Cycle regimens for frozen‐thawed embryo transfer

Tarek Ghobara; Tarek A Gelbaya; Reuben Olugbenga Ayeleke

doi:10.1002/14651858.CD003414.pub3

Regímenes cíclicos para la transferencia de embriones congelados‐descongelados

Appendices

Appendix 1. Cochrane Gynaecology and Fertility Specialised Register search strategy

Gynaecology and Fertility database search from inception to 13 December 2016

PROCITE platform

Keywords CONTAINS "cryopreservation" or "frozen embryo transfer" or "frozen embryos" or "frozen‐thawed cycle" or "frozen‐thawed embryo transfer" or "frozen‐thawed embryos" or "FET" or "cryopreserved embryos" or "cryopreserved‐thawed embryos" or "embryo vitrification" or "vitrification" or "vitrified" or "vitrified‐warmed embryos" or "frozen‐thawed" or "embryo vitrification" or Title CONTAINS "cryopreservation" or "frozen embryo transfer" or "frozen embryos" or "frozen‐thawed cycle" or "frozen‐thawed embryo transfer" or "frozen‐thawed embryos" or "FET" or "cryopreserved embryos" or "cryopreserved‐thawed embryos" or "embryo vitrification" or "vitrification" or "vitrified" or "vitrified‐warmed embryos" or "embryo vilification"

AND

Keywords CONTAINS "ovulation induction" or "endometrial preparation" or "*Clomiphene" or "clomiphene citrate" or "menotrophin" or "menotropin" or "HMG" or "human menopausal gonadotrophin" or "gonadotropin‐releasing hormone" or "gonadotropin releasing hormone agonist" or "gonadotrophin stimulation" or "Gonadotrophin releasing hormones" or "Gonadorelin" or "GnRh" or "GnRHa" or "GnRH a" or "GnRH agonist"or "GnRH agonists" or "GnRHa‐gonadotropin" or "rFSH" or "Fsh" or "FSH HMG" or "follicle stimulating hormone" or "follitropin" or "natural cycle" or "natural cycles" or "artificial cycle" or" modified natural cycle" or" estrogen" or "Estrogens" or "Progesterone" or "Estradiol" or "hormone therapy" or "hormone therapy estrogen" or "hormone replacement therapy" or "letrozole" or "tamoxifen" or "stimulated cycle" or "stimulation of endometrium embryo transfer" or "stimulation protocol" or Title CONTAINS "natural cycle"or "natural cycles" or "artificial cycle" or "endometrial preparation" or "*Clomiphene" or "modified natural cycle" (155 hits)

Appendix 2. CENTRAL Register of Studies Online (CRSO) search strategy

Searched 13th December 2016

Web platform

1 Cryopreservation/ (253)
2 (Cryopreserv$ adj7 embryo$).tw. (176)
3 (Cryopreserv$ adj7 blastocyst$).tw. (32)
4 freezing/ or vitrification/ (95)
5 (vitrification adj7 embryo$).tw. (45)
6 (vitrification adj7 blastocyst$).tw. (34)
7 (frozen adj5 embryo$).tw. (196)
8 (freez$ adj5 embryo$).tw. (55)
9 (freez$ adj5 blastocyst$).tw. (7)
10 (frozen adj5 blastocyst$).tw. (25)
11 FET.tw. (94)
12 (Cryo‐preserv$ adj7 embryo$).tw. (0)
13 (Cryo‐preserv$ adj7 blastocyst$).tw. (0)
14 or/1‐13 (728)
15 exp Ovulation Induction/ (1030)
16 ((ovar$ adj5 stimula$) or (ovulat$ adj5 induct$)).tw. (1683)
17 (endometri$ adj2 prepar$).tw. (89)
18 Clomiphene.tw. or Clomiphene/ (875)
19 clomid.tw. (26)
20 exp Menotropins/ (358)
21 (Menotropin$ or menopausal gonadotrop$ or HMG).tw. (1421)
22 exp Follicle Stimulating Hormone/ (1639)
23 (Follicle Stimulating Hormone or FSH).tw. (2873)
24 Gonadotropin‐Releasing Hormone/ad, ag, aa, de, pd, tu [Administration & Dosage, Agonists, Analogs & Derivatives, Drug Effects, Pharmacology, Therapeutic Use] (137)
25 Gonadotrop?in‐Releasing Hormone$.tw. (1194)
26 GnRH$.tw. (2051)
27 exp Estrogens/ (5949)
28 (?estrogen$ or ?estradiol).tw. (8709)
29 exp Progesterone/ or progesterone.tw. (4154)
30 (natural$ adj4 cycle$).tw. (157)
31 (artificial$ adj2 cycle$).tw. (34)
32 (cycle$ adj2 regimen$).tw. (266)
33 pituitary suppression.tw. (103)
34 human menopausal.tw. (401)
35 spontaneous ovulation.tw. (24)
36 HCG trigger$.tw. (52)
37 (stimulat$ adj3 cycle$).tw. (438)
38 (hormone$ adj2 replacement).tw. (2088)
39 (endometri$ adj2 stimulat$).tw. (87)
40 HRT.tw. (1234)
41 or/15‐40 (18545)
42 14 and 41 (208)

Appendix 3. MEDLINE search strategy

From inception to 13th December 2016

Ovid platform

1 Cryopreservation/ (21360)
2 (Cryopreserv$ adj7 embryo$).tw. (3130)
3 (Cryopreserv$ adj7 blastocyst$).tw. (445)
4 freezing/ or vitrification/ (23937)
5 (vitrifi$ adj5 embryo$).tw. (957)
6 (vitrifi$ adj5 blastocyst$).tw. (641)
7 (frozen adj5 embryo$).tw. (2517)
8 (freez$ adj5 embryo$).tw. (1110)
9 (freez$ adj5 blastocyst$).tw. (175)
10 (frozen adj5 blastocyst$).tw. (335)
11 FET.tw. (2142)
12 (Cryo‐preserv$ adj7 embryo$).tw. (10)
13 or/1‐12 (47595)
14 exp Ovulation Induction/ (11949)
15 ((ovar$ adj5 stimula$) or (ovulat$ adj5 induc$)).tw. (16099)
16 (endometri$ adj2 prepar$).tw. (460)
17 hormon$ regimen$.tw. (279)
18 Clomiphene.tw. or Clomiphene/ (6564)
19 clomid.tw. (175)
20 (Tamoxifen or Letrozole).tw. (23668)
21 aromatase inhibitor$.tw. (6705)
22 anti‐?estrogen$.tw. (2427)
23 exp Menotropins/ (3127)
24 (Menotropin$ or menopausal gonadotrop$ or HMG).tw. (15378)
25 exp Follicle Stimulating Hormone/ (37398)
26 (Follicle Stimulating Hormone or FSH or rFSH or rhFSH).tw. (39284)
27 Gonadotropin‐Releasing Hormone/ad, ag, aa, de, pd, tu [Administration & Dosage, Agonists, Analogs & Derivatives, Drug Effects, Pharmacology, Therapeutic Use] (15972)
28 Gonadotrop?in‐Releasing Hormone$.tw. (16126)
29 GnRH$.tw. (21800)
30 exp Estrogens/ (162202)
31 (?estrogen$ or ?estradiol).tw. (177832)
32 exp Progesterone/ or progesterone.tw. (108635)
33 exogenous steroid$.tw. (506)
34 (natural$ adj4 cycle$).tw. (2642)
35 (artificial$ adj3 cycle$).tw. (482)
36 (cycle$ adj2 regimen$).tw. (278)
37 pituitary suppression.tw. (320)
38 human menopausal.tw. (2109)
39 spontaneous ovulation.tw. (408)
40 (HCG adj3 trigger$).tw. (263)
41 hormone therapy.tw. (12827)
42 (stimulat$ adj3 cycle$).tw. (3805)
43 (hormone$ adj2 replacement).tw. (15866)
44 (endometri$ adj2 stimulat$).tw. (547)
45 (HRT or HT).tw. (70350)
46 or/14‐45 (464462)
47 randomized controlled trial.pt. (469833)
48 controlled clinical trial.pt. (95075)
49 randomized.ab. (405868)
50 randomised.ab. (81587)
51 placebo.tw. (197475)
52 clinical trials as topic.sh. (189503)
53 randomly.ab. (286433)
54 trial.ti. (179694)
55 (crossover or cross‐over or cross over).tw. (76212)
56 or/47‐55 (1211177)
57 exp animals/ not humans.sh. (4669484)
58 56 not 57 (1117076)
59 13 and 46 and 58 (262)

Appendix 4. Embase search strategy

From inception to 13th December 2016

Ovid platform

1 cryopreservation/ (33757)
2 (Cryopreserv$ adj7 embryo$).tw. (4445)
3 (Cryo‐preserv$ adj7 embryo$).tw. (33)
4 (Cryopreserv$ adj7 blastocyst$).tw. (826)
5 freezing/ or vitrification/ (35415)
6 (vitrifi$ adj5 embryo$).tw. (1716)
7 (vitrifi$ adj5 blastocyst$).tw. (1242)
8 (frozen adj5 embryo$).tw. (3976)
9 (freez$ adj5 embryo$).tw. (1588)
10 (freez$ adj5 blastocyst$).tw. (283)
11 (frozen adj5 blastocyst$).tw. (688)
12 FET.tw. (2754)
13 freeze thawing/ or freezing/ (36470)
14 vitrification/ (4402)
15 or/1‐14 (71558)
16 exp ovulation induction/ (13019)
17 ((ovar$ adj5 stimula$) or (ovulat$ adj5 induc$)).tw. (20432)
18 (endometri$ adj2 prepar$).tw. (701)
19 hormon$ regimen$.tw. (316)
20 Clomiphene.tw. or Clomiphene/ (9591)
21 clomid.tw. (1068)
22 (Tamoxifen or Letrozole).tw. (30044)
23 aromatase inhibitor$.tw. (9118)
24 exp human menopausal gonadotropin/ (9848)
25 (Menotropin$ or menopausal gonadotrop$ or HMG).tw. (17974)
26 exp follitropin/ (55231)
27 (Follicle Stimulating Hormone or FSH or rFSH or rhFSH).tw. (46559)
28 gonadorelin/ (35623)
29 Gonadotrop?in‐Releasing Hormone$.tw. (16598)
30 GnRH$.tw. (25145)
31 exp estrogen/ (255742)
32 (?estrogen$ or ?estradiol).tw. (194821)
33 exp progesterone/ (85120)
34 exp Progesterone/ or progesterone.tw. (117583)
35 (natural$ adj2 cycle$).tw. (2548)
36 (artificial$ adj2 cycle$).tw. (425)
37 (cycle$ adj2 regimen$).tw. (523)
38 pituitary suppression.tw. (409)
39 human menopausal.tw. (2323)
40 spontaneous ovulation.tw. (478)
41 (HCG adj3 trigger$).tw. (693)
42 (stimulat$ adj3 cycle$).tw. (4793)
43 exogenous steroid$.tw. (560)
44 exogenous steroid$.tw. (560)
45 (hormone adj2 therap$).tw. (33347)
46 (endometri$ adj2 stimulat$).tw. (682)
47 or/16‐46 (491845)
48 15 and 47 (5220)
49 Clinical Trial/ (1004097)
50 Randomized Controlled Trial/ (465768)
51 exp randomization/ (83937)
52 Single Blind Procedure/ (27791)
53 Double Blind Procedure/ (137638)
54 Crossover Procedure/ (54096)
55 Placebo/ (323380)
56 Randomi?ed controlled trial$.tw. (150645)
57 Rct.tw. (22599)
58 random allocation.tw. (1637)
59 randomly allocated.tw. (26733)
60 allocated randomly.tw. (2210)
61 (allocated adj2 random).tw. (844)
62 Single blind$.tw. (18743)
63 Double blind$.tw. (173480)
64 ((treble or triple) adj blind$).tw. (657)
65 placebo$.tw. (248420)
66 prospective study/ (389403)
67 or/49‐66 (1790257)
68 case study/ (93504)
69 case report.tw. (324719)
70 abstract report/ or letter/ (989413)
71 or/68‐70 (1398438)
72 67 not 71 (1739458)
73 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (5736041)
74 72 not 73 (1678022)
75 48 and 74 (720)

Appendix 5. PsycINFO search strategy

From inception to 13th December 2016

Ovid platform

1 exp reproductive technology/ (1610)
2 (frozen adj5 embryo$).tw. (27)
3 ((frozen‐thawed or cryopreserv$) adj5 embryo$).tw. (28)
4 exp Embryo/ (1632)
5 FET.tw. (56)
6 ((embry$ adj5 transf$) or embryo replacement or embryo deposition).tw. (272)
7 or/1‐6 (3386)
8 exp Ovulation/ (346)
9 ((ovar$ adj5 stimula$) or (ovulat$ adj5 induct$)).tw. (172)
10 (endometri$ adj2 prepar$).tw. (1)
11 Clomiphene.tw. (46)
12 clomid.tw. (1)
13 (Menotropin$ or menopausal gonadotrop$ or HMG).tw. (205)
14 (Follicle Stimulating Hormone or FSH).tw. (659)
15 exp Gonadotropic Hormones/ (4043)
16 Gonadotropin‐Releasing Hormone$.tw. (689)
17 GnRH$.tw. (887)
18 exp Estrogens/ (6065)
19 Estrogen$.tw. (7196)
20 exp Progesterone/ (2010)
21 Progesterone.tw. (3831)
22 oestrogen$.tw. (690)
23 (natural$ adj2 cycle$).tw. (127)
24 (artificial$ adj2 cycle$).tw. (28)
25 (cycle$ adj2 regimen$).tw. (5)
26 or/8‐25 (15793)
27 7 and 26 (80)
28 random.tw. (48495)
29 control.tw. (375857)
30 double‐blind.tw. (20313)
31 clinical trials/ (10039)
32 placebo/ (4746)
33 exp Treatment/ (669890)
34 or/28‐33 (1034673)
35 27 and 34 (36)

Appendix 6. CINAHL search strategy

From inception to 13th December 2016

EBSCO platform

#	Query	Results
S48	S35 AND S47	30
S47	S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43 OR S44 OR S45 OR S46	1,097,934
S46	TX allocat* random*	5,898
S45	(MH "Quantitative Studies")	15,110
S44	(MH "Placebos")	9,934
S43	TX placebo*	42,609
S42	TX random* allocat*	5,898
S41	(MH "Random Assignment")	42,016
S40	TX randomi* control* trial*	115,809
S39	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*) )	866,076
S38	TX clinic* n1 trial*	196,374
S37	PT Clinical trial	79,958
S36	(MH "Clinical Trials+")	207,314
S35	S12 AND S34	107
S34	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 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33	20,839
S33	TX(stimulat* N3 cycle*)	229
S32	TX spontaneous* ovulat*	23
S31	TX pituitary suppression	79
S30	TX(cycle* N2 regimen*)	91
S29	TX(artificial* N2 cycle*)	8
S28	TX(natural* N2 cycle*)	120
S27	TX Progesterone	4,593
S26	(MM "Progesterone")	1,105
S25	TX estrogen* or TX oestrogen*	14,913
S24	(MM "Estrogens")	2,993
S23	TX GnRH*	499
S22	TX Gonadotrop?in‐Releasing Hormone*	90
S21	(MM "Gonadorelin") OR (MM "Pituitary Hormone Release Inhibiting Hormones")	479
S20	TX(Follicle Stimulating Hormone or FSH)	1,763
S19	(MM "Follicle‐Stimulating Hormone")	262
S18	TX(Menotropin* or menopausal gonadotrop* or HMG)	722
S17	TX Clomiphene or TX clomid	360
S16	(MM "Clomiphene")	121
S15	TX(endometri* N2 prepar*)	18
S14	TX((ovar* N5 stimula) or (ovulat N5 induct*))	877
S13	(MM "Ovulation Induction")	260
S12	S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11	1,100
S11	TX FET	101
S10	TX(frozen N5 blastocyst*)	5
S9	TX(freez* N5 blastocyst*)	0
S8	TX(freez* N5 embryo*)	51
S7	TX(frozen N5 embryo*)	129
S6	TX(vitrification N7 blastocyst*)	8
S5	TX(vitrification N7 embryo*)	18
S4	(MM "Freezing")	136
S3	TX(Cryopreserv* N7 blastocyst*)	12
S2	TX(Cryopreserv* N7 embryo*)	170
S1	(MM "Cryopreservation+")	668

Figure 1

Study flow diagram

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Figure 2

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

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Figure 3

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

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Analysis 1.1

Comparison 1 Natural cycle FET versus HT FET, Outcome 1 Clinical pregnancy rate per woman.

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Analysis 1.2

Comparison 1 Natural cycle FET versus HT FET, Outcome 2 Multiple pregnancy rate per woman.

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Analysis 2.1

Comparison 2 Natural cycle FET versus HT + GnRHa FET, Outcome 1 Live birth rate per woman.

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Analysis 2.2

Comparison 2 Natural cycle FET versus HT + GnRHa FET, Outcome 2 Clinical pregnancy rate per woman.

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Analysis 2.3

Comparison 2 Natural cycle FET versus HT + GnRHa FET, Outcome 3 Multiple pregnancy rate per woman.

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Analysis 3.1

Comparison 3 Natural cycle FET versus modified natural cycle FET (HCG trigger), Outcome 1 Live birth rate per woman.

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Analysis 3.2

Comparison 3 Natural cycle FET versus modified natural cycle FET (HCG trigger), Outcome 2 Miscarriage rate per woman.

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Analysis 3.3

Comparison 3 Natural cycle FET versus modified natural cycle FET (HCG trigger), Outcome 3 Ongoing pregnancy rate per woman.

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Analysis 3.4

Comparison 3 Natural cycle FET versus modified natural cycle FET (HCG trigger), Outcome 4 Clinical pregnancy rate per woman.

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Analysis 4.1

Comparison 4 Modified natural cycle FET (HCG trigger) versus HT FET, Outcome 1 Live birth rate per woman.

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Analysis 4.2

Comparison 4 Modified natural cycle FET (HCG trigger) versus HT FET, Outcome 2 Ongoing pregnancy rate per woman.

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Analysis 4.3

Comparison 4 Modified natural cycle FET (HCG trigger) versus HT FET, Outcome 3 Clinical pregnancy rate per woman.

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Analysis 4.4

Comparison 4 Modified natural cycle FET (HCG trigger) versus HT FET, Outcome 4 Cycle cancellation rate per woman.

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Analysis 4.5

Comparison 4 Modified natural cycle FET (HCG trigger) versus HT FET, Outcome 5 Endometrial thickness.

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Analysis 5.1

Comparison 5 Modified natural cycle FET (HCG trigger) versus HT + GnRH‐a FET, Outcome 1 Live birth rate per woman.

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Analysis 5.2

Comparison 5 Modified natural cycle FET (HCG trigger) versus HT + GnRH‐a FET, Outcome 2 Miscarriage rate per woman.

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Analysis 5.3

Comparison 5 Modified natural cycle FET (HCG trigger) versus HT + GnRH‐a FET, Outcome 3 Clinical pregnancy rate per woman.

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Analysis 5.4

Comparison 5 Modified natural cycle FET (HCG trigger) versus HT + GnRH‐a FET, Outcome 4 Endometrial thickness.

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Analysis 6.1

Comparison 6 HT FET versus HT + GnRH‐a, Outcome 1 Live birth rate per woman.

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Analysis 6.2

Comparison 6 HT FET versus HT + GnRH‐a, Outcome 2 Miscarriage rate per woman.

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Analysis 6.3

Comparison 6 HT FET versus HT + GnRH‐a, Outcome 3 Ongoing pregnancy rate per woman.

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Analysis 6.4

Comparison 6 HT FET versus HT + GnRH‐a, Outcome 4 Clinical pregnancy rate per woman.

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Analysis 6.5

Comparison 6 HT FET versus HT + GnRH‐a, Outcome 5 Cycle cancellation rate per woman.

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Analysis 6.6

Comparison 6 HT FET versus HT + GnRH‐a, Outcome 6 Endometrial thickness.

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Analysis 7.1

Comparison 7 HT FET versus FSH FET, Outcome 1 Clinical pregnancy rate per woman.

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Analysis 7.2

Comparison 7 HT FET versus FSH FET, Outcome 2 Cycle cancellation rate per woman.

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Analysis 7.3

Comparison 7 HT FET versus FSH FET, Outcome 3 Endometrial thickness.

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Analysis 8.1

Comparison 8 HMG FET versus clomiphene + HMG FET, Outcome 1 Live birth rate per woman.

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Analysis 8.2

Comparison 8 HMG FET versus clomiphene + HMG FET, Outcome 2 Miscarriage rate per woman.

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Analysis 8.3

Comparison 8 HMG FET versus clomiphene + HMG FET, Outcome 3 Multiple pregnancy rate per woman.

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Summary of findings for the main comparison. Natural cycle FET versus HT FET

Natural cycle FET versus HT FET
Population: subfertile women Settings: assisted reproductive technology clinics Intervention: natural cycle FET Comparison: HT FET
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	HT FET	Natural cycle FET
Live birth rate per woman	No data available		Not estimable	‐
Miscarriage rate per woman	No data available		Not estimable	‐
Ongoing pregnancy rate per woman	No data available		Not estimable	‐
Multiple pregnancy rate per woman	See comment		OR 2.48 (0.09 to 68.14)	21 (1 study)	⊕⊝⊝⊝ very low^1,2	No events in the control group
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. 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; FET: frozen‐thawed embryo transfer; HT: hormone therapy; OR: odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Downgraded one level for serious risk of bias: study at unclear risk of bias in all domains. ²Downgraded two levels due to very serious imprecision: single study, very few events. Confidence intervals compatible with benefit in either group or with no effect.

Summary of findings for the main comparison. Natural cycle FET versus HT FET

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Summary of findings 2. Natural cycle FET versus HT plus GnRHa suppression FET

Natural cycle FET versus HT + GnRHa suppression FET
Population: subfertile women Settings: assisted reproductive technology clinics Comparison: HT + GnRHa FET
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	HT + GnRHa FET	Natural cycle FET
Live birth rate per woman	316 per 1000	262 per 1000 (153 to 414)	OR 0.77 (0.39 to 1.53)	159 (1 study)	⊕⊕⊝⊝ low¹	Only 46 events
Miscarriage rate per woman	No data available		Not estimable	‐
Ongoing pregnancy rate per woman	No data available		Not estimable	‐
Multiple pregnancy rate per woman	63 per 1000	38 per 1000 (9 to 144)	OR 0.58 (0.13 to 2.50)	159 (1 study)	⊕⊕⊝⊝ low¹	Only 8 events
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. 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; FET: frozen‐thawed embryo transfer; GnRHA: gonadotrophin‐releasing hormone agonist; HT: hormone therapy; OR: odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Downgraded two levels due to very serious imprecision: single study, few events, confidence interval compatible with benefit in either group or with no effect.

Summary of findings 2. Natural cycle FET versus HT plus GnRHa suppression FET

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Summary of findings 3. Natural cycle FET versus modified natural cycle FET (HCG trigger)

Natural cycle FET versus other regimens for primary or secondary subfertility
Population: subfertile women Settings: assisted reproductive technology clinics Intervention: natural cycle FET Comparison: natural cycle plus HCG trigger FET¹
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Modified natural cycle FET (HCG trigger)	Natural cycle FET
Live birth rate per woman	267 per 1000	167 per 1000 (55 to 413)	OR 0.55 (0.16 to 1.93)	60 (1 study)	⊕⊝⊝⊝ Very low^2,3	Only 13 events
Miscarriage rate per woman	24 per 1000	5 per 1000 (0 to 92)	OR 0.20 (0.01 to 4.13)	168 (1 study)	⊕⊝⊝⊝ Very low^2,4	Only 2 events
Ongoing pregnancy rate per woman	107 per 1000	226 per 1000 (110 to 408)	OR 2.44 (1.03 to 5.76)	168 (1 study)	⊕⊝⊝⊝ Very low^2,4	Only 28 events
Multiple pregnancy per woman	No data available
The basis for the assumed risk* is the mean 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; FET: frozen‐thawed embryo transfer; GnRHa: gonadotrophin releasing hormone agonist;HCG: human chorionic gonadotrophin; HT: hormone therapy; OR: odds ratio.
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹One other study compared natural cycle FET versus natural cycle plus human menopausal gonadotrophin, but did not report any per‐woman data. ²Downgraded two levels due to very serious imprecision: single study, few events, confidence interval compatible with benefit in the modified natural cycle only or with no effect. ³Downgraded one level due to serious risk of bias: high attrition rate, baseline characteristics unequal. ⁴Downgraded one level due to serious risk of bias: no allocation concealment.

Summary of findings 3. Natural cycle FET versus modified natural cycle FET (HCG trigger)

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Summary of findings 4. Modified natural cycle FET (HCG trigger) versus HT FET

Modified natural cycle FET (HCG trigger) versus HT FET
Population: subfertile women Settings: assisted reproductive technology clinics Intervention: modified natural cycle FET (HCG trigger) Comparison: HT FET
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	HT FET	Modified natural cycle FET (HCG trigger)
Live birth rate per woman	88 per 1000	114 per 1000 (78 to 165)	OR 1.34 (0.88 to 2.05)	959 (1 study)	⊕⊕⊝⊝ low^1,2
Miscarriage rate per woman	No data available		Not estimable	‐
Ongoing pregnancy rate per woman	97 per 1000	115 per 1000 (79 to 164)	OR 1.21 (0.80 to 1.83)	959 (1 study)	⊕⊕⊝⊝ low^1,2
Multiple pregnancy rate per woman	No data available		Not estimable	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. 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; FET: frozen‐thawed embryo transfer;HCG: human chorionic gonadotrophin; HT: hormone therapy; OR: odds ratio.
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Downgraded one level due to serious risk of bias: high attrition rate, unclear risk of allocation concealment ²Downgraded one level due to serious imprecision: confidence intervals compatible with benefit in either group or with no effect

Summary of findings 4. Modified natural cycle FET (HCG trigger) versus HT FET

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Summary of findings 5. Modified natural cycle FET (HCG trigger) versus HT + GnRHa suppression FET

Modified natural cycle FET (HCG trigger) versus HT + GnRHa FET
Population: subfertile women Settings: assisted reproductive technology clinics Intervention: modified natural cycle FET (HCG trigger) Comparison: HT + GnRHa FET
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	HT + GnRHa FET	Modified natural cycle FET (HCG trigger)
Live birth rate per woman	398 per 1000	423 per 1000 (304 to 553)	OR 1.11 (0.66 to 1.87)	236 (1 study)	⊕⊕⊝⊝ low^1,2
Miscarriage rate per woman	68 per 1000	51 per 1000 (18 to 138)	OR 0.74 (0.25 to 2.19)	236 (1 study)	⊕⊕⊝⊝ low^1,2
Ongoing pregnancy rate	No data available		Not estimable	‐
Multiple pregnancy rate per woman	No data available		Not estimable	‐
The basis for the assumed risk* is the mean 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; FET: frozen‐thawed embryo transfer; GnRHa: gonadotrophin releasing hormone agonist;HCG: human chorionic gonadotrophin; HT: hormone therapy; OR: odds ratio.
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Downgraded one level due to serious risk of bias: study at unclear risk of in most domains of bias (allocation concealment, blinding, selective reporting and other sources of bias). ²Downgraded one level due to serious imprecision: confidence intervals compatible with benefit in either group or with no effect.

Summary of findings 5. Modified natural cycle FET (HCG trigger) versus HT + GnRHa suppression FET

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Summary of findings 6. HT FET versus HT + GnRHa FET

HT FET versus other regimens for primary or secondary subfertility
Population: women with primary or secondary subfertility Settings: assisted reproductive technology clinics Intervention: HT FET Comparison: HT plus GnRHa trigger
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	HT + GnRHa FET	HT FET
Live birth rate per woman	742 per 1000	223 per 1000 (103 to 463)	OR 0.10 (0.04 to 0.30)	75 (1 study)	⊕⊕⊝⊝ Low^1,2	Only 33 events
Miscarriage rate per woman	48 per 1000	31 per 1000 (18 to 53)	OR 0.64 (0.37 to 1.12)	991 (6 studies)	⊕⊕⊝⊝ Low^3,4	‐
Ongoing pregnancy rate per woman	132 per 1000	207 per 1000 (85 to 424)	OR 1.72 (0.61 to 4.85)	106 (1 study)	⊕⊝⊝⊝ Very low^4,5	Only 18 events
Multiple pregnancy rate per woman	No data available
The basis for the assumed risk* is the mean 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; FET: frozen‐thawed embryo transfer; GnRHa: gonadotrophin releasing hormone agonist;HT: hormone therapy; OR: odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Downgraded one level due to serious imprecision: single study, few events. ²Downgraded one level due to serious inconsistency: clinical pregnancy rate in this study was higher than in six other studies in the same analysis (none of which reported live birth) and this study accounted for all inconsistency in the analysis for clinical pregnancy (I² = 46%). ³Downgraded one level due to serious imprecision: confidence intervals compatible with benefit in HT‐only arm or with no effect. ⁴Downgraded one level due to serious risk of bias: method of allocation concealment unclear in all studies/only study. ⁵Downgraded two levels due to very serious imprecision: single study, few events.

Summary of findings 6. HT FET versus HT + GnRHa FET

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Summary of findings 7. HMG FET versus clomiphene + HMG FET

HMG FET versus clomiphene + HMG FET
Population: subfertile women Settings: assisted reproductive technology clinics Intervention: HMG FET Comparison: clomiphene + HMG FET
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Clomiphene+ HMG FET	HMG FET
Live birth rate per woman	84 per 1000	186 per 1000 (89 to 347)	OR 2.49 (1.07 to 5.80)	209 (1 study)	⊕⊝⊝⊝ very low^1,2	Only 26 events
Miscarriage rate per woman	37 per 1000	49 per 1000 (13 to 164)	OR 1.33 (0.35 to 5.09)	209 (1 study)	⊕⊝⊝⊝ very low^1,3	Only 9 events
Ongoing pregnancy rate per woman	No data available		Not estimable	‐
Multiple pregnancy rate per woman	28 per 1000	39 per 1000 (9 to 157)	OR 1.41 (0.31 to 6.48)	209 (1 study)	⊕⊝⊝⊝ very low^1,3	Only 7 events
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. 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; FET: frozen‐thawed embryo transfer; HMG: human menopausal gonadotrophin; HT: hormone therapy; OR: odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Downgraded one level for serious risk of bias: study at unclear risk of bias in all domains. ²Downgraded two levels due to very serious imprecision: single study, few events. Confidence intervals compatible with benefit in the HMG‐only group or with no clinically meaningful effect. ³Downgraded two levels due to very serious imprecision: single study, very few events. Confidence intervals compatible with benefit in either group or with no effect.

Summary of findings 7. HMG FET versus clomiphene + HMG FET

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Table 1. Live birth rate: per embryo transfer data

Study	Intervention (number of embryo transfer)	Control (number of embryo transfer)	Live birth rate	P value
Peeraer 2015	Natural cycle FET (n = 332)	HMG FET (n = 340)	32/332 vs 45/340	n/s
FET: frozen‐thawed embryo transfer; HMG: human menopausal gonadotrophin; n/s: not significant.

Table 1. Live birth rate: per embryo transfer data

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Table 2. Miscarriage rate: per embryo transfer data

Study	Intervention (number of embryo transfer)	Control (number of embryo transfer)	Miscarriage rate	P value
Karimzadeh 2012	Natural cycle FET	HT FET	41.7% vs 22.2%	n/s
FET: frozen‐thawed embryo transfer; HT: hormone therapy; n/s: not significant.

Table 2. Miscarriage rate: per embryo transfer data

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Table 3. Ongoing pregnancy rate: per embryo transfer data

Study	Intervention (number of embryo transfer)	Control (number of embryo transfer)	Ongoing pregnancy rate	P value
Karimzadeh 2012	Natural cycle FET	HT FET	24.1% vs 21.9%	n/s
FET: frozen‐thawed embryo transfer; HT: hormone therapy; n/s: not significant.

Table 3. Ongoing pregnancy rate: per embryo transfer data

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Table 4. Clinical pregnancy rate: per cycle data

Study	Intervention (number of cycles)	Control (number of cycles)	Clinical pregnancy rate	P value
Loh 2001	Clomiphene‐induced ovulation (n = 35)	HT (n = 52)	3/35 vs 5/52	n/s
Loh 2001	Clomiphene‐induced ovulation (n = 32)	HT plus GnRHa trigger (n = 37)	2/32 vs 6/37	n/s
GnRHa: gonadotrophin releasing hormone agonist; HT: hormone therapy; n/s: not significant.

Table 4. Clinical pregnancy rate: per cycle data

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Table 5. Clinical pregnancy rate: per embryo transfer data

Study	Intervention (number of embryo transfer)	Control (number of embryo transfer)	Clinical pregnancy rate	P value
Karimzadeh 2012	Natural cycle FET	HT FET	27.6% vs 25%	n/s
FET: frozen‐thawed embryo transfer; HT: hormone therapy; n/s: not significant.

Table 5. Clinical pregnancy rate: per embryo transfer data

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Table 6. Endometrial thickness: data not suitable for analysis

Study	Intervention (number of cycles/embryo transfer)	Control (number of cycles/embryo transfer)	Endometrial thickness	P value
Loh 2001	Clomiphene‐induced ovulation (n = 67)	HT alone or HT plus GnRHa suppression (n = 37)	9.7 vs 9.8	n/s
Peeraer 2015	Natural cycle FET (n = 332)	HMG FET (n = 340)	8.9 vs 8.9	n/s
FET: frozen‐thawed embryo transfer; GnRHa: gonadotrophin releasing hormone agonist; HMG: human menopausal gonadotrophin; HT: hormone therapy; n/s: not significant.

Table 6. Endometrial thickness: data not suitable for analysis

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Comparison 1. Natural cycle FET versus HT FET

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical pregnancy rate per woman Show forest plot	1	100	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.40, 2.80]

2 Multiple pregnancy rate per woman Show forest plot	1	21	Odds Ratio (M‐H, Fixed, 95% CI)	2.48 [0.09, 68.14]

Comparison 1. Natural cycle FET versus HT FET

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Comparison 2. Natural cycle FET versus HT + GnRHa FET

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per woman Show forest plot	1	159	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.39, 1.53]

2 Clinical pregnancy rate per woman Show forest plot	1	159	Odds Ratio (M‐H, Fixed, 95% CI)	0.87 [0.45, 1.71]

3 Multiple pregnancy rate per woman Show forest plot	1	159	Odds Ratio (M‐H, Fixed, 95% CI)	0.58 [0.13, 2.50]

Comparison 2. Natural cycle FET versus HT + GnRHa FET

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Comparison 3. Natural cycle FET versus modified natural cycle FET (HCG trigger)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per woman Show forest plot	1	60	Odds Ratio (M‐H, Fixed, 95% CI)	0.55 [0.16, 1.93]

2 Miscarriage rate per woman Show forest plot	1	168	Odds Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 4.13]

3 Ongoing pregnancy rate per woman Show forest plot	1	168	Odds Ratio (M‐H, Fixed, 95% CI)	2.44 [1.03, 5.76]

4 Clinical pregnancy rate per woman Show forest plot	1	60	Odds Ratio (M‐H, Fixed, 95% CI)	1.0 [0.32, 3.14]

Comparison 3. Natural cycle FET versus modified natural cycle FET (HCG trigger)

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Comparison 4. Modified natural cycle FET (HCG trigger) versus HT FET

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per woman Show forest plot	1	959	Odds Ratio (M‐H, Fixed, 95% CI)	1.34 [0.88, 2.05]

2 Ongoing pregnancy rate per woman Show forest plot	1	959	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [0.80, 1.83]

3 Clinical pregnancy rate per woman Show forest plot	1	959	Odds Ratio (M‐H, Fixed, 95% CI)	1.22 [0.87, 1.70]

4 Cycle cancellation rate per woman Show forest plot	1	959	Odds Ratio (M‐H, Fixed, 95% CI)	0.70 [0.52, 0.95]

5 Endometrial thickness Show forest plot	1	959	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.13, 0.33]

Comparison 4. Modified natural cycle FET (HCG trigger) versus HT FET

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Comparison 5. Modified natural cycle FET (HCG trigger) versus HT + GnRH‐a FET

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per woman Show forest plot	1	236	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.66, 1.87]

2 Miscarriage rate per woman Show forest plot	1	236	Odds Ratio (M‐H, Fixed, 95% CI)	0.74 [0.25, 2.19]

3 Clinical pregnancy rate per woman Show forest plot	1	236	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.64, 1.78]

4 Endometrial thickness Show forest plot	1	236	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.54, 0.14]

Comparison 5. Modified natural cycle FET (HCG trigger) versus HT + GnRH‐a FET

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Comparison 6. HT FET versus HT + GnRH‐a

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per woman Show forest plot	1	75	Odds Ratio (M‐H, Fixed, 95% CI)	0.10 [0.04, 0.30]

2 Miscarriage rate per woman Show forest plot	6	991	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.37, 1.12]

3 Ongoing pregnancy rate per woman Show forest plot	1	106	Odds Ratio (M‐H, Fixed, 95% CI)	1.72 [0.61, 4.85]

4 Clinical pregnancy rate per woman Show forest plot	5	872	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.65, 1.25]

5 Cycle cancellation rate per woman Show forest plot	3	636	Odds Ratio (M‐H, Fixed, 95% CI)	2.73 [0.79, 9.38]

6 Endometrial thickness Show forest plot	3	625	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐0.41, 0.09]

Comparison 6. HT FET versus HT + GnRH‐a

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Comparison 7. HT FET versus FSH FET

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical pregnancy rate per woman Show forest plot	1	175	Odds Ratio (M‐H, Fixed, 95% CI)	1.09 [0.45, 2.62]

2 Cycle cancellation rate per woman Show forest plot	1	175	Odds Ratio (M‐H, Fixed, 95% CI)	0.99 [0.49, 2.00]

3 Endometrial thickness Show forest plot	1	175	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.31, 0.31]

Comparison 7. HT FET versus FSH FET

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Comparison 8. HMG FET versus clomiphene + HMG FET

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per woman Show forest plot	1	209	Odds Ratio (M‐H, Fixed, 95% CI)	2.49 [1.07, 5.80]

2 Miscarriage rate per woman Show forest plot	1	209	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [0.35, 5.09]

3 Multiple pregnancy rate per woman Show forest plot	1	209	Odds Ratio (M‐H, Fixed, 95% CI)	1.41 [0.31, 6.48]

Comparison 8. HMG FET versus clomiphene + HMG FET

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Appendices

Appendix 1. Cochrane Gynaecology and Fertility Specialised Register search strategy

Appendix 2. CENTRAL Register of Studies Online (CRSO) search strategy

Appendix 3. MEDLINE search strategy

Appendix 4. Embase search strategy

Appendix 5. PsycINFO search strategy

Appendix 6. CINAHL search strategy

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Appendices

Appendix 1. Cochrane Gynaecology and Fertility Specialised Register search strategy

Appendix 2. CENTRAL Register of Studies Online (CRSO) search strategy

Appendix 3. MEDLINE search strategy

Appendix 4. Embase search strategy

Appendix 5. PsycINFO search strategy

Appendix 6. CINAHL search strategy

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