Fresh versus frozen embryo transfers in assisted reproduction

Kai Mee Wong; Madelon van Wely; Femke Mol; Sjoerd Repping; Sebastiaan Mastenbroek

doi:10.1002/14651858.CD011184.pub2

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Figure 1

Study flow diagram.

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Figure 2

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

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Figure 3

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 4

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.1 Live birth rate.

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Figure 5

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.2 OHSS.

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Figure 6

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.3 Ongoing pregnancy rate.

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Figure 7

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.4 Clinical pregnancy rate.

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Figure 8

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.5 Multiple pregnancy rate.

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Figure 9

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.6 Miscarriage rate.

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Figure 10

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.7 Pregnancy complications.

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Figure 11

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.8 Birth weight of babies born.

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Figure 12

Forest plot of comparison: 3 Freeze‐all vs conventional IVF, congenital abnormalities per live‐born children plus number of foetuses therapeutically terminated, outcome: 3.1 Congenital abnormalities.

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Analysis 1.1

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 1 Live birth rate.

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Analysis 1.2

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 2 OHSS.

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Analysis 1.3

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 3 Ongoing pregnancy rate.

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Analysis 1.4

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 4 Clinical pregnancy rate.

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Analysis 1.5

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 5 Multiple pregnancy rate.

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Analysis 1.6

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 6 Miscarriage rate.

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Analysis 1.7

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 7 Pregnancy complications.

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Analysis 1.8

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 8 Birth weight of babies born.

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Analysis 2.1

Comparison 2 Freeze‐all versus conventional IVF, adverse events per clinical pregnancy, Outcome 1 Multiple pregnancy.

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Analysis 2.2

Comparison 2 Freeze‐all versus conventional IVF, adverse events per clinical pregnancy, Outcome 2 Miscarriage.

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Analysis 2.3

Comparison 2 Freeze‐all versus conventional IVF, adverse events per clinical pregnancy, Outcome 3 Pregnancy complications.

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Analysis 3.1

Comparison 3 Freeze‐all versus conventional IVF, congenital abnormalities per live‐born children plus number of foetuses therapeutically terminated, Outcome 1 Congenital abnormalities.

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Summary of findings for the main comparison. Fresh versus frozen embryo transfers in assisted reproduction

Fresh versus frozen embryo transfers in assisted reproduction
Patient or population: women undergoing assisted reproduction Setting: assisted reproduction clinic Intervention: frozen embryo transfers only Comparison: fresh and frozen embryo transfers
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with fresh and frozen embryo transfers	Risk with frozen embryo transfers only	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Live birth rate cumulatively for all embryo stages of transfer	579 per 1000	600 per 1000 (556 to 643)	OR 1.09 (0.91 to 1.31)	1892 (4 RCTs)	⊕⊕⊕⊝ MODERATE ¹
Ovarian hyperstimulation syndrome per cycle with ovarian hyperstimulation	70 per 1000	18 per 1000 (11 to 28)	OR 0.24 (0.15 to 0.38)	1633 (2 RCTs)	⊕⊕⊝⊝ LOW ^1,2
Multiple pregnancy per woman after first ET	161 per 1000	176 per 1000 (141 to 217)	OR 1.11 (0.85 to 1.44)	1630 (2 RCTs)	⊕⊕⊝⊝ LOW ^1,2
Miscarriage per woman after first ET	184 per 1000	131 per 1000 (105 to 162)	OR 0.67 (0.52 to 0.86)	1892 (4 RCTs)	⊕⊕⊝⊝ LOW ^1,2
Pregnancy complications per woman after first ET	110 per 1000	151 per 1000 (118 to 191)	OR 1.44 (1.08 to 1.92)	1633 (2 RCTs)	⊕⊕⊝⊝ LOW ^1,2
Time to pregnancy	Not reported in any of the included studies
The risk in the intervention group (and its 95% confidence interval) is based on the mean risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI:* confidence interval; ET: embryo transfer; OR: odds ratio; RCT: randomised clinical trial
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 associated with lack of power calculation (unclear what determined end of study) and/or use of interim analysis that was calculated per transfer (unit of analysis error) with absence of adequate stopping rules (possible overestimation of treatment effect). ²Downgraded one level due to serious imprecision: event rate < 300.

Summary of findings for the main comparison. Fresh versus frozen embryo transfers in assisted reproduction

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Table 1. Sensitivity analysis for cumulative live birth rate

Studies, number of participants

OR, 95% CI, fixed effect

OR, 95% CI, random effect

RR, 95% CI, fixed effect

RR, 95% CI, random effect

Ferraretti 1999 (n = 125)

Shapiro 2011a (n = 103)

Shapiro 2011b (n = 122)

Chen 2016 (n = 1508)

1.09 (0.91, 1.31)

1.04 (0.96, 1.12)

CI: confidence interval
OR: odds ratio
RR: risk ratio

Table 1. Sensitivity analysis for cumulative live birth rate

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Table 2. Live birth rate after first transfer

Outcome	Number of studies	Number of participants	Analysis method	OR
Live birth rate after first embryo transfer for all embryo stages of transfer	4	1892	Odds ratio (Mantel‐Haenszel, fixed, 95% confidence interval)	1.34 (1.12, 1.61)
Live birth rate after first transfer with cleavage‐stage embryos	2	1633	Odds ratio (Mantel‐Haenszel, fixed, 95% confidence interval)	1.31 (1.08, 1.59)
Live birth rate after first transfer with blastocyst‐stage embryo	2	259	Odds ratio (Mantel‐Haenszel, fixed, 95% confidence interval)	1.54 (0.94, 2.52)
Live birth rate calculated per first transfer is added for illustrative purposes as this comparison is often reported in the literature. It possibly shows differences in outcome for a stimulated and an unstimulated uterus, although this does not take into account the number of embryos that were thawed for transfer. This outcome is less relevant for women undergoing treatment since at the same time of first transfer in a freeze‐all strategy, they would already have received the second transfer (in case of sufficient number of embryos) in a conventional strategy that includes fresh transfer.

Table 2. Live birth rate after first transfer

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Comparison 1. Freeze‐all versus conventional IVF, outcomes per woman

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate Show forest plot	4	1892	Odds Ratio (M‐H, Fixed, 95% CI)	1.09 [0.91, 1.31]

1.1 Live birth rate: cumulatively for cleavage stage transfer	2	1633	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.91, 1.35]
1.2 Live birth rate: cumulatively for blastocyst stage transfer	2	259	Odds Ratio (M‐H, Fixed, 95% CI)	0.99 [0.60, 1.62]
2 OHSS Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

2.1 Per cycle with ovarian hyperstimulation	2	1633	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.24 [0.15, 0.38]
3 Ongoing pregnancy rate Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Cumulatively	2	259	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.64, 1.73]
4 Clinical pregnancy rate Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Cumulatively	1	125	Odds Ratio (M‐H, Fixed, 95% CI)	1.08 [0.54, 2.19]
5 Multiple pregnancy rate Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 After first ET	2	1630	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.85, 1.44]
6 Miscarriage rate Show forest plot	4		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 After first ET	4	1892	Odds Ratio (M‐H, Fixed, 95% CI)	0.67 [0.52, 0.86]
7 Pregnancy complications Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

7.1 After first ET	2	1633	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.44 [1.08, 1.92]
8 Birth weight of babies born Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

8.1 Birth weight of singletons	1	462	Mean Difference (IV, Fixed, 95% CI)	161.80 [57.11, 266.49]
8.2 Birth weight of multiples	1	453	Mean Difference (IV, Fixed, 95% CI)	‐2.0 [‐94.08, 90.08]

Comparison 1. Freeze‐all versus conventional IVF, outcomes per woman

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Comparison 2. Freeze‐all versus conventional IVF, adverse events per clinical pregnancy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Multiple pregnancy Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 After first ET	2	939	Odds Ratio (M‐H, Fixed, 95% CI)	1.02 [0.77, 1.37]
2 Miscarriage Show forest plot	4		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 After first ET	4	1058	Odds Ratio (M‐H, Fixed, 95% CI)	0.56 [0.41, 0.77]
3 Pregnancy complications Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

3.1 After first ET	2	914	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.43 [1.05, 1.95]

Comparison 2. Freeze‐all versus conventional IVF, adverse events per clinical pregnancy

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Comparison 3. Freeze‐all versus conventional IVF, congenital abnormalities per live‐born children plus number of foetuses therapeutically terminated

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Congenital abnormalities Show forest plot	1	923	Odds Ratio (M‐H, Fixed, 95% CI)	1.25 [0.66, 2.37]

Comparison 3. Freeze‐all versus conventional IVF, congenital abnormalities per live‐born children plus number of foetuses therapeutically terminated

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