institution: Fertility Unit, Homerton University Hospital, London, UK

Email: [email protected]

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "simple randomization procedure was followed"

Allocation concealment (selection bias)

Low risk

Quote: "allocation concealment was achieved by using individual, consecutively numbered opaque envelopes"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "due to the nature of the trial, blinding was not possible"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "this is unlikely to affect the outcome of the trial, as the outcome was objective"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: outcome data of all participants reported

Selective reporting (reporting bias)

Low risk

Judgement comment: all relevant outcome reported

Other bias

Low risk

Judgement comment: no other sources of bias detected

Methods

Study design: randomised controlled trial

Study grouping: parallel group

Participants

Baseline characteristics

EM

• Female age: 33 (3.1) years

• Duration of infertility: 1.9 (0.5) years

OS‐IUI

• Female age: 33 (2.4) years

• Duration of infertility: 2.0 (0.5) years

Sample size: EM (n = 126); OS‐IUI (n = 127)

Included criteria: couple had not conceived after at least a year of frequent unprotected intercourse; the woman was younger than 39 years; and the woman had a regular menstrual cycle. Couples with unexplained subfertility and an intermediate prognosis of a spontaneous ongoing pregnancy within the next 12 months were eligible for this study. The basic fertility assessment included medical history, cycle monitoring, semen analysis, post‐coital test, and investigation of tubal function

Excluded criteria: NA

Pretreatment: NA

Interventions

Intervention characteristics

EM

• Description: couples assigned expectant management were followed up until an ongoing pregnancy occurred, or for 6 months if no pregnancy occurred. If a pregnancy miscarried, follow‐up continued until the next pregnancy or the end of 6 months. Hysterosalpingography or laparoscopy was allowed in these 6 months

OS‐IUI

• Description: women started daily subcutaneous injections of follicle‐stimulating hormone (Gonal F (Serono Benelux, The Hague, Netherlands) or Puregon (Organon, Oss, Netherlands)) or human menopausal gonadotropin (Menopur (Ferring, Hoofddorp, Netherlands)) in mean doses of 75 IU, ranging from 37 IU to 150 IU, until transvaginal sonography showed at least 1 follicle ≥ 16 mm in diameter. Ovulation was then induced with 5000 IU or 10,000 IU of human chorionic gonadotropin (Pregnyl (Organon)), and women were inseminated 36 to 40 hours later. We withheld human chorionic gonadotropin and intrauterine insemination if there were more than 3 follicles with diameter ≥ 16 mm, or 5 with diameter ≥ 12 mm. We did not give luteal support. We processed semen samples within 1 hour of ejaculation by density‐gradient centrifugation followed by washing with culture medium. The volume of semen that was inseminated varied between 0.2 mL and 1.0 mL. We did the insemination irrespective of the total motile count after preparation on the scheduled day

Outcomes

Clinical pregnancy

Live birth

Multiple pregnancy

OHSS

Identification

Sponsorship source: this study was supported by grant 945/12/002 from ZonMW (Netherlands Organization for Health Research and Development, The Hague, Netherlands)

Country: Netherlands

Setting: 26 fertility centres in Netherland

Author's name: Pieternel Steures

Institution: Centre for Reproductive Medicine, Academic Medical Centre, Amsterdam, Netherlands

Email: [email protected]

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "the randomisation sequence was computer generated in balanced block multiples of two or four, stratified by centre"

Allocation concealment (selection bias)

Low risk

Quote: "the sequence was concealed, and sealed opaque envelopes containing details of the treatment allocation were assembled by an independent person. Clinicians in the participating centres enrolled the couple and subsequently opened the next envelope. The inclusion was then confirmed to the trial coordinator by fax"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Judgement comment: blinding impossible due to the nature of the interventions

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: non‐blinding unlikely to affect objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: OS‐IUI: 3/127 lost to follow‐up, EM: 2/126 lost to follow‐up, 2 still pregnant

Selective reporting (reporting bias)

Low risk

Judgement comment: all relevant outcomes reported

Other bias

Low risk

Judgement comment: no other sources of bias detected