Intra‐uterine insemination for unexplained subfertility

Susanne M Veltman‐Verhulst; Ben J Cohlen; Edward Hughes; Maas Jan Heineman

doi:10.1002/14651858.CD001838.pub3

Inseminación intrauterina para la subfertilidad de causa desconocida

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Referencias

Referencias de los estudios incluidos en esta revisión

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estudios excluidos
estudios a la espera de valoración
otras referencias

Agarwal S, Mittal S. A randomised prospective trial of intrauterine insemination versus timed intercourse in superovulated cycles with clomiphene. Indian Journal of Medical Research 2004;120(6):519‐22.

Arcaini L, Bianchi S, Baglioni A, Marchini M, Tozzi L, Fedele L. Superovulation and intrauterine insemination vs. superovulation alone in the treatment of unexplained infertility. A randomized study. Journal of Reproductive Medicine 1996;41(8):614‐8.

Arici A, Byrd W, Bradshaw K, Kutteh WH, Marshburn P, Carr BR. Evaluation of clomiphene citrate and human chorionic gonadotropin treatment: A prospective, randomized, crossover study during intrauterine insemination cycles. Fertility and Sterility 1994;61(2):314‐8.

Bhattacharya S, Harrild K, Mollison J, Wordsworth S, Tay C, Harrold A, et al. Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: pragmatic randomised controlled trial. BMJ 2008;7(337):a716.

Chung CC, Fleming R, Jamieson ME, Yates RWS, Coutts JRT. Randomized comparison of ovulation induction with and without intrauterine insemination in the treatment of unexplained infertility. Human Reproduction 1995;10:3139‐41.

Crosignani PG, Walters DE, Soliani A. The ESHRE multicentre trial on the treatment of unexplained infertility: A preliminary report (Centre 19: Martinez, Amsterdam). Human Reproduction 1991;6(7):953‐8.

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Crosignani PG, Walters DE, Soliani A. The ESHRE multicentre trial on the treatment of unexplained infertility: A preliminary report (Centre 16: Pellicer, Valencia). Human Reproduction 1991;6(7):953‐8.

Crosignani PG, Walters DE, Soliani A. The ESHRE multicentre trial on the treatment of unexplained infertility: A preliminary report (data from centre 10: Hedon , Montpellier). Human Reproduction 1991;6(7):953‐8.

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Goverde AJ, McDonnell J, Vermeiden JP, Schats R, Rutten FF, Schoemaker J. Intrauterine insemination or in‐vitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost‐effectiveness analysis. Lancet 2000;355(9197):13‐8.

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Referencias de los estudios excluidos de esta revisión

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estudios a la espera de valoración
otras referencias

Aboulghar MA, Mansour RT, Serour GI, Amin Y, Abbas AM, Salah IM. Ovarian superstimulation and intrauterine insemination for the treatment of unexplained infertility. Fertility and Sterility 1993;60(2):303‐6.

Doyle M, DeCherney A. The value of empiric intrauterine insemination (IUI) with superovulation: a prospective‐ randomised clinical trial. Fertility and Sterility 1991;56:S34.

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Gregoriou O, Vitoratos N, Papadias C, Konidaris S, Gargaropoulos A, Louridas C. Controlled ovarian hyperstimulation with or without intrauterine insemination for the treatment of unexplained infertility. International Journal of Gynaecology and Obstetrics 1995;48:55‐9.

Ho P, Yeung W, So W, Lau E. A randomised trial comparing the efficacy of ovarian stimulation and intrauterine insemination versus ovarian stimulation alone in the treatment of male infertility and unexplained infertility. British Journal of Obstetrics and Gynaecology 1998;105(suppl 17):43.

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Kirby C, Flaherty S, Godfrey B, Warnes G, Matthews C. A prospective trial of intrauterine insemination of motile spermatozoa versus timed intercourse. Fertility and Sterility 1991;56(1):102‐7.

Martinez AR, Bernardus RE, Voorhorst FJ, Vermeiden JP, Schoemaker J. Intrauterine insemination does and clomiphene citrate does not improve fecundity in couples with infertility due to male or idiopathic factors: a prospective, randomized, controlled study. Fertility and Sterility 1990;53(5):847‐53.

Martinez AR, Bernardus RE, Voorhorst FJ, Vermeiden JP, Schoemaker J. Pregnancy rates after timed intercourse or intrauterine insemination after human menopausal gonadotropin stimulation of normal ovulatory cycles: a controlled study. Fertility and Sterility 1991;55(2):258‐65.

Randomized prospective trial of pergonal (HMG) superovulation with intrauterine insemination (IUI) versus IUI alone. Nulsen JC, Dumez S, Metzger DA. Fertility and Sterility 1990;54:S57.

Nulsen JC, Walsh S, Dumez S, Metzger DA. A randomized and longitudinal study of human menopausal gonadotropin with intrauterine insemination in the treatment of infertility. Obstetrics and Gynecology 1993;82(5):780‐6.

Prentice A, Sacks GP, Morton NC, Deary AJ, Smith SK. Controlled ovarian stimulation (superovulation) and intrauterine insemination for the treatment of unexplained and minor male factor infertility. Human Reproduction 1995;10:112.

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Serhal PF, Katz M, Little V, Woronowski H. Unexplained infertility ‐ the value of Pergonal superovulation combined with intrauterine insemination. Fertility and Sterility 1988;49(4):602‐6.

Tummon IS, Asher LJ, Martin JS, Tulandi T. Randomized controlled trial of superovulation and insemination for infertility associated with minimal or mild endometriosis. Fertility and Sterility 1997;68(1):8‐12.

Zikopoulos K, West C, Thong P, Kacser E, Morrison J, Wu F. Homologous intra‐uterine insemination has no advantage over timed natural intercourse when used in combination with ovulation induction for the treatment of unexplained infertility. Human Reproduction 1993;8(4):563‐7.

Referencias de los estudios en espera de evaluación

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S. Wordsworth, J. Buchanan, J. Mollison, K. Harrild, L. Robertson, C. Tay, A. Harrold, D. McQueen, H. Lyall, L. Johnston, J. Burrage, S. Grossett, H. Walton, J. Lynch, A. Johnstone, S. Kini, A. Raja, A. Templeton, S. Bhattacharya. Clomifene citrate and intrauterine insemination as first‐line treatments for unexplained infertility: are they cost‐effective?. Human Reproduction 2011;26(2):369‐75.

Referencias adicionales

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estudios incluidos
estudios excluidos
estudios a la espera de valoración

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Besselink DE, Farquhar C, Kremer JAM, Marjoribanks J, O'Brien PA. Cervical insemination versus intra‐uterine insemination of donor sperm for subfertility. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: 10.1002/14651858]

Cantineau AE, Cohlen BJ. Ovarian stimulation protocols (anti‐oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/14651858]

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Costello MF. Systematic review of the treatment of ovulatory infertility with clomiphene citrate and intrauterine insemination. Australian and New Zealand Journal of Obstetrics and Gynaecology 2004;44(2):93‐102.

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Daya S. Pitfalls in the design and analysis of efficacy trials in subfertility. Human Reproduction 2003;18(5):1005‐9.

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Dickey RP. Risk factors for high‐order multiple pregnancy and multiple birth after controlled ovarian hyperstimulation: results of 4,062 intrauterine insemination cycles. Fertility and Sterility 2005;83(3):671‐83.

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Fauser BC, Devroey P, Macklon NS. Multiple birth resulting from ovarian stimulation for subfertility treatment. Lancet 2005;365(9473):1807‐16.

Gleicher N, Oleske DM, Tur‐Kaspa I, Vidali A, Karande V. Reducing the risk of high‐order multiple pregnancy after ovarian stimulation with gonadotropins. New England Journal of Medicine 2000;343(1):2‐7.

Goverde AJ, Lambalk CB, McDonnell J, Schats R, Homburg R, Vermeiden JP. Further considerations on natural or mild hyperstimulation cycles for intrauterine insemination treatment: effects on pregnancy and multiple pregnancy rates. Human Reproduction 2005;20(11):3141‐6.

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Hughes EG. The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta‐analysis. Human Reproduction 1997;12(9):1865‐72.

Hughes EG. Stimulated intra‐uterine insemination is not a natural choice for the treatment of unexplained subfertility.'Effective treatment' or 'not a natural choice'?. Human Reproduction 2003;18(5):912‐14.

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van Rumste MM, den Hartog JE, Dumoulin JC, Evers JL, Land JA. Is controlled ovarian stimulation in intrauterine insemination an acceptable therapy in couples with unexplained non‐conception in the perspective of multiple pregnancies?. Human reproduction 2006;21(3):701‐4.

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Agarwal 2004

Methods	Trial design: parallel Single centre Randomisation: random number table Allocation concealment: sealed opaque envelopes Nr of Pt randomised: IUI+OH 70; TI+OH 70 Nr of withdrawals: IUI+OH 26 (37%); TI+OH 1 (total 19%)
Participants	Couples with unexplained subfertility Age: IUI+OH 29.52 (±3.65); TI+OH 28.83 (±4.76) Duration of subfertility: IUI+OH 4.91 (±2.72); TI+OH 4.93 (±3.27) Basic fertility work up normal, semen normal according to WHO 1987 Previous treatment: no
Interventions	Comparison: IUI+OH versus TI+OH Stimulation method: 50‐150 mg CC/day, day 3‐7 Ovulation: 10000 IU hCG when not more than 4 follicles of >16mm were present Timing of IUI and TI: 36‐40hr after HCG Duration of treatment: 6 cycles max
Outcomes	Live birth and PR per couple and per cycle Miscarriage rate Ectopic PR Multiple pregnancies Pregnancy confirmed by USS showing gestational sac
Notes	ITT‐analysis: possible Author provided additional information Unbalanced groups: dropouts 37% in IUI group, 1% in TI group
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number table
Allocation concealment (selection bias)	Low risk	A ‐ Adequate; sealed opaque envelopes
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	High risk	There was an unequal dropout in the treatment group due to financial reasons.
Selective reporting (reporting bias)	Unclear risk	Reported on live birth, however authors provided additional information on ongoing pregnancies and twin pregnancies resulting in different data used for meta‐analysis
Other bias	High risk	The financial constraints causing unbalanced groups could also have influenced patient selection, follow‐up and treatment compliance.

Arcaini 1996

Methods	Trial design: parallel Single centre Randomisation: method unclear Allocation concealment: unclear Nr of Pt randomised: IUI+OH 36; TI+OH 32 Nr of withdrawals: 14 (20.6%)
Participants	Couples with unexplained subfertility Age: IUI+OH 34.6 (±4.9); TI+OH 33.4 (±4.7) Duration of subfertility: IUI+OH 4.2 (±1.6); TI+OH 3.9 (± 2.3) Basic fertility work up normal, semen normal, not further specified Previous treatment: not stated
Interventions	Comparison: IUI+OH versus TI+OH Stimulation method: 100mg CC/day, day 3‐7 and 1‐3 ampoule hMG/day Ovulation: 10000 IU hCG when 2‐6 follicles of >17mm were present Timing IUI or TI: 24hr and 48 hr after hCG Duration of treatment: 5 cycles max
Outcomes	PR per couple Miscarriage rate Ectopic PR Multiple pregnancies OHSS Pregnancy confirmed by USS
Notes	ITT‐analysis: yes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	Low risk	A total of 16 cancelled treatment cycles is described and analysed according to intention to treat. Patients who dropped out are clearly stated in a table.
Selective reporting (reporting bias)	Unclear risk	Did not report on live birth, however, did not intend to report on live birth.

Arici 1994

Methods	Trial design: crossover (after 1 cycle) Single centre Randomisation: computer generated random number table Allocation concealment: computer system utilising locked files Nr of Pt randomised: 26 Nr of withdrawals: not clear
Participants	Couples with unexplained subfertility and couples with male factor subfertility Age: mean 33 yrs (range 24‐41) Duration of subfertility: mean 3.5 yrs (range 1‐15 yr) Unexplained subfertility: basic fertility work up normal, semen normal according to WHO 1987 criteria Previous treatment: no
Interventions	Comparison: IUI+NC versus IUI+OH Stimulation method: 50 mg CC/day, day 5‐9 Timing: Natural cycle: urinary LH test, IUI on day of LH peak and the next day Stimulated cycle: 10000 IU hCG when at least 1 follicle of 18mm was present; IUI 32 hr after hCG No cancellation criteria were given Duration of treatment: 4 cycles max
Outcomes	Live birth and PR per couple PR per 1st cycle PR per cycle Miscarriage rate Ectopic PR Multiple pregnancies Pregnancy confirmed by USS showing gestational sac
Notes	ITT analysis: yes Author provided additional information 5 Pt with treated minimal endometriosis were included as unexplained subfertility
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random number table
Allocation concealment (selection bias)	Low risk	A ‐ Adequate; computer system utilizing locked files
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	Low risk	Author gave additional information on dropout rates of the couples with unexplained subfertility. Of the 26 women with unexplained subfertility, dropout occurred after 1 treatment cycle. Post‐crossover data are not included in the meta‐analysis.
Selective reporting (reporting bias)	Low risk	Live birth data were obtained from the author

Bhattacharya 2008

Methods	Trial design: parallel Multi centre (four teaching hospitals, one general hospital Scotland) Randomisation: computer generated randomisation schedule Allocation concealment: central telephone system Nr of Pt randomised: 509 with unexplained subfertility only (total 580). Nr of withdrawals: 4
Participants	Couples with unexplained subfertility, (mild male factor infertility and minimal endometriosis) Age: TI+NC 32 (±3.4); TI+OH 32 (±3.5); IUI+NC 32 (±3.7) Duration of subfertility: minimal 2 years, median 30 months all groups Basic fertility work up normal, semen normal according to WHO (sperm motility<20% included) Previous treatment: not stated
Interventions	Comparison: TI (expectant management) +NC versus TI+OH versus IUI+NC Stimulation method: 50 mg CC/day (starting dose), day 2‐6 Ovulation: confirmed by progesterone measure in TI+OH group, and urinary LH surge in IUI+NC group Timing of IUI and TI: IUI 20‐30hr after LH surge, Timing intercourse advised on cycle day 12‐18 Duration of treatment: 6 cycles max
Outcomes	Live birth and PR per couple Miscarriage rate Ectopic PR Multiple pregnancies Pregnancy confirmed by USS showing gestational sac and fetal hart beat
Notes	The author provided additional data on the couples with unexplained subfertility only. The baseline characteristics of the patients reported are from the group total. ITT analysis was therefore possible and performed. Author provided additional information.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sequence generated by independent statistician
Allocation concealment (selection bias)	Low risk	A ‐ Adequate; central telephone randomisation system
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up and patients who received alternative treatment are presented in a flow‐chart.
Selective reporting (reporting bias)	Low risk	Live birth data and adverse events are published

Chung 1995

Methods	Trial design: parallel Single centre Randomisation: blocked randomisation scheme Allocation concealment: numbered sealed envelopes Nr of Pt randomised: 100 Total dropouts: 12 (12%)
Participants	Couples with unexplained subfertility Age: IUI+OH 31.8 (±3.1); TI+OH 32.1 (±4.0) Duration of subfertility: IUI +OH 4.7 (±2.0); TI+OH 5.3 (±2.6) Basic fertility work up normal and semen 15 million motile per ejaculate Previous treatment: not stated
Interventions	Comparison: IUI+OH versus TI+OH Stimulation method: FSH 150 IU/day and GnRH nasal spray from day 21 on Ovulation: 5000IU hCG when <4 follicles >16mm hCG post ovulatory for luteal support Timing TI: 24 + 48 hr after hCG Timing IUI: 36‐48 hr after hCG Duration of treatment: 3 cycles max
Outcomes	PR per couple and per cycle Total delivered Multiple pregnancies Ectopic Miscarriage rate
Notes	ITT‐analysis: possible IUI was not possible on Sundays
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Blocked randomisation scheme
Allocation concealment (selection bias)	Low risk	A ‐ Adequate; numbered sealed envelopes
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	8/50 withdrawn and 6 treatment cycles cancelled in TI group, 4/50 withdrawn and 11 treatment cycles cancelled in IUI group. Reason for cycle cancellation was excessive response. Reason for withdrawal was not stated.
Selective reporting (reporting bias)	Low risk	Live birth data and complication numbers were reported.

Crosignani 1991

Methods	Data from centre 10: Hedon, Montpellier, France Trial design: cross over (after 1 cycle) Multi centre (19 European fertility centres, 4 centres comparing IUI versus TI) Randomisation: not clear Allocation concealment: unclear Nr of Pt randomised: unclear Nr of Pt analysed: total 90 (centre 10; 18 patients) Nr of withdrawals: unclear
Participants	Couples with unexplained subfertility Age: <38yrs Duration of subfertility: >3yrs Basic fertility work up normal, semen normal according to WHO 1987 Previous treatment: not stated
Interventions	Comparison: IUI+OH versus TI+OH Stimulation method: not stated Ovulation: not described Timing: not described No cancellation criteria were given Duration of treatment: 2 cycles max
Outcomes	PR per 1st cycle PR per cycle
Notes	ITT‐analysis: not possible Author replied; could not provide additional information Multicentre ESHRE trial. Only 4 infertility centres compared IUI with superovulation alone. These centres were included in the analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Each centre used own randomisation method. The per centre method could not be obtained.
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear; each centre used own treatment allocation method. The per centre method could not be obtained.
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	High risk	Details on patient withdrawal or loss to follow‐up were not stated
Selective reporting (reporting bias)	Unclear risk	Live birth data were not reported

Crosignani 1991b

Methods	Data from centre 13: Willemsen, Nijmegen, the Netherlands Nr of Pt analysed: 7
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Blinding (performance bias and detection bias) All outcomes	High risk

Crosignani 1991c

Methods	Data from centre 16: Pellicer, Valencia, Italy Nr of Pt analysed: 35
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Blinding (performance bias and detection bias) All outcomes	High risk

Crosignani 1991d

Methods	Data from centre 19: Martinez, Amsterdam, the Netherlands Nr of Pt analysed: 30
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Blinding (performance bias and detection bias) All outcomes	High risk

Deaton 1990

Methods	Trial design: crossover (after 4 cycles) Single centre Randomisation: unclear Allocation concealment: unclear Nr of Pt randomised: 67 Nr of Pt analysed: 51 total, unexplained: 24 Nr of withdrawals: 4 pre‐crossover (6%)
Participants	Couples with unexplained subfertility and couples with surgically treated endometriosis Age: 33 (±4.0) Duration of subfertility: 3.5 (±1.7) Basic fertility work up normal, semen normal according to WHO criteria 1987 Previous treatment: not stated
Interventions	Comparison: IUI+OH versus TI+NC Stimulation method: 50 mg CC/day, day 5‐9 Timing: Natural cycle: urinary LH and BBT timed intercourse Stimulated cycle: 10000 IU hCG when lead follicle was estimated to be at least 18mm. IUI 36hr after hCG injection. No cancellation criteria were given Duration of treatment: 8 cycles max
Outcomes	Ongoing pregnancy rate Multiple pregnancies Ectopic pregnancies Miscarriage rate OHSS Pregnancy: not further defined
Notes	ITT‐analysis: not possible Patients with unexplained subfertility and endometriosis were included in this study; three patients with moderate and no patients with severe endometriosis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Sequence generation not stated
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	Low risk	16/67 patients excluded from analysis due to anovulation, poor semen quality or inability to follow the treatment protocol. Of the remaining 51 patients, 6 couples did not complete treatment because of illness or relocation. 4/51 dropped out before cross‐over.
Selective reporting (reporting bias)	Unclear risk	Live birth rate was not reported.

Goverde 2000

Methods	Trial design: parallel Single centre Randomisation: computer generated randomisation schedule Allocation concealment: numbered, masked and sealed envelopes A power calculation was performed Nr of patients randomised: 120 (unexplained IUI+NC and IUI+TI), 258 total Nr of withdrawals: unclear
Participants	Couples with unexplained subfertility and couples with male factor subfertility Age: IUI+NC 31.6 (±3.7); IUI+OH 31.7 (±3.9) Duration of subfertility: IUI+NC 3.9 (±1.7); IUI+OH 4.2 (±1.9) Basic fertility work up normal, semen normal when >20 million progressive motile in ejaculate Previous treatment: not stated
Interventions	Comparison: IUI+NC versus IUI+OH (versus IVF) Stimulation method: 75 IU FSH (starting dose) until 1‐3 follicles of 18mm were seen on USS hCG was withheld if >3 follicles of 18mm or > 6 of 14 mm were present Timing: Stimulated cycle: 10000 IU hCG, IUI 40‐42 hr after hCG; Natural cycle: IUI 20‐30 hr after detection of urinary LH‐surge. Cycles were cancelled when >3 follicles of 18mm or >6 follicles of 14 mm were present Duration of treatment: 6 cycles max
Outcomes	Live birth per couple OHSS
Notes	ITT‐analysis: yes Some dropouts because of spontaneous pregnancy
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated randomisation schedule
Allocation concealment (selection bias)	Low risk	A ‐ Adequate; numbered, masked and sealed envelopes
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	7/120 withdrew before 1st treatment cycle. Details on dropout not separately available for unexplained subfertility. Some patients dropped out because of spontaneous pregnancy. It is not known whether these patients are included in the IUI unexplained subfertility group.
Selective reporting (reporting bias)	Low risk	Live birth and complication data were reported

Guzick 1999

Methods	Trial design: Parallel Multi centre (10 clinical sites) Randomisation: computer generated permuted block Allocation concealment: locked computer files Nr of Pt randomised: 932 (465 treated with IUI) Nr of Pt with unexplained subfertility: 211 Nr of withdrawals: 72 total (15%)
Participants	Couples with unexplained subfertility and couples with stage I or II treated endometriosis or male factor subfertility Age: IUI+NC 32 (±4) IUI+OH 32 (±4) Duration of subfertility: IUI+NC 3.8 (±2.6); IUI+OH 3.5 (±2.2) Basic fertility work up normal, semen normal (according to WHO 1992) Previous treatment: No previous treatment. (Pt excluded if previous ART)
Interventions	Comparison: IUI+NC versus IUI+OH Stimulation method: 150 IU FSH/day, day 3‐7 Ovulation: IUI+OH: 10000 IU hCG when 2 follicles of > 18mm were present IUI+NC: urine LH testing Timing: IUI+OH: 36‐40 hr after hCG IUI+NC: IUI the day after urinary LH surge Cycles were cancelled if serum E2 concentration >3000pg/ml Duration of treatment: 4 cycles max
Outcomes	Live birth per couple PR per couple Miscarriage rate Ectopic PR Multiple pregnancies OHSS Pregnancy defined by two positive HCG tests. Confirmed by live birth
Notes	ITT‐analysis: not possible Author replied; provided additional information
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated permuted block
Allocation concealment (selection bias)	Low risk	A ‐ Adequate; locked computer files
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Withdrawal rates of the total group were presented: 4/465 treatment related withdrawal, 27/465 not treatment related. Numbers for unexplained subfertility group are not known.
Selective reporting (reporting bias)	Low risk	Live birth and complication data were reported

Janko 1998

Methods	Trial design: parallel Single centre Randomisation: not clear Allocation concealment: unclear Nr of Pt randomised: 72 Nr of withdrawals: not stated
Participants	Couples with unexplained subfertility Age: not stated Duration of subfertility: >3 yrs Basic fertility work up normal, semen normal not further specified Previous treatment: not stated
Interventions	Comparison: IUI+OH versus TI+OH Stimulation method: hMG (10 amp per cycle) Ovulation: 10000 IU hCG Timing: not specified No cancellation criteria were given. Duration of treatment: 3 cycles max
Outcomes	PR per cycle Pregnancy not further defined
Notes	ITT‐analysis: possible Abstract only. Data calculated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear; not stated
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	High risk	Not available
Selective reporting (reporting bias)	High risk	In this abstract the reported outcome data are minimal

Karlstrom 1993

Methods	Trial design: Parallel Single centre Randomisation: not clear Allocation concealment: unclear Nr of Pt randomised: not clear Nr of Pt analysed: 79 Nr of withdrawals: not clear
Participants	Couples with unexplained subfertility and minimal or mild endometriosis Age: 32 (range 21‐38) Duration of subfertility: 5 (range 2‐14) Basic fertility work up normal, semen normal according to WHO 1987. Previous treatment: no
Interventions	Comparison: IUI+OH versus TI+OH (vs DIPI+OH vs IUI and DIPI+OH) Stimulation method 1: 150IU hMG starting dose, till one follicle of at least 17 mm was present or the detection of a LH surge in serum or urine. Monitoring: USS and serum E2 Ovulation: 10000 IU hCG Timing: IUI 36‐41 hr after hCG or 24 hr after detection of LH surge. TI the two following nights after hCG injection. Cycles were cancelled according to serum E2 rise. Duration of treatment: 1 cycle max
Outcomes	PR per cycle Ectopic PR Pregnancy not further defined
Notes	ITT‐analysis: not possible When ovulation occurred during the weekend, Pt were transferred to TI group.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear; not stated
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	Low risk	4 withdrawals in clomiphene group due to absent LH surge, 5 withdrawals in hMG group due to absent LH surge, fast oestrogen rise or personal reasons.
Selective reporting (reporting bias)	Unclear risk	Live birth data were not reported

Karlstrom 1993 b

Methods	See Karlstrom 1993a Group underwent different stimulation method
Participants
Interventions	Stimulation method 2: 100mg CC/day for 5 days Monitoring + Ovulation: urinary LH timed. Timing: IUI 20‐28 hr after LH surge, TI day of LH surge and day after.
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Blinding (performance bias and detection bias) All outcomes	High risk

Melis 1995

Methods	Trial design: parallel Randomisation: computer generated random number list Allocation concealment: numbered opaque sealed envelopes Nr of Pt randomised: 108 Nr of Pt analysed: 103 Nr of withdrawals: 5 (4.6%)
Participants	Couples with unexplained and couples with mild male factor subfertility Age: 33.1 (±5.2) Duration of subfertility: 4.3 (±1.4) Basic fertility work up normal, semen normal according to WHO 1987 criteria Previous treatment: yes, all couples
Interventions	Comparison: IUI+OH versus TI+OH Stimulation method: 3 amp FSH/day Monitoring: USS and plasma E2 Ovulation: 10000 IU hCG when at least 2 follicles of 16mm were present Timing: TI 12 hr after HCG, IUI 30‐36 hr after HCG Cycles cancelled when plasma E2 level > 1500pg/ml Duration of treatment: 3 cycles max
Outcomes	Live birth per couple PR/couple Miscarriage Multiple pregnancies OHSS Pregnancy confirmed by USS showing fetal heart activity
Notes	ITT analysis: possible Author provided additional information All patients have had previous fertility treatment Pt with minor abnormalities were excluded from the study
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random number list
Allocation concealment (selection bias)	Low risk	A ‐ Adequate; numbered opaque sealed envelopes
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	Low risk	Exclusion numbers were published for the overall group.The author provided additional information: 1/52 (IUI+OH group) withdrew, 4/56 (TI+OH group) withdrew. Reasons for dropout were family problems, poor response or exaggerated response.
Selective reporting (reporting bias)	Low risk	Live birth data and complication numbers were available for analysis

Murdoch 1991

Methods	Trial design: parallel Randomisation: random number sequence Allocation concealment: via sequentially numbered opaque sealed envelopes Nr of Pt randomised: 39 IUI+ NC 19; IUI+OH 20 Nr of withdrawals: 5 (13%)
Participants	Couples with unexplained subfertility Age: IUI+NC 30.5 (±3.1); IUI+OH 30.1 (±2.9) Duration of subfertility: IUI+NC 5.7 (±2.4); IUI+OH 5.1 (±1.9) Basic fertility work up done, semen normal (according to WHO 1987) Previous treatment: no
Interventions	Comparison: IUI+NC versus IUI+OH (vs GIFT) Stimulation method: 75 IU hMG/day and 200 micro gram buserelin 4 times daily intranasal Ovulation: 5000 IU hCG, when < 4 follicles of >16mm were seen. Timing: 30‐36 hr after hCG Natural cycle: IUI on alternate days until ovulation confirmed on USS Cycles were cancelled if >4 dominant follicles were present Duration of treatment: 3 cycles max
Outcomes	PR per couple and per cycle Live birth Multiple pregnancies Clinical pregnancy defined by USS showing fetal heart activity
Notes	ITT analysis: yes Author provided additional information 1 pregnancy between treatment cycles 10 cycles were abandoned because no treatment available at the weekend
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random number sequence
Allocation concealment (selection bias)	Low risk	A ‐ Adequate; numbered opaque sealed envelopes
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	Low risk	Drop‐out rate 3/19 (IUI+NC), and 2/20 (IUI+OH). Reasons not stated. Data on cycle cancellation are reported.
Selective reporting (reporting bias)	Low risk	Live birth data were provided

Steures 2006

Methods	Trial design: parallel Multi centre: 26 fertility centres in the Netherlands Randomisation: computer generated sequence in balanced blocks Allocation concealment: via opaque sealed envelopes Nr of Pt randomised: 253 IUI+OH 127; TI (expectant management)+NC 126 Nr of withdrawals: 3 (IUI+OH) and 2 (TI+NC), 2 still pregnant (TI + NC)
Participants	Couples with unexplained subfertility and an intermediate prognosis of conceiving within the next 12 months (Hunault 30‐40%) Age: IUI+OH 33 (±3.4); TI+NC 33 (±3.19) Duration of subfertility: IUI+OH 2.0 (±0.5);TI+NC 1.91 (±0.5) Basic fertility work up done, semen analysis according to WHO 1987, normal postcoital test Previous treatment: not stated
Interventions	Comparison: IUI+OH versus TI (expectant management)+NC Stimulation method: FSH 37‐150 IU/day or 50‐150 mg CC/day Monitoring: USS Ovulation: 5000 or 10000 IU hCG Timing: IUI 36‐40 hr after hCG Cycles were cancelled when >3 follicles of 16mm or >5 follicles of 12mm were present. Duration of treatment: 6 months
Outcomes	Live birth/couple PR/couple Miscarriage rate Multiple pregnancies
Notes	ITT analysis: yes Author provided additional information. Only couples with an intermediate prognosis of conceiving were included, this influences the possible treatment effect.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated sequence in balanced blocks
Allocation concealment (selection bias)	Low risk	A ‐ Adequate; via opaque sealed envelopes
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible because of the nature of the interventions
Incomplete outcome data (attrition bias) All outcomes	Low risk	IUI+OH group 3 patients lost to follow up, TI+NC group 2 lost to follow up 2 still pregnant
Selective reporting (reporting bias)	Low risk	Live birth and complications reported

CC: clomiphene citrate
DIPI: direct intraperitoneal insemination
FSH: follicle stimulating hormone
hCG: human chorionic gonadotropin
hMG: human menopausal gonadotropin
IUI: intra‐uterine insemination
OH: ovarian hyperstimulation
USS: ultrasound scan

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Aboulghar 1993	The trial was not randomised
Doyle 1991	No pre‐crossover data available
Evans 1991	No pre‐crossover data available
Gregoriou 1995	No pre‐crossover data available
Ho 1998	Abstract, full article not available. No separate data for couples with unexplained subfertility
Kirby 1991	No pre‐crossover data available
Martinez 1990	No per woman data. Biochemical pregnancies only reported
Martinez 1991	No pre‐crossover data available
Nulsen 1990	The trial (published as full paper in 1993) was not randomised
Nulsen 1993	The trial (also published as an abstract in 1990) was not randomised
Prentice 1995	This trial was quasi randomised, on the basis of hospital case record number
Serhal 1988	The trial was not randomised
Tummon 1997	The participants in this trial were all diagnosed with endometriosis
Zikopoulos 1993	No pre‐crossover data available

Data and analyses

Open in table viewer

Comparison 1. IUI versus TI or expectant management both in natural cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.1 Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 1 Live birth rate per couple (all cycles).
2 Pregnancy rate per couple (all cycles) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.2 Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 2 Pregnancy rate per couple (all cycles).
3 Multiple pregnancy rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.3 Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 3 Multiple pregnancy rate per couple.
4 Miscarriage rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.4 Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 4 Miscarriage rate per couple.
5 Ectopic pregnancy rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.5 Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 5 Ectopic pregnancy rate per couple.

Open in table viewer

Comparison 2. IUI versus TI both in stimulated cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [0.88, 2.88]
Open in figure viewer Analysis 2.1 Comparison 2 IUI versus TI both in stimulated cycle, Outcome 1 Live birth rate per couple (all cycles).
1.1 Gonadotropins	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [0.88, 2.88]
2 Pregnancy rate per couple (all cycles) Show forest plot	10	517	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [1.13, 2.50]
Open in figure viewer Analysis 2.2 Comparison 2 IUI versus TI both in stimulated cycle, Outcome 2 Pregnancy rate per couple (all cycles).
2.1 Clomiphene Citrate	1	40	Odds Ratio (M‐H, Fixed, 95% CI)	0.30 [0.03, 2.93]
2.2 Gonadotropins	4	319	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [1.03, 2.75]
2.3 Clomiphene Citrate and Gonadotropins	1	68	Odds Ratio (M‐H, Fixed, 95% CI)	2.62 [0.98, 6.98]
2.4 Clomiphene citrate OR Gonadotropins	4	90	Odds Ratio (M‐H, Fixed, 95% CI)	1.62 [0.52, 5.05]
3 Ovarian Hyperstimulation Syndrome rate per women Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.3 Comparison 2 IUI versus TI both in stimulated cycle, Outcome 3 Ovarian Hyperstimulation Syndrome rate per women.
3.1 Gonadotropins	1	108	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Clomiphene Citrate and Gonadotropins	1	68	Odds Ratio (M‐H, Fixed, 95% CI)	2.75 [0.11, 69.83]
4 Multiple pregnancy rate per couple Show forest plot	4	316	Odds Ratio (M‐H, Fixed, 95% CI)	1.46 [0.55, 3.87]
Open in figure viewer Analysis 2.4 Comparison 2 IUI versus TI both in stimulated cycle, Outcome 4 Multiple pregnancy rate per couple.
4.1 Clomiphene Citrate	1	40	Odds Ratio (M‐H, Fixed, 95% CI)	0.43 [0.02, 11.18]
4.2 Gonadotropins	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.61 [0.44, 5.89]
4.3 Clomiphene Citrate and Gonadotropins	1	68	Odds Ratio (M‐H, Fixed, 95% CI)	1.88 [0.32, 11.00]
5 Miscarriage rate per couple Show forest plot	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.66 [0.56, 4.88]
Open in figure viewer Analysis 2.5 Comparison 2 IUI versus TI both in stimulated cycle, Outcome 5 Miscarriage rate per couple.
5.1 Gonadotropins	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.66 [0.56, 4.88]
6 Ectopic pregnancy rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.6 Comparison 2 IUI versus TI both in stimulated cycle, Outcome 6 Ectopic pregnancy rate per couple.
6.1 Gonadotropins	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Open in table viewer

Comparison 3. IUI in natural cycle versus IUI in stimulated cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	4	396	Odds Ratio (M‐H, Fixed, 95% CI)	2.07 [1.22, 3.50]
Open in figure viewer Analysis 3.1 Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 1 Live birth rate per couple (all cycles).
1.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	3.75 [0.29, 47.99]
1.2 Gonadotropins	3	370	Odds Ratio (M‐H, Fixed, 95% CI)	2.02 [1.18, 3.45]
2 Pregnancy rate per couple (all cycles) Show forest plot	4	396	Odds Ratio (M‐H, Fixed, 95% CI)	2.14 [1.26, 3.61]
Open in figure viewer Analysis 3.2 Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 2 Pregnancy rate per couple (all cycles).
2.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	6.43 [0.56, 73.35]
2.2 Gonadotropins	3	370	Odds Ratio (M‐H, Fixed, 95% CI)	2.02 [1.18, 3.45]
3 Ovarian Hyperstimulation Syndrome rate per women Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 3.3 Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 3 Ovarian Hyperstimulation Syndrome rate per women.
3.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Gonadotropins	2	159	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Multiple pregnancy rate per couple Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 3.4 Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 4 Multiple pregnancy rate per couple.
4.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Gonadotropins	1	39	Odds Ratio (M‐H, Fixed, 95% CI)	3.0 [0.11, 78.27]
5 Miscarriage rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 3.5 Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 5 Miscarriage rate per couple.
5.1 Clomiphene Citrate	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Gonadotropins	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Ectopic pregnancy rate per couple Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 3.6 Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 6 Ectopic pregnancy rate per couple.
6.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Gonadotropins	2	250	Odds Ratio (M‐H, Fixed, 95% CI)	6.48 [0.33, 127.09]

Open in table viewer

Comparison 4. IUI in stimulated cycle versus TI or expectant management in natural cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 4.1 Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 1 Live birth rate per couple (all cycles).
2 Pregnancy rate per couple (all cycles) Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.2 Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 2 Pregnancy rate per couple (all cycles).
2.1 Clomiphene Citrate	1	51	Odds Ratio (M‐H, Fixed, 95% CI)	3.2 [0.82, 12.50]
2.2 Clomiphene Citrate or Gonadotropins	1	253	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.45, 1.42]
3 Ovarian Hyperstimulation Syndrome rate per women Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 4.3 Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 3 Ovarian Hyperstimulation Syndrome rate per women.
3.1 Clomiphene Citrate	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Clomiphene Citrate or Gonadotropins	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Multiple pregnancy rate per couple Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 4.4 Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 4 Multiple pregnancy rate per couple.
4.1 Clomiphene Citrate	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Clomiphene Citrate or Gonadotropins	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Miscarriage rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 4.5 Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 5 Miscarriage rate per couple.

Open in table viewer

Comparison 5. IUI in natural cycle versus TI in stimulated cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 5.1 Comparison 5 IUI in natural cycle versus TI in stimulated cycle, Outcome 1 Live birth rate per couple (all cycles).
2 Pregnancy rate per couple (all cycles) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 5.2 Comparison 5 IUI in natural cycle versus TI in stimulated cycle, Outcome 2 Pregnancy rate per couple (all cycles).
3 Multiple pregnancy rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 5.3 Comparison 5 IUI in natural cycle versus TI in stimulated cycle, Outcome 3 Multiple pregnancy rate per couple.
4 Miscarriage rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 5.4 Comparison 5 IUI in natural cycle versus TI in stimulated cycle, Outcome 4 Miscarriage rate per couple.
5 Ectopic pregnancy rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 5.5 Comparison 5 IUI in natural cycle versus TI in stimulated cycle, Outcome 5 Ectopic pregnancy rate per couple.

Figure 1

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Figure 2

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Figure 3

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Analysis 1.1

Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 1 Live birth rate per couple (all cycles).

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Analysis 1.2

Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 2 Pregnancy rate per couple (all cycles).

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Analysis 1.3

Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 3 Multiple pregnancy rate per couple.

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Analysis 1.4

Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 4 Miscarriage rate per couple.

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Analysis 1.5

Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 5 Ectopic pregnancy rate per couple.

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Analysis 2.1

Comparison 2 IUI versus TI both in stimulated cycle, Outcome 1 Live birth rate per couple (all cycles).

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Analysis 2.2

Comparison 2 IUI versus TI both in stimulated cycle, Outcome 2 Pregnancy rate per couple (all cycles).

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Analysis 2.3

Comparison 2 IUI versus TI both in stimulated cycle, Outcome 3 Ovarian Hyperstimulation Syndrome rate per women.

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Analysis 2.4

Comparison 2 IUI versus TI both in stimulated cycle, Outcome 4 Multiple pregnancy rate per couple.

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Analysis 2.5

Comparison 2 IUI versus TI both in stimulated cycle, Outcome 5 Miscarriage rate per couple.

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Analysis 2.6

Comparison 2 IUI versus TI both in stimulated cycle, Outcome 6 Ectopic pregnancy rate per couple.

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Analysis 3.1

Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 1 Live birth rate per couple (all cycles).

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Analysis 3.2

Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 2 Pregnancy rate per couple (all cycles).

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Analysis 3.3

Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 3 Ovarian Hyperstimulation Syndrome rate per women.

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Analysis 3.4

Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 4 Multiple pregnancy rate per couple.

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Analysis 3.5

Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 5 Miscarriage rate per couple.

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Analysis 3.6

Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 6 Ectopic pregnancy rate per couple.

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Analysis 4.1

Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 1 Live birth rate per couple (all cycles).

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Analysis 4.2

Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 2 Pregnancy rate per couple (all cycles).

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Analysis 4.3

Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 3 Ovarian Hyperstimulation Syndrome rate per women.

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Analysis 4.4

Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 4 Multiple pregnancy rate per couple.

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Analysis 4.5

Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 5 Miscarriage rate per couple.

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Analysis 5.1

Comparison 5 IUI in natural cycle versus TI in stimulated cycle, Outcome 1 Live birth rate per couple (all cycles).

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Analysis 5.2

Comparison 5 IUI in natural cycle versus TI in stimulated cycle, Outcome 2 Pregnancy rate per couple (all cycles).

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Analysis 5.3

Comparison 5 IUI in natural cycle versus TI in stimulated cycle, Outcome 3 Multiple pregnancy rate per couple.

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Analysis 5.4

Comparison 5 IUI in natural cycle versus TI in stimulated cycle, Outcome 4 Miscarriage rate per couple.

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Analysis 5.5

Comparison 5 IUI in natural cycle versus TI in stimulated cycle, Outcome 5 Ectopic pregnancy rate per couple.

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Table 1. Quality features of included studies

Study ID	Randomisation method	Concealed allocation	Design	Total Pt randomised	Drop‐outs	Cancelled cycles	Intention to treat	Power calculation
1.	IUI versus Timed intercourse both in natural cycle	1 study
Bhattacharya 2008	Computer generated randomisation scheme	Central telephone system	Parallel	334 unexplained (386 total)	Total: 2 (0.6%) in IUI + NC	Approximately 3% in the IUI group	Yes	Yes
2.	IUI versus Timed intercourse both in stimulated cycle	7 studies
Agarwal 2004	Random number table	Sealed opaque envelopes	Parallel	140	Total 19% IUI+OH: 37% TI+OH: 1%	Not clear	Possible, but not representative: unbalanced groups	No
Arcaini 1996	Not clear	Not clear	Parallel	68	Total: 14 (20.6%)	16 of 231 (7%)	Yes	No
Chung 1995	Blocked randomisation scheme	Numbered sealed envelopes	Parallel	100	Total: 12 (12%)	17 of 257 (6.6%)	Yes, possible	No
Crosignani 1991	Not clear	Not clear	Crossover	90	Not clear	Not clear	Not possible	No
Janko 1998	Not clear	Not clear	Parallel	72	Not clear	Not clear	Yes, possible	No
Karlstrom 1993	Not clear	Not clear	Parallel	79 a 39 b 40	Not clear	Not clear	Not possible	No
Melis 1995	Computer generated random number list	Numbered sealed envelopes	Parallel	108	Total: 5 (4.6%)	Not clear	Not possible	No

3.	IUI in natural cycle versus IUI in stimulated cycle
Arici 1994	Random number table	Computer system utilising locked files	Crossover	26	1st cycle: 0 (0%) Total: 16 (62%)	Not clear	Yes, possible	No
Goverde 2000	Computer generated randomisation schedule	Numbered, masked and sealed envelopes	Parallel	120	Not clear	Not clear	Not clear	Yes
Guzick 1999	Computer generated permuted block procedure	Computer system utilising locked files	Parallel	211 unexplained 932 total	72 (15.5%)	130 (5.6%)	Not possible	No
Murdoch 1991	Random number sequence	Sequentially numbered opaque sealed envelopes	Parallel	39	Total: 5 (13%)	30 of 111 (27%) (10 cancelled because no treatment in weekend available)	Yes, possible	No

4.	IUI with OH versus TI in natural cycle	1 study
Deaton 1990	Not clear	Not clear	Crossover (after 4 cycles)	51	Not clear	Not clear	Not possible	No
Steures 2006	Computer generated randomisation sequence in balanced blocks	Opaque sealed envelopes	Parallel	253	Not clear	63 (14%)	Yes	Yes

5.	IUI in natural cycle versus TI with OH	No studies
Bhattacharya 2008	Computer generated randomisation scheme	Central telephone system	Parallel	342 unexplained (387 total)	Total: 4 2 in both groups	Approximately 4% in clomiphene group	Yes	Yes

Table 1. Quality features of included studies

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Table 2. Prognostic factors table

Study ID	Age distribution	Subfertility years	Prim/Sec infertility	Previous treatment	Stimulation Method	Single insemination
1.	IUI versus Timed intercourse both in natural cycle	1 study
Bhattacharya 2008	TI+NC: 32 (±3.4) IUI+NC: 32 (±3.7) (TI is expectant management)	TI+NC: 30 (25 ‐ 38) IUI+NC:30 (25 ‐ 40) _{months (Inter quartile range)}	Mixed 117/386 (30%) Secondary	Not stated	No stimulation	Single
2.	IUI versus Timed intercourse both in stimulated cycle	7 studies
Agarwal 2004	IUI+OH: 29.52 (±3.65) TI +OH: 28,83 (±4,76)	IUI+OH: 4.91(±2.72) TI+OH: 4.93 (±3.27)	Mixed 32/113 (28%) secondary	No	CC 50‐150 mg	Single
Arcaini 1996	IUI+OH: 34.6 (±4.9) TI+OH: 33.4 (±4.7)	IUI+OH: 4.2 (±1.6) TI+OH: 3.9 (±2.3)	Mixed 7/68 (10%) secondary	Not stated	High dose: CC100mg and hMG 75‐225IU	Double
Chung 1995	IUI+OH: 31.8 (±3.1) TI+OH: 32.1 (±4.0)	IUI+OH: 4.7 (±2.0) TI+OH: 5.3 (±2.6)	Not clear	Not stated	hMG 150IU starting dose and GnRHa	IUI: Single TI: Double
Crosignani 1991	< 38 yrs	> 3 yrs	Not clear	Probably	Not stated	Not stated
Janko 1998	Not stated	> 3 yrs	Not clear	Not stated	hMG (10 amp per cycle)	Not stated
Karlstrom 1993	32 (range 21‐38)	5 (range 2‐14)	Mixed 49/148 (33%) secondary (incl Pt in DIPI groups)	No	hMG (low dose step up) 75 IU starting dose OR CC 100mg	IUI: Single TI: Double
Melis 1995	33.1 (±5.2)	4.3 (±1.4)	Not clear	Yes, all patients	High dose: FSH 225IU	Single
3.	IUI in natural cycle versus IUI in stimulated cycle
Arici 1994	33 (range 24‐41)	3.5 (range 1‐15)	Not clear	No	CC 50 mg	IUI+NC: Double IUI+OH: Single
Goverde 2000	IUI+NC: 31.6 (±3.7) IUI+OH: 31.7 (± 3.9)	IUI+NC: 3.9 (±1.7) IUI+OH: 4.2 (±1.9)	Mixed 13.5% secondary	Not stated	hMG 75IU starting dose	Single
Guzick 1999	IUI+NC: 32 (±4) IUI+OH: 32 (±4) <40 yrs	IUI+NC: 3.8 (±2.6) IUI+OH: 3.5 (±2.2)	Mixed 40% secondary	No	FSH 150IU	Single
Murdoch 1991	IUI+NC: 30.5 (±3.1) IUI+OH: 30.1 (±2.9)	IUI+NC: 5.7 (±2.4) IUI+OH: 5.1 (±1.9)	Mixed 5/34 (15%) secondary	No	hMG (low dose) 75IU + GnRHa	IUI+OH: Single IUI+NC: till USS evidence of ovulation
4.	IUI with OH versus TI in natural cycle	1 study
Deaton 1990	33 (±4.0)	3.5 (±1.7)	Mixed 21/51 (41%) secondary	Not stated	CC 50 mg	Single
Steures 2006	IUI+OH: 33 (±3.4) TI+NC: 33 (±3.1) (TI is expectant management)	IUI+OH: 2.0 (±0.5) TI+NC: 1.9 (±0.5)	Mixed 58/253 (23%) secondary	Not stated	FSH 37‐150 IU or CC 50‐150 mg	Not stated
5.	IUI in natural cycle versus TI with OH
Bhattacharya 2008	TI+OH: 32 (±3.5) IUI+NC: 32 (±3.7)	TI+OH: 30 (24 ‐ 38) IUI+NC: 30 (25 ‐ 40) _{months (Inter quartile range)}	Mixed 109/387 (28%)	Not stated	CC 25‐50 mg	Single
	* Mean age in years (± SD) or range	* Mean duration in years (± SD) or range			* Daily dose

Table 2. Prognostic factors table

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Table 3. Summary of analyses: intra‐uterine insemination (IUI) versus timed intercourse (TI) both in a stimulated cycle

	Analysis	Number of studies	OR	95% CI	Heterogeneity (P)	I² (%)
LIVE BIRTH RATE	Main analysis (All cycles, by ITT, fixed effect, Agarwal 2004 excluded)	2	1.59	0.88 ‐ 2.88	0.06	71.7
	Not by ITT	2	1.46	0.80 ‐ 2.66	0.06	71
	Random effect	2	1.65	0.52 ‐ 5.23	0.06	71.7
	Agarwal 2004 included	3	0.81	0.51 ‐ 1.28	0.0002	88.2

PREGNANCY RATE	Main analysis (All cycles, by ITT, fixed effect, Agarwal 2004 excluded)	10	1.68	1.13 ‐ 2.50	0.40	4.7
	Not by ITT	10	1.63	1.09 ‐ 2.43	0.39	5.5
	Random effect	10	1.71	1.11‐ 2.63	0.40	4.7
	Agarwal 2004 included	11	1.09	0.77 ‐ 1.54	0.001	65.4
	Adequate methodology (Chung 1995, Melis 1995)	2	1.70	0.96 ‐ 3.02	0.06	71.7
	Previous treatment excluded (Melis 1995 excluded)	9	2.00	1.26 ‐ 3.20	0.50	0
	Calculated data excluded (Janko 1998 excluded)	9	1.69	1.11 ‐ 2.59	0.31	15.2
	Trials including pt with endometriosis excluded (Karlstrom 1993 excluded)	8	1.81	1.19 ‐ 2.76	0.42	1.7

	Duration of subfertility at least 3 years	7	1.67	1.05 ‐ 2.66	0.37	7.1
	Duration of treatment: First cycle only	7	1.48	0.71 ‐ 3.11	0.48	0
	Duration of treatment: 1 ‐ 3 Cycles	9	1.54	1.00 ‐ 2.38	0.38	6.5
	Duration of treatment: > 3 Cycles	1	2.62	0.98 ‐ 6.98	NA	NA
	Ovarian hyperstimulation: Clomiphene	1	0.30	0.03 ‐ 2.93	NA	NA
	Ovarian hyperstimulation: Gonadotropins	4	1.68	1.03 ‐ 2.75	0.32	15.2

ADVERSE EVENTS	Multiple pregnancy rate	4	1.46	0.55 ‐ 3.87	0.76	0
	Miscarriage rate (similar results with Agarwal 2004 included)	2	1.66	0.56 ‐ 4.88	0.52	0
	Ectopic pregnancy rate (only 1 event)	3	3.06	0.12 ‐ 76.95	NA	NA
	OHSS rate	2	2.75	0.11 ‐ 69.83	NA	NA

Table 3. Summary of analyses: intra‐uterine insemination (IUI) versus timed intercourse (TI) both in a stimulated cycle

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Table 4. Summary of analyses: IUI in a natural cycle versus IUI in a stimulated cycle

	Analysis	Number of studies	OR	95% CI	Heterogeneity (p)	I2 (%)
LIVE BIRTH RATE	Main analysis (All cycles, by ITT, fixed effect)	4	2.07	1.22 ‐ 3.50	0.55	0
	Not by ITT	4	2.02	1.19 ‐ 3.42	0.53	0
	Random effect	4	2.08	1.22 ‐ 3.54	0.55	0
	Cross over trials excluded (Arici 1994 excluded)	3	2.02	1.18 ‐ 3.45	0.39	0
	Adequate Methodology (Guzick 1999 excluded, Randomisation not per unexplained pt)	3	1.69	0.83 ‐ 3.44	0.47	0
	Endometriosis (Arici 1994, Guzick 1999 excl)	2	1.57	0.75 ‐ 3.32	0.29	9.4
	Ovarian hyperstimulation: Clomiphene	1	3.75	0.29 ‐ 47.99	NA	NA
	Ovarian hyperstimulation: Gonadotropins	3	2.02	1.18 ‐ 3.45	0.39	0
	Duration of treatment: First cycle only	1	3.75	0.29 ‐ 47.99	NA	NA

PREGNANCY RATE	Main analysis (PR+LB) (All cycles, by ITT, fixed effect)	4	2.14	1.26 ‐ 3.61	0.44	0
	Pregnancy rates only (All cycles, by ITT, fixed effect)	2	1.74	0.38 ‐ 8.01	0.13	55.6
	Not by ITT	4	2.08	1.23 ‐ 3.52	0.41	0
	Random effect	4	2.14	1.25 ‐ 3.64	0.44	0
	Duration of treatment: First cycle only	4	2.14	1.26 ‐ 3.61	0.44	0

ADVERSE EVENTS	Multiple pregnancy rate	2	3.0	0.11 ‐ 78.27	NA	NA
	Miscarriage rate	1	5.21	0.19 ‐ 141.08	NA	NA
	Ectopic pregnancy rate	3	6.48	0.33 ‐ 127.09	NA	NA
	OHSS rate	3		No events	NA	NA

Table 4. Summary of analyses: IUI in a natural cycle versus IUI in a stimulated cycle

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Comparison 1. IUI versus TI or expectant management both in natural cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Pregnancy rate per couple (all cycles) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Multiple pregnancy rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Miscarriage rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Ectopic pregnancy rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 1. IUI versus TI or expectant management both in natural cycle

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Comparison 2. IUI versus TI both in stimulated cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [0.88, 2.88]

1.1 Gonadotropins	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [0.88, 2.88]
2 Pregnancy rate per couple (all cycles) Show forest plot	10	517	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [1.13, 2.50]

2.1 Clomiphene Citrate	1	40	Odds Ratio (M‐H, Fixed, 95% CI)	0.30 [0.03, 2.93]
2.2 Gonadotropins	4	319	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [1.03, 2.75]
2.3 Clomiphene Citrate and Gonadotropins	1	68	Odds Ratio (M‐H, Fixed, 95% CI)	2.62 [0.98, 6.98]
2.4 Clomiphene citrate OR Gonadotropins	4	90	Odds Ratio (M‐H, Fixed, 95% CI)	1.62 [0.52, 5.05]
3 Ovarian Hyperstimulation Syndrome rate per women Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Gonadotropins	1	108	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Clomiphene Citrate and Gonadotropins	1	68	Odds Ratio (M‐H, Fixed, 95% CI)	2.75 [0.11, 69.83]
4 Multiple pregnancy rate per couple Show forest plot	4	316	Odds Ratio (M‐H, Fixed, 95% CI)	1.46 [0.55, 3.87]

4.1 Clomiphene Citrate	1	40	Odds Ratio (M‐H, Fixed, 95% CI)	0.43 [0.02, 11.18]
4.2 Gonadotropins	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.61 [0.44, 5.89]
4.3 Clomiphene Citrate and Gonadotropins	1	68	Odds Ratio (M‐H, Fixed, 95% CI)	1.88 [0.32, 11.00]
5 Miscarriage rate per couple Show forest plot	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.66 [0.56, 4.88]

5.1 Gonadotropins	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.66 [0.56, 4.88]
6 Ectopic pregnancy rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6.1 Gonadotropins	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 2. IUI versus TI both in stimulated cycle

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Comparison 3. IUI in natural cycle versus IUI in stimulated cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	4	396	Odds Ratio (M‐H, Fixed, 95% CI)	2.07 [1.22, 3.50]

1.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	3.75 [0.29, 47.99]
1.2 Gonadotropins	3	370	Odds Ratio (M‐H, Fixed, 95% CI)	2.02 [1.18, 3.45]
2 Pregnancy rate per couple (all cycles) Show forest plot	4	396	Odds Ratio (M‐H, Fixed, 95% CI)	2.14 [1.26, 3.61]

2.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	6.43 [0.56, 73.35]
2.2 Gonadotropins	3	370	Odds Ratio (M‐H, Fixed, 95% CI)	2.02 [1.18, 3.45]
3 Ovarian Hyperstimulation Syndrome rate per women Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Gonadotropins	2	159	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Multiple pregnancy rate per couple Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Gonadotropins	1	39	Odds Ratio (M‐H, Fixed, 95% CI)	3.0 [0.11, 78.27]
5 Miscarriage rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5.1 Clomiphene Citrate	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Gonadotropins	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Ectopic pregnancy rate per couple Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Gonadotropins	2	250	Odds Ratio (M‐H, Fixed, 95% CI)	6.48 [0.33, 127.09]

Comparison 3. IUI in natural cycle versus IUI in stimulated cycle

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Comparison 4. IUI in stimulated cycle versus TI or expectant management in natural cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Pregnancy rate per couple (all cycles) Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Clomiphene Citrate	1	51	Odds Ratio (M‐H, Fixed, 95% CI)	3.2 [0.82, 12.50]
2.2 Clomiphene Citrate or Gonadotropins	1	253	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.45, 1.42]
3 Ovarian Hyperstimulation Syndrome rate per women Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Clomiphene Citrate	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Clomiphene Citrate or Gonadotropins	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Multiple pregnancy rate per couple Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.1 Clomiphene Citrate	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Clomiphene Citrate or Gonadotropins	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Miscarriage rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 4. IUI in stimulated cycle versus TI or expectant management in natural cycle

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Comparison 5. IUI in natural cycle versus TI in stimulated cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Pregnancy rate per couple (all cycles) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Multiple pregnancy rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Miscarriage rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Ectopic pregnancy rate per couple Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 5. IUI in natural cycle versus TI in stimulated cycle

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Referencias

Referencias de los estudios incluidos en esta revisión

Agarwal 2004 {published and unpublished data}

Arcaini 1996 {published data only}

Arici 1994 {published and unpublished data}

Bhattacharya 2008 {published data only}

Chung 1995 {published data only}

Crosignani 1991 {published data only}

Crosignani 1991b {published data only}

Crosignani 1991c {published data only}

Crosignani 1991d {published data only}

Deaton 1990 {published data only}

Goverde 2000 {published data only}

Guzick 1999 {published data only}

Janko 1998 {published data only}

Karlstrom 1993 {published data only}

Karlstrom 1993 b {published data only}

Melis 1995 {published and unpublished data}

Murdoch 1991 {published and unpublished data}

Steures 2006 {published data only}

Referencias de los estudios excluidos de esta revisión

Aboulghar 1993 {published data only}

Doyle 1991 {published data only}

Evans 1991 {published data only}

Gregoriou 1995 {published data only}

Ho 1998 {published data only}

Kirby 1991 {published data only}

Martinez 1990 {published data only}

Martinez 1991 {published data only}

Nulsen 1990 {published data only}

Nulsen 1993 {published data only (unpublished sought but not used)}

Prentice 1995 {published data only}

Serhal 1988 {published data only (unpublished sought but not used)}

Tummon 1997 {published data only}

Zikopoulos 1993 {published data only}

Referencias de los estudios en espera de evaluación

Wordsworth 2011 {published data only}

Referencias adicionales

Aboulghar 2003

Balasch 2004

Besselink 2008

Cantineau 2009

Cochrane Handbook 2011

Cohlen 1998

Cohlen 2005

Costello 2004

Daya 1993

Daya 2003

Dias 2008

Dickey 2005

ESHRE 2006

Fauser 2005

Gleicher 2000

Goverde 2005

Guzick 1998

Healy 2004

Hughes 1997

Hughes 2003

Johnson 2003

Kerin 1984

Khan 1996

Land 2003

McDonnell 2004

Min 2004

Nan 1994

NICE 2004

Norman 2000

Ombelet 2005

Ragni 2006

RCOG 1998

Ripps 1994

Rumste 2006

Ryan 2004

Snick 2008

Steures 2006a

Stewart 2003

te Velde 1999

Tur 2005