Scolaris Content Display Scolaris Content Display

Base de datos Cochrane de Revisiones Sistemáticas Revisión - Intervención

Inhibitory aromatazy (letrozol) w indukcji owulacji u niepłodnych kobiet z zespołem policystycznych jajników

Declaraciones de intereses de los autores

Versión publicada: 27 septiembre 2022 Historial de versiones

https://doi.org/10.1002/14651858.CD010287.pub4
Contraer todo Desplegar todo

Abstract

disponible en

Background

Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 5% to 20% of women worldwide and often leads to anovulatory infertility. Aromatase inhibitors (AIs) are a class of drugs that were introduced for ovulation induction in 2001. Since about 2001 clinical trials have reached differing conclusions as to whether the AI, letrozole, is at least as effective as the first‐line treatment clomiphene citrate (CC), a selective oestrogen receptor modulator (SERM).

Objectives

To evaluate the effectiveness and safety of AIs (letrozole) (with or without adjuncts) compared to SERMs (with or without adjuncts) for infertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination.

Search methods

We searched the following sources, from their inception to 4 November 2021, to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase and PsycINFO. We also checked reference lists of relevant trials, searched the trial registers and contacted experts in the field for any additional trials. We did not restrict the searches by language or publication status.

Selection criteria

We included all RCTs of AIs used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS.

Data collection and analysis

Two review authors independently selected trials, extracted the data and assessed risks of bias using RoB 1. We pooled trials where appropriate using a fixed‐effect model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes, and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth rate and OHSS rate. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy rates. We assessed the certainty of the evidence for each comparison using GRADE methods.

Main results

This is a substantive update of a previous review; of six previously included trials, we excluded four from this update and moved two to 'awaiting classification' due to concerns about validity of trial data. We included five additional trials for this update that now includes a total of 41 RCTs (6522 women). The AI, letrozole, was used in all trials.

Letrozole compared to SERMs with or without adjuncts followed by timed intercourse

Live birth rates were higher with letrozole (with or without adjuncts) compared to SERMs followed by timed intercourse (OR 1.72, 95% CI 1.40 to 2.11; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; 11 trials, 2060 participants; high‐certainty evidence). This suggests that in women with a 20% chance of live birth using SERMs, the live birth rate in women using letrozole with or without adjuncts would be 27% to 35%. There is high‐certainty evidence that OHSS rates are similar with letrozole or SERMs (0.5% in both arms: risk difference (RD) −0.00, 95% CI −0.01 to 0.01; I2 = 0%; 10 trials, 1848 participants; high‐certainty evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.69, 95% CI 1.45 to 1.98; I2 = 0%; NNTB = 10; 23 trials, 3321 participants; high‐certainty evidence). This suggests that in women with a 24% chance of clinical pregnancy using SERMs, the clinical pregnancy rate in women using letrozole with or without adjuncts would be 32% to 39%. There is little or no difference between treatment groups in the rate of miscarriage per pregnancy (25% with SERMs versus 24% with letrozole: OR 0.94, 95% CI 0.66 to 1.32; I2 = 0%; 15 trials, 736 participants; high‐certainty evidence) and multiple pregnancy rate (2.2% with SERMs versus 1.6% with letrozole: OR 0.74, 95% CI 0.42 to 1.32; I2 = 0%; 14 trials, 2247 participants; high‐certainty evidence). However, a funnel plot showed mild asymmetry, indicating that some trials in favour of SERMs might be missing. 

Letrozole compared to laparoscopic ovarian drilling (LOD)

One trial reported very low‐certainty evidence that live birth rates may be higher with letrozole compared to LOD (OR 2.07, 95% CI 0.99 to 4.32; 1 trial, 141 participants; very low‐certainty evidence). This suggests that in women with a 22% chance of live birth using LOD with or without adjuncts, the live birth rate in women using letrozole with or without adjuncts would be 24% to 47%. No trial reported OHSS rates. Due to the low‐certainty evidence we are uncertain if letrozole improves pregnancy rates compared to LOD (OR 1.47, 95% CI 0.95 to 2.28; I² = 0%; 3 trials, 367 participants; low‐certainty evidence). This suggests that in women with a 29% chance of clinical pregnancy using LOD with or without adjuncts, the clinical pregnancy rate in women using letrozole with or without adjuncts would be 28% to 45%. There seems to be no evidence of a difference in miscarriage rates per pregnancy comparing letrozole to LOD (OR 0.65, 95% CI 0.22 to 1.92; I² = 0%; 3 trials, 122 participants; low‐certainty evidence). This also applies to multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 1 trial, 141 participants; very low‐certainty evidence).

Authors' conclusions

Letrozole appears to improve live birth rates and pregnancy rates in infertile women with anovulatory PCOS, compared to SERMs, when used for ovulation induction, followed by intercourse. There is high‐certainty evidence that OHSS rates are similar with letrozole or SERMs. There was high‐certainty evidence of no difference in miscarriage rate and multiple pregnancy rate. We are uncertain if letrozole increases live birth rates compared to LOD. In this update, we added good quality trials and removed trials with concerns over data validity, thereby upgrading the certainty of the evidence base.

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.

Inhibitory aromatazy w leczeniu niepłodności u kobiet z zespołem policystycznych jajników

Pytanie badawcze: Autorzy Cochrane zbadali dane dotyczące stosowania inhibitorów aromatazy w leczeniu niepłodności u kobiet z zespołem policystycznych jajników (PCOS).

Wprowadzenie: PCOS jest najczęstszą przyczyną rzadkich miesiączek lub ich braku i dotyczy około 5% do 20% kobiet na całym świecie. Często powoduje niepłodność bezowulacyjną (niepłodność związaną z niezdolnością do owulacji). Inhibitory aromatazy (AI) są stosowane w celu wywołania owulacji. Od 2001 roku badania kliniczne dostarczają odmiennych wniosków, czy letrozol będący inhibitorem aromatazy jest co najmniej tak samo skuteczny w leczeniu niepłodności jak najczęściej stosowany cytrynian klomifenu.

Charakterystyka badań: Przegląd obejmuje badania kliniczne, w których uczestnicy zostali losowo przydzieleni do interwencji (letrozol) lub do grupy porównawczej (tj. cytrynian klomifenu). Badania te nazywane są randomizowanymi badaniami z grupą kontrolną. Nasz przegląd obejmuje 41 badań z randomizacją z udziałem 6522 kobiet. We wszystkich badaniach stosowanym inhibitorem aromatazy był letrozol. Komparatory obejmowały cytrynian klomifenu, który był stosowany w 26 randomizowanych badaniach kontrolowanych, oraz laparoskopowe wiercenie jajników (technika chirurgiczna stosowana w celu wywołania owulacji), które było stosowane w czterech randomizowanych badaniach kontrolowanych. Kilka badań obejmowało inne metody leczenia.

Główne wyniki: Letrozol wydaje się poprawiać wskaźniki żywych urodzeń i ciąż w porównaniu z cytrynianem klomifenu, gdy jest stosowany w celu wywołania owulacji, po której następuje stosunek płciowy w odpowiednim czasie. Nie stwierdzono różnic w odniesieniu do odsetka poronień lub ciąż mnogich. Zespół hiperstymulacji jajników będący poważnym zdarzeniem niepożądanym w przypadku stymulacji hormonalnej występował bardzo rzadko, w wielu badaniach nie wystąpił. Pewność danych naukowych dla wszystkich tych wyników była wysoka i wydaje się być wiarygodna.

Wydaje się, że istnieją dane naukowe o bardzo niskiej pewności dotyczące wyższego wskaźnika żywych urodzeń w przypadku letrozolu w porównaniu z laparoskopowym wierceniem jajników, chociaż było tylko jedno odpowiednie badanie. Wynik dla klinicznego wskaźnika ciąż był niepewny. Nie mamy pewności, czy letrozol zmniejsza liczbę poronień i ciąż mnogich w porównaniu z laparoskopowym wierceniem jajników. Nie zgłoszono badań dotyczących zespołu hiperstymulacji jajników. Dane naukowe są aktualne do listopada 2021 r.

Pewność danych naukowych: Ogólne zaufanie do danych naukowych było zróżnicowane ‐ od bardzo niskiego do wysokiego. Obniżyliśmy ocenę danych naukowych, gdy mieliśmy małe badania z niewielką liczbą kobiet lub gdy metody były niejasne.

Authors' conclusions

Implications for practice

Letrozole appears to improve live birth and pregnancy rates in infertile women with anovulatory PCOS, compared to SERMs, when used for ovulation induction, followed by intercourse. There is high‐certainty evidence that OHSS rates are similar with letrozole or SERMs. There was high‐certainty evidence of no difference in miscarriage rate and multiple pregnancy rate. We are uncertain if letrozole increases live birth rates compared to LOD. In this update, we added good quality trials and removed trials with concerns over data validity, thereby upgrading the certainty of the evidence base.

Implications for research

For letrozole compared to placebo, additional trials are not necessary, since there is evidence in favour of letrozole compared to CC, which was proven to be more effective compared to placebo for live birth and pregnancy rates (Bayar 2006; Dehbashi 2009; Nazik 2012; Sh‐El‐Arab Elsedeek 2011). Further RCTs could also be conducted, investigating a 5‐ or 10‐day administration protocol and day 3 to 5 or day 5 to 9 administration of letrozole.  

Overall, it is very important for fertility trials to report on the standardised core outcome set for fertility trials as suggested by Duffy 2020. 

Summary of findings

Open in table viewer
Summary of findings 1. Letrozole with or without adjuncts compared to SERMs with or without adjuncts followed by timed intercourse for infertile women with polycystic ovary syndrome

Letrozole with or without adjuncts compared to SERMs with or without adjuncts followed by timed intercourse for infertile women with polycystic ovary syndrome

Patient or population: infertile women with polycystic ovary syndrome
Setting: (fertility) clinics or outpatient settings
Intervention: letrozole with or without adjuncts followed by timed intercourse
Comparison: SERMs (clomiphene citrate) with or without adjuncts followed by timed intercourse

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(trials)

Certainty of the evidence
(GRADE)

Comments

Risk with SERMs with or without adjuncts

Risk with letrozole with or without adjuncts

Live birth rate

204 per 1000

307 per 1000
(265 to 352)

OR 1.72
(1.40 to 2.11)

2060
(11 RCTs)

⊕⊕⊕⊕
High

 

Ovarian hyperstimulation syndrome rate

7 per 1000

5 per 1000
(5 to 5)

RD −0.00
(−0.01 to 0.01)

1848
(10 RCTs)

⊕⊕⊕⊕
High

 

Clinical pregnancy rate

242 per 1000

350 per 1000
(316 to 387)

OR 1.69
(1.45 to 1.98)

3321
(23 RCTs)

⊕⊕⊕⊕
High

 

Miscarriage rate per pregnancy

252 per 1000

240 per 1000
(182 to 307)

OR 0.94
(0.66 to 1.32)

736
(15 RCTs)

⊕⊕⊕⊕
High

 

Multiple pregnancy rate

22 per 1000

16 per 1000
(9 to 28)

OR 0.74
(0.42 to 1.32)

2247
(14 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; OR: odds ratio; RD: risk difference; RCT: randomised controlled trial

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.

Open in table viewer
Summary of findings 2. Letrozole compared to laparoscopic ovarian drilling for infertile women with polycystic ovary syndrome

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

Patient or population: infertile women with polycystic ovary syndrome
Setting: (fertility) clinics or outpatient settings
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
(trials)

Certainty of the evidence
(GRADE)

Comments

Risk with LOD

Risk with letrozole

Live birth rate

229 per 1000

380 per 1000
(227 to 561)

OR 2.07
(0.99 to 4.32)

141
(1 RCT)

⊕⊝⊝⊝
Very Lowa,b,c

 

Ovarian hyperstimulation syndrome rate

No trials reported on this outcome

Clinical pregnancy rate

290 per 1000

375 per 1000
(279 to 482)

OR 1.47
(0.95 to 2.28)

376
(3 RCTs)

⊕⊕⊝⊝
Lowa,b

 

Miscarriage rate per pregnancy

151 per 1000

104 per 1000
(38 to 254)

OR 0.65
(0.22 to 1.92)

122
(3 RCTs)

⊕⊕⊝⊝
Lowa,b

 

Multiple pregnancy rate

0 per 1000

0 per 1000
(0 to 0)

OR 3.00
(0.12 to 74.90)

141
(1 RCT)

⊕⊝⊝⊝
Very Lowa,b,c

 

*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; OR: odds ratio; RCT: randomised controlled trial

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 trials ‐ 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.
cAnalysis is based on only one trial ‐ downgraded one additional level for imprecision.
 

Background

Description of the condition

Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea), affecting about 5% to 20% of women worldwide in their fertile years (Abu 2012; Lizneva 2016). Many of these women are infertile, but for most of them it just takes longer to become pregnant naturally and only a small percentage need fertility treatment.

The mechanisms causing PCOS are very complex and the exact pathogenesis remains unknown, but some of the symptoms are believed to be caused by abnormal levels of the pituitary hormone, luteinising hormone (LH) and of the male hormones (androgens) which interfere with the normal function of the ovaries (Azziz 2006).

The diagnosis can be made based on the 'Rotterdam Criteria 2003', jointly proposed by the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) (Rotterdam 2003). The woman must have two of the following three criteria to be diagnosed with PCOS.

  • Oligoovulation (infrequent ovulation) or anovulation (absence of ovulation), or both

  • High male hormone levels (hyperandrogenism) diagnosed either clinically (excessive hair growth, hirsutism) or biochemically (raised serum testosterone levels)

  • Ovaries which appear to be polycystic on vaginal sonogram, defined by the presence of 12 or more antral follicles in an ovary or an ovarian volume of more than 10 mL. Antral follicles are defined as measuring between 2 mm and 9 mm in diameter.

Other definitions of PCOS include the National Institutes of Health Criteria (NIH), defined in 1990. They included only the presence of clinical and/or biochemical hyperandrogenism and oligo/amenorrhoea anovulation (Zawadski 1992). The Androgen Excess Society (AES) defined PCOS as hyperandrogenism with ovarian dysfunction or polycystic ovaries (Azziz 2006). Based on the definition, the phenotype of women identified with PCOS can be very different, as could be the morbidity and hence the success of treatment (Lizneva 2016). 

Description of the intervention

There are many possible options for treatment of infertility in women with anovulatory PCOS.

Clomiphene citrate (CC) is a selective oestrogen receptor modulator (SERM), and is the most common medication used for treating the condition. It was first introduced in 1960 for treatment of World Health Organization (WHO) type II anovulation (a type of infertility where hormone levels stay normal) in infertile women, and has been the first‐line treatment ever since. CC is given orally and is relatively safe and inexpensive, but there are also adverse effects associated with it, such as negative changes in endometrium and cervical mucus due to the down‐regulation of oestrogen receptors that might impair implantation after successful induction of ovulation (Casper 2006).

Aromatase inhibitors (AIs) are a newer class of drugs that were introduced for ovulation induction in 2001 by Mitwally and Casper (Mitwally 2001). Since about 2001, data from many clinical trials have been collected and there is evidence that the AI, letrozole, might be as effective as CC, but the outcome data vary. AIs are administered orally, but due to their short half‐life elimination time of 48 hours, there are fewer adverse effects on oestrogen target tissues such as the endometrium and cervix compared with CCs (Baruah 2009; Jirge 2010; Samani 2009). Despite evidence of effectiveness and safety in well‐designed large randomised controlled trials (RCTs), letrozole is still used off‐label for ovulation induction, since it has not been approved by the US Food and Drug Administration (FDA) for this indication (Amer 2017; Legro 2014). A 2005 study (Biljan 2005), including 150 babies, raised some concerns about the teratogenicity of letrozole, but there were major methodological flaws in this study, as the intervention group was not well controlled. Two other large trials, including 911 and 470 infants respectively, compared the use of letrozole to CC in spontaneously‐conceiving women. Both reported no higher levels of minor or major congenital malformations or cardiac abnormalities in newborns after use of letrozole for ovulation induction (Forman 2007; Tulandi 2006).

Due to the short half‐life elimination time of letrozole, it should be completely cleared out of the system before implantation takes place. Some clinicians recommend testing the blood levels of beta‐human chorionic gonadotropin (ß‐hCG) prior to treatment with letrozole to exclude pregnancy (Casper 2011). CC and AIs are usually both given for 5 days, starting on day 3 of the cycle. The dose for CC ranges from 50 mg to 150 mg a day, and for letrozole from 2.5 mg to 7.5 mg a day (Lee 2011).

Since many women with PCOS experience insulin resistance or impaired glucose tolerance, metformin and other insulin‐sensitising agents were thought to be a superior drug for treatment of ovulation induction (Velázquez 1997). However, the latest version of the Cochrane Review on oral agents for ovulation induction concludes that the use of metformin and other insulin‐sensitising agents as an adjunct is limited, and might be favourable only in women who are resistant to CC alone (Brown 2016).

Human menopausal gonadotropins (hMGs) were introduced into clinical practice in 1961 for ovulation induction. They exert a central role in ovulation induction in CC‐resistant infertile normogonadotropic anovulatory women (Lunenfeld 2004). However, women with PCOS are at particular risk for complications such as ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies. Ovarian hyperstimulation syndrome is a rare complication that can occur in women taking medication to stimulate egg growth and ovulation induction. The pathophysiology is not completely understood, but high levels of vascular endothelial growth factor (VEGF), secreted from many stimulated follicles under the prolonged effect of hCG, lead to a capillary leak and a fluid shift into the third space. This can result in ascites and hypovolaemia with subsequent circulatory, respiratory and renal problems (Soares 2008). 

A low‐dose step‐up protocol was introduced to reach the follicle stimulating hormone (FSH) threshold gradually in order to minimise the risks of OHSS and multiple pregnancies (White 1996). The use of FSH for ovulation induction in women with PCOS appears to be safe and effective (Homburg 2011).

For all the above‐mentioned drugs for ovulation induction, follicular growth should be monitored during a stimulation cycle to reassure effectiveness and also to minimise the occurrence of adverse events, such as multiple pregnancy (Von Hofe 2015). 

Finally, another possible option for ovulation induction in cases of CC resistance is laparoscopic ovarian diathermy (or drilling, LOD), during which the damaging of localised areas in the ovarian cortex and stroma seems to have similar success rates compared with gonadotropin therapy (Farquhar 2002). It is not fully understood how the partial destruction of the ovary results in follicle development and ovulation induction (Farquhar 2012), however, long‐term outcomes of a study with 8 to 12 years of follow‐up indicate that LOD is safe and effective (Nahuis 2011).

How the intervention might work

AIs down‐regulate the production of oestrogen by inhibiting the cytochrome P450 isoenzymes 2A6 and 2C19 of the aromatase enzyme complex (Cole 1990). They inhibit the negative feedback loop of oestrogen in the hypothalamus, and result in stronger gonadotropin‐releasing hormone (GnRH) pulses. The elevated levels of GnRH stimulate the pituitary gland to produce more FSH, which induces development of follicles in the ovaries. Because AIs do not deplete oestrogen receptors, in contrast to CC, the central feedback mechanism remains intact, and as the dominant follicle grows and oestrogen levels rise, normal negative feedback occurs centrally. This results in suppression of FSH and the smaller‐growing follicles will undergo atresia, leading to a single dominant follicle and mono‐ovulation (ovulation of a single egg) in most cases (Casper 2006; Lee 2011). Therefore, by leaving the central mechanism intact, the AIs might lower the risk of high‐multiple ovulation and OHSS compared to CC.

Why it is important to do this review

Because evidence for and against the effectiveness and safety of AIs has fluctuated over the last decade, and new data based on recent RCTs have become available, an update of the existing Cochrane Review was necessary to provide up‐to‐date information for daily practice.

This review evaluates the effectiveness and safety of AIs compared to other agents for ovulation induction or laparoscopic ovarian drilling, to provide evidence about whether or not AIs should be used in infertile women with PCOS who are trying to conceive.

Objectives

To evaluate the effectiveness and safety of AIs (letrozole) (with or without adjuncts) compared to SERMs (with or without adjuncts) for infertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination.

Methods

Criteria for considering studies for this review

Types of studies

We considered randomised controlled trials (RCTs) for inclusion in the review. We excluded cross‐over trials unless phase one data were available separately.

Types of participants

Women of reproductive age with anovulatory PCOS (WHO type II anovulation in women with normogonadotropic normoestrogenic anovulation), diagnosed according to the Rotterdam Criteria (Rotterdam 2003), the NIH consensus criteria (Zawadski 1992), or the AES criteria (Azziz 2009).

Exclusion criteria

We excluded RCTs of women with hyperprolactinaemia or Cushing’s syndrome, or both. We also excluded trials covering women with WHO type I anovulation (hypogonadotropic hypogonadal anovulation). Women in this group have amenorrhoea, low or low‐normal serum FSH concentrations and low serum estradiol concentrations due to decreased hypothalamic secretion of GnRH or pituitary unresponsiveness to GnRH. We excluded trials using methods other than ovulation induction followed by intercourse or intrauterine insemination, for example, in vitro fertilisation (IVF).

Types of interventions

We considered for inclusion AIs (letrozole) for ovulation induction, alone or in conjunction with medical adjuncts, e.g. metformin or FSH compared to SERMs with or without adjuncts followed by sexual intercourse or intrauterine insemination in women with anovulatory infertility. 

Types of outcome measures

Primary outcomes
Effectiveness

  • Live birth rate, defined as delivery of a live foetus after 20 completed weeks of gestational age

Adverse events

  • OHSS rate, as defined by the trial authors

Secondary outcomes

  • Clinical pregnancy rate, defined as viable intrauterine pregnancy confirmed by ultrasound

  • Miscarriage rate per woman, defined as the involuntary loss of a clinical pregnancy before 20 weeks of gestation, including partial loss of a multiple pregnancy

  • Miscarriage rate per pregnancy, defined as the involuntary loss of a clinical pregnancy before 20 weeks of gestation, including partial loss of a multiple pregnancy

  • Multiple pregnancy rate, defined as more than one intrauterine pregnancy, confirmed by ultrasound or delivery

Search methods for identification of studies

We searched for all published and unpublished RCTs investigating the use of AIs for ovulation induction in anovulatory women with PCOS in consultation with the Cochrane Gynaecology and Fertility (CGF) Information Specialist. We used both indexed and free‐text terms, and applied no language or date restrictions.

Electronic searches

We searched the following databases.

  • The Cochrane Gynaecology and Fertility (CGF) Specialised Register, ProCite platform, searched from inception to 4 November 2021 (Appendix 1).

  • CENTRAL, via the Cochrane Register of Studies Online (CRSO), Web platform, searched from inception to 4 November 2021 (Appendix 2).

  • MEDLINE, Ovid platform, searched from 1946 to 4 November 2021 (Appendix 3).

  • Embase, Ovid platform, searched from 1980 to 4 November 2021 (Appendix 4).

  • PsycINFO, Ovid platform, searched from 1806 to 4 November 2021 (Appendix 5).

We combined the MEDLINE search with the Cochrane highly‐sensitive search strategy for identifying randomised trials which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Cochrane Handbook) (Version 6.2 chapter 4, 4.4.7) (Lefebvre 2021). We combined the Embase search with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/what-we-do/methodology/search-filters).

Searching other resources

We checked the references of relevant systematic reviews and RCTs obtained by the search, and contacted experts in the field and manufacturers of AIs, to pick up any additional, relevant trials.

We also searched the following up to November 2021 for grey literature of additional trials that had not been indexed in major databases.

Data collection and analysis

We conducted data collection and analysis in accordance with the Cochrane Handbook (Higgins 2021).

Selection of studies

For this update of the review, two review authors (SF and QL) independently selected the trials to be included, in accordance with the aforementioned criteria. We excluded trials from the review if they made comparisons other than those specified above. Studies from non‐English language journals were translated if necessary. If a trial was published more than once, we only included the most complete and up‐to‐date data. We contacted authors of primary studies if papers did not contain enough information to enable an accurate assessment of eligibility for inclusion. We provide a list of excluded studies, showing the reasons for exclusion in the Characteristics of excluded studies table.

Data extraction and management

For this update of the review, two review authors (SF and QL) independently extracted the data, resolving any disagreements by recourse to a third party. We used a data extraction form designed and piloted by the review authors. All data collected for our analyses were dichotomous. If studies had multiple publications, we included only the main trial report. The review authors contacted trial investigators to resolve any data queries, as required.

Assessment of risk of bias in included studies

We assessed the included trials for risks of bias, using the Cochrane RoB 1 tool (Higgins 2017). We evaluated the following seven domains of possible bias.

  • Random sequence generation

  • Allocation concealment

  • Blinding of participants and personnel

  • Blinding of outcome assessment

  • Incomplete outcome data

  • Selective reporting

  • Other potential bias

We judged the different types of bias using the criteria from the Cochrane Handbook (Higgins 2017). Two review authors (SF and SE) checked these domains of bias independently and rated them as being at high, low or unclear risk of bias. The assessments were compared and any disagreements resolved by consensus or by discussion with a third review author (CF). The conclusions are presented in the risk of bias table and were incorporated into the interpretation of the review findings by means of sensitivity analyses.

Measures of treatment effect

Where dichotomous data measures were used, we have expressed the results in the control and intervention groups of each trial as odds ratios (ORs) with 95% confidence intervals (CIs). For the very rare outcome, OHSS, we have used a risk difference (RD) analysis to allow CIs for the difference in percentage points. A RD approach was chosen over OR due to zero events in one or more trial arms. Based on the specified outcomes, there were no continuous data measures.

Unit of analysis issues

The primary analysis was per woman randomised. We also analysed the secondary outcome of miscarriage rate per pregnancy. We contacted authors of trials that used cycles as the denominator rather than women, for additional information; if we could not obtain it, we did not include the trial in the analysis. If there were multiple cycles, the unit of analysis remained as the woman randomised. We used only the first phase of cross‐over trials in the analysis, as successful treatment prevents a cross‐over. We treated multiple live births as one event.

Dealing with missing data

If data were missing from included studies, we contacted the investigators to request the relevant missing data. If this was not possible, we imputed individual values for the primary and secondary outcomes. In participants without a reported outcome, we assumed that live births had not occurred. For other outcomes, we analysed only the available data. We subjected any imputation to sensitivity analysis. We analysed the data on an intention‐to‐treat (ITT) basis, as far as possible.

Assessment of heterogeneity

We tested the results of the included trials for heterogeneity by measuring the scatter in the data points on the graph and the overlap in their CIs. We used the I2 statistic, which describes the percentage of total variation across the trials that is due to heterogeneity rather than to chance (Higgins 2021). The values of the I2 statistic lie between 0% (no heterogeneity) and 100% (extreme heterogeneity). We take values above 50% to indicate moderate heterogeneity and we explored them within sensitivity and subgroup analyses.

Assessment of reporting biases

In view of the difficulty of detecting and correcting for publication bias and other reporting biases, we aimed to minimise their potential impact by ensuring a comprehensive search for eligible trials and by being alert to duplication of data. We compared all outcome measures stated in the Methods section to the outcomes reported in the Results section, to ensure comparability. If there were more than 10 trials included in a comparison, we produced a funnel plot to test for reporting bias.

Data synthesis

We used a fixed‐effect model to combine the data from the primary studies if they were sufficiently similar. We conducted statistical analysis with Review Manager 5 (Review Manager 2020), in accordance with the guidelines for statistical analysis developed by Cochrane (Higgins 2021).

Our comparisons were:

  • letrozole compared to placebo;

  • letrozole compared to SERMs with or without adjuncts followed by timed intercourse;

  • letrozole compared to SERMs with or without adjuncts followed by intrauterine insemination;

  • letrozole compared to LOD with or without adjuncts;

  • letrozole compared to FSH;

  • letrozole compared to anastrozole;

  • letrozole compared to berberine;

  • comparison of different administration protocols of letrozole;

  • dosage studies of letrozole.

Increases in the odds of an outcome, either beneficial (e.g. live birth rate) or detrimental (e.g. OHSS rate) are shown in the forest plots of the meta‐analysis to the right of the centre line.
 

Subgroup analysis and investigation of heterogeneity

We performed subgroup analysis for primary outcomes only, to evaluate the evidence for a trial population with an average body mass index (BMI) > 25 compared to women with an average BMI < 25 within their trial group. We conducted a further subgroup analysis comparing women with no previous treatment for ovulation induction to women that were CC‐resistant. We intended to perform subgroup analyses on other parameters, such as the age of the woman, the duration of infertility and the duration and drug dosages, but this was not possible due to the lack of data.  

Sensitivity analysis

We conducted a sensitivity analysis for the primary outcomes to evaluate whether the conclusions are robust to arbitrary decisions made about the eligibility and analysis of trials. This analysis includes consideration of whether the review conclusions would have differed if:

  • eligibility was restricted to trials without high or unclear risk of bias;

  • we had used a random‐effects model;

  • we had implemented alternative imputation strategies;

  • the summary effect measure had been the risk ratio (RR) instead of the OR.

Summary of findings and assessment of the certainty of the evidence

We generated summary of findings tables using GRADE (Schünemann 2013) and GRADEpro GDT software (GRADEpro GDT), to evaluate the overall certainty of the body of evidence for: aromatase inhibitors (letrozole) with or without adjuncts compared to SERMs, with or without adjuncts (summary of findings table 1); and aromatase inhibitors (letrozole) compared to LOD (summary of findings table 2). GRADE criteria includes: trial limitations (risk of bias), consistency of effect, imprecision, indirectness and publication bias. Judgements about evidence certainty (high, moderate, low or very low) were justified, documented and incorporated into the reporting of results for each outcome. Two review authors independently evaluated the overall certainty of the evidence for the main outcomes of the review (live birth rate, OHSS rate, clinical pregnancy rate, miscarriage rate per pregnancy, multiple pregnancy rate). There are no summary of findings tables for the remaining comparisons of the review, because we considered them less clinically important. The results of these comparisons are discussed within the text of the review.

Results

Description of studies

Results of the search

The previous version of this review included 42 trials. The searches for the 2021 review update resulted in the retrieval of 25 full‐text papers (Figure 1). We included five new trials (Characteristics of included studies). We excluded four new trials (Characteristics of excluded studies). Seven new trials are awaiting classification (Characteristics of studies awaiting classification); we have contacted their authors and still await a response. Six new trials are ongoing (Characteristics of ongoing studies). We have moved four trials from included to excluded (Abu Hashim 2010; Badawy 2008; Badawy 2009a; Badawy 2009b), and two trials from included to awaiting classification due to concerns about validity of the trial data (Abu Hashim 2010a; Abdellah 2011). The review update contains 41 included trials (Figure 1).

Figure 1
Study flow diagram for update 2021

Study flow diagram for update 2021

Included studies

Study design and setting

We include 41 parallel‐designed RCTs in this 2021 updated review.

The trials were done in different parts of the world.

The following different settings recruited women into the trials.

Participants

The trials included 6522 women who were infertile due to anovulatory PCOS. The ages of the women ranged from 18 to 40 years.

Interventions

See Characteristics of included studies.

Outcomes

See Characteristics of included studies.

Excluded studies

We excluded 38 trials from the review. Eight of these were identified for the 2021 update (Abu Hashim 2010; Al‐Obaidi 2018; Badawy 2008; Badawy 2009a; Badawy 2009b; Huang 2019; NCT03135301; Wang 2019). The primary reasons for exclusion of the trials were inclusion criteria, interventions, concerns about the validity of the trial data (study retraction/expression of concern) and no randomisation (see Characteristics of excluded studies). 

Studies awaiting classification 

Fourteen studies are awaiting classification (Abdellah 2011; Abu Hashim 2010a; Aygen 2007; Ghoneim 2020; Jindal 2019; Kamel 2019; Lorzadeh 2011; NCT02551367; NCT02703649; NCT03664050; Rezk 2018; Safdarian 2012; Saha 2020; Shirin 2009). 

Ongoing studies

Seven studies are ongoing (ChiCTR2100042082; CTRI/2018/04/013343; Cutler 2018; Huang 2020; IRCT2016030926962N2; NCT03009838; Priest 2019).  

Risk of bias in included studies

See Characteristics of included studies; Figure 2; Figure 3.

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

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

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

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

Allocation

Twenty‐four trials were at low risk of selection bias related to random sequence generation. They used computer randomisation, a random‐number table or lottery. The remaining 17 trials did not fully describe their method of randomisation and the contacted authors did not respond, so we rated them at unclear risk of this bias (Figure 2).

Ten trials were at low risk of selection bias related to allocation concealment. They used sequentially‐numbered, sealed (opaque) envelopes and the list was kept by a third party during the procedure, or the randomisation schedule was produced by an interactive voice response system vendor. The other 31 trials did not describe allocation concealment sufficiently and the authors did not respond to our emails, so we rated them at unclear risk of bias (Figure 2).

Blinding

Eight out of 41 trials described the blinding of participants and personnel, and were thus rated at low risk of performance bias. Twenty‐six trials did not mention blinding of participants of personnel and the authors did not respond to our emails, so we rated them at unclear risk of bias. Seven trials stated that there was no blinding of participants or personnel or both, and were at high risk of bias (Figure 2).

Eleven of 41 trials reported that the outcome assessors were blinded and were therefore at low risk of bias. Twenty‐five trials did not mention blinding of outcome assessors and the authors did not respond to our email contact, so were rated at unclear risk of bias. Five trials were at high risk of detection bias, because they reported that the outcome assessors were not blinded (Figure 2).

Incomplete outcome data

Thirty‐six of 41 trials included all or nearly all women they had randomised (more than 90%) and were therefore at low risk of attrition bias. Three trials were at unclear risk of attrition bias. One trial had peculiar group numbers and none of the other biases were addressed, so we tried without success to contact the authors (Ray 2012). Another two trials did not report how many women were originally randomised (Sharief 2015; Salazar‐Ortiz 2016). Two more trials were at high risk of attrition bias: one trial because 13 of 80 women were not analysed. Four women were excluded after randomisation due to an ovarian cyst on sonography on day 3. Nine more women were lost to follow‐up without any reasons given (Ramezanzadeh 2011). The second trial excluded 28 of 268 women from analysis; 13 were lost to follow‐up, three were excluded, and 12 had complications (Liu 2017; Figure 2).

Selective reporting

Thirty of the 41 included trials reported the outcomes they had stated in the Methods section, and we therefore judged them to be at low risk of bias. In 11 of the 41 trials only a few outcomes were presented and the contacted authors did not respond, so we rated them at unclear risk of reporting bias (Figure 2).

Other potential sources of bias

In one trial there were substantial baseline differences in age and duration of infertility between the two groups and we deemed the risk of bias to be high (Nazik 2012). In a second trial, the methods were not well described and the clinical trial registration number led to a different trial (Zarei 2015). In a third trial, the methods were also not well described in general and the sample size was very small (Salazar‐Ortiz 2016). In a fourth trial the power calculation implied a very strong effect in favour of letrozole compared to CC (Ashfaq 2018). We judged two trials to be at unclear risk of other bias (Hendawy 2011; Liu 2015). We found no potential sources of within‐study bias in the other trials (Figure 2).

Effects of interventions

See: Summary of findings 1 Letrozole with or without adjuncts compared to SERMs with or without adjuncts followed by timed intercourse for infertile women with polycystic ovary syndrome; Summary of findings 2 Letrozole compared to laparoscopic ovarian drilling for infertile women with polycystic ovary syndrome

1. Letrozole compared to placebo

Primary outcomes
1.1 Live birth rate

Two trials including 167 participants compared an AI (letrozole) with placebo (Kamath 2010; Zarei 2015). Only one trial reported live birth rate, and there was insufficient evidence to suggest a difference in live birth rate (odds ratio (OR) 3.17, 95% confidence interval (CI) 0.12 to 83.17; 1 trial, 36 participants; Analysis 1.1).

1.2 OHSS rate

A risk difference (RD) analysis for OHSS rate showed insufficient evidence of a difference in frequency of this adverse event (RD 0.00, 95% CI −0.05 to 0.05; I2 = 0%; 2 trials, 167 participants; Analysis 1.2).

Secondary outcomes
1.3 Clinical pregnancy rate

The clinical pregnancy rate was higher using letrozole compared to placebo (OR 2.88, 95% CI 1.08 to 7.66; I2 = 0%; 2 trials, 167 participants; Analysis 1.3).

1.4 Miscarriage rate per woman and per pregnancy

Due to a wide CI in our analysis for miscarriage rate, compared to placebo, we are uncertain if letrozole decreases miscarriage rate per woman (OR 1.60, 95% CI 0.26 to 9.89; 2 trials, 167 participants; Analysis 1.4) or per pregnancy (OR 0.55, 95% CI 0.07 to 4.56; 1 trial, 20 participants; Analysis 1.5). 

1.5 Multiple pregnancy rate

Multiple pregnancy rate was not estimable because there were no cases reported. Sensitivity and subgroup analyses were not possible because there were too few trials.

2. Letrozole with or without adjuncts compared to SERMs with or without adjuncts followed by timed intercourse

23 trials including 3321 women compared letrozole to SERMs, with or without adjuncts (Amer 2017; Atay 2006; Bayar 2006; Begum 2009; Chen 2016; Davar 2011; Dehbashi 2009; El‐Gharib 2015; El‐Khayat 2016; Foroozanfard 2011; Ghahiri 2016; Legro 2014; Liu 2017; Moussa 2016; Nazik 2012; Ray 2012; Roy 2012; Salazar‐Ortiz 2016; Selim 2012; Seyedoshohadaei 2016; Sharief 2015; Sh‐El‐Arab Elsedeek 2011; Sohrabvand 2006).

  • Letrozole (2.5 mg to 7.5 mg/day) versus SERMs such as CC (50 mg to 150 mg/day), either alone or in combination with metformin (1000 mg to 1500 mg daily); 75 IU hMG to 150 IU hMG in one or both arms; estradiol valerate 4 mg/day.

Primary outcomes
2.1 Live birth rate

Eleven trials including 2060 women compared letrozole to SERMs, with or without adjuncts in one or both arms, and reported live birth rate (Amer 2017; Bayar 2006; Begum 2009; Dehbashi 2009; Foroozanfard 2011; Legro 2014; Liu 2017; Ray 2012; Roy 2012; Seyedoshohadaei 2016; Sohrabvand 2006). Letrozole resulted in an increased live birth rate compared to SERMs for ovulation induction (OR 1.72, 95% CI 1.40 to 2.11; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; 11 trials, 2060 participants; high‐certainty evidence; Figure 4; Analysis 2.1). This suggests that in women with a 20% chance of live birth using SERMs with or without adjuncts, the live birth rate in women using letrozole with or without adjuncts would be 27% to 35%. 

Figure 4
Forest plot of comparison: 2 Aromatase inhibitors compared to selective oestrogen receptor modulators (SERMs), outcome: 2.1 Live birth rate.

Forest plot of comparison: 2 Aromatase inhibitors compared to selective oestrogen receptor modulators (SERMs), outcome: 2.1 Live birth rate.

Eight of the 11 trials compared letrozole alone with CC alone (OR 1.79, 95% CI 1.42 to 2.25; I2 = 0%; 1646 participants)

Subgroup analysis showed insufficient evidence to suggest a difference by mean BMI above or below 25 (P = 0.87). Another subgroup analysis showed insufficient evidence to suggest a difference in women that were CC‐resistant versus women who had no previous treatment for ovulation induction (P = 0.80) (analysis not shown). 

Sensitivity analysis excluding one trial with high risk of detection bias showed no substantive influence on the treatment effect (Begum 2009). A sensitivity analysis comparing trials with unclear and low risk for allocation bias also showed insufficient evidence for a difference in treatment effect between the two subgroups (P = 0.36). In our other sensitivity analyses, findings for live birth were not influenced by the use of a random‐effects model, alternative imputation strategies, or RR rather than OR. A funnel plot for live birth rate was symmetrical, indicating that our findings might not be influenced by publication bias (Figure 5).

Figure 5
Funnel plot of comparison: 2 AIs compared to SERMs with or without adjuncts, followed by timed intercourse, outcome: 2.1 Live birth rate.

Funnel plot of comparison: 2 AIs compared to SERMs with or without adjuncts, followed by timed intercourse, outcome: 2.1 Live birth rate.

2.2 OHSS rate

Ten trials including 1848 women compared letrozole to SERMs, with or without adjuncts in one or both arms, and reported the occurrence of OHSS (Bayar 2006; Begum 2009; Chen 2016; El‐Khayat 2016; Foroozanfard 2011; Ghahiri 2016; Legro 2014; Nazik 2012; Roy 2012; Selim 2012). Our RD analysis showed that there is high‐certainty evidence of a similar frequency of this adverse event in both groups (RD −0.00, 95% CI −0.01 to 0.01; I2 = 0%; 10 trials, 1848 participants; high‐certainty evidence; Figure 6; Analysis 2.7). This suggests that the risk of OHSS was 0.5% in both groups. No OHSS occurred in women that were treated with letrozole alone. A subgroup analysis showed insufficient evidence to suggest a difference by BMI mean (P = 0.79) (analysis not shown). No differences in results were observed in our prespecified sensitivity analyses. A funnel plot for OHSS was insufficient for detection of a potential publication bias because there were no events in most of the trials (analysis not shown).

Figure 6
Forest plot of comparison: 2 Aromatase inhibitors compared to selective oestrogen receptor modulators SERMs, outcome: 2.6 Ovarian hyperstimulation syndrome rate.

Forest plot of comparison: 2 Aromatase inhibitors compared to selective oestrogen receptor modulators SERMs, outcome: 2.6 Ovarian hyperstimulation syndrome rate.

Secondary outcomes
2.3 Clinical pregnancy rate

Clinical pregnancy rate was reported in 23 trials, including 3321 women (Amer 2017; Atay 2006; Bayar 2006; Begum 2009; Chen 2016; Davar 2011; Dehbashi 2009; El‐Gharib 2015; El‐Khayat 2016; Foroozanfard 2011; Ghahiri 2016; Legro 2014; Liu 2017; Moussa 2016; Nazik 2012; Ray 2012; Roy 2012; Salazar‐Ortiz 2016; Selim 2012; Seyedoshohadaei 2016; Sharief 2015; Sh‐El‐Arab Elsedeek 2011; Sohrabvand 2006). Use of letrozole resulted in a higher clinical pregnancy rate compared to SERMs, with or without adjuncts in one or both arms (OR 1.69, 95% CI 1.45 to 1.98; I2 = 0%; NNTB = 10; 23 trials, 3321 participants; high‐certainty evidence; Analysis 2.9). This suggests that in women with a 24% chance of clinical pregnancy using SERMs with or without adjuncts, the clinical pregnancy rate in women using letrozole with or without adjuncts would be 32% to 39%. No differences in results were observed in our prespecified sensitivity analyses. A funnel plot for clinical pregnancy rate was symmetrical, indicating that our findings might not be influenced by publication bias (analysis not shown).

2.4 Miscarriage rate per woman and per pregnancy

Miscarriage rate was reported in 15 trials, including 2422 women (Bayar 2006; Begum 2009; Chen 2016; Davar 2011; Dehbashi 2009; El‐Khayat 2016; Foroozanfard 2011; Ghahiri 2016; Legro 2014; Liu 2017; Nazik 2012; Ray 2012; Roy 2012; Seyedoshohadaei 2016; Sohrabvand 2006). The analysis of miscarriage rate per woman showed little evidence for a difference in favour of SERMs with or without adjuncts in one or both arms (OR 1.37, 95% CI 1.01 to 1.87; I2 = 0%; 15 trials, 2422 participants; high‐certainty evidence; Analysis 2.11). However, the results of the analysis of miscarriage rate per pregnancy showed little or no difference between the groups (OR 0.94, 95% CI 0.66 to 1.32; I2 = 0%; 15 trials, 736 participants; high‐certainty evidence; Analysis 2.12). This suggests that in women with a 25% risk of miscarriage per pregnancy using SERMs with or without adjuncts, the miscarriage rate in women using letrozole with or without adjuncts would be 18% to 30%. 

2.5 Multiple pregnancy rate

Multiple pregnancy rate was reported in 14 trials, including 2247 women (Amer 2017; Atay 2006; Bayar 2006; Begum 2009; Chen 2016; Dehbashi 2009; El‐Khayat 2016; Foroozanfard 2011; Hendawy 2011; Legro 2014; Nazik 2012; Roy 2012; Selim 2012; Sharief 2015). The analysis of multiple pregnancy rate per woman showed high‐certainty evidence of no difference in multiple pregnancy rate for letrozole compared to SERMs (OR 0.74, 95% CI 0.42 to 1.32; I2 = 0%; 14 trials, 2247 participants; high‐certainty evidence; Figure 7; Analysis 2.13). This suggests that in women with a 2.2% chance of multiple pregnancy using SERMs with or without adjuncts, the multiple pregnancy rate in women using letrozole with or without adjuncts would be 1.6% to 2.8%. 

Figure 7
Forest plot of comparison: 2 Aromatase inhibitors compared to selective oestrogen receptor modulators SERMs, outcome: 2.5 Multiple pregnancy rate.

Forest plot of comparison: 2 Aromatase inhibitors compared to selective oestrogen receptor modulators SERMs, outcome: 2.5 Multiple pregnancy rate.

Publication bias 

We produced a funnel plot for both primary outcomes and for the outcome of clinical pregnancy rate. A funnel plot for live birth rate was symmetrical, indicating that our findings might not be influenced by publication bias (Figure 5). A funnel plot for OHSS was insufficient for detection of a potential publication bias because there were no events in most of the trials (analysis not shown). The funnel plot for the secondary outcome clinical pregnancy rate showed some asymmetries, with a gap on the left side. This indicates that there were possibly some trials with effects in favour of SERMs which were not reported, and therefore the results of our meta‐analysis might have overestimated the effect of letrozole on pregnancy rate.

3. Letrozole compared to SERMs with or without adjuncts followed by intrauterine insemination

Three trials including 1597 women compared the use of letrozole with or without adjuncts to SERMs followed by intrauterine insemination (Ganesh 2009; Kar 2012; Zeinalzadeh 2010).

  • Letrozole (2.5 mg to 5 mg daily, cycle days 3 to 7 or 2 to 6) versus SERMs such as CC (50 mg to 150 mg daily, cycle days 3 to 7 or 2 to 6) with or without adjuncts or recombinant follicle‐stimulating hormone (rFSH) only (rFSH 75 IU to 100 IU from day 2 until the day of hCG administration).

Primary outcomes
3.1 Live birth rate

No trials comparing letrozole to SERMs reported live birth rate.

3.2 OHSS rate

Two trials reported OHSS rate comparing use of letrozole to SERMs (Ganesh 2009; Zeinalzadeh 2010). Our RD analysis showed insufficient evidence of a difference in frequency of this adverse event between the two treatment groups (RD −0.00, 95% CI −0.01 to 0.00; I2 = 0%; 2 trials, 1494 participants; Analysis 3.1). Sensitivity and subgroup analyses were not possible because there were too few trials.

Secondary outcomes
3.3 Clinical pregnancy rate

Clinical pregnancy rate was reported in three trials comparing letrozole to SERMs (Ganesh 2009; Kar 2012; Zeinalzadeh 2010). The analysis showed evidence in favour of letrozole compared to SERMs for ovulation induction followed by intrauterine insemination (OR 1.71, 95% CI 1.30 to 2.25; I2 = 0%; 3 trials, 1597 participants; Analysis 3.2).

3.4 Miscarriage rate per woman and per pregnancy

Miscarriage rate was reported in two trials comparing letrozole to SERMs (Ganesh 2009; Kar 2012). There was insufficient evidence of a difference between the two groups for miscarriage rate per woman (OR 1.22, 95% CI 0.62 to 2.40; I2 = 30%; 2 trials, 1490 participants; Analysis 3.3) or per pregnancy (OR 0.76, 95% CI 0.37 to 1.57; I2 = 0%; 2 trials, 260 participants; Analysis 3.4).

3.5 Multiple pregnancy rate

Multiple pregnancy rate was reported in three trials comparing letrozole to SERMs, with or without adjuncts (Ganesh 2009; Kar 2012; Zeinalzadeh 2010). There was insufficient evidence of a difference between the two groups (OR 1.03, 95% CI 0.49 to 2.13; I2 = 0%; 3 trials, 1597 participants; Analysis 3.5).

4. Letrozole compared to LOD

Three trials including 367 women compared letrozole with or without metformin to LOD (Elgafor 2013; Ibrahim 2017; Liu 2015).

  • Letrozole (2.5 mg to 5 mg daily, cycle days 3 to 7) with or without metformin (850 mg to 1700 mg daily for 6 to 8 weeks) versus laparoscopic ovarian drilling.

Primary outcomes
4.1 Live birth rate

Live birth rate was reported in one trial including 141 women, comparing letrozole to LOD (Liu 2015). There was very low‐certainty evidence of a higher live birth rate in favour of letrozole compared to LOD (OR 2.07, 95% CI 0.99 to 4.32; 1 trial, 141 participants; Analysis 4.1). This suggests that in women with a 22% chance of live birth using LOD with or without adjuncts, the live birth rate in women using letrozole with or without adjuncts would be 24% to 47%. Subgroup and sensitivity analyses were not possible because there was only one trial.

4.2 OHSS rate

No trials comparing letrozole to LOD reported OHSS rate.

Secondary outcomes
4.3 Clinical pregnancy rate

Clinical pregnancy rate was reported in three trials including 367 women, comparing letrozole with or without metformin to LOD (Elgafor 2013; Ibrahim 2017; Liu 2015). There was low‐certainty evidence of no difference between the two groups (OR 1.47, 95% CI 0.95 to 2.28; I2 = 0%; 3 trials, 367 participants; Analysis 4.2). This suggests that in women with a 29% chance of clinical pregnancy using LOD with or without adjuncts, the clinical pregnancy rate in women using letrozole with or without adjuncts would be 28% to 45%.

4.4 Miscarriage rate per woman and per pregnancy

Miscarriage rate was reported in three trials including 367 women, comparing letrozole with or without metformin to LOD (Elgafor 2013; Ibrahim 2017; Liu 2015). There was low‐certainty evidence of no difference between the two groups for miscarriage rate per woman (OR 0.87, 95% CI 0.31 to 2.44; I2 = 0%; 3 trials, 367 participants; Analysis 4.3) and per pregnancy (OR 0.65, 95% CI 0.22 to 1.38; I2 = 0%; 3 trials, 122 participants; Analysis 4.4). This suggests that in women with a 16% risk of miscarriage per pregnancy using LOD with or without adjuncts, the risk of miscarriage in women using letrozole with or without adjuncts would be 4% to 21%.

4.5 Multiple pregnancy rate

Multiple pregnancy rate was reported in one trial including 141 women, comparing letrozole to LOD (Liu 2015). There was low‐certainty evidence of no difference between the two groups for multiple pregnancy rate per woman (OR 3.00, 95% CI 0.12 to 74.90; I2 = 0%; 1 trial, 141 participants; Analysis 4.5). The risk of multiple pregnancy was below 1% in both treatment groups.

5. Letrozole compared to FSH

Two trials including 236 women compared use of letrozole to FSH (Hassan 2017; Shi 2019).

  • Letrozole 2.5 mg twice daily for 5 days versus urinary FSH (uFSH) 75 IU a day for 7 days (Hassan 2017) or human menopausal gonadotropin (hMG) 75 IU a day for 5 days (Shi 2019), both groups starting on the third day of menstruation.

Primary outcomes
5.1 Live birth rate

Live birth rate was reported in one trial comparing letrozole to hMG (Shi 2019). There was insufficient evidence of a difference between the two groups (OR 1.00, 95% CI 0.34 to 2.93; 1 trial, 96 participants; Analysis 5.1).

5.2 OHSS rate

OHSS was reported in two trials comparing letrozole to gonadotropins (Hassan 2017; Shi 2019). A RD analysis showed insufficient evidence of a difference between the two treatment groups (RD ‐0.03, 95% CI −0.08 to 0.01; 2 trials, 236 participants; Analysis 5.2).

Secondary outcomes
5.3 Clinical pregnancy rate

Clinical pregnancy rate was reported in two trials comparing letrozole to gonadotropins (Hassan 2017; Shi 2019). There was insufficient evidence of a difference between the two groups (OR 0.81, 95% CI 0.46 to 1.43; 2 trials, 236 participants; Analysis 5.3).

5.4 Miscarriage rate per woman and per pregnancy

Miscarriage rate was reported in two trials comparing letrozole to gonadotropins (Hassan 2017; Shi 2019). There was insufficient evidence of a difference between the two groups for miscarriage rate per woman (OR 0.61, 95% CI 0.19 to 1.92; 2 trials, 236 participants; Analysis 5.4) or per pregnancy (OR 0.74, 95% CI 0.11 to 4.90; 1 trial, 140 participants; Analysis 5.5).

5.5 Multiple pregnancy rate

Multiple pregnancy rate was reported in two trials comparing letrozole to FSH (Hassan 2017; Shi 2019). There was insufficient evidence to suggest a difference between the two treatment groups (OR 0.22, 95% CI 0.04 to 1.32; 2 trials, 236 participants; Analysis 5.6).

6. Letrozole compared to anastrozole

One trial including 40 women compared letrozole to the AI, anastrozole (Al‐Omari 2004).

  • Letrozole 2.5 mg/day versus anastrozole 1 mg/day for 5 days, both starting on cycle day 3.

Primary outcomes
6.1 Live birth rate

No trials comparing letrozole to anastrozole reported live birth rate.

6.2 OHSS rate

No trials comparing letrozole to anastrozole reported OHSS rate.

Secondary outcomes
6.3 Clinical pregnancy rate

Clinical pregnancy rate was reported in one trial comparing letrozole to anastrozole (Al‐Omari 2004). There was insufficient evidence of a difference between the two groups (OR 1.88, 95% CI 0.40 to 8.88; 40 participants; 1 trial; Analysis 6.1).

6.4 Miscarriage rate per woman and per pregnancy

No trials comparing letrozole to anastozole reported miscarriage rate per woman or per pregnancy.

6.5 Multiple pregnancy rate

Multiple pregnancy rate was reported in one trial comparing letrozole to anastrozole (Al‐Omari 2004). This trial did not report any cases of multiple pregnancies and an OR was therefore not estimable (Al‐Omari 2004; Analysis 6.2).

7. Letrozole compared to berberine followed by timed intercourse

One trial including 644 women compared letrozole to berberine (Wu 2016).

  • Letrozole 2.5 mg/day starting on cycle day 3 versus berberine 1.5 g for 6 months

Primary outcomes
7.1 Live birth rate

Live birth rate was reported in one trial comparing letrozole to berberine (Wu 2016). Letrozole resulted in an increased live birth rate compared to berberine (OR 1.94, 95% CI 1.33 to 2.84; 1 trial, 644 participants; Analysis 7.1).

7.2 OHSS rate

No trials comparing letrozole to berberine reported OHSS rate.

Secondary outcomes
7.3 Clinical pregnancy rate

Clinical pregnancy rate was reported in one trial comparing letrozole to berberine (Wu 2016). Letrozole resulted in an increased pregnancy rate compared to berberine (OR 2.15, 95% CI 1.48 to 3.13; 1 trial, 644 participants; Analysis 7.2).

7.4 Miscarriage rate per woman and per pregnancy

Miscarriage rate was reported in one trial comparing letrozole to berberine (Wu 2016). There was insufficient evidence of a difference between the two groups for miscarriage rate per women randomised (OR 1.60, 95% CI 0.26 to 9.89; 1 trial, 644 participants; Analysis 7.3) and for miscarriage rate per pregnancy (OR 4.53, 95% CI 0.24 to 84.46; 1 trial, 644 participants; Analysis 7.4).

7.5 Multiple pregnancy rate

Multiple pregnancy rate was reported in one trial comparing letrozole to anastrozole (Al‐Omari 2004). This trial did not report any cases of multiple pregnancies and an OR was therefore not estimable (Al‐Omari 2004; Analysis 6.2).

8. Different administration protocols of letrozole

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

One trial including 70 women compared starting letrozole on day 3 with day 5 administration protocol (Ghomian 2015).

Primary outcomes
8.1 Live birth rate

This trial did not report live birth rate.

8.2 OHSS rate

This trial did not report OHSS rate.

Secondary outcomes
8.3 Clinical pregnancy rate

The analysis showed insufficient evidence of a difference between the two groups in clinical pregnancy rate (OR 1.38, 95% CI 0.28 to 6.66; 1 trial, 70 participants; Analysis 8.1).

8.4 Miscarriage rate

This trial did not report miscarriage rate.

8.5 Multiple pregnancy rate

This trial did not report multiple pregnancy rate.

9. Dosage studies of letrozole

One trial compared a 5 mg/day administration of letrozole to a 7.5 mg/day administration protocol (Ramezanzadeh 2011).

Primary outcomes
9.1 Live birth rate

This trial did not report live birth rate.

9.2 OHSS rate

A RD analysis on OHSS rate showed insufficient evidence to suggest a difference in occurrence of OHSS between the two treatment groups (RD 0.00, 95% CI −0.05 to 0.05; 1 trial, 80 participants; Analysis 9.1).

Secondary outcomes
9.3 Clinical pregnancy rate

The results show insufficient evidence of a difference between the groups in clinical pregnancy rate (OR 1.00, 95% CI 0.32 to 3.17; 1 trial, 80 participants; Analysis 9.2).

9.4 Miscarriage rate per woman and per pregnancy

The results show insufficient evidence of a difference between the groups in miscarriage rate per woman (OR 0.33, 95% CI 0.01 to 8.22; 1 trial, 80 participants; Analysis 9.3), or miscarriage rate per pregnancy (OR 0.29, 95% CI 0.01 to 8.39; 1 trial, 80 participants; Analysis 9.4).

9.5 Multiple pregnancy rate

The results show insufficient evidence of a difference between the groups in multiple pregnancy rate (OR 1.00, 95% CI 0.06 to 16.56; 1 trial, 80 participants; Analysis 9.5).

Discussion

Summary of main results

Letrozole compared to placebo

Two trials compared letrozole to placebo. There is a lack of evidence with only two small studies with small numbers of participants.

Letrozole compared to SERMs with or without adjuncts followed by timed intercourse

The results of our analysis of 23 trials comparing letrozole to SERMs followed by timed intercourse suggest that letrozole improves the live birth rate and pregnancy rate compared to SERMs (summary of findings Table 1).

A funnel plot for live birth rate was symmetrical, indicating that our findings might not be influenced by publication bias (Figure 5).

Letrozole resulted in 10% more pregnancies, consequently the miscarriage rate expressed per woman was also higher. However, the miscarriage rate expressed per pregnancy was comparable between letrozole and SERMs. A RD analysis suggested that letrozole and CC are equally safe in terms of ovarian hyperstimulation and miscarriage rates (summary of findings Table 1).

The funnel plot for clinical pregnancy rate was symmetrical, suggesting that our findings might not be influenced by publication bias. A funnel plot investigating the impact of possible allocation bias on clinical pregnancy rate showed some asymmetry, suggesting that the results might be influenced by allocation bias in favour of letrozole.

All analyses had absent or low levels of statistical heterogeneity (I2 < 25%).

Six of our 23 trials in this analysis included women resistant to CC (Begum 2009; Davar 2011; El‐Gharib 2015; Foroozanfard 2011; Seyedoshohadaei 2016; Sohrabvand 2006); the other 17 trials included women not resistant to CC (Bayar 2006; Dehbashi 2009; Legro 2014; Nazik 2012; Salazar‐Ortiz 2016; Sh‐El‐Arab Elsedeek 2011), or it was not mentioned (Amer 2017; Atay 2006; Chen 2016; El‐Khayat 2016; Ghahiri 2016; Liu 2017; Moussa 2016; Selim 2012; Sharief 2015; Ray 2012; Roy 2012).

Data based on findings from Legro 2014 found that the interventions had comparable treatment costs. This suggests that, given its higher effectiveness, letrozole is more cost‐effective than SERMs (Reproductive Medicine Network 2013).

Letrozole compared to SERMs with or without adjuncts followed by intrauterine insemination

Three trials compared letrozole to SERMs for ovulation induction followed by intrauterine insemination (Ganesh 2009; Kar 2012; Zeinalzadeh 2010). None reported live birth. Two reported OHSS: only three cases occurred and there was insufficient evidence of a difference despite a trial population of 1494 women. Clinical pregnancy rates were increased in women treated with letrozole, compared to SERMs and FSH. There was insufficient evidence of a difference in rates of miscarriage or multiple pregnancy.

Letrozole compared to LOD

Three trials compared letrozole to LOD in CC‐resistant women (summary of findings Table 2). There was very low‐certainty evidence of higher live birth rates with letrozole compared to LOD. However, we note that trials reporting live birth tended to report higher clinical pregnancy rates in the letrozole group than trials that failed to report live birth, with insufficient evidence of a difference in miscarriage rates per pregnancy. This suggests that findings might be less favourable to letrozole if all trials reported live birth. OHSS was not reported. There was low‐certainty evidence of no difference in rates of pregnancy, miscarriage or multiple pregnancy rate.

Letrozole compared to FSH

Two trials, including 236 women, compared use of letrozole to FSH (Hassan 2017; Shi 2019). Live birth rate was not reported and there were no events of OHSS. There was insufficient evidence of a difference for clinical pregnancy, miscarriage or multiple pregnancy rates.

Letrozole compared to anastrozole

Letrozole was compared to anastrozole in one trial including 40 women (Al‐Omari 2004). Live birth rate, OHSS rate and miscarriage rate were not reported. There was insufficient evidence of a difference for rates of clinical pregnancy and multiple pregnancies.

Letrozole compared to berberine

The results of one trial comparing letrozole to berberine followed by timed intercourse suggest that letrozole improves the live birth rate and pregnancy rate compared to berberine (Wu 2016). The OHSS rate was not reported. There was insufficient evidence of a difference for rates of miscarriage and multiple pregnancies.

Different administration protocols of letrozole

Letrozole day 3‐7 administration versus day 5‐9 administration protocol

A single trial including 70 women compared a day 3 to 5 versus day 5 to 9 administration protocol. Only pregnancy rate was reported and there was insufficient evidence for a difference.

Dosage studies of letrozole

We intended to analyse different doses of letrozole in the range from 2.5 mg/day to 5 mg/day, but we found only one trial including 80 women comparing a dosage of 5 mg/day to 7.5 mg/day. There was insufficient evidence of a difference in effectiveness as only seven pregnancies were reported in each group. There was also insufficient evidence of a difference in adverse events, but the size of the trial population might have been too small because only one or no cases were reported in each group for OHSS, miscarriage and multiple pregnancy rate.

Overall completeness and applicability of evidence

For our main comparison of letrozole compared to SERMs with or without adjuncts followed by timed intercourse, we found sufficient trials for our analysis of live birth and OHSS rates to answer our research question. For all other comparisons except for the comparison of letrozole versus placebo, more trials could improve the certainty of evidence. 

Most of the trials included were conducted in Egypt or the Middle East. There are, however, two large trials from the USA and Europe confirming the results (Amer 2017; Legro 2014).

Certainty of the evidence

We included 41 trials with 6522 women in the review. We rated the overall certainty of the evidence as high for all outcomes for our main comparison: letrozole versus SERMs, with or without adjuncts followed by timed intercourse (summary of findings Table 1). Based on the large numbers of participants (number of trials ranging from 10 to 23 depending on the outcome) and the addition of trials at low risk of bias, it is unlikely that additional trials are going to alter the effect estimates of our main comparison.

The other comparisons included only one to five trials. We downgraded much of the evidence for risks of bias and imprecision (summary of findings Table 2). We rated the certainty of the evidence for live birth and multiple pregnancy rates as very low, and as low for clinical pregnancy and miscarriage rates.

Potential biases in the review process

We conducted a comprehensive search with the help of an experienced Information Specialist, and ran extensive manual searches in order to identify all relevant trials and in an effort to minimise the risk of publication bias. We generated a funnel plot for the outcomes of live birth and pregnancy rates in the comparison of letrozole versus SERMs, which was symmetrical and therefore indicated there is no publication bias.

We followed Cochrane guidelines to select trials, extract data and assess the certainty and potential risks of different types of biases in all our included trials, in order to minimise the chance of error and bias by the review authors.

We requested further information from trial author teams; we did not receive a response from five of them.

Agreements and disagreements with other studies or reviews

Our meta‐analysis shows evidence for increased live birth rates in favour of letrozole when compared to CC in women with PCOS. This differs from a previous review, which did not detect a difference (Misso 2012). This is most likely due to the limited number of trials included in the previous review. They included six RCTs, comparing the pregnancy rate between letrozole and CC, including 889 women in total (odds ratio (OR) 1.53, 95% CI 0.91 to 2.58). Another recent meta‐analysis is in accordance with our findings of increased live birth rate (risk ratio (RR) 1.55, 95% CI 1.26 to 1.90; I2 = 0%; 5 trials, 1289 participants) and pregnancy rate (RR 1.38, 95% CI 1.05 to 1.83; I2 = 61%; 7 trials, 1833 participants), as well as no difference for miscarriage and multiple pregnancy rates (Roque 2015).

Study flow diagram for update 2021

Figuras y tablas -
Figure 1

Study flow diagram for update 2021

Ir a la figura de la revisiónAbrir en una pestaña nueva

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.

Ir a la figura de la revisiónAbrir en una pestaña nueva

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.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Forest plot of comparison: 2 Aromatase inhibitors compared to selective oestrogen receptor modulators (SERMs), outcome: 2.1 Live birth rate.

Figuras y tablas -
Figure 4

Forest plot of comparison: 2 Aromatase inhibitors compared to selective oestrogen receptor modulators (SERMs), outcome: 2.1 Live birth rate.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Funnel plot of comparison: 2 AIs compared to SERMs with or without adjuncts, followed by timed intercourse, outcome: 2.1 Live birth rate.

Figuras y tablas -
Figure 5

Funnel plot of comparison: 2 AIs compared to SERMs with or without adjuncts, followed by timed intercourse, outcome: 2.1 Live birth rate.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Forest plot of comparison: 2 Aromatase inhibitors compared to selective oestrogen receptor modulators SERMs, outcome: 2.6 Ovarian hyperstimulation syndrome rate.

Figuras y tablas -
Figure 6

Forest plot of comparison: 2 Aromatase inhibitors compared to selective oestrogen receptor modulators SERMs, outcome: 2.6 Ovarian hyperstimulation syndrome rate.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Forest plot of comparison: 2 Aromatase inhibitors compared to selective oestrogen receptor modulators SERMs, outcome: 2.5 Multiple pregnancy rate.

Figuras y tablas -
Figure 7

Forest plot of comparison: 2 Aromatase inhibitors compared to selective oestrogen receptor modulators SERMs, outcome: 2.5 Multiple pregnancy rate.

Ir a la figura de la revisiónAbrir en una pestaña nueva

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Letrozole compared to placebo, Outcome 4: Miscarriage rate per woman

Figuras y tablas -
Analysis 1.4

Comparison 1: Letrozole compared to placebo, Outcome 4: Miscarriage rate per woman

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Letrozole compared to placebo, Outcome 5: Miscarriage rate per pregnancy

Figuras y tablas -
Analysis 1.5

Comparison 1: Letrozole compared to placebo, Outcome 5: Miscarriage rate per pregnancy

Ir a la figura de la revisiónAbrir en una pestaña nueva

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM with or without adjuncts, followed by timed intercourse, Outcome 1: Live birth rate

Figuras y tablas -
Analysis 2.1

Comparison 2: Letrozole compared to SERM with or without adjuncts, followed by timed intercourse, Outcome 1: Live birth rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM 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 SERM with or without adjuncts, followed by timed intercourse, Outcome 2: Live birth rate by BMI

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM 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 SERM with or without adjuncts, followed by timed intercourse, Outcome 3: Live birth rate by first‐ or second‐line treatment

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM 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 SERM with or without adjuncts, followed by timed intercourse, Outcome 4: Impact of allocation bias for live birth rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM 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 SERM with or without adjuncts, followed by timed intercourse, Outcome 5: Impact of detection bias for live birth rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM 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 SERM with or without adjuncts, followed by timed intercourse, Outcome 6: Impact of attrition bias for live birth rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM 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 SERM with or without adjuncts, followed by timed intercourse, Outcome 7: Ovarian hyperstimulation syndrome rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM with or without adjuncts, followed by timed intercourse, Outcome 8: Ovarian hyperstimulation syndrome rate by BMI

Figuras y tablas -
Analysis 2.8

Comparison 2: Letrozole compared to SERM with or without adjuncts, followed by timed intercourse, Outcome 8: Ovarian hyperstimulation syndrome rate by BMI

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM with or without adjuncts, followed by timed intercourse, Outcome 9: Clinical pregnancy rate

Figuras y tablas -
Analysis 2.9

Comparison 2: Letrozole compared to SERM with or without adjuncts, followed by timed intercourse, Outcome 9: Clinical pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM 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 SERM with or without adjuncts, followed by timed intercourse, Outcome 10: Impact of allocation bias for clinical pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM with or without adjuncts, followed by timed intercourse, Outcome 11: Miscarriage rate per woman

Figuras y tablas -
Analysis 2.11

Comparison 2: Letrozole compared to SERM with or without adjuncts, followed by timed intercourse, Outcome 11: Miscarriage rate per woman

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM with or without adjuncts, followed by timed intercourse, Outcome 12: Miscarriage rate per pregnancy

Figuras y tablas -
Analysis 2.12

Comparison 2: Letrozole compared to SERM with or without adjuncts, followed by timed intercourse, Outcome 12: Miscarriage rate per pregnancy

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2: Letrozole compared to SERM with or without adjuncts, followed by timed intercourse, Outcome 13: Multiple pregnancy rate

Figuras y tablas -
Analysis 2.13

Comparison 2: Letrozole compared to SERM with or without adjuncts, followed by timed intercourse, Outcome 13: Multiple pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3: Letrozole compared to SERMs with our without adjuncts, followed by IUI, Outcome 1: Ovarian hyperstimulation syndrome rate

Figuras y tablas -
Analysis 3.1

Comparison 3: Letrozole compared to SERMs with our without adjuncts, followed by IUI, Outcome 1: Ovarian hyperstimulation syndrome rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3: Letrozole compared to SERMs with our without adjuncts, followed by IUI, Outcome 2: Clinical pregnancy rate

Figuras y tablas -
Analysis 3.2

Comparison 3: Letrozole compared to SERMs with our without adjuncts, followed by IUI, Outcome 2: Clinical pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3: Letrozole compared to SERMs with our without adjuncts, followed by IUI, Outcome 3: Miscarriage rate per woman

Figuras y tablas -
Analysis 3.3

Comparison 3: Letrozole compared to SERMs with our without adjuncts, followed by IUI, Outcome 3: Miscarriage rate per woman

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3: Letrozole compared to SERMs with our without adjuncts, followed by IUI, Outcome 4: Miscarriage rate per pregnancy

Figuras y tablas -
Analysis 3.4

Comparison 3: Letrozole compared to SERMs with our without adjuncts, followed by IUI, Outcome 4: Miscarriage rate per pregnancy

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3: Letrozole compared to SERMs with our without adjuncts, followed by IUI, Outcome 5: Multiple pregnancy rate

Figuras y tablas -
Analysis 3.5

Comparison 3: Letrozole compared to SERMs with our without adjuncts, followed by IUI, Outcome 5: Multiple pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 4: Letrozole compared to laparoscopic ovarian drilling, Outcome 2: Clinical pregnancy rate

Figuras y tablas -
Analysis 4.2

Comparison 4: Letrozole compared to laparoscopic ovarian drilling, Outcome 2: Clinical pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 4: Letrozole compared to laparoscopic ovarian drilling, Outcome 3: Miscarriage rate per woman

Figuras y tablas -
Analysis 4.3

Comparison 4: Letrozole compared to laparoscopic ovarian drilling, Outcome 3: Miscarriage rate per woman

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 4: Letrozole compared to laparoscopic ovarian drilling, Outcome 4: Miscarriage rate per pregnancy

Figuras y tablas -
Analysis 4.4

Comparison 4: Letrozole compared to laparoscopic ovarian drilling, Outcome 4: Miscarriage rate per pregnancy

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 4: Letrozole compared to laparoscopic ovarian drilling, Outcome 5: Multiple pregnancy rate

Figuras y tablas -
Analysis 4.5

Comparison 4: Letrozole compared to laparoscopic ovarian drilling, Outcome 5: Multiple pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 5: Letrozole compared to FSH, Outcome 1: Live birth

Figuras y tablas -
Analysis 5.1

Comparison 5: Letrozole compared to FSH, Outcome 1: Live birth

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 5: Letrozole compared to FSH, Outcome 2: Ovarian hyperstimulation syndrome rate

Figuras y tablas -
Analysis 5.2

Comparison 5: Letrozole compared to FSH, Outcome 2: Ovarian hyperstimulation syndrome rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 5: Letrozole compared to FSH, Outcome 3: Clinical pregnancy rate

Figuras y tablas -
Analysis 5.3

Comparison 5: Letrozole compared to FSH, Outcome 3: Clinical pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 5: Letrozole compared to FSH, Outcome 4: Miscarriage rate per woman

Figuras y tablas -
Analysis 5.4

Comparison 5: Letrozole compared to FSH, Outcome 4: Miscarriage rate per woman

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 5: Letrozole compared to FSH, Outcome 5: Miscarriage rate per pregnancy

Figuras y tablas -
Analysis 5.5

Comparison 5: Letrozole compared to FSH, Outcome 5: Miscarriage rate per pregnancy

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 5: Letrozole compared to FSH, Outcome 6: Multiple pregnancy rate

Figuras y tablas -
Analysis 5.6

Comparison 5: Letrozole compared to FSH, Outcome 6: Multiple pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 6: Letrozole compared to anastrozole, Outcome 1: Clinical pregnancy rate

Figuras y tablas -
Analysis 6.1

Comparison 6: Letrozole compared to anastrozole, Outcome 1: Clinical pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 6: Letrozole compared to anastrozole, Outcome 2: Multiple pregnancy rate

Figuras y tablas -
Analysis 6.2

Comparison 6: Letrozole compared to anastrozole, Outcome 2: Multiple pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 7: Letrozole compared to berberine, followed by timed intercourse, Outcome 1: Live birth rate

Figuras y tablas -
Analysis 7.1

Comparison 7: Letrozole compared to berberine, followed by timed intercourse, Outcome 1: Live birth rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 7: Letrozole compared to berberine, followed by timed intercourse, Outcome 2: Clinical pregnancy rate

Figuras y tablas -
Analysis 7.2

Comparison 7: Letrozole compared to berberine, followed by timed intercourse, Outcome 2: Clinical pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 7: Letrozole compared to berberine, followed by timed intercourse, Outcome 3: Miscarriage rate per woman

Figuras y tablas -
Analysis 7.3

Comparison 7: Letrozole compared to berberine, followed by timed intercourse, Outcome 3: Miscarriage rate per woman

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 7: Letrozole compared to berberine, followed by timed intercourse, Outcome 4: Miscarriage rate per pregnancy

Figuras y tablas -
Analysis 7.4

Comparison 7: Letrozole compared to berberine, followed by timed intercourse, Outcome 4: Miscarriage rate per pregnancy

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 7: Letrozole compared to berberine, followed by timed intercourse, Outcome 5: Multiple pregnancy rate

Figuras y tablas -
Analysis 7.5

Comparison 7: Letrozole compared to berberine, followed by timed intercourse, Outcome 5: Multiple pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 8: Different administration protocols of letrozole, Outcome 1: Clinical pregnancy rate

Figuras y tablas -
Analysis 8.1

Comparison 8: Different administration protocols of letrozole, Outcome 1: Clinical pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 9: Dosage studies of letrozole, Outcome 1: Ovarian hyperstimulation syndrome rate

Figuras y tablas -
Analysis 9.1

Comparison 9: Dosage studies of letrozole, Outcome 1: Ovarian hyperstimulation syndrome rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 9: Dosage studies of letrozole, Outcome 2: Clinical pregnancy rate

Figuras y tablas -
Analysis 9.2

Comparison 9: Dosage studies of letrozole, Outcome 2: Clinical pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 9: Dosage studies of letrozole, Outcome 3: Miscarriage rate per woman

Figuras y tablas -
Analysis 9.3

Comparison 9: Dosage studies of letrozole, Outcome 3: Miscarriage rate per woman

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 9: Dosage studies of letrozole, Outcome 4: Miscarriage rate per pregnancy

Figuras y tablas -
Analysis 9.4

Comparison 9: Dosage studies of letrozole, Outcome 4: Miscarriage rate per pregnancy

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 9: Dosage studies of letrozole, Outcome 5: Multiple pregnancy rate

Figuras y tablas -
Analysis 9.5

Comparison 9: Dosage studies of letrozole, Outcome 5: Multiple pregnancy rate

Ir a la figura de la revisiónAbrir en una pestaña nueva
Summary of findings 1. Letrozole with or without adjuncts compared to SERMs with or without adjuncts followed by timed intercourse for infertile women with polycystic ovary syndrome

Letrozole with or without adjuncts compared to SERMs with or without adjuncts followed by timed intercourse for infertile women with polycystic ovary syndrome

Patient or population: infertile women with polycystic ovary syndrome
Setting: (fertility) clinics or outpatient settings
Intervention: letrozole with or without adjuncts followed by timed intercourse
Comparison: SERMs (clomiphene citrate) with or without adjuncts followed by timed intercourse

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(trials)

Certainty of the evidence
(GRADE)

Comments

Risk with SERMs with or without adjuncts

Risk with letrozole with or without adjuncts

Live birth rate

204 per 1000

307 per 1000
(265 to 352)

OR 1.72
(1.40 to 2.11)

2060
(11 RCTs)

⊕⊕⊕⊕
High

 

Ovarian hyperstimulation syndrome rate

7 per 1000

5 per 1000
(5 to 5)

RD −0.00
(−0.01 to 0.01)

1848
(10 RCTs)

⊕⊕⊕⊕
High

 

Clinical pregnancy rate

242 per 1000

350 per 1000
(316 to 387)

OR 1.69
(1.45 to 1.98)

3321
(23 RCTs)

⊕⊕⊕⊕
High

 

Miscarriage rate per pregnancy

252 per 1000

240 per 1000
(182 to 307)

OR 0.94
(0.66 to 1.32)

736
(15 RCTs)

⊕⊕⊕⊕
High

 

Multiple pregnancy rate

22 per 1000

16 per 1000
(9 to 28)

OR 0.74
(0.42 to 1.32)

2247
(14 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; OR: odds ratio; RD: risk difference; RCT: randomised controlled trial

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.

Figuras y tablas -
Summary of findings 1. Letrozole with or without adjuncts compared to SERMs with or without adjuncts followed by timed intercourse for infertile women with polycystic ovary syndrome
Ir a la tabla de la revisión
Summary of findings 2. Letrozole compared to laparoscopic ovarian drilling for infertile women with polycystic ovary syndrome

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

Patient or population: infertile women with polycystic ovary syndrome
Setting: (fertility) clinics or outpatient settings
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
(trials)

Certainty of the evidence
(GRADE)

Comments

Risk with LOD

Risk with letrozole

Live birth rate

229 per 1000

380 per 1000
(227 to 561)

OR 2.07
(0.99 to 4.32)

141
(1 RCT)

⊕⊝⊝⊝
Very Lowa,b,c

 

Ovarian hyperstimulation syndrome rate

No trials reported on this outcome

Clinical pregnancy rate

290 per 1000

375 per 1000
(279 to 482)

OR 1.47
(0.95 to 2.28)

376
(3 RCTs)

⊕⊕⊝⊝
Lowa,b

 

Miscarriage rate per pregnancy

151 per 1000

104 per 1000
(38 to 254)

OR 0.65
(0.22 to 1.92)

122
(3 RCTs)

⊕⊕⊝⊝
Lowa,b

 

Multiple pregnancy rate

0 per 1000

0 per 1000
(0 to 0)

OR 3.00
(0.12 to 74.90)

141
(1 RCT)

⊕⊝⊝⊝
Very Lowa,b,c

 

*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; OR: odds ratio; RCT: randomised controlled trial

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 trials ‐ 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.
cAnalysis is based on only one trial ‐ downgraded one additional level for imprecision.
 

Figuras y tablas -
Summary of findings 2. Letrozole compared to laparoscopic ovarian drilling for infertile women with polycystic ovary syndrome
Ir a la tabla de la revisión
Comparison 1. Letrozole compared to placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Live birth rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.2 Ovarian hyperstimulation syndrome rate Show forest plot

2

167

Risk Difference (M‐H, Fixed, 95% CI)

0.00 [‐0.05, 0.05]

1.3 Clinical pregnancy rate Show forest plot

2

167

Odds Ratio (M‐H, Fixed, 95% CI)

2.88 [1.08, 7.66]

1.4 Miscarriage rate per woman Show forest plot

2

167

Odds Ratio (M‐H, Fixed, 95% CI)

1.60 [0.26, 9.89]

1.5 Miscarriage rate per pregnancy Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.6 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
Ir a la tabla de la revisión
Comparison 2. Letrozole compared to SERM with or without adjuncts, followed by timed intercourse

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Live birth rate Show forest plot

11

2060

Odds Ratio (M‐H, Fixed, 95% CI)

1.72 [1.40, 2.11]

2.1.1 AIs versus clomiphene citrate

8

1646

Odds Ratio (M‐H, Fixed, 95% CI)

1.79 [1.42, 2.25]

2.1.2 Aromatase inhibitor + metformin compared to clomiphene + metformin

2

194

Odds Ratio (M‐H, Fixed, 95% CI)

1.70 [0.89, 3.23]

2.1.3 Aromatase inhibitor + FSH compared to clomiphene + FSH

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

1.18 [0.53, 2.61]

2.1.4 AIs versus clomiphene + estradiol valerate

1

100

Odds Ratio (M‐H, Fixed, 95% CI)

1.48 [0.54, 4.06]

2.2 Live birth rate by BMI Show forest plot

9

1880

Odds Ratio (M‐H, Fixed, 95% CI)

1.74 [1.41, 2.15]

2.2.1 BMI > 25

6

1428

Odds Ratio (M‐H, Fixed, 95% CI)

1.84 [1.44, 2.35]

2.2.2 BMI < 25

3

452

Odds Ratio (M‐H, Fixed, 95% CI)

1.49 [0.98, 2.25]

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

11

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.3.1 No previous ovulation induction

4

1089

Odds Ratio (M‐H, Fixed, 95% CI)

1.61 [1.22, 2.14]

2.3.2 CC‐resistant women

4

344

Odds Ratio (M‐H, Fixed, 95% CI)

1.78 [1.08, 2.93]

2.3.3 Unclear or mixed study cohort

3

627

Odds Ratio (M‐H, Fixed, 95% CI)

1.88 [1.31, 2.69]

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

11

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.4.1 Unclear risk of allocation

8

1031

Odds Ratio (M‐H, Fixed, 95% CI)

1.90 [1.42, 2.54]

2.4.2 Low risk of allocation

3

1029

Odds Ratio (M‐H, Fixed, 95% CI)

1.57 [1.18, 2.08]

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

11

2060

Odds Ratio (M‐H, Fixed, 95% CI)

1.72 [1.40, 2.11]

2.5.1 High risk of detection

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

2.60 [0.83, 8.13]

2.5.2 Low risk of detection

5

1189

Odds Ratio (M‐H, Fixed, 95% CI)

1.65 [1.26, 2.16]

2.5.3 Unclear risk of detection

5

807

Odds Ratio (M‐H, Fixed, 95% CI)

1.76 [1.27, 2.44]

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

11

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.6.1 Unclear risk of attrition

1

147

Odds Ratio (M‐H, Fixed, 95% CI)

2.04 [0.93, 4.50]

2.6.2 Low risk of attrition

9

1645

Odds Ratio (M‐H, Fixed, 95% CI)

1.75 [1.39, 2.19]

2.6.3 High risk of attrition

1

268

Odds Ratio (M‐H, Fixed, 95% CI)

1.46 [0.85, 2.50]

2.7 Ovarian hyperstimulation syndrome rate Show forest plot

10

1848

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.01]

2.7.1 AIs versus clomiphene citrate

8

1572

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

2.7.2 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Risk Difference (M‐H, Fixed, 95% CI)

0.00 [‐0.04, 0.04]

2.8 Ovarian hyperstimulation syndrome rate by BMI Show forest plot

9

Risk Difference (M‐H, Fixed, 95% CI)

Subtotals only

2.8.1 BMI > 25

4

1163

Risk Difference (M‐H, Fixed, 95% CI)

‐0.01 [‐0.01, 0.00]

2.8.2 BMI < 25

5

605

Risk Difference (M‐H, Fixed, 95% CI)

0.00 [‐0.02, 0.02]

2.9 Clinical pregnancy rate Show forest plot

23

3321

Odds Ratio (M‐H, Fixed, 95% CI)

1.69 [1.45, 1.98]

2.9.1 Aromatase inhibitor versus clomiphene citrate

17

2516

Odds Ratio (M‐H, Fixed, 95% CI)

1.70 [1.42, 2.03]

2.9.2 Aromatase inhibitor + metformin versus clomiphene + metformin

3

294

Odds Ratio (M‐H, Fixed, 95% CI)

1.86 [1.05, 3.29]

2.9.3 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Odds Ratio (M‐H, Fixed, 95% CI)

1.37 [0.82, 2.27]

2.9.4 AIs versus tamoxifen

2

135

Odds Ratio (M‐H, Fixed, 95% CI)

1.58 [0.64, 3.90]

2.9.5 AIs versus clomiphene + estradiol valerate

1

100

Odds Ratio (M‐H, Fixed, 95% CI)

2.47 [0.94, 6.46]

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

21

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.10.1 Unclear risk of allocation

17

1931

Odds Ratio (M‐H, Fixed, 95% CI)

1.74 [1.41, 2.14]

2.10.2 Low risk of allocation

4

580

Odds Ratio (M‐H, Fixed, 95% CI)

1.56 [1.10, 2.21]

2.11 Miscarriage rate per woman Show forest plot

15

2422

Odds Ratio (M‐H, Fixed, 95% CI)

1.37 [1.01, 1.87]

2.11.1 AIs versus clomiphene citrate

10

1752

Odds Ratio (M‐H, Fixed, 95% CI)

1.40 [0.98, 1.99]

2.11.2 Aromatase inhibitor + metformin versus clomiphene + metformin

3

294

Odds Ratio (M‐H, Fixed, 95% CI)

1.21 [0.52, 2.82]

2.11.3 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Odds Ratio (M‐H, Fixed, 95% CI)

0.84 [0.31, 2.27]

2.11.4 AIs versus clomiphene + estradiol valerate

1

100

Odds Ratio (M‐H, Fixed, 95% CI)

12.21 [0.66, 226.97]

2.12 Miscarriage rate per pregnancy Show forest plot

15

736

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.66, 1.32]

2.12.1 AIs versus clomiphene citrate

10

529

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.63, 1.42]

2.12.2 Aromatase inhibitor + metformin versus clomiphene + metformin

3

79

Odds Ratio (M‐H, Fixed, 95% CI)

0.80 [0.32, 2.02]

2.12.3 Aromatase inhibitor + hMG versus clomiphene + hMG

2

104

Odds Ratio (M‐H, Fixed, 95% CI)

0.67 [0.23, 1.96]

2.12.4 AIs versus clomiphene + estradiol valerate

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

8.13 [0.39, 167.90]

2.13 Multiple pregnancy rate Show forest plot

14

2247

Odds Ratio (M‐H, Fixed, 95% CI)

0.74 [0.42, 1.32]

2.13.1 Aromatase inhibitor versus clomiphene citrate

12

1971

Odds Ratio (M‐H, Fixed, 95% CI)

0.69 [0.35, 1.34]

2.13.2 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.29, 3.05]
Figuras y tablas -
Comparison 2. Letrozole compared to SERM with or without adjuncts, followed by timed intercourse
Ir a la tabla de la revisión
Comparison 3. Letrozole compared to SERMs with our without adjuncts, followed by IUI

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Ovarian hyperstimulation syndrome rate Show forest plot

2

1494

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

3.1.1 AI versus clomiphene

1

107

Risk Difference (M‐H, Fixed, 95% CI)

‐0.02 [‐0.07, 0.03]

3.1.2 AI versus clomiphene + rFSH and rFSH only

1

1387

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

3.2 Clinical pregnancy rate Show forest plot

3

1597

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [1.30, 2.25]

3.2.1 AI versus clomiphene

2

210

Odds Ratio (M‐H, Fixed, 95% CI)

2.09 [0.97, 4.53]

3.2.2 AI versus clomiphene + rFSH and rFSH only

1

1387

Odds Ratio (M‐H, Fixed, 95% CI)

1.66 [1.23, 2.22]

3.3 Miscarriage rate per woman Show forest plot

2

1490

Odds Ratio (M‐H, Fixed, 95% CI)

1.22 [0.62, 2.40]

3.3.1 AI versus clomiphene

1

103

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 8.06]

3.3.2 AI versus clomiphene + rFSH and rFSH only

1

1387

Odds Ratio (M‐H, Fixed, 95% CI)

1.32 [0.66, 2.65]

3.4 Miscarriage rate per pregnancy Show forest plot

2

260

Odds Ratio (M‐H, Fixed, 95% CI)

0.76 [0.37, 1.57]

3.4.1 AI versus clomiphene

1

15

Odds Ratio (M‐H, Fixed, 95% CI)

0.10 [0.00, 3.09]

3.4.2 AI versus clomiphene + rFSH and rFSH only

1

245

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.40, 1.79]

3.5 Multiple pregnancy rate Show forest plot

3

1597

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.49, 2.13]

3.5.1 AI versus clomiphene

2

210

Odds Ratio (M‐H, Fixed, 95% CI)

3.48 [0.14, 87.49]

3.5.2 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 SERMs with our without adjuncts, followed by IUI
Ir a la tabla de la revisión
Comparison 4. Letrozole compared to laparoscopic ovarian drilling

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

4.1 Live birth rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.2 Clinical pregnancy rate Show forest plot

3

367

Odds Ratio (M‐H, Fixed, 95% CI)

1.47 [0.95, 2.28]

4.2.1 AI versus LOD

2

221

Odds Ratio (M‐H, Fixed, 95% CI)

1.69 [0.96, 2.97]

4.2.2 AI + metformin versus LOD

1

146

Odds Ratio (M‐H, Fixed, 95% CI)

1.20 [0.60, 2.39]

4.3 Miscarriage rate per woman Show forest plot

3

367

Odds Ratio (M‐H, Fixed, 95% CI)

0.87 [0.31, 2.44]

4.3.1 AI versus LOD

2

221

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.14, 2.50]

4.3.2 AI + metformin versus LOD

1

146

Odds Ratio (M‐H, Fixed, 95% CI)

1.35 [0.29, 6.27]

4.4 Miscarriage rate per pregnancy Show forest plot

3

122

Odds Ratio (M‐H, Fixed, 95% CI)

0.65 [0.22, 1.92]

4.4.1 AI versus LOD

2

73

Odds Ratio (M‐H, Fixed, 95% CI)

0.38 [0.08, 1.72]

4.4.2 AI + metformin versus LOD

1

49

Odds Ratio (M‐H, Fixed, 95% CI)

1.21 [0.24, 6.09]

4.5 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Figuras y tablas -
Comparison 4. Letrozole compared to laparoscopic ovarian drilling
Ir a la tabla de la revisión
Comparison 5. Letrozole compared to FSH

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

5.1 Live birth Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

5.2 Ovarian hyperstimulation syndrome rate Show forest plot

2

236

Risk Difference (M‐H, Fixed, 95% CI)

‐0.03 [‐0.08, 0.01]

5.3 Clinical pregnancy rate Show forest plot

2

236

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.46, 1.43]

5.4 Miscarriage rate per woman Show forest plot

2

236

Odds Ratio (M‐H, Fixed, 95% CI)

0.61 [0.19, 1.92]

5.5 Miscarriage rate per pregnancy Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5.6 Multiple pregnancy rate Show forest plot

2

236

Odds Ratio (M‐H, Fixed, 95% CI)

0.22 [0.04, 1.32]
Figuras y tablas -
Comparison 5. Letrozole compared to FSH
Ir a la tabla de la revisión
Comparison 6. Letrozole compared to anastrozole

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

6.1 Clinical pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

6.2 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Figuras y tablas -
Comparison 6. Letrozole compared to anastrozole
Ir a la tabla de la revisión
Comparison 7. Letrozole compared to berberine, followed by timed intercourse

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

7.1 Live birth rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

7.2 Clinical pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

7.3 Miscarriage rate per woman Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

7.4 Miscarriage rate per pregnancy Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

7.5 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Figuras y tablas -
Comparison 7. Letrozole compared to berberine, followed by timed intercourse
Ir a la tabla de la revisión
Comparison 8. Different administration protocols of letrozole

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

8.1 Clinical pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

8.1.1 Letrozole day 3‐7 administration versus day 5‐9 administration

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected
Figuras y tablas -
Comparison 8. Different administration protocols of letrozole
Ir a la tabla de la revisión
Comparison 9. Dosage studies of letrozole

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

9.1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

9.1.1 5 mg versus 7.5 mg letrozole

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

9.2 Clinical pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.2.1 5 mg versus 7.5 mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.3 Miscarriage rate per woman Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.3.1 5 mg versus 7.5 mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.4 Miscarriage rate per pregnancy Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.4.1 5 mg versus 7.5 mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.5 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.5.1 5 mg versus 7.5 mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected
Figuras y tablas -
Comparison 9. Dosage studies of letrozole
Ir a la tabla de la revisión