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Вспомогательные репродуктивные технологии при мужской субфертильности

Appendices

Appendix 1. MDSG search strategy

From inception to 14 April 2015

Keywords CONTAINS "subfertility‐male" or "idiopathic asthenospermia" or "idiopathic oligozoospermia" or "oligo‐asthenozoospermia" or "Oligoasthenospermia" or "oligoasthenoteratozoospermia"or"oligospermia"or"oligozoospermia" or "asthenospermia" or "asthenozoospermia"or"azoospermia"or"varicocele"or"varicocele‐embolization"or"varicocele ligation" or "varicocele‐outcome" or "varicocelectomized " or "varicocelectomy" or "Male" or "male factor" or "male fertility" or "male infertility" or "male subfertility" or "unexplained infertility" or "unexplained subfertility" or "teratozoospermic" or "sperm damage" or "sperm disorders" or "sperm DNA damage" or "sperm DNA integrity" or "sperm extraction techniques" or "sperm motility"
AND
Keywords CONTAINS "IVF" or "ICSI" or "in‐vitro fertilisation " or "in‐vitro fertilisation procedure" or "in vitro fertilization" or "intracytoplasmic sperm injection" or "intracytoplasmic morphologically selected sperm injection" or "superovulation" or "superovulation induction" or "IUI" or "insemination, intrauterine " or "Intrauterine Insemination" or "ART" or "artificial insemination" or "assisted reproduction techniques" or "controlled ovarian hyperstimulation" or "controlled ovarian stimulation" or "COH" or "COH IUI" or "ovulation induction" or "ovulation stimulation" or "timed intercourse" or "expectant management" or "Natural cycle" or "natural cycles" or "coitus" or "wait and see" or Title CONTAINS"IVF" or "ICSI" or "in‐vitro fertilisation " or "in‐vitro fertilisation procedure" or "in vitro fertilization" or "intracytoplasmic sperm injection" or "intracytoplasmic morphologically selected sperm injection" or "superovulation" or "controlled ovarian hyperstimulation" (22 hits)

Appendix 2. CENTRAL search strategy

From inception to 14 April 2015

1 exp embryo transfer/ or exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/ (1753)
2 embryo transfer$.tw. (1135)
3 vitro fertili?ation.tw. (1571)
4 ivf.tw. (2386)
5 icsi.tw. (910)
6 intracytoplasmic sperm injection$.tw. (518)
7 (blastocyst adj2 transfer$).tw. (121)
8 exp reproductive techniques, assisted/ or exp insemination, artificial/ or exp ovulation induction/ (2457)
9 assisted reproduct$.tw. (510)
10 artificial insemination.tw. (97)
11 iui.tw. (380)
12 intrauterine insemination$.tw. (489)
13 ovulation induc$.tw. (566)
14 (ovari$ adj2 stimulat$).tw. (966)
15 superovulat$.tw. (154)
16 ovarian hyperstimulation.tw. (668)
17 COH.tw. (162)
18 (ovari$ adj2 induction).tw. (32)
19 timed intercourse.tw. (38)
20 expectant management.tw. (318)
21 natural cycle$.tw. (106)
22 exp Coitus/ (270)
23 coitus.tw. (92)
24 intra‐uterine insemination$.tw. (41)
25 watchful waiting.tw. (226)
26 or/1‐25 (6305)
27 exp male infertility/ (506)
28 (asthenozoospermia or oligospermia or azoospermia).tw. (219)
29 Asthenospermia.tw. (33)
30 Teratospermia.tw. (2)
31 (male$ adj2 subfertil$).tw. (66)
32 (male$ adj2 infertil$).tw. (360)
33 (subfertil$ adj2 men).tw. (22)
34 (infertil$ adj2 men).tw. (142)
35 (male$ adj2 fertility).tw. (59)
36 oligoasthenoteratozoospermi$.tw. (17)
37 (idiopathic adj3 infertil$).tw. (80)
38 (idiopathic adj3 subfertil$).tw. (11)
39 Oligozoospermi$.tw. (99)
40 Aspermi$.tw. (2)
41 Teratospermia.tw. (2)
42 unexplained subfertility.tw. (15)
43 unexplained infertility.tw. (274)
44 or/27‐43 (1183)
45 26 and 44 (553)

Appendix 3. MEDLINE search strategy

From inception to 14 April 2015

1 exp embryo transfer/ or exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/ (33481)
2 embryo transfer$.tw. (8656)
3 vitro fertili?ation.tw. (17653)
4 ivf.tw. (17313)
5 icsi.tw. (5854)
6 intracytoplasmic sperm injection$.tw. (5221)
7 (blastocyst adj2 transfer$).tw. (598)
8 exp reproductive techniques, assisted/ or exp insemination, artificial/ or exp ovulation induction/ (54694)
9 assisted reproduct$.tw. (9783)
10 artificial insemination.tw. (5138)
11 iui.tw. (1280)
12 intrauterine insemination$.tw. (1897)
13 ovulation induc$.tw. (3509)
14 (ovari$ adj2 stimulat$).tw. (5151)
15 superovulat$.tw. (2972)
16 ovarian hyperstimulation.tw. (4003)
17 COH.tw. (1191)
18 (ovari$ adj2 induction).tw. (232)
19 timed intercourse.tw. (108)
20 expectant management.tw. (1780)
21 natural cycle$.tw. (929)
22 exp Coitus/ (6553)
23 coitus.tw. (2519)
24 intra‐uterine insemination$.tw. (185)
25 watchful waiting.tw. (1698)
26 or/1‐25 (83004)
27 exp male infertility/ (23103)
28 (asthenozoospermia or oligospermia or azoospermia).tw. (5858)
29 Asthenospermia.tw. (281)
30 Teratospermia.tw. (143)
31 (male$ adj2 subfertil$).tw. (625)
32 (male$ adj2 infertil$).tw. (8353)
33 (subfertil$ adj2 men).tw. (439)
34 (infertil$ adj2 men).tw. (3434)
35 (male$ adj2 fertility).tw. (4268)
36 oligoasthenoteratozoospermi$.tw. (301)
37 (idiopathic adj3 infertil$).tw. (940)
38 (idiopathic adj3 subfertil$).tw. (62)
39 Oligozoospermi$.tw. (1809)
40 Aspermi$.tw. (220)
41 Teratospermia.tw. (143)
42 unexplained subfertility.tw. (78)
43 unexplained infertility.tw. (1577)
44 or/27‐43 (32348)
45 26 and 44 (7523)
46 randomized controlled trial.pt. (391583)
47 controlled clinical trial.pt. (89189)
48 randomized.ab. (316291)
49 randomised.ab. (62637)
50 placebo.tw. (165382)
51 clinical trials as topic.sh. (172188)
52 randomly.ab. (228234)
53 trial.ti. (136301)
54 (crossover or cross‐over or cross over).tw. (63611)
55 or/46‐54 (994662)
56 exp animals/ not humans.sh. (4023388)
57 55 not 56 (916956)
58 45 and 57 (667)

Appendix 4. EMBASE search strategy

From inception to 14 April 2015

1 exp embryo transfer/ or exp fertilization in vitro/ or exp intracytoplasmic sperm injection/ (55222)
2 embryo$ transfer$.tw. (13466)
3 in vitro fertili?ation.tw. (21550)
4 icsi.tw. (10216)
5 intracytoplasmic sperm injection$.tw. (6647)
6 (blastocyst adj2 transfer$).tw. (1178)
7 ivf.tw. (26204)
8 exp infertility therapy/ or exp artificial insemination/ or exp intrauterine insemination/ or exp ovulation induction/ (80903)
9 assisted reproduct$.tw. (14085)
10 artificial insemination.tw. (4861)
11 iui.tw. (2090)
12 intrauterine insemination$.tw. (2619)
13 ovulation induc$.tw. (4466)
14 (ovari$ adj2 stimulat$).tw. (7397)
15 superovulat$.tw. (3129)
16 ovarian hyperstimulation.tw. (5490)
17 COH.tw. (1597)
18 (ovar$ adj2 induction).tw. (305)
19 timed intercourse.tw. (166)
20 expectant management.tw. (2456)
21 natural cycle$.tw. (1323)
22 exp coitus/ (5440)
23 coitus.tw. (2448)
24 intra‐uterine insemination$.tw. (303)
25 watchful waiting.tw. (2368)
26 or/1‐25 (108525)
27 exp male infertility/ (32048)
28 (asthenozoospermia or oligospermia or azoospermia).tw. (6986)
29 Asthenospermia.tw. (340)
30 Teratospermia.tw. (177)
31 (male$ adj2 subfertil$).tw. (772)
32 (male$ adj2 infertil$).tw. (10861)
33 (subfertil$ adj2 men).tw. (496)
34 (infertil$ adj2 men).tw. (4297)
35 (male$ adj2 fertility).tw. (4919)
36 oligoasthenoteratozoospermi$.tw. (386)
37 (idiopathic adj3 infertil$).tw. (1242)
38 (idiopathic adj3 subfertil$).tw. (72)
39 Oligozoospermi$.tw. (2043)
40 Aspermi$.tw. (195)
41 Teratospermia.tw. (177)
42 unexplained subfertility.tw. (100)
43 unexplained infertility.tw. (2132)
44 or/27‐43 (41854)
45 26 and 44 (11456)
46 Clinical Trial/ (842028)
47 Randomized Controlled Trial/ (366567)
48 exp randomization/ (65714)
49 Single Blind Procedure/ (19913)
50 Double Blind Procedure/ (119287)
51 Crossover Procedure/ (42210)
52 Placebo/ (253674)
53 Randomi?ed controlled trial$.tw. (113414)
54 Rct.tw. (16495)
55 random allocation.tw. (1392)
56 randomly allocated.tw. (21964)
57 allocated randomly.tw. (2006)
58 (allocated adj2 random).tw. (720)
59 Single blind$.tw. (15500)
60 Double blind$.tw. (148801)
61 ((treble or triple) adj blind$).tw. (434)
62 placebo$.tw. (211189)
63 prospective study/ (283895)
64 or/46‐63 (1442620)
65 case study/ (31021)
66 case report.tw. (278028)
67 abstract report/ or letter/ (918503)
68 or/65‐67 (1221392)
69 64 not 68 (1403772)
70 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (5242944)
71 69 not 70 (1348753)
72 45 and 71 (1405)

Appendix 5. PsycINFO search strategy

From inception to 14 April 2015

1 exp reproductive technology/ (1385)
2 in vitro fertili?ation.tw. (568)
3 ivf‐et.tw. (17)
4 (ivf or et).tw. (101465)
5 icsi.tw. (50)
6 intracytoplasmic sperm injection$.tw. (42)
7 (blastocyst adj2 transfer$).tw. (4)
8 assisted reproduct$.tw. (590)
9 artificial insemination.tw. (227)
10 iui.tw. (24)
11 intrauterine insemination$.tw. (19)
12 ovulation induc$.tw. (22)
13 (ovari$ adj2 stimulat$).tw. (49)
14 ovarian hyperstimulation.tw. (10)
15 COH.tw. (75)
16 superovulat$.tw. (5)
17 (ovari$ adj2 induction).tw. (5)
18 timed intercourse.tw. (5)
19 expectant management.tw. (20)
20 natural cycle$.tw. (41)
21 exp "Sexual Intercourse (Human)"/ (12585)
22 coitus.tw. (767)
23 intra‐uterine insemination$.tw. (0)
24 watchful waiting.tw. (117)
25 or/1‐24 (116058)
26 exp Infertility/ (1743)
27 (asthenozoospermia or oligospermia or azoospermia).tw. (38)
28 (male$ adj2 subfertil$).tw. (6)
29 (male$ adj2 infertil$).tw. (165)
30 (infertil$ adj2 men).tw. (73)
31 (male$ adj2 fertility).tw. (125)
32 oligoasthenoteratozoospermi$.tw. (1)
33 Asthenospermia.tw. (2)
34 (idiopathic adj3 infertil$).tw. (12)
35 Oligozoospermi$.tw. (4)
36 Aspermi$.tw. (5)
37 unexplained subfertility.tw. (1)
38 unexplained infertility.tw. (27)
39 or/26‐38 (1930)
40 random.tw. (43215)
41 control.tw. (335612)
42 double‐blind.tw. (18726)
43 clinical trials/ (8513)
44 placebo/ (4032)
45 exp Treatment/ (610630)
46 or/40‐45 (936137)
47 25 and 39 and 46 (180)

Appendix 6. CINAHL search strategy

From inception to 14 April 2015

#

Query

Results

S60

S58 AND S59

31

S59

EM 2014* or EM 2015*

439,602

S58

S45 AND S57

264

S57

S46 OR S47 OR S48 OR S49 OR S50 OR S51 OR S52 OR S53 OR S54 OR S55 OR S56

954,451

S56

TX allocat* random*

4,243

S55

(MH "Quantitative Studies")

13,282

S54

(MH "Placebos")

9,173

S53

TX placebo*

33,620

S52

TX random* allocat*

4,243

S51

(MH "Random Assignment")

38,985

S50

TX randomi* control* trial*

85,907

S49

TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) )

763,614

S48

TX clinic* n1 trial*

170,899

S47

PT Clinical trial

77,668

S46

(MH "Clinical Trials+")

186,062

S45

S26 AND S44

930

S44

S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 OR S35 OR S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43

3,570

S43

TX unexplained infertility

102

S42

TX unexplained subfertility

20

S41

TX Oligozoospermi*

28

S40

TX (idiopathic adj3 subfertil*)

3

S39

TX (idiopathic adj3 subfertil*)

0

S38

TX(idiopathic N3 infertil*)

30

S37

TX oligoasthenoteratozoospermi*

9

S36

TX (male fertil*)

259

S35

TX (infertil* N2 men)

169

S34

TX (subfertil* N2 men)

18

S33

TX (male* N2 infertil*)

485

S32

TX (male* N2 subfertil*)

34

S31

TX Asthenospermia

3

S30

TX (asthenozoospermia or oligospermia or azoospermia)

141

S29

TX sperm*

3,014

S28

(MH "Sperm Motility") OR (MH "Spermatozoa") OR (MH "Sperm Count") OR "sperm"

2,161

S27

"male infertility"

327

S26

S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25

8,262

S25

TX intra‐uterine insemination

9

S24

TX coitus

1,743

S23

(MM "Coitus")

762

S22

TX natural cycle*

118

S21

TX expectant management

398

S20

TX timed intercourse

19

S19

TX (ovari* N2 induction)

12

S18

TX COH

62

S17

TX ovarian hyperstimulation

333

S16

TX superovulat*

23

S15

TX ovulation induc*

574

S14

TX intrauterine insemination

149

S13

TX IUI

79

S12

TX artificial insemination

453

S11

TX assisted reproduct*

1,296

S10

(MM "Insemination, Artificial")

242

S9

(MM "Reproduction Techniques+")

3,949

S8

TX intracytoplasmic sperm injection*

234

S7

TX embryo* N3 transfer*

769

S6

TX ovar* N3 hyperstimulat*

336

S5

TX ovari* N3 stimulat*

246

S4

TX IVF or TX ICSI

1,248

S3

(MM "Fertilization in Vitro")

1,445

S2

TX vitro fertilization

2,849

S1

TX vitro fertilisation

266

Appendix 7. Other electronic sources search strategy (PubMed)

timed intercourse; expectant management; natural cycle; intrauterine; intra uterine; intra‐uterine; insemination; inseminate; IUI; artificial insemination; AI; artificial insemination husband; AIH; ovarian hyperstimulation; in vitro fertilization; IVF; intracytoplasmic sperm injection; ICSI; male infertility; male subfertility; oligoasthenoteratozoospermia; oligospermia; asthenospermia; teratospermia; (randomised controlled trial [Publication Type], controlled clinical trials [Publication Type], randomised controlled trials, random allocation, double‐blind method, single‐blind method, clinical trial [Publication Type], clinical trials, (clinical AND trial*)).

Appendix 8. Data extraction table

Type of studies
Randomised controlled trials (RCTs) only.

Trial quality
1. Randomisation:

  • truly randomised, e.g. blocked randomisation list, on‐site computer system, centralised randomisation scheme, random number tables or drawing lots;

  • stated without further description, or not stated.

2. Concealment of allocation:

  • adequate (low risk of bias), e.g. sealed opaque envelopes or third party randomisation;

  • inadequate (high risk of bias), e.g. open list of random numbers, open envelops, tables;

  • stated without further description or not stated (unclear risk of bias)

3. Study design:

  • parallel design, cross‐over design or not clear (we included only parallel group studies or pre‐cross‐over data in the meta‐analysis);

  • single centre or multicentre.

4. Blinding:

  • if appropriate, were the couple, the care provider and the outcome assessor blinded?

5. Analysis:

  • by intention to treat (ITT);

  • power calculation (prospective power calculation, no power calculation or not stated).

6. Drop‐outs:

  • number or percentage of drop‐outs;

  • reasons for and details on drop‐outs (selective drop‐out?).

7. Cancelled cycles:

  • number or percentage of cancelled cycles;

  • reasons for cancelled cycles.

Study participants

8. Prognostic factors:

  • type of subfertility;

  • woman's age;

  • duration of subfertility;

  • primary or secondary subfertility.

9. Male subfertility:

  • definition;

  • number of semen samples

10. Basic fertility work‐up:

  • regular menstrual cycles with basal body temperature (BBT) charts, normal mid‐luteal progesterone or sonographic evidence of ovulation;

  • patent tubes on hysterosalpingography or laparoscopy, or low risk for tubal pathology according to the medical history (Coppus 2007);

  • postcoital test.

11. Previous fertility treatment

12. Exclusion criteria

Type of interventions

13. Comparison of treatment:

  • timed intercourse or expectant management (with or without ovarian hyperstimulation (OH));

  • intra‐uterine insemination (IUI) (with or without OH);

  • in vitro fertilisation (IVF);

  • intracytoplasmic sperm injection (ICSI).

14. Stimulation protocols:

  • type and dosage of drugs for mild OH;

  • days of ovarian stimulation;

  • use and timing of ovulation induction;

  • cancellation criteria, risk of multiple pregnancies or ovarian hyperstimulation syndrome (OHSS);

  • use of luteal support.

15. Semen sample preparation techniques:

  • amount of semen injected, number of motile spermatozoa;

  • method of sperm preparation (washing and centrifugation technique, swim up technique, other).

16. Insemination characteristics

  • use of single or double insemination;

  • number of treatment cycles;

  • actual timing of IUI (time form luteinising hormone (LH) surge, time from human chorionic gonadotrophin (hCG) administration to IUI).

Type of outcome measures

17. Primary outcomes:

  • live birth rate per couple;

  • incidence OHSS.

18 Secondary outcomes:

  • pregnancy rate per couple;

  • incidence of multiple pregnancies;

  • incidence of miscarriage;

  • incidence of total fertilisation failure during IVF.

Study flow diagram.
Figuras y tablas -
Figure 1

Study flow diagram.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison: 1 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in natural cycles (NC), outcome: 1.1 Pregnancy rate per couple (all cycles).
Figuras y tablas -
Figure 4

Forest plot of comparison: 1 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in natural cycles (NC), outcome: 1.1 Pregnancy rate per couple (all cycles).

Forest plot of comparison: 2 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH), outcome: 2.3 Pregnancy rate per couple (all cycles).
Figuras y tablas -
Figure 5

Forest plot of comparison: 2 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH), outcome: 2.3 Pregnancy rate per couple (all cycles).

Forest plot of comparison: 4 Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus timed intercourse (TI) in natural cycles (NC), outcome: 4.2 Pregnancy rate per couple (all cycles).
Figuras y tablas -
Figure 6

Forest plot of comparison: 4 Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus timed intercourse (TI) in natural cycles (NC), outcome: 4.2 Pregnancy rate per couple (all cycles).

Forest plot of comparison: 5 Intra‐uterine insemination (IUI) in natural cycles (NC) versus IUI in cycles with ovarian hyperstimulation (OH) versus IUI in natural cycles (NC), outcome: 5.2 Pregnancy rate per couple (all cycles).
Figuras y tablas -
Figure 7

Forest plot of comparison: 5 Intra‐uterine insemination (IUI) in natural cycles (NC) versus IUI in cycles with ovarian hyperstimulation (OH) versus IUI in natural cycles (NC), outcome: 5.2 Pregnancy rate per couple (all cycles).

Forest plot of comparison: 8 In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in natural cycles (NC), outcome: 8.1 Live birth rate per couple (all cycles).
Figuras y tablas -
Figure 8

Forest plot of comparison: 8 In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in natural cycles (NC), outcome: 8.1 Live birth rate per couple (all cycles).

Forest plot of comparison: 9 In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH), outcome: 9.1 Live birth rate per couple (all cycles).
Figuras y tablas -
Figure 9

Forest plot of comparison: 9 In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH), outcome: 9.1 Live birth rate per couple (all cycles).

Comparison 1 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in natural cycles (NC), Outcome 1 Pregnancy rate per couple (all cycles).
Figuras y tablas -
Analysis 1.1

Comparison 1 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in natural cycles (NC), Outcome 1 Pregnancy rate per couple (all cycles).

Comparison 2 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH), Outcome 1 Live birth rate per couple (all cycles).
Figuras y tablas -
Analysis 2.1

Comparison 2 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH), Outcome 1 Live birth rate per couple (all cycles).

Comparison 2 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH), Outcome 2 OHSS per couple.
Figuras y tablas -
Analysis 2.2

Comparison 2 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH), Outcome 2 OHSS per couple.

Comparison 2 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH), Outcome 3 Pregnancy rate per couple (all cycles).
Figuras y tablas -
Analysis 2.3

Comparison 2 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH), Outcome 3 Pregnancy rate per couple (all cycles).

Comparison 2 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH), Outcome 4 Multiple pregnancy rate per couple.
Figuras y tablas -
Analysis 2.4

Comparison 2 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH), Outcome 4 Multiple pregnancy rate per couple.

Comparison 2 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH), Outcome 5 Miscarriage rate per couple.
Figuras y tablas -
Analysis 2.5

Comparison 2 Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH), Outcome 5 Miscarriage rate per couple.

Comparison 4 Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus timed intercourse (TI) in natural cycles (NC), Outcome 1 Live birth rate per couple (all cycles).
Figuras y tablas -
Analysis 4.1

Comparison 4 Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus timed intercourse (TI) in natural cycles (NC), Outcome 1 Live birth rate per couple (all cycles).

Comparison 4 Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus timed intercourse (TI) in natural cycles (NC), Outcome 2 Pregnancy rate per couple (all cycles).
Figuras y tablas -
Analysis 4.2

Comparison 4 Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus timed intercourse (TI) in natural cycles (NC), Outcome 2 Pregnancy rate per couple (all cycles).

Comparison 5 Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus IUI in natural cycles (NC), Outcome 1 Live birth rate per couple (all cycles).
Figuras y tablas -
Analysis 5.1

Comparison 5 Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus IUI in natural cycles (NC), Outcome 1 Live birth rate per couple (all cycles).

Comparison 5 Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus IUI in natural cycles (NC), Outcome 2 Pregnancy rate per couple (all cycles).
Figuras y tablas -
Analysis 5.2

Comparison 5 Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus IUI in natural cycles (NC), Outcome 2 Pregnancy rate per couple (all cycles).

Comparison 5 Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus IUI in natural cycles (NC), Outcome 3 Miscarriage rate per couple.
Figuras y tablas -
Analysis 5.3

Comparison 5 Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus IUI in natural cycles (NC), Outcome 3 Miscarriage rate per couple.

Comparison 8 In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in natural cycles (NC), Outcome 1 Live birth rate per couple (all cycles).
Figuras y tablas -
Analysis 8.1

Comparison 8 In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in natural cycles (NC), Outcome 1 Live birth rate per couple (all cycles).

Comparison 9 In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH), Outcome 1 Live birth rate per couple (all cycles).
Figuras y tablas -
Analysis 9.1

Comparison 9 In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH), Outcome 1 Live birth rate per couple (all cycles).

Comparison 9 In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH), Outcome 2 OHSS per couple.
Figuras y tablas -
Analysis 9.2

Comparison 9 In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH), Outcome 2 OHSS per couple.

Comparison 9 In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH), Outcome 3 Pregnancy rate per couple (all cycles).
Figuras y tablas -
Analysis 9.3

Comparison 9 In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH), Outcome 3 Pregnancy rate per couple (all cycles).

Summary of findings for the main comparison. IUI in natural cycles compared to TI in natural cycles for male subfertility

IUI in natural cycles compared to TI in natural cycles for male subfertility

Patient or population: couples with male subfertility
Settings: single centre (Australia, Italy)
Intervention: IUI in natural cycles
Comparison: TI in natural cycles

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of couples (studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

TI in natural cycles

IUI in natural cycles

Live birth rate

Not reported in any included studies

OHSS

Not reported in any included studies

Pregnancy rate per couple (all cycles)
Follow‐up: 9‐12 months

0 per 1000

0 per 1000
(0 to 0)

OR 4.57
(0.21 to 101.61)

62
(2 studies)

⊕⊝⊝⊝
very low1,2

*The basis for the assumed risk was the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; IUI: intra‐uterine insemination; OHSS: ovarian hyperstimulation syndrome; OR: odds ratio; TI: timed intercourse.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Risk of bias was very serious: 1. Francavilla 2009, allocation concealment: high risk (on chronological basis), 2. Francavilla 2009, other bias: high risk (no stratification by diagnosis category of subfertility).
2 There was very serious imprecision, with small sample sizes and very few events.

Figuras y tablas -
Summary of findings for the main comparison. IUI in natural cycles compared to TI in natural cycles for male subfertility
Summary of findings 2. IUI in stimulated cycles compared to TI in stimulated cycles for male subfertility

IUI in stimulated cycles compared to TI in stimulated cycles for male subfertility

Patient or population: couples with male subfertility
Settings: single centre (Greece, Italy, The Netherlands)
Intervention: IUI in stimulated cycles
Comparison: TI in stimulated cycles

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of couples (studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

TI in stimulated cycles

IUI in stimulated cycles

Live birth rate per couple (all cycles)
Follow‐up: 3 months

220 per 1000

200 per 1000
(78 to 421)

OR 0.89
(0.30 to 2.59)

81
(1 study)

⊕⊕⊝⊝
low1

OHSS per couple

Follow‐up: 6 months

See comment

See comment

Not estimable

59

(1 study)

⊕⊕⊝⊝
low1

Pregnancy rate per couple (all cycles)
Follow‐up: 3‐6 months

175 per 1000

243 per 1000
(136 to 395)

OR 1.51
(0.74 to 3.07)

202
(3 studies)

⊕⊝⊝⊝
very low1,2

Multiple pregnancy rate per couple
Follow‐up: 3 months

0 per 1000

0 per 1000
(0 to 0)

OR 3.15
(0.12 to 79.69)

81
(1 study)

⊕⊕⊝⊝
low3

Miscarriage rate per couple
Follow‐up: 3 months

73 per 1000

75 per 1000
(15 to 300)

OR 1.03
(0.19 to 5.42)

81
(1 study)

⊕⊕⊝⊝
low3

*The basis for the assumed risk was the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; IUI: intra‐uterine insemination; OHSS: ovarian hyperstimulation syndrome; OR: odds ratio; TI: timed intercourse.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 There was very serious imprecision, with small sample size.
2 Inconsistency was serious between Melis 1995 (favoured TI + OH) and Gregoriou 1996 and Nan 1994 (favoured IUI + OH).
3 There was very serious imprecision, with small sample sizes and findings were compatible with substantial benefit in either group.

Figuras y tablas -
Summary of findings 2. IUI in stimulated cycles compared to TI in stimulated cycles for male subfertility
Summary of findings 3. IUI in stimulated cycles compared to TI in natural cycles for male subfertility

IUI in stimulated cycles compared to TI in natural cycles for male subfertility

Patient or population: couples with male subfertility
Settings: single centre (Italy)
Intervention: IUI in stimulated cycles
Comparison: TI in natural cycles

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of couples (studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

TI in natural cycles

IUI in stimulated cycles

Live birth rate per couple (all cycles)
Follow‐up: 9 months

0 per 1000

0 per 1000
(0 to 0)

OR 3.14
(0.12 to 81.35)

44
(1 study)

⊕⊝⊝⊝
very low1,2

OHSS

Not reported in any included studies

Pregnancy rate per couple (all cycles)
Follow‐up: 9 months

0 per 1000

0 per 1000
(0 to 0)

OR 3.14
(0.12 to 81.35)

44
(1 study)

⊕⊝⊝⊝
very low1,2

*The basis for the assumed risk was the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; IUI: intra‐uterine insemination; OHSS: ovarian hyperstimulation syndrome; OR: odds ratio; TI: timed intercourse.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Risk of bias was very serious: 1. Allocation concealment: high risk (on chronological basis), 2. Other bias: high risk (no stratification by diagnosis category of subfertility).
2 There was very serious imprecision, with small sample sizes and very few events.

Figuras y tablas -
Summary of findings 3. IUI in stimulated cycles compared to TI in natural cycles for male subfertility
Summary of findings 4. IUI in stimulated cycles compared to IUI in natural cycles for male subfertility

IUI in stimulated cycles compared to IUI in natural cycles for male subfertility

Patient or population: couples with male subfertility
Settings: single and multicentre (Italy, the Netherlands, USA)
Intervention: IUI in stimulated cycles
Comparison: IUI in natural cycles

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of couples
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

IUI in natural cycles

IUI in stimulated cycles

Live birth rate per couple (all cycles)
Follow‐up: 6‐9 months

172 per 1000

218 per 1000
(138 to 326)

OR 1.34
(0.77 to 2.33)

346
(3 studies)

⊕⊝⊝⊝
very low1,2,3

OHSS

Not reported in any included studies

Pregnancy rate per couple (all cycles)
Follow‐up: 4‐9 months

148 per 1000

226 per 1000
(148 to 329)

OR 1.68
(1.00 to 2.82)

399
(4 studies)

⊕⊝⊝⊝
very low1,3,4

Miscarriage rate per couple
Follow‐up: 6‐9 months

53 per 1000

56 per 1000
(11 to 238)

OR 1.06
(0.20 to 5.63)

115
(2 studies)

⊕⊝⊝⊝
very low5,6

*The basis for the assumed risk was the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; IUI: intra‐uterine insemination; OHSS: ovarian hyperstimulation syndrome; OR: odds ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Risk of bias was very serious: 1. Francavilla 2009, allocation concealment: high risk (on chronological basis), 2. Arici 1994, Francavilla 2009, and Guzick 1999, other bias: high risk (no stratification by diagnosis category of subfertility.
2 Inconsistency was serious between Cohlen 1998a and Goverde 2000 (favoured IUI in natural cycles) and Arici 1994, Francavilla 2009, and Guzick 1999 (favoured IUI in stimulated cycles).
3 There was serious imprecision, with small sample sizes.
4 Inconsistency was serious between Cohlen 1998a (favoured IUI in natural cycles) and Arici 1994, Francavilla 2009, and Guzick 1999 (favoured IUI in stimulated cycles).
5 Risk of bias was very serious: Francavilla 2009, allocation concealment: high risk (on chronological basis) and other bias: high risk (no stratification by diagnosis category of subfertility).
6 There was serious imprecision, findings were compatible with no benefit in either group.

Figuras y tablas -
Summary of findings 4. IUI in stimulated cycles compared to IUI in natural cycles for male subfertility
Summary of findings 5. IVF compared to IUI in natural cycles for male subfertility

IVF compared to IUI in natural cycles for male subfertility

Patient or population: couples with male subfertility
Settings: single centre (the Netherlands)
Intervention: IVF
Comparison: IUI in natural cycles

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of couples (studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

IUI in natural cycles

IVF

Live birth rate per couple (all cycles)
Follow‐up: 6 months

407 per 1000

346 per 1000
(147 to 618)

OR 0.77
(0.25 to 2.35)

53
(1 study)

⊕⊕⊝⊝
low1

OHSS

Not reported in any included studies

*The basis for the assumed risk was the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; IUI: intra‐uterine insemination; IVF: in vitro fertilisation; OHSS: ovarian hyperstimulation syndrome; OR: odds ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 There was very serious imprecision, with small sample sizes.

Figuras y tablas -
Summary of findings 5. IVF compared to IUI in natural cycles for male subfertility
Summary of findings 6. IVF compared to IUI in stimulated cycles for male subfertility

IVF compared to IUI in stimulated cycles for male subfertility

Patient or population: couples with male subfertility
Settings: single and multicentre (the Netherlands)
Intervention: IVF
Comparison: IUI in stimulated cycles

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of couples (studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

IUI in stimulated cycles

IVF

Live birth rate per couple (all cycles)
Follow‐up: 6‐12 months

452 per 1000

460 per 1000
(262 to 669)

OR 1.03
(0.43 to 2.45)

86
(2 studies)

⊕⊝⊝⊝
very low1,2

OHSS per couple
Follow‐up: 6 months

See comment

See comment

Not estimable

36
(1 study)

⊕⊝⊝⊝
very low1,2

No OHSS occurred

Pregnancy rate per couple (all cycles)
Follow‐up: 6 months

611 per 1000

666 per 1000
(341 to 886)

OR 1.27
(0.33 to 4.97)

36
(1 study)

⊕⊝⊝⊝
very low1,2

*The basis for the assumed risk was the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; IUI: intra‐uterine insemination; IVF: in vitro fertilisation; OHSS: ovarian hyperstimulation syndrome; OR: odds ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Risk of bias was serious: Bensdorp 2015, other bias: high risk (no stratification by diagnosis category of subfertility).
2 There was very serious imprecision, with small sample sizes.

Figuras y tablas -
Summary of findings 6. IVF compared to IUI in stimulated cycles for male subfertility
Comparison 1. Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in natural cycles (NC)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Pregnancy rate per couple (all cycles) Show forest plot

2

62

Odds Ratio (M‐H, Fixed, 95% CI)

4.57 [0.21, 101.61]

Figuras y tablas -
Comparison 1. Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in natural cycles (NC)
Comparison 2. Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH)

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

81

Odds Ratio (M‐H, Fixed, 95% CI)

0.89 [0.30, 2.59]

2 OHSS per couple Show forest plot

1

59

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Pregnancy rate per couple (all cycles) Show forest plot

3

202

Odds Ratio (M‐H, Fixed, 95% CI)

1.51 [0.74, 3.07]

4 Multiple pregnancy rate per couple Show forest plot

1

81

Odds Ratio (M‐H, Fixed, 95% CI)

3.15 [0.12, 79.69]

5 Miscarriage rate per couple Show forest plot

1

81

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.19, 5.42]

Figuras y tablas -
Comparison 2. Intra‐uterine insemination (IUI) versus timed intercourse (TI) both in cycles with ovarian hyperstimulation (OH)
Comparison 4. Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus timed intercourse (TI) in natural cycles (NC)

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

44

Odds Ratio (M‐H, Fixed, 95% CI)

3.14 [0.12, 81.35]

2 Pregnancy rate per couple (all cycles) Show forest plot

1

44

Odds Ratio (M‐H, Fixed, 95% CI)

3.14 [0.12, 81.35]

Figuras y tablas -
Comparison 4. Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus timed intercourse (TI) in natural cycles (NC)
Comparison 5. Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus IUI in natural cycles (NC)

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

3

346

Odds Ratio (M‐H, Fixed, 95% CI)

1.34 [0.77, 2.33]

1.1 Gonadotrophins

2

305

Odds Ratio (M‐H, Fixed, 95% CI)

1.31 [0.75, 2.29]

1.2 Gonadotrophins + clomiphene citrate (CC)

1

41

Odds Ratio (M‐H, Fixed, 95% CI)

2.72 [0.10, 70.79]

2 Pregnancy rate per couple (all cycles) Show forest plot

4

399

Odds Ratio (M‐H, Fixed, 95% CI)

1.68 [1.00, 2.82]

2.1 Gonadotrophins

2

328

Odds Ratio (M‐H, Fixed, 95% CI)

1.60 [0.94, 2.73]

2.2 CC

1

30

Odds Ratio (M‐H, Fixed, 95% CI)

4.83 [0.18, 128.79]

2.3 Gonadotrophins + CC

1

41

Odds Ratio (M‐H, Fixed, 95% CI)

2.72 [0.10, 70.79]

3 Miscarriage rate per couple Show forest plot

2

115

Odds Ratio (M‐H, Fixed, 95% CI)

1.06 [0.20, 5.63]

Figuras y tablas -
Comparison 5. Intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH) versus IUI in natural cycles (NC)
Comparison 8. In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in natural cycles (NC)

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

53

Odds Ratio (M‐H, Fixed, 95% CI)

0.77 [0.25, 2.35]

Figuras y tablas -
Comparison 8. In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in natural cycles (NC)
Comparison 9. In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH)

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

86

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.43, 2.45]

2 OHSS per couple Show forest plot

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Pregnancy rate per couple (all cycles) Show forest plot

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

1.27 [0.33, 4.97]

Figuras y tablas -
Comparison 9. In vitro fertilisation (IVF) versus intra‐uterine insemination (IUI) in cycles with ovarian hyperstimulation (OH)