Cycle regimens for frozen‐thawed embryo transfer

Tarek Ghobara; Tarek A Gelbaya; Reuben Olugbenga Ayeleke

doi:10.1002/14651858.CD003414.pub3

Cochrane Database of Systematic Reviews

Regímenes cíclicos para la transferencia de embriones congelados‐descongelados

Información

DOI:

https://doi.org/10.1002/14651858.CD003414.pub3 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

05 julio 2017see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Ginecología y fertilidad

Copyright:

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Tarek Ghobara

Correspondencia a: Center for Reproductive Medicine, University Hospital Coventry & Warwickshire, Coventry, UK

[email protected]
Tarek A Gelbaya

Assisted Conception, University Hospitals of Leicester, Leicester, UK
Reuben Olugbenga Ayeleke

Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand

Contributions of authors

For the 2017 update:

TG: performed the updated search, selection of included studies, data extraction, and contributed to the writing and updating of the review.

TAG: contributed to the writing and updating of the review.

ROA: performed the updated search, selection of included studies and data extraction, created the 'Summary of findings' tables, and contributed to the writing and updating of the review.

For the previous update:

TG and Patrick Vanderkerchove (PV) shared the writing of the protocol, searching for and assessing the relevant studies and the writing up of the review. TG and PV shared the update of the review including search for relevant randomized controlled trials (RCTs), selection of included RCTs and writing up the updated review.

Sources of support

Internal sources

Gynaecology and Fertility Cochrane Subgroup, New Zealand.

External sources

None, Other.

Declarations of interest

Tarek Ghobara: no known conflict of interest
Tarek A Gelbaya: no known conflict of interest
Reuben Olugbenga Ayeleke: no known conflict of interest

Acknowledgements

The authors would like to thank the Cochrane Gynaecology and Fertility editorial staff for their advice and support through the review process. The authors of the 2017 update thank Patrick Vanderkerchove for his contributions to previous versions of this review.

Version history

Published

Title

Stage

Authors

Version

2017 Jul 05

Cycle regimens for frozen‐thawed embryo transfer

Review

Tarek Ghobara, Tarek A Gelbaya, Reuben Olugbenga Ayeleke

https://doi.org/10.1002/14651858.CD003414.pub3

2008 Jan 23

Cycle regimens for frozen‐thawed embryo transfer

Review

Tarek Ghobara, Patrick Vanderkerchove

https://doi.org/10.1002/14651858.CD003414.pub2

2002 Jan 21

Cycle regimes for frozen‐thawed embryo transfer

Protocol

Tarek Ghobara, Patrick Vandekerckhove

https://doi.org/10.1002/14651858.CD003414

Differences between protocol and review

We edited Objectives and 'Types of interventions' section to clarify that comparisons between types of modality are eligible: this was also the case in the previous version of the review but was not stated very clearly.

We rearranged outcomes, with 'Miscarriage rate per woman' now being the second primary outcome in the review and 'Clinical pregnancy rate' becoming a secondary outcome. We added one secondary outcome, 'Number of centre visits to monitor FET cycle'.

We amended the definition of the primary outcome 'Live birth' to be "delivery of a live fetus after 24 completed weeks of gestational age".

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Female; Humans; Pregnancy;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

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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