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Cochrane Database of Systematic Reviews

Ингибиторы ароматазы (летрозол) в лечении репродуктивной недостаточности (субфертильности) у женщин с синдромом поликистозных яичников

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Información

DOI:
https://doi.org/10.1002/14651858.CD010287.pub3Copiar DOI
Base de datos:
  1. Cochrane Database of Systematic Reviews
Versión publicada:
  1. 24 mayo 2018see what's new
Tipo:
  1. Intervention
Etapa:
  1. Review
Grupo Editorial Cochrane:
  1. Grupo Cochrane de Ginecología y fertilidad

Copyright:
  1. Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Contraer

Autores

  • Sebastian Franik

    Correspondencia a: Department of Obstetrics and Gynaecology, University Hospital Münster, Münster, Germany

    [email protected]

    [email protected]

  • Stephanie M Eltrop

    Department of Obstetrics and Gynaecology, University Hospital Münster, Münster, Germany

  • Jan AM Kremer

    Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands

  • Ludwig Kiesel

    Department of Obstetrics and Gynaecology, University Hospital Münster, Münster, Germany

  • Cindy Farquhar

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

Contributions of authors

SF wrote the protocol and drafted the full review.
JK and CF acted as clinical experts and commented on the protocol and full review.
SF, SE and LK updated the 2018 version of the review.
CF acted as clinical expert and commented on the full review update in 2018.

Sources of support

Internal sources

  • Cochrane Gynaecology and Fertility Group, New Zealand.

    editorial support

External sources

  • None, Other.

Declarations of interest

No declarations of interest.

Acknowledgements

We would like to thank Marian Showell (Information Specilaist) for writing and running the search, Vanessa Jordan for assistance with methodological questions, Helen Nagels (Managing Editor of CGFG) for helping us to develop the protocol and answering our questions, and Julie Brown for assistance with writing the full review. We would like to thank our peer reviewers for giving very constructive feedback, leading to great improvement of the review.

The authors of the 2018 update thank Dr. Willianne Nelen for her contributions to the previous version of this review.

Version history

Published

Title

Stage

Authors

Version

2022 Sep 27

Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome

Review

Sebastian Franik, Quang-Khoi Le, Jan AM Kremer, Ludwig Kiesel, Cindy Farquhar

https://doi.org/10.1002/14651858.CD010287.pub4

2018 May 24

Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome

Review

Sebastian Franik, Stephanie M Eltrop, Jan AM Kremer, Ludwig Kiesel, Cindy Farquhar

https://doi.org/10.1002/14651858.CD010287.pub3

2014 Feb 24

Aromatase inhibitors for subfertile women with polycystic ovary syndrome

Review

Sebastian Franik, Jan AM Kremer, Willianne LDM Nelen, Cindy Farquhar

https://doi.org/10.1002/14651858.CD010287.pub2

2012 Dec 12

Aromatase inhibitors for subfertile women with polycystic ovary syndrome

Protocol

Sebastian Franik, Jan AM Kremer, Willianne LDM Nelen, Cindy Farquhar

https://doi.org/10.1002/14651858.CD010287

Differences between protocol and review

A new secondary outcome has been added as an amendment: Miscarriage rate by pregnancies.

Keywords

MeSH

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.

Study flow diagram for update 2018
Figuras y tablas -
Figure 1

Study flow diagram for update 2018

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 2

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

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 3

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

Forest plot of comparison: 2 Aromatase inhibitors compared to other ovulation induction agents, outcome: 2.1 Live birth rate.
Figuras y tablas -
Figure 4

Forest plot of comparison: 2 Aromatase inhibitors compared to other ovulation induction agents, outcome: 2.1 Live birth rate.

Funnel plot of comparison: 2 Aromatase inhibitors compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, outcome: 2.1 Live birth rate.
Figuras y tablas -
Figure 5

Funnel plot of comparison: 2 Aromatase inhibitors compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, outcome: 2.1 Live birth rate.

Forest plot of comparison: 2 Aromatase inhibitors compared to other ovulation induction agents, outcome: 2.6 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Figure 6

Forest plot of comparison: 2 Aromatase inhibitors compared to other ovulation induction agents, outcome: 2.6 Ovarian hyperstimulation syndrome rate.

Comparison 1 Letrozole compared to placebo, Outcome 1 Live birth rate.
Figuras y tablas -
Analysis 1.1

Comparison 1 Letrozole compared to placebo, Outcome 1 Live birth rate.

Comparison 1 Letrozole compared to placebo, Outcome 2 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 1.2

Comparison 1 Letrozole compared to placebo, Outcome 2 Ovarian hyperstimulation syndrome rate.

Comparison 1 Letrozole compared to placebo, Outcome 3 Clinical pregnancy rate.
Figuras y tablas -
Analysis 1.3

Comparison 1 Letrozole compared to placebo, Outcome 3 Clinical pregnancy rate.

Comparison 1 Letrozole compared to placebo, Outcome 4 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 1.4

Comparison 1 Letrozole compared to placebo, Outcome 4 Miscarriage rate by woman randomised.

Comparison 1 Letrozole compared to placebo, Outcome 5 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 1.5

Comparison 1 Letrozole compared to placebo, Outcome 5 Miscarriage rate by pregnancies.

Comparison 1 Letrozole compared to placebo, Outcome 6 Multiple pregnancy rate.
Figuras y tablas -
Analysis 1.6

Comparison 1 Letrozole compared to placebo, Outcome 6 Multiple pregnancy rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 1 Live birth rate.
Figuras y tablas -
Analysis 2.1

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 1 Live birth rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 2 Live birth rate by BMI.
Figuras y tablas -
Analysis 2.2

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 2 Live birth rate by BMI.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 3 Live birth rate by first‐ or second‐line treatment.
Figuras y tablas -
Analysis 2.3

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 3 Live birth rate by first‐ or second‐line treatment.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 4 Impact of allocation bias for live birth rate.
Figuras y tablas -
Analysis 2.4

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 4 Impact of allocation bias for live birth rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 5 Impact of detection bias for live birth rate.
Figuras y tablas -
Analysis 2.5

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 5 Impact of detection bias for live birth rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 6 Impact of attrition bias for live birth rate.
Figuras y tablas -
Analysis 2.6

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 6 Impact of attrition bias for live birth rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 7 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 2.7

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 7 Ovarian hyperstimulation syndrome rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 8 Ovarian hyperstimulation syndrome rate per BMI.
Figuras y tablas -
Analysis 2.8

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 8 Ovarian hyperstimulation syndrome rate per BMI.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 9 Clinical pregnancy rate.
Figuras y tablas -
Analysis 2.9

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 9 Clinical pregnancy rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 10 Impact of allocation bias for clinical pregnancy rate.
Figuras y tablas -
Analysis 2.10

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 10 Impact of allocation bias for clinical pregnancy rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 11 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 2.11

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 11 Miscarriage rate by woman randomised.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 12 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 2.12

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 12 Miscarriage rate by pregnancies.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 13 Multiple pregnancy rate.
Figuras y tablas -
Analysis 2.13

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 13 Multiple pregnancy rate.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 1 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 3.1

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 2 Clinical pregnancy rate.
Figuras y tablas -
Analysis 3.2

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 2 Clinical pregnancy rate.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 3 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 3.3

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 3 Miscarriage rate by woman randomised.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 4 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 3.4

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 4 Miscarriage rate by pregnancies.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 5 Multiple pregnancy rate.
Figuras y tablas -
Analysis 3.5

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 5 Multiple pregnancy rate.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 1 Live birth rate.
Figuras y tablas -
Analysis 4.1

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 1 Live birth rate.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 2 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 4.2

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 2 Ovarian hyperstimulation syndrome rate.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 3 Clinical pregnancy rate.
Figuras y tablas -
Analysis 4.3

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 3 Clinical pregnancy rate.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 4 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 4.4

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 4 Miscarriage rate by woman randomised.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 5 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 4.5

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 5 Miscarriage rate by pregnancies.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 6 Multiple pregnancy rate.
Figuras y tablas -
Analysis 4.6

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 6 Multiple pregnancy rate.

Comparison 5 Letrozole compared to FSH, Outcome 1 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 5.1

Comparison 5 Letrozole compared to FSH, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 5 Letrozole compared to FSH, Outcome 2 Clinical pregnancy rate.
Figuras y tablas -
Analysis 5.2

Comparison 5 Letrozole compared to FSH, Outcome 2 Clinical pregnancy rate.

Comparison 5 Letrozole compared to FSH, Outcome 3 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 5.3

Comparison 5 Letrozole compared to FSH, Outcome 3 Miscarriage rate by woman randomised.

Comparison 5 Letrozole compared to FSH, Outcome 4 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 5.4

Comparison 5 Letrozole compared to FSH, Outcome 4 Miscarriage rate by pregnancies.

Comparison 5 Letrozole compared to FSH, Outcome 5 Multiple pregnancy rate.
Figuras y tablas -
Analysis 5.5

Comparison 5 Letrozole compared to FSH, Outcome 5 Multiple pregnancy rate.

Comparison 6 Letrozole compared to anastrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 6.1

Comparison 6 Letrozole compared to anastrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 6 Letrozole compared to anastrozole, Outcome 2 Clinical pregnancy rate.
Figuras y tablas -
Analysis 6.2

Comparison 6 Letrozole compared to anastrozole, Outcome 2 Clinical pregnancy rate.

Comparison 6 Letrozole compared to anastrozole, Outcome 3 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 6.3

Comparison 6 Letrozole compared to anastrozole, Outcome 3 Miscarriage rate by woman randomised.

Comparison 6 Letrozole compared to anastrozole, Outcome 4 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 6.4

Comparison 6 Letrozole compared to anastrozole, Outcome 4 Miscarriage rate by pregnancies.

Comparison 6 Letrozole compared to anastrozole, Outcome 5 Multiple pregnancy rate.
Figuras y tablas -
Analysis 6.5

Comparison 6 Letrozole compared to anastrozole, Outcome 5 Multiple pregnancy rate.

Comparison 7 Different administration protocols of letrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 7.1

Comparison 7 Different administration protocols of letrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 7 Different administration protocols of letrozole, Outcome 2 Clinical pregnancy rate.
Figuras y tablas -
Analysis 7.2

Comparison 7 Different administration protocols of letrozole, Outcome 2 Clinical pregnancy rate.

Comparison 7 Different administration protocols of letrozole, Outcome 3 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 7.3

Comparison 7 Different administration protocols of letrozole, Outcome 3 Miscarriage rate by woman randomised.

Comparison 7 Different administration protocols of letrozole, Outcome 4 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 7.4

Comparison 7 Different administration protocols of letrozole, Outcome 4 Miscarriage rate by pregnancies.

Comparison 7 Different administration protocols of letrozole, Outcome 5 Multiple pregnancy rate.
Figuras y tablas -
Analysis 7.5

Comparison 7 Different administration protocols of letrozole, Outcome 5 Multiple pregnancy rate.

Comparison 8 Dosage studies of letrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 8.1

Comparison 8 Dosage studies of letrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 8 Dosage studies of letrozole, Outcome 2 Clinical pregnancy rate.
Figuras y tablas -
Analysis 8.2

Comparison 8 Dosage studies of letrozole, Outcome 2 Clinical pregnancy rate.

Comparison 8 Dosage studies of letrozole, Outcome 3 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 8.3

Comparison 8 Dosage studies of letrozole, Outcome 3 Miscarriage rate by woman randomised.

Comparison 8 Dosage studies of letrozole, Outcome 4 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 8.4

Comparison 8 Dosage studies of letrozole, Outcome 4 Miscarriage rate by pregnancies.

Comparison 8 Dosage studies of letrozole, Outcome 5 Multiple pregnancy rate.
Figuras y tablas -
Analysis 8.5

Comparison 8 Dosage studies of letrozole, Outcome 5 Multiple pregnancy rate.

Summary of findings for the main comparison. Letrozole with or without adjuncts compared to clomiphene citrate (CC) with or without adjuncts for subfertile women with polycystic ovary syndrome

Letrozole with or without adjuncts compared to clomiphene citrate (CC) with or without adjuncts for subfertile women with polycystic ovary syndrome

Patient or population: subfertile women with polycystic ovary syndrome
Setting: fertility clinics
Intervention: letrozole with or without adjuncts followed by timed intercourse
Comparison: CC with or without adjuncts followed by timed intercourse

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with CC with or without adjuncts

Risk with letrozole with or without adjuncts

Live birth rate

214 per 1000

314 per 1000
(279 to 352)

OR 1.68
(1.42 to 1.99)

2954
(13 RCTs)

⊕⊕⊕⊝
Moderate a

Ovarian hyperstimulation syndrome rate

5 per 1000

5 per 1000
(5 to 5)

RD 0.00
(−0.01 to 0.00)

2536
(12 RCTs)

⊕⊕⊕⊕
High

Clinical pregnancy rate

264 per 1000

359 per 1000
(330 to 390)

OR 1.56
(1.37 to 1.78)

4629
(25 RCTs)

⊕⊕⊕⊝
Moderate b

Miscarriage rate by pregnancies

201 per 1000

191 per 1000
(150 to 240)

OR 0.94
(0.70 to 1.26)

1210
(18 RCTs)

⊕⊕⊕⊕
High

Multiple pregnancy rate

17 per 1000

13 per 1000
(7 to 21)

OR 0.69
(0.41 to 1.16)

3579
(17 RCTs)

⊕⊕⊕⊕
High

*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; RD: Risk difference: OR: Odds ratio;

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: 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 certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded one level for serious risk of bias associated with potential selective reporting: Studies that reported live birth tended to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth, suggesting that results might be less favourable to letrozole if all studies reported live birth.
bDowngraded one level for serious risk of publication bias: a funnel plot analysis strongly suggests that there might be more publications without a significant effect which were not published.

Figuras y tablas -
Summary of findings for the main comparison. Letrozole with or without adjuncts compared to clomiphene citrate (CC) with or without adjuncts for subfertile women with polycystic ovary syndrome
Summary of findings 2. Letrozole compared to laparoscopic ovarian drilling for subfertile women with polycystic ovary syndrome

Letrozole compared to laparoscopic ovarian drilling compared to placebo for subfertile women with polycystic ovary syndrome

Patient or population: Subfertile women with polycystic ovary syndrome
Setting: Fertility clinics
Intervention: Letrozole with or without adjuncts followed by timed intercourse
Comparison: Laparoscopic ovarian drilling (LOD) followed by timed intercourse

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with LOD

Risk with letrozole

Live birth rate

236 per 1000

299 per 1000
(227 to 385)

OR 1.38
(0.95 to 2.02)

548
(3 RCTs)

⊕⊕⊕⊝
Low a,b

Ovarian hyperstimulation syndrome rate

0 per 1000

0 per 1000
(0 to 0)

RD 0.00
(−0.01 to 0.01)

260
(1 RCT)

⊕⊕⊝⊝
Low c

Clinical pregnancy rate

284 per 1000

336 per 1000
(271 to 408)

OR 1.28
(0.94 to 1.74)

774
(5 RCTs)

⊕⊕⊕⊝
Low a,b

Miscarriage rate by pregnancies

145 per 1000

101 per 1000
(49 to 196)

OR 0.66
(0.30 to 1.43)

240
(5 RCTs)

⊕⊕⊕⊝
Moderate a

Multiple pregnancy rate

0 per 1000

0 per 1000
(0 to 0)

OR 3.00
(0.12 to 74.90)

548
(3 RCTs)

⊕⊕⊝⊝
Low a,b

*The risk in the intervention group (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; RD: Risk difference; OR: Odds ratio;

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: 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 certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aInsufficient data to allow judgement of risk of bias in some studies ‐ downgraded one level for serious risk of bias.
bThere is insufficient data to determine if there is a difference as opposed to no evidence of a difference ‐ downgraded one level for imprecision.
cEvidence is based on a single study and there were no events, which may increase the likelihood of imprecision ‐ downgraded two levels.

Figuras y tablas -
Summary of findings 2. Letrozole compared to laparoscopic ovarian drilling for subfertile women with polycystic ovary syndrome
Comparison 1. Letrozole compared to placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth rate Show forest plot

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

3.17 [0.12, 83.17]

2 Ovarian hyperstimulation syndrome rate Show forest plot

2

167

Risk Difference (M‐H, Fixed, 95% CI)

0.00 [‐0.05, 0.05]

3 Clinical pregnancy rate Show forest plot

2

167

Odds Ratio (M‐H, Fixed, 95% CI)

2.88 [1.08, 7.66]

4 Miscarriage rate by woman randomised Show forest plot

2

167

Odds Ratio (M‐H, Fixed, 95% CI)

1.60 [0.26, 9.89]

5 Miscarriage rate by pregnancies Show forest plot

1

20

Odds Ratio (M‐H, Fixed, 95% CI)

0.55 [0.07, 4.56]

6 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 1. Letrozole compared to placebo
Comparison 2. Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth rate Show forest plot

13

2954

Odds Ratio (M‐H, Fixed, 95% CI)

1.68 [1.42, 1.99]

1.1 AIs versus clomiphene citrate

8

1646

Odds Ratio (M‐H, Fixed, 95% CI)

1.79 [1.42, 2.25]

1.2 AI versus clomiphene + metformin

1

250

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.60, 1.81]

1.3 Aromatase inhibitor + metformin compared to clomiphene + metformin

2

194

Odds Ratio (M‐H, Fixed, 95% CI)

1.70 [0.89, 3.23]

1.4 Aromatase inhibitor + FSH compared to clomiphene + FSH

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

1.18 [0.53, 2.61]

1.5 AIs versus clomiphene + estradiol valerate

1

100

Odds Ratio (M‐H, Fixed, 95% CI)

1.48 [0.54, 4.06]

1.6 AIs +/‐ berberine versus berberine

1

644

Odds Ratio (M‐H, Fixed, 95% CI)

1.94 [1.33, 2.84]

2 Live birth rate by BMI Show forest plot

11

2774

Odds Ratio (M‐H, Fixed, 95% CI)

1.69 [1.42, 2.02]

2.1 BMI > 25

7

1678

Odds Ratio (M‐H, Fixed, 95% CI)

1.67 [1.34, 2.09]

2.2 BMI < 25

4

1096

Odds Ratio (M‐H, Fixed, 95% CI)

1.73 [1.31, 2.28]

3 Live birth rate by first‐ or second‐line treatment Show forest plot

13

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 No previous ovulation induction

4

1089

Odds Ratio (M‐H, Fixed, 95% CI)

1.61 [1.22, 2.14]

3.2 CC‐resistant women

4

344

Odds Ratio (M‐H, Fixed, 95% CI)

1.78 [1.08, 2.93]

3.3 Unclear or mixed study cohort

5

1521

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [1.35, 2.16]

4 Impact of allocation bias for live birth rate Show forest plot

13

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Unclear risk of allocation

8

1031

Odds Ratio (M‐H, Fixed, 95% CI)

1.90 [1.42, 2.54]

4.2 Low risk of allocation

5

1923

Odds Ratio (M‐H, Fixed, 95% CI)

1.58 [1.29, 1.95]

5 Impact of detection bias for live birth rate Show forest plot

13

2954

Odds Ratio (M‐H, Fixed, 95% CI)

1.68 [1.42, 1.99]

5.1 High risk of detection

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

2.6 [0.83, 8.13]

5.2 Low risk of detection

7

2083

Odds Ratio (M‐H, Fixed, 95% CI)

1.63 [1.33, 1.99]

5.3 Unclear risk of detection

5

807

Odds Ratio (M‐H, Fixed, 95% CI)

1.76 [1.27, 2.44]

6 Impact of attrition bias for live birth rate Show forest plot

13

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

6.1 Unclear risk of attrition

1

147

Odds Ratio (M‐H, Fixed, 95% CI)

2.04 [0.93, 4.50]

6.2 Low risk of attrition

11

2539

Odds Ratio (M‐H, Fixed, 95% CI)

1.69 [1.41, 2.03]

6.3 High risk of attrition

1

268

Odds Ratio (M‐H, Fixed, 95% CI)

1.46 [0.85, 2.50]

7 Ovarian hyperstimulation syndrome rate Show forest plot

12

2536

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

7.1 AIs versus clomiphene citrate

9

2010

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

7.2 AI versus clomiphene + metformin

1

250

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [‐0.02, 0.02]

7.3 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [‐0.04, 0.04]

8 Ovarian hyperstimulation syndrome rate per BMI Show forest plot

11

Risk Difference (M‐H, Fixed, 95% CI)

Subtotals only

8.1 BMI > 25

6

1851

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

8.2 BMI < 25

5

605

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [‐0.02, 0.02]

9 Clinical pregnancy rate Show forest plot

25

4629

Odds Ratio (M‐H, Fixed, 95% CI)

1.56 [1.37, 1.78]

9.1 AIs versus clomiphene citrate

17

2930

Odds Ratio (M‐H, Fixed, 95% CI)

1.50 [1.28, 1.76]

9.2 AI versus clomiphene + metformin

1

250

Odds Ratio (M‐H, Fixed, 95% CI)

1.01 [0.60, 1.71]

9.3 Aromatase inhibitor + metformin versus clomiphene + metformin

3

294

Odds Ratio (M‐H, Fixed, 95% CI)

1.86 [1.05, 3.29]

9.4 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Odds Ratio (M‐H, Fixed, 95% CI)

1.37 [0.82, 2.27]

9.5 AIs versus tamoxifen

2

135

Odds Ratio (M‐H, Fixed, 95% CI)

1.58 [0.64, 3.90]

9.6 AIs versus clomiphene + estradiol valerate

1

100

Odds Ratio (M‐H, Fixed, 95% CI)

2.47 [0.94, 6.46]

9.7 AIs ± berberine versus berberine

1

644

Odds Ratio (M‐H, Fixed, 95% CI)

2.15 [1.48, 3.13]

10 Impact of allocation bias for clinical pregnancy rate Show forest plot

23

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

10.1 Unclear risk of allocation

16

1907

Odds Ratio (M‐H, Fixed, 95% CI)

1.77 [1.43, 2.18]

10.2 Low risk of allocation

7

1912

Odds Ratio (M‐H, Fixed, 95% CI)

1.36 [1.12, 1.65]

11 Miscarriage rate by woman randomised Show forest plot

18

3754

Odds Ratio (M‐H, Fixed, 95% CI)

1.39 [1.07, 1.81]

11.1 AIs versus clomiphene citrate

11

2190

Odds Ratio (M‐H, Fixed, 95% CI)

1.37 [0.97, 1.93]

11.2 AI versus clomiphene + metformin

1

250

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.25, 4.23]

11.3 Aromatase inhibitor + metformin versus clomiphene + metformin

3

294

Odds Ratio (M‐H, Fixed, 95% CI)

1.21 [0.52, 2.82]

11.4 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Odds Ratio (M‐H, Fixed, 95% CI)

0.84 [0.31, 2.27]

11.5 AIs versus clomiphene + estradiol valerate

1

100

Odds Ratio (M‐H, Fixed, 95% CI)

12.21 [0.66, 226.97]

11.6 AIs +/‐ berberine versus berberine

1

644

Odds Ratio (M‐H, Fixed, 95% CI)

1.63 [0.87, 3.04]

12 Miscarriage rate by pregnancies Show forest plot

18

1210

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.70, 1.26]

12.1 AIs versus clomiphene citrate

11

705

Odds Ratio (M‐H, Fixed, 95% CI)

0.96 [0.65, 1.42]

12.2 AI versus clomiphene + metformin

1

85

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.24, 4.40]

12.3 Aromatase inhibitor + metformin versus clomiphene + metformin

3

79

Odds Ratio (M‐H, Fixed, 95% CI)

0.80 [0.32, 2.02]

12.4 Aromatase inhibitor + hMG versus clomiphene + hMG

2

104

Odds Ratio (M‐H, Fixed, 95% CI)

0.67 [0.23, 1.96]

12.5 AIs versus clomiphene + estradiol valerate

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

8.13 [0.39, 167.90]

12.6 AIs +/‐ berberine versus berberine

1

213

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.43, 1.80]

13 Multiple pregnancy rate Show forest plot

17

3579

Odds Ratio (M‐H, Fixed, 95% CI)

0.69 [0.41, 1.16]

13.1 AIs versus clomiphene citrate

13

2409

Odds Ratio (M‐H, Fixed, 95% CI)

0.61 [0.32, 1.16]

13.2 AI versus clomiphene + metformin

1

250

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 2.82]

13.3 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.29, 3.05]

13.4 AIs +/‐ berberine versus berberine

1

644

Odds Ratio (M‐H, Fixed, 95% CI)

4.53 [0.24, 84.46]

Figuras y tablas -
Comparison 2. Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse
Comparison 3. Letrozole compared to clomiphene citrate, followed by IUI

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

2

1494

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

1.1 AI versus Clomiphene

1

107

Risk Difference (M‐H, Fixed, 95% CI)

‐0.02 [‐0.07, 0.03]

1.2 AI versus Clomiphene +rFSH and rFSH only

1

1387

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

2 Clinical pregnancy rate Show forest plot

3

1597

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [1.30, 2.25]

2.1 AI versus Clomiphene

2

210

Odds Ratio (M‐H, Fixed, 95% CI)

2.09 [0.97, 4.53]

2.2 AI versus Clomiphene +rFSH and rFSH only

1

1387

Odds Ratio (M‐H, Fixed, 95% CI)

1.66 [1.23, 2.22]

3 Miscarriage rate by woman randomised Show forest plot

2

1490

Odds Ratio (M‐H, Fixed, 95% CI)

1.22 [0.62, 2.40]

3.1 AI versus Clomiphene

1

103

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 8.06]

3.2 AI versus Clomiphene +rFSH and rFSH only

1

1387

Odds Ratio (M‐H, Fixed, 95% CI)

1.32 [0.66, 2.65]

4 Miscarriage rate by pregnancies Show forest plot

2

260

Odds Ratio (M‐H, Fixed, 95% CI)

0.76 [0.37, 1.57]

4.1 AI versus Clomiphene

1

15

Odds Ratio (M‐H, Fixed, 95% CI)

0.10 [0.00, 3.09]

4.2 AI versus Clomiphene +rFSH and rFSH only

1

245

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.40, 1.79]

5 Multiple pregnancy rate Show forest plot

3

1597

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.49, 2.13]

5.1 AI versus Clomiphene

2

210

Odds Ratio (M‐H, Fixed, 95% CI)

3.48 [0.14, 87.49]

5.2 AI versus Clomiphene +rFSH and rFSH only

1

1387

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.44, 2.03]

Figuras y tablas -
Comparison 3. Letrozole compared to clomiphene citrate, followed by IUI
Comparison 4. Letrozole compared to laparoscopic ovarian drilling

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth rate Show forest plot

3

548

Odds Ratio (M‐H, Fixed, 95% CI)

1.38 [0.95, 2.02]

2 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

3 Clinical pregnancy rate Show forest plot

5

774

Odds Ratio (M‐H, Fixed, 95% CI)

1.28 [0.94, 1.74]

3.1 AI versus LOD

4

628

Odds Ratio (M‐H, Fixed, 95% CI)

1.30 [0.93, 1.83]

3.2 AI + metformin versus LOD

1

146

Odds Ratio (M‐H, Fixed, 95% CI)

1.20 [0.60, 2.39]

4 Miscarriage rate by woman randomised Show forest plot

5

774

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.38, 1.70]

4.1 AI versus LOD

4

628

Odds Ratio (M‐H, Fixed, 95% CI)

0.69 [0.29, 1.63]

4.2 AI + metformin versus LOD

1

146

Odds Ratio (M‐H, Fixed, 95% CI)

1.35 [0.29, 6.27]

5 Miscarriage rate by pregnancies Show forest plot

5

240

Odds Ratio (M‐H, Fixed, 95% CI)

0.66 [0.30, 1.43]

5.1 AI versus LOD

4

191

Odds Ratio (M‐H, Fixed, 95% CI)

0.54 [0.22, 1.33]

5.2 AI + metformin versus LOD

1

49

Odds Ratio (M‐H, Fixed, 95% CI)

1.21 [0.24, 6.09]

6 Multiple pregnancy rate Show forest plot

3

548

Odds Ratio (M‐H, Fixed, 95% CI)

3.00 [0.12, 74.90]

Figuras y tablas -
Comparison 4. Letrozole compared to laparoscopic ovarian drilling
Comparison 5. Letrozole compared to FSH

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

2 Clinical pregnancy rate Show forest plot

1

140

Odds Ratio (M‐H, Fixed, 95% CI)

0.82 [0.40, 1.67]

3 Miscarriage rate by woman randomised Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4 Miscarriage rate by pregnancies Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5 Multiple pregnancy rate Show forest plot

1

140

Odds Ratio (M‐H, Fixed, 95% CI)

0.19 [0.01, 4.12]

Figuras y tablas -
Comparison 5. Letrozole compared to FSH
Comparison 6. Letrozole compared to anastrozole

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

2 Clinical pregnancy rate Show forest plot

2

260

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.51, 1.43]

3 Miscarriage rate by woman randomised Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4 Miscarriage rate by pregnancies Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5 Multiple pregnancy rate Show forest plot

2

260

Odds Ratio (M‐H, Fixed, 95% CI)

5.0 [0.24, 105.35]

Figuras y tablas -
Comparison 6. Letrozole compared to anastrozole
Comparison 7. Different administration protocols of letrozole

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

1.1 Five days compared to 10 days administration protocol of letrozole

1

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Clinical pregnancy rate Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.1 Five days compared to 10 days administration protocol of letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Letrozole day 3‐7 administratio versus day 5‐9 administration

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Miscarriage rate by woman randomised Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 Five days compared to 10 days administration protocol of letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Miscarriage rate by pregnancies Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4.1 Five days compared to 10 days administration protocol of letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5.1 Five days compared to 10 days administration protocol of letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 7. Different administration protocols of letrozole
Comparison 8. Dosage studies of letrozole

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

1.1 5mg vs 7.5mg letrozole

1

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Clinical pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.1 5mg vs 7.5mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Miscarriage rate by woman randomised Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 5mg vs 7.5mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Miscarriage rate by pregnancies Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4.1 5mg vs 7.5mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5.1 5mg vs 7.5mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 8. Dosage studies of letrozole