Recombinant luteinizing hormone (rLH) and recombinant follicle stimulating hormone (rFSH) for ovarian stimulation in IVF/ICSI cycles
Abstract
Background
One of the various ovarian stimulation regimens used for in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles is the use of recombinant follicle‐stimulating hormone (rFSH) in combination with a gonadotrophin‐releasing hormone (GnRH) analogue. GnRH analogues prevent premature luteinizing hormone (LH) surges. Since they deprive the growing follicles of LH, the question arises as to whether supplementation with recombinant LH (rLH) would increase live birth rates. This is an updated Cochrane Review; the original version was published in 2007.
Objectives
To compare the effectiveness and safety of recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) for ovarian stimulation compared to rFSH alone in women undergoing in‐vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI).
Search methods
For this update we searched the following databases in June 2016: the Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO and ongoing trials registers, and checked the references of retrieved articles.
Selection criteria
We included randomised controlled trials (RCTs) comparing rLH combined with rFSH versus rFSH alone in IVF/ISCI cycles.
Data collection and analysis
Two review authors independently selected studies, assessed risk of bias, and extracted data. We combined data to calculate odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I2 statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. Our primary outcomes were live birth rate and incidence of ovarian hyperstimulation syndrome (OHSS). Secondary outcomes included ongoing pregnancy rate, miscarriage rate and cancellation rates (for poor response or imminent OHSS).
Main results
We included 36 RCTs (8125 women). The quality of the evidence ranged from very low to moderate. The main limitations were risk of bias (associated with poor reporting of methods) and imprecision.
Live birth rates: There was insufficient evidence to determine whether there was a difference between rLH combined with rFSH versus rFSH alone in live birth rates (OR 1.32, 95% CI 0.85 to 2.06; n = 499; studies = 4; I2 = 63%, very low‐quality evidence). The evidence suggests that if the live birth rate following treatment with rFSH alone is 17% it will be between 15% and 30% using rLH combined with rFSH.
OHSS: There may be little or no difference between rLH combined with rFSH versus rFSH alone in OHSS rates (OR 0.38, 95% CI 0.14 to 1.01; n = 2178; studies = 6; I2 = 10%, low‐quality evidence). The evidence suggests that if the rate of OHSS following treatment with rFSH alone is 1%, it will be between 0% and 1% using rLH combined with rFSH.
Ongoing pregnancy rate: The use of rLH combined with rFSH probably improves ongoing pregnancy rates, compared to rFSH alone (OR 1.20, 95% CI 1.01 to 1.42; participants = 3129; studies = 19; I2 = 2%, moderate‐quality evidence). The evidence suggests that if the ongoing pregnancy rate following treatment with rFSH alone is 21%, it will be between 21% and 27% using rLH combined with rFSH.
Miscarriage rate: The use of rLH combined with rFSH probably makes little or no difference to miscarriage rates, compared to rFSH alone (OR 0.93, 95% CI 0.63 to 1.36; n = 1711; studies = 13; I2 = 0%, moderate‐quality evidence). The evidence suggests that if the miscarriage rate following treatment with rFSH alone is 7%, the miscarriage rate following treatment with rLH combined with rFSH will be between 4% and 9%.
Cancellation rates: There may be little or no difference between rLH combined with rFSH versus rFSH alone in rates of cancellation due to low response (OR 0.77, 95% CI 0.54 to 1.10; n = 2251; studies = 11; I2 = 16%, low quality evidence). The evidence suggests that if the risk of cancellation due to low response following treatment with rFSH alone is 7%, it will be between 4% and 7% using rLH combined with rFSH.
We are uncertain whether use of rLH combined with rFSH improves rates of cancellation due to imminent OHSS compared to rFSH alone. Use of a fixed effect model suggested a benefit in the combination group (OR 0.60, 95% CI 0.40 to 0.89; n = 2976; studies = 8; I2 = 60%, very low quality evidence) but use of a random effects model did not support the conclusion that there was a difference between the groups (OR 0.82, 95% CI 0.34 to 1.97).
Authors' conclusions
We found no clear evidence of a difference between rLH combined with rFSH and rFSH alone in rates of live birth or OHSS. The evidence for these comparisons was of very low‐quality for live birth and low quality for OHSS. We found moderate quality evidence that the use of rLH combined with rFSH may lead to more ongoing pregnancies than rFSH alone. There was also moderate‐quality evidence suggesting little or no difference between the groups in rates of miscarriage. There was no clear evidence of a difference between the groups in rates of cancellation due to low response or imminent OHSS, but the evidence for these outcomes was of low or very low quality.
We conclude that the evidence is insufficient to encourage or discourage stimulation regimens that include rLH combined with rFSH in IVF/ICSI cycles.
PICOs
Plain language summary
Recombinant luteinizing hormone (rLH) and recombinant follicle‐stimulating hormone (rFSH) for ovarian stimulation in IVF/ICSI cycles
Review question
What is the effectiveness and safety of a combination of recombinant luteinizing hormone (rLH) and recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone for ovarian stimulation in women undergoing in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI)?
Background
In natural ovarian cycles, luteinizing hormone and follicle‐stimulating hormone (FSH) are necessary for the maturation of ovarian follicles. One of the various stimulation regimens in IVF or ICSI cycles is ovarian stimulation with rFSH in combination with a gonadotrophin‐releasing hormone (GnRH) analogue. GnRH analogues prevent premature luteinizing hormone surges. Since they deprive the growing follicles of luteinizing hormone, the question arises as to whether supplementation with recombinant luteinizing hormone (rLH) would increase live birth rates.
Study characteristics
We found 36 randomized controlled trials comparing rLH combined with rFSH versus rFSH alone among 8125 women undergoing IVF/ICSI. This is an update of a previous Cochrane Review, first published in 2007. The evidence is current to June 2016. Only seven of the 36 studies clearly stated that they were funded by government or research institutes. Six were funded by pharmaceutical companies and the rest did not state their source of funding.
Key results
We found no clear evidence of a difference between rLH combined with rFSH and rFSH alone in rates of live birth or OHSS. The evidence for these comparisons was of very low‐quality for live birth and low quality for OHSS. We found moderate quality evidence that the use of rLH combined with rFSH may lead to more ongoing pregnancies than rFSH alone. There was also moderate‐quality evidence suggesting little or no difference between the groups in rates of miscarriage. There was no clear evidence of a difference between the groups in rates of cancellation due to low response or imminent OHSS, but the evidence for these outcomes was of low or very low quality.
We conclude that the evidence is too limited to encourage or discourage stimulation regimens that include rLH combined with rFSH in IVF/ICSI cycles.
Quality of evidence
The quality of the evidence ranged from very low to moderate. The main limitations were risk of bias (associated with poor reporting of methods) and imprecision.
Authors' conclusions
Summary of findings
| Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone | ||||||
| Population: women undergoing ovarian stimulation in IVF or ICSI treatment cycles | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| rFSH alone | rLH plus rFSH | |||||
| Live birth rate | 173 per 1000 | 217 per 1000 | OR 1.32 | 499 | ⊕⊕⊝⊝ | |
| OHSS incidence | 13 per 1000 | 5 per 1000 | OR 0.38 | 2178 | ⊕⊕⊝⊝ | |
| Ongoing pregnancy rate | 206 per 1000 | 237 per 1000 | OR 1.20 | 3129 | ⊕⊕⊝⊝ | |
| Miscarriage rate | 70 per 1000 | 65 per 1000 (45 to 93) | OR 0.93 (0.63 to 1.36) | 1711 (13 studies) | ⊕⊕⊝⊝ moderate1 | |
| Cancellation rate for low response | 67 per 1000 | 52 per 1000 (37 to 73) | OR 0.77 (0.54 to 1.10) | 2251 (11 studies) | ⊕⊕⊝⊝ | |
| Cancellation rate for imminent OHSS | 44 per 1000 | 27 per 1000 (18 to 40) | OR 0.60 (0.40 to 0.89) | 2976 (8 studies) | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to imprecision: effect estimate with wide confidence interval (wider than the interval 0.75 to 1.25) or low event rate. 4 Downgraded one level due to inconsistency (I2 >50%) 5Downgraded one level due to imprecision: findings are sensitive to choice of statistical model and are not statistically significant with use of a random effects model (OR 0.82, 95% CI 0.34 to 1.97) | ||||||
Background
Description of the condition
About 15% of couples fail to achieve conception after a year of unprotected intercourse (Te Velde 2000). Such couples may choose to undergo an assisted reproductive technology procedure such as in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).
Description of the intervention
One of the various stimulation regimens in IVF or ICSI consists of daily administration of subcutaneous injections of recombinant follicle‐stimulating hormone (rFSH) to induce multiple follicle growth in the ovaries. An integral part of this stimulation regimen is daily subcutaneous injections of a gonadotrophin‐releasing hormone (GnRH) analogue to prevent a premature luteinizing hormone (LH) surge. Two kinds of GnRH analogues are available, a GnRH agonist or a GnRH antagonist.
The intervention to be compared with this stimulation regimen is the addition of daily subcutaneous injections of recombinant luteinizing hormone (rLH) to rFSH.
How the intervention might work
Growing follicles become increasingly sensitive to, and ultimately dependent on, the presence of both luteinizing hormone (LH) and follicle‐stimulating hormone (FSH) for their development. As described in the classic 'two cell ‐ two gonadotrophin' theory, LH is needed to provide the granulosa cells with androgen precursors for estradiol biosynthesis by FSH (Short 1962). LH is also needed for the resumption of meiosis and for progesterone production after ovulation to sustain the endometrium. The profound pituitary downregulation with GnRH agonists blocks the output of LH for at least 10 days after cessation of the GnRH agonist and deprives the growing follicles completely of LH stimulation during the entire stimulation phase (Broekmans 1992; Smitz 1988), while during downregulation with a GnRH antagonist, the output of LH remains present during the stimulation phase and the blockage of LH takes place periovulatory for only three to five days.
In view of the endocrinology of the normal menstrual cycle and the negative impact of the pituitary downregulation on folliculogenesis, the intervention of ovarian stimulation with rLH combined with rFSH in downregulated IVF/ICSI cycles may have beneficial effects for growing follicles and may lead to better pregnancy outcomes compared to rFSH alone. A meta‐analysis showed that urinary human menopausal gonadotrophins (HMG), a combination of FSH and hCG in a 1:1 ratio, leads to significantly higher rates in live birth and ongoing pregnancy than rFSH in IVF or ICSI cycles, emphasising a possible role for hCG/LH (van Wely 2011).
Why it is important to do this review
This is an update of a review first published in 2007 (Mochtar 2007). International guidelines do not specify a particular stimulation regimen for IVF or ICSI as regimen of first choice (European Society of Human Reproduction and Embryology (ESHRE), American Society for Reproductive Medicine (ASRM), National Institute for Health and Care Excellence (NICE), Nederlandse Vereniging voor Obstetrie en Gynaecologie (NVOG)). Since 2006 a substantial amount of new data on rLH combined with rFSH in comparison to rFSH became available. The continuing uncertainty regarding a role for rLH in ovarian stimulation is still ongoing due to conflicting results from a large number of trials.
Objectives
To compare the effectiveness and safety of recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) for ovarian stimulation compared to rFSH alone in women undergoing in‐vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI).
Methods
Criteria for considering studies for this review
Types of studies
Truly randomized controlled studies (RCTs) were eligible for inclusion. We excluded pseudo‐randomised studies as they are associated with a high risk of bias (Vail 2003).
Types of participants
Women undergoing in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).
Types of interventions
We compared recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) to rFSH alone as stimulation protocols in in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) followed by embryo transfer.
Types of outcome measures
Primary outcomes
1. Live birth rate; defined as delivery of a live foetus after 20 completed weeks of gestation.
2. Primary safety outcome: incidence of ovarian hyperstimulation syndrome (mild, moderate, or severe).
Secondary outcomes
3. Ongoing pregnancy rate; defined as foetal heartbeat at 12 weeks gestation.
4. Clinical pregnancy rate; defined as gestational sac at ultrasound, with or without foetal heartbeat, any time before 12 weeks gestation.
5. Miscarriage rate; defined as any pregnancy loss before 20 weeks of gestation.
6. Cancellation rate due to low response.
7. Cancellation rate due to imminent ovarian hyperstimulation syndrome.
Search methods for identification of studies
We searched for all relevant studies describing RCTs of women undergoing ovarian stimulation with recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) and rFSH alone for IVF or ICSI, without language restriction. The original search was performed in 2006 and updated in 2010 and 2012. In the latest update, we searched relevant studies from 2012 up to 9 June 2016.
We carried out all searches in consultation with the Gynaecology and Fertility Group (formerly Menstrual Disorders and Subfertility Group (MDSG)) Information Specialist.
Electronic searches
We searched the following electronic databases, trial registers and websites.
The Gynaecology and Fertility (formerly Menstrual Disorders and Subfertility) Group Specialised Register of Controlled Trials (from 2010 to June 2016) (Appendix 1); the Cochrane Central Register of Studies Online (CRSO) (from 2012 to June 2016) (Appendix 2); MEDLINE (from 2012 to June 2016) (Appendix 3); Embase (from 2012 to June 2016) (Appendix 4); and PsycINFO (from 2012 to June 2016) (Appendix 5). The MEDLINE search was combined with the Cochrane highly sensitive search strategy for identifying randomized trials, which appears in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011). The Embase, PsycINFO and CINAHL searches were combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/methodology/filters).
Other electronic sources of trials included:
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trial registers for ongoing and registered trials;
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www.ClinicalTrials.gov (a service of the US National Institutes of Health) (up to June 2016);
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www.who.int/trialsearch (The World Health Organization International Trials Registry Platform search portal); (up to June 2016)
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DARE (Database of Abstracts of Reviews of Effects) on the Cochrane Library at onlinelibrary.wiley.com (for reference lists from relevant non‐Cochrane reviews) (up to June 2016);
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the Web of Knowledge (wokinfo.com) (another source of trials and conference abstracts) (June 2016);
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OpenGrey ‐ (www.opengrey.eu) for unpublished literature from Europe (up to June 2016);
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LILACS database (regional.bvsalud.org) (for trials from the Portuguese and Spanish speaking world) (up to June 2016);
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PubMed and Google Scholar (for recent trials not yet indexed in MEDLINE) (up to June 2016).
Searching other resources
We handsearched reference lists of articles retrieved by the search. We also handsearched relevant journals and conference abstracts that are not covered in the Gynaecology and Fertility Group Register, in liaison with the Information Specialist.
Data collection and analysis
Selection of studies
After an initial screen of titles and abstracts retrieved by the search, we retrieved the full‐text of all potentially eligible studies. Two review authors (ND and RA) independently examined these full‐text articles for compliance with the inclusion criteria and selected studies eligible for inclusion in the review. Disagreements as to study eligibility were resolved by discussion with a third review author (MM). We documented the selection process with a PRISMA flow chart (Moher 2009; Figure 1).
Study flow diagram.
Data extraction and management
Two review authors (ND and RA) independently extracted date from eligible studies using forms designed according to Cochrane guidelines. We resolved any disagreements by discussion or by a third review author (MM). We extracted study characteristics and have presented outcome data from the included studies in the Characteristics of included studies table.
Assessment of risk of bias in included studies
Two authors (ND and RA) independently assessed the included studies for risk of bias using the 'Risk of bias' assessment tool of Cochrane (Higgins 2011). Disagreements were resolved by discussion or by a third review author (MM). We assessed selection (random sequence generation and allocation concealment); performance (blinding of participants and personnel); detection (blinding of outcome assessors); attrition (incomplete outcome data); reporting (selective reporting); and other bias, such as significant differences in demographic characteristics between treatment groups at baseline. We described all judgements and presented the conclusions in the 'Risk of bias' table.
(1) Random sequence generation
We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We assessed the method as:
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low risk of bias (any truly random process, e.g. random number table; computer random number generator);
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unclear risk of bias.
(2) Allocation concealment
We described for each included study the method used to conceal allocation to interventions prior to assignment and assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We assessed the methods as:
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low risk of bias (e.g. web or telephone randomization; consecutively numbered sealed opaque envelopes);
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high risk of bias (open list of random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
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unclear risk of bias.
(3.1) Blinding of participants and personnel
No blinding is unlikely to introduce bias, so we assessed the methods at low risk of bias.
(3.2) Blinding of outcome assessment
No blinding is unlikely to introduce bias, so we assessed the methods at low risk of bias.
(4) Incomplete outcome data
We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total number of randomized participants), reasons for attrition or exclusion, where reported, and whether missing data were balanced across groups or were related to outcomes.
We assessed methods as:
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low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
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high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure from intervention received from that assigned at randomization);
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unclear risk of bias.
(5) Selective reporting
We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed the methods as:
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low risk of bias, where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported;
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high risk of bias, where not all the study’s prespecified outcomes were reported; one or more reported primary outcomes were not prespecified; outcomes of interest were reported incompletely and so cannot be used; failure to include results of a key outcome that would have been expected to have been reported;
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unclear risk of bias.
(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)
We described for each included study any important concerns we had about other possible sources of bias.
Measures of treatment effect
We performed statistical analyses in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We reported only dichotomous outcomes and for such outcomes; we used the numbers of events in the control and intervention groups of each study to calculate Mantel‐Haenszel odds ratios (ORs). We presented 95% confidence intervals (CIs) for all outcomes and we used the Review Manager software for statistical analysis (RevMan 2014). For reporting purposes, we translated primary outcomes to absolute risks.
Unit of analysis issues
The primary analysis was ‘per woman randomized’.
Dealing with missing data
We analyzed the data on an intention‐to‐treat basis, as far as possible, and we made attempts to obtain missing data from the original trialists. If data were not obtainable from the trial authors, we assumed that live births had not occurred. For other outcomes, we analyzed only the available data.
Assessment of heterogeneity
We considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We assessed statistical heterogeneity by the measure of the I2 statistic. An I2 measurement greater than 50% was taken to indicate substantial heterogeneity (Higgins 2003; Higgins 2011).
Assessment of reporting biases
We aimed to minimise the impact of reporting biases by ensuring a comprehensive search for eligible studies, while being alert to duplication of data. If there were 10 or more studies in an analysis, we used a funnel plot to explore the possibility of small study effects, since there is a tendency for estimates of the intervention effect to be more beneficial in smaller studies.
Data synthesis
If studies were sufficiently similar, we combined the data using a fixed‐effect model.
Subgroup analysis and investigation of heterogeneity
Where there were sufficient data, we performed subgroup analyses for the following variables, for live birth, ovarian hyperstimulation syndrome, and ongoing pregnancy.
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Downregulating agent used for oocyte maturation GnRH agonist, or GnRH antagonist.
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Poor ovarian response, defined according to the Bologna criteria (Ferraretti 2011).
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Women of advanced age, defined as above 35 years of age.
Where we detected substantial heterogeneity, we explored possible explanations in sensitivity analyses. We took any statistical heterogeneity into account when interpreting the results, especially where there was any variation in the direction of effect.
Sensitivity analysis
Where we identified substantial heterogeneity, we conducted sensitivity analyses. The analyses included the use of a random‐effects model instead of a fixed‐effect model and the use of risk ratios (RRs) rather than ORs.
Overall quality of the body of evidence: 'Summary of findings' table
We prepared a 'Summary of findings' table using GRADEpro GDT (GRADEpro GDT 2014). This table evaluates the overall quality of the body of evidence for all review outcomes (summary of findings Table for the main comparison). We assessed the quality of the evidence using GRADE criteria (Atkins 2004): risk of bias, consistency of effect, imprecision, indirectness, and publication bias. Two review authors working independently, made judgements about evidence quality (high, moderate, low or very low), with disagreements resolved by discussion. We justified, documented, and incorporated judgements into the reporting of results for each outcome.
Results
Description of studies
Results of the search
For the 2017 update, we identified 496 records. We retrieved 15 potentially eligible full‐text articles. Twelve studies met our inclusion criteria (these were in addition to the 24 studies included in the original review in 2007). We excluded three studies because they did not make the comparison of interest (Fei Yang 2013; Fermin 2013) or were not randomized (Barberi 2012). See Characteristics of included studies; Characteristics of excluded studies.
The screening and selection process is presented in a PRISMA flow chart (Moher 2009; Figure 1).
Included studies
Study design and setting
We included a total of 36 RCTs in this update, of which 20 were single‐centred (Abdelmassih 2006; Allegra 2011; Balasch 2001; Barrenetxea 2008; Berkkanoglu 2007; Bosch 2011; Demirol 2005; Fábreques 2006; Fernandez‐Ramirez 2006; Ferraretti 2004; Ferraretti 2014; Griesinger 2005; Humaidan 2004; Kovacs 2010; Levi‐Setti 2006; Lisi 2005; Lisi 2012; Matorras 2009; Razi 2014; Ruvolo 2007), and seven were multicentred (Caserta 2011; De Placido 2005; Van der Houwen 2011; Konig 2013; Musters 2012; Marrs 2003; Nyboe Andersen 2008). In the remaining nine studies this was not reported (Dravid 2015; Evangelio 2011; Fabregues 2011; Mohseni 2013; Nazzaro 2012; Pezzuto 2010; Tarlatzis 2006; Vuong 2015; Younis 2014).
Participants
We included a total of 8125 women undergoing in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) in these studies. Their mean age across studies ranged from 28 to 41 years.
Eight studies included poor responders (De Placido 2005; Demirol 2005; Dravid 2015; Evangelio 2011; Ferraretti 2004; Ferraretti 2014; Ruvolo 2007; Younis 2014). In five studies, poor responders were defined as women with a previous low response in an IVF/ICSI cycle in terms of follicle growth, which was not further specified (De Placido 2005; Ferraretti 2004; Ferraretti 2014; Ruvolo 2007; Younis 2014). One study defined poor responders as women with at least two cycles with one of the following criteria: three oocytes retrieved, three follicles of 16 mm diameter on hCG day and maximal E2 (estradiol) < 500 pg/ml (Demirol 2005). One study defined poor responders on the basis of their low AMH (anti‐mullerian hormone) levels and antral follicle count (Dravid 2015). One other study defined poor responders when they were 37 years or younger or had a basal follicle‐stimulating hormone (FSH) level of > 10 or had four or less follicles in a previous IVF/ICSI cycle (Evangelio 2011).
One study excluded poor responders (defined as having a previous unsuccessful IVF cycle due to two or less oocytes recovered) (Tarlatzis 2006).
Twelve studies included women of advanced age (Allegra 2011; Barrenetxea 2008; Bosch 2011; Fabregues 2011; Fábreques 2006; Konig 2013; Matorras 2009; Musters 2012; Nazzaro 2012; Van der Houwen 2011; Vuong 2015; Younis 2014). Definitions of advanced age varied amongst the studies. Three studies defined advanced age as 35 years or older (Van der Houwen 2011; Vuong 2015; Younis 2014); six studies as between 35 and 41 years of age (Fabregues 2011; Fábreques 2006; Konig 2013; Matorras 2009; Musters 2012; Nazzaro 2012); one study as between 38 and 44 years of age (Allegra 2011); one study as between 36 and 39 years of age (Bosch 2011); and one study as 40 years or older (Barrenetxea 2008).
Interventions
rLH combined with rFSH to rFSH alone in GnRH agonist downregulated cycles
Twenty‐five studies totalling 6100 women compared rLH combined with rFSH to rFSH alone in GnRH agonist downregulated IVF or ICSI cycles (Abdelmassih 2006; Allegra 2011; Balasch 2001; Barrenetxea 2008; Berkkanoglu 2007; Caserta 2011; De Placido 2005; Fabregues 2011; Fábreques 2006; Ferraretti 2004; Ferraretti 2014; Humaidan 2004; Kovacs 2010; Lisi 2005; Lisi 2012; Marrs 2003; Matorras 2009; Mohseni 2013; Musters 2012; Nazzaro 2012; Nyboe Andersen 2008; Pezzuto 2010; Razi 2014; Ruvolo 2007; Tarlatzis 2006).
Nineteen of 25 studies started the GnRH agonist downregulation in the mid luteal phase of the preceding cycle (Abdelmassih 2006; Allegra 2011; Balasch 2001; Caserta 2011; Fabregues 2011; Fábreques 2006; Ferraretti 2004; Ferraretti 2014; Humaidan 2004; Kovacs 2010; Lisi 2005; Lisi 2012; Marrs 2003; Matorras 2009; Mohseni 2013; Musters 2012; Nyboe Andersen 2008; Pezzuto 2010; Razi 2014); and six started in the follicular phase (Barrenetxea 2008; Berkkanoglu 2007; De Placido 2005; Nazzaro 2012; Ruvolo 2007; Tarlatzis 2006).
Seven of the 25 studies started with an initial dose of rFSH for ovarian stimulation of 150 IU with a dose of rLH of 37.5 IU, 75 IU, or 150 IU (Caserta 2011; Ferraretti 2004; Griesinger 2005; Kovacs 2010; Lisi 2005; Lisi 2012; Tarlatzis 2006). Twelve studies used an initial dose for ovarian stimulation of ≥ 225 IU rFSH (Abdelmassih 2006; Allegra 2011; Balasch 2001; Barrenetxea 2008; Berkkanoglu 2007; Fábreques 2006; Ferraretti 2014; Marrs 2003; Matorras 2009; Musters 2012; Nazzaro 2012; Pezzuto 2010); and a rLH dose of 75 IU (Abdelmassih 2006; Allegra 2011; Balasch 2001; Berkkanoglu 2007; Fabregues 2011; Kovacs 2010; Lisi 2005; Lisi 2012; Pezzuto 2010; Tarlatzis 2006); or 150 IU (Barrenetxea 2008; Ferraretti 2004; Humaidan 2004; Musters 2012; Nazzaro 2012). Four studies adjusted the initial rFSH dose (150 IU to 225 IU to 300 IU) and the dose of rLH (75 IU to 150 IU) according to the age of the patient (De Placido 2005; Ferraretti 2004; Humaidan 2004; Nyboe Andersen 2008). Three studies used a stepdown rFSH stimulation protocol: Balasch 2001 used 75 IU rLH or 150 IU rLH; Fábreques 2006 used 150 IU rLH; and Fabregues 2011 used 37.5 IU rLH or 75 IU rLH. In one study the FSH dose was unknown (Mohseni 2013). In four studies, the rLH was started on stimulation day six, two on stimulation day seven and two on stimulation day eight. In two studies the start of rLH depended on follicular response (Mohseni 2013; Tarlatzis 2006). All studies, except Tarlatzis 2006, continued rLH until hCG.
rLH combined with rFSH to rFSH alone in GnRH antagonist downregulated cycles
Eleven studies totaling 2025 women compared rLH combined with rFSH to rFSH alone in GnRH antagonist downregulated IVF or ICSI cycles (Bosch 2011; Demirol 2005; Dravid 2015; Evangelio 2011; Fernandez‐Ramirez 2006; Griesinger 2005; Konig 2013; Levi‐Setti 2006; Van der Houwen 2011; Vuong 2015; Younis 2014).
Ten studies started rLH combined with rFSH together with a GnRH antagonist and continued until day of hCG (Bosch 2011; Demirol 2005; Evangelio 2011; Fernandez‐Ramirez 2006; Griesinger 2005; Konig 2013; Levi‐Setti 2006; Van der Houwen 2011; Vuong 2015; Younis 2014). One study started the GnRH antagonist on stimulation day six (Dravid 2015). Four studies used an initial dose for ovarian stimulation of ≥ 225 IU rFSH (Fernandez‐Ramirez 2006; Konig 2013; Van der Houwen 2011; Younis 2014). Two studies used 225 IU rFSH in the rFSH alone group and 150 IU in the rLH combined with rFSH group (Bosch 2011; Levi‐Setti 2006). One study used 150 IU rFSH in both groups (Dravid 2015). One study used a step‐down rFSH stimulation protocol (Demirol 2005). Two studies adjusted the initial rFSH dose to the antral follicle count (Evangelio 2011; Vuong 2015). In four studies, 75 IU rLH was used (Bosch 2011; Dravid 2015; Fernandez‐Ramirez 2006; Levi‐Setti 2006), and in five studies, 150 IU rLH was used (Demirol 2005; Griesinger 2005; Konig 2013; Van der Houwen 2011; Younis 2014). One study adjusted the rLH dose to the individual patient characteristics in a 1:2 or 1:3 rate to rFSH (Evangelio 2011). Another study supplemented 75 IU rLH or 150 IU rLH (Vuong 2015).
Outcomes
Regarding the primary outcomes on effectiveness and safety, four of the included studies reported the live birth rate (Ferraretti 2004; Ferraretti 2014; Tarlatzis 2006; Vuong 2015), and six studies reported ovarian hyperstimulation syndrome (Bosch 2011; Caserta 2011; Fabregues 2011; Fábreques 2006; Levi‐Setti 2006; Tarlatzis 2006).
A total of 19 studies reported ongoing pregnancy (Balasch 2001, Barrenetxea 2008; Bosch 2011; Demirol 2005; De Placido 2005; Fernandez‐Ramirez 2006; Ferraretti 2004;Griesinger 2005; Van der Houwen 2011; Konig 2013; Kovacs 2010; Levi‐Setti 2006; Lisi 2005; Matorras 2009; Musters 2012; Nyboe Andersen 2008; Ruvolo 2007; Tarlatzis 2006); 23 studies reported on clinical pregnancy (Abdelmassih 2006; Allegra 2011; Balasch 2001, Caserta 2011; Dravid 2015; De Placido 2005; Fábreques 2006; Fabregues 2011; Fernandez‐Ramirez 2006; Ferraretti 2004;;Humaidan 2004; Van der Houwen 2011; Konig 2013; Kovacs 2010; ; Lisi 2005; Lisi 2012; Marrs 2003; Matorras 2009; Musters 2012; Nyboe Andersen 2008; Pezzuto 2010; Razi 2014;Vuong 2015); 13 studies reported on miscarriages (Balasch 2001,.De Placido 2005;Fábreques 2006; Fabregues 2011; Ferraretti 2004; Ferraretti 2014; Griesinger 2005; Humaidan 2004; Konig 2013; Musters 2012; Razi 2014;Tarlatzis 2006; Vuong 2015); 11 studies reported on the cancellation rate due to low response (Allegra 2011; Bosch 2011; De Placido 2005; Evangelio 2011; Fábreques 2006; Fabregues 2011; Ferraretti 2014; Konig 2013; Musters 2012; Tarlatzis 2006; Vuong 2015); and eight studies reported on the cancellation rate due to imminent ovarian hyperstimulation syndrome (Allegra 2011; Bosch 2011; Caserta 2011; Ferraretti 2004; Griesinger 2005; Konig 2013; Marrs 2003; Vuong 2015).
Excluded studies
We excluded 21 studies; 14 studies used interventions that were not relevant to the review, five used designs that were not relevant to the review, and two included participants who did not meet inclusion criteria.
Further information on the excluded studies is available in the Characteristics of excluded studies table.
Risk of bias in included studies
See Figure 2 and Figure 3 for details.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Sequence generation
We rated 19 studies at low risk of selection bias for sequence generation, since they used computer randomization or random number tables for sequence generation. For 17 studies the method used in sequence generation was not fully described and we rated them at unclear risk of selection bias in relation to sequence generation.
Allocation concealment
Fourteen studies used adequate methods in concealing the allocation, and we judged them at low risk of bias. In the remaining 22 studies, the process involved in concealing the allocation was not adequately described, and we rated them at unclear risk of bias.
Blinding
Perfomance bias
Clinicians and participants were not blinded to the interventions in some of the included studies, while others did not report sufficient information on whether or not clinicians and participants were blinded. Non‐blinding of clinicians and participants may not be likely to affect the outcomes of interest, as they are objectively assessed. We, therefore, judged all included studies to be at low risk of bias.
Detection bias
Outcome assessors were not blinded in some of the included studies while others did not report sufficient information on whether or not outcome assessors were blinded. Non‐blinding of outcome assessment may not be likely to affect some outcomes of interest as they are objectively assessed. We, therefore, judged all included studies to be at low risk of bias.
Incomplete outcome data
We rated 11 studies at low risk of incomplete outcome data either because there were no withdrawals or losses to follow‐up, or the proportions of withdrawals and reasons for withdrawals were similar across treatment groups and data were analyzed on the basis of intention‐to‐treat.
Eighteen studies did not report enough information to make conclusive judgements in respect to attrition bias, and thus we rated them at unclear risk of bias.
In the remaining seven studies, the proportions of withdrawals and reasons for withdrawals or losses to follow‐up differed significantly between the treatment groups, and not all women randomized at baseline were included in data analysis; we judged these studies at high risk of bias.
Selective reporting
We judged 20 studies to be at low risk of reporting bias since the methods were prespecified. We rated this domain as unclear in 11 studies because we found no sufficient information in the methods section. We rated reporting bias as high in the remaining five studies because there was evidence of selective reporting of outcomes, as data were not available on all the outcomes prespecified in the methods section.
Other potential sources of bias
With respect to other sources of bias, we assessed studies for significant differences in baseline demographic characteristics of participants. We rated 22 studies at low risk of bias, since there were no conflict of interests and there were no other potential sources of bias, such as differences in baseline demographic characteristics. We rated the risk of bias as unclear in 14 studies, because there was insufficient information on differences in baseline characteristics of participants.
Effects of interventions
Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) versus rFSH alone in agonist or antagonist cycles
Primary outcomes
1. Live birth rate
Applying a fixed‐effect model to pool the data, there was no evidence of a difference in live birth rate between ovarian stimulation with rLH combined with rFSH and ovarian stimulation with rFSH alone (odds ratio (OR) 1.32, 95% confidence interval (CI) 0.85 to 2.06; n = 499; studies = 4; I2 = 63%, very low‐quality of evidence) (summary of findings Table for the main comparison). The evidence suggests that if the live birth rate following treatment with rFSH alone is 17%, the range of live birth rate varies between 15% and 30% using rLH combined with rFSH (Analysis 1.1, Figure 4). Applying a random‐effects model to pool the data resulted in an OR of 1.43 (95% CI 0.85 to 2.06).
Forest plot of comparison: 1 rLH plus rFSH versus rFSH alone for OS in IVF or ICSI treatment cycles, outcome: 1.1 Live birth rate.
Subgroup analysis 1.1: Downregulating agent used
There was no good evidence that the effects of the intervention differed by type of analogue (test for subgroup differences: Chi² = 1.73, df = 1 (P = 0.19), I² = 42.3%), but there were too few studies to reach any conclusions. Analysis 1.1
Subgroup analysis 1.2: Ovarian response
When studies of women identified as low responders were compared with studies not restricted to women identified as low responders, the single study of low responders suggested a benefit in the intervention group, but there were too few studies to reach any firm conclusions and the test for subgroup differences was not statistically significant (Chi² = 3.33, df = 1 (P = 0.07), I² = 69.9%). Analysis 1.2
Subgroup analysis 1.3: Advanced age
A single study was restricted to women of advanced age (Vuong 2015). There was no good evidence that the effects of the intervention differed between this study and the subgroup of studies not restricted to women of advanced age (test for subgroup differences: Chi² = 1.73, df = 1 (P = 0.19), I² = 42.3%), but there were too few studies to reach any conclusions. Analysis 1.3
2. Ovarian hyperstimulation syndrome
There was no evidence of a difference in ovarian hyperstimulation syndrome between ovarian stimulation with rLH combined with rFSH and ovarian stimulation with rFSH alone (OR 0.38, 95% CI 0.14 to 1.01; n = 2178; studies = 6; I2 = 10%, low‐quality evidence) (summary of findings Table for the main comparison). The evidence suggests that if the risk of ovarian hyperstimulation syndrome following treatment with rFSH alone is 1%, the range of ovarian hyperstimulation syndrome varies between 0% and 1% using rLH combined with rFSH (Analysis 1.4).
Subgroup analysis 2.1: Downregulating agent used
There was no good evidence that the effects of the intervention differed by type of analogue (test for subgroup differences: Chi² = 2.15, df = 1 (P = 0.14), I² = 53.5%), but there were too few studies to reach any conclusions. Analysis 1.4
Subgroup analysis 2.2: Ovarian response
No conclusions could be reached as there were no studies reporting ovarian hyperstimulation syndrome in women with low ovarian response.
Subgroup analysis 2.3: Advanced age
No conclusions could be reached as only two studies reported ovarian hyperstimulation syndrome in women of advanced age (Fabregues 2011; Fábreques 2006), and there were no cases of ovarian hyperstimulation syndrome in either study.
Secondary outcomes
3. Ongoing pregnancy rate
The use of rLH combined with rFSH was associated with a higher ongoing pregnancy rate than rFSH alone (OR 1.20, 95% CI 1.01 to 1.42; n = 3129; studies = 19; I2 = 2%, moderate‐quality evidence) (summary of findings Table for the main comparison). The evidence suggests that if the ongoing pregnancy rate following treatment with rFSH alone is 21%, the range of ongoing pregnancy rate varies between 21% and 27% using rLH combined with rFSH (Analysis 1.5).
Subgroup analysis 3.1: Downregulating agent used
Effects did not appear to differ by type of analogue (test for subgroup differences: Chi² = 0.75, df = 1 (P = 0.39), I² = 0%) (Analysis 1.5).
Subgroup analysis 3.2: Ovarian response
When studies of women identified as low responders were compared with studies not restricted to women identified as low responders, the benefits of the intervention appeared to be stronger in women identified as low responders (OR 2.06, 95% CI 1.20 to 3.53, 79 women, 3 RCTs, I2=0%) and there was a significant difference between the subgroups (test for subgroup differences: Chi² = 4.33, df = 1 (P = 0.04), I² = 76.9%). This finding requires very cautious interpretation as the subgroup of low responders was very small (n = 79) and subgroup analyses should be regarded as exploratory, as they are not randomized comparisons (Analysis 1.6).
Subgroup analysis 3.3: Advanced age
When studies restricted to women of advanced age were compared with studies not restricted by age, effects did not appear to differ between the two subgroups (Chi² = 0.46, df = 1 (P = 0.50), I² = 0%) (Analysis 1.7).
4. Clinical pregnancy rate
The use of rLH combined with rFSH was associated with a higher clinical pregnancy rate than rFSH alone (OR 1.18, 95% CI 1.03 to 1.34; n = 5071; studies = 23; I2 = 33%). The evidence suggests that if the clinical pregnancy rate following treatment with rFSH alone is 24%, the range of the clinical pregnancy rate varies between 23% and 29% using rLH combined with rFSH (Analysis 1.8). One study described higher but no significant clinical pregnancy rates in patients treated with rLH combined with rFSH compared to rFSH alone, without showing absolute numbers (Mohseni 2013).
5. Miscarriage rate
The combination of rLH combined with rFSH was not associated with a difference in miscarriage rate compared to rFSH alone (OR 0.93, 95% CI 0.63 to 1.36; n = 1711; studies = 13; I2 = 0%, moderate‐quality evidence) (Analysis 1.9; summary of findings Table for the main comparison). The evidence suggests that if the miscarriage rate following treatment with rFSH alone is 7%, the miscarriage rate following treatment with rLH combined with rFSH ranges between 4% and 9%.
6. Cancellation due to low response
There was no evidence of a difference in cancellation rate due to low response between rLH combined with rFSH and rFSH alone (OR 0.77, 95% CI 0.54 to 1.10; n = 2251; studies = 11; I2 = 16%) (Analysis 1.10). The evidence suggests that if the risk of cancellation due to low response following treatment with rFSH alone is 7%, the range of the cancellation rate due to low response varies between 4% and 7% using rLH combined with rFSH.
7. Cancellation due to imminent ovarian hyperstimulation syndrome
Applying a fixed‐effect model to pool the data, cancellation rates due to imminent ovarian hyperstimulation syndrome were lower in women who received rLH combined with rFSH than in those who received rFSH alone (OR 0.60, 95% CI 0.40 to 0.89; n = 2976; studies = 8; I2 = 60%) (Analysis 1.11). The evidence suggests that if the risk of cancellation due to imminent ovarian hyperstimulation syndrome following treatment with rFSH alone is 4%, the range of the cancellation due to imminent ovarian hyperstimulation syndrome varies between 2% and 4% using rLH combined with rFSH. However, heterogeneity was high (I2=60%) and applying a random‐effects model to pool the data resulted in an OR of 0.82 (95% CI 0.34 to 1.97).
Investigation of publication bias
Visual scanning of funnel plots for clinical pregnancy (Analysis 1.8; Figure 5), and cancellation due to low response (Analysis 1.10; Figure 6), suggested a tendency towards publication bias, with smaller negative studies less likely to be included in the review. However, visual inspection of funnel plots for ongoing pregnancy (Analysis 1.5), and miscarriage (Analysis 1.9), did not reveal such a tendency towards publication bias in favour of larger studies with positive outcomes.
Funnel plot of comparison: 1 rLH plus rFSH versus rFSH alone for ovarian stimulation in IVF or ICSI treatment cycles, outcome: 1.8 Clinical pregnancy.
Funnel plot of comparison: 1 rLH plus rFSH versus rFSH alone for OS in IVF or ICSI treatment cycles, outcome: 1.10 Adverse events (cancellation due to low response).
Discussion
Summary of main results
There was no evidence of a difference in the live birth rate between women undergoing ovarian stimulation with recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) and women undergoing ovarian stimulation with rFSH alone, regardless of the type of downregulation.
There was no evidence of a difference in the ovarian hyperstimulation syndrome rate or the miscarriage rate following ovarian stimulation with rLH combined with rFSH compared to rFSH alone in gonadotrophin‐releasing hormone (GnRH) analogue downregulated in‐vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycles. There was also no clear evidence of a difference between the groups in rates of cancellation due to low response or imminent OHSS.
However the evidence suggested a higher ongoing pregnancy rate in women treated with rLH combined with rFSH compared to rFSH alone in GnRH analogue downregulated IVF/ICSI cycles.
When studies of women identified as low responders were compared with studies not restricted to women identified as low responders, the ongoing pregnancy rate was higher in women identified as low responders. However the subgroup of low responders was very small (n = 79). This finding requires very cautious interpretation and should be regarded as exploratory.
Overall completeness and applicability of evidence
This Cochrane Review sought to evaluate the effectiveness of rLH combined with rFSH compared to rFSH alone for ovarian stimulation in downregulated IVF or ICSI cycles. We included 36 RCTs, totaling 8125 women. The sample sizes in the studies ranged between 30 and 999. Only four of the included studies, totalling 499 women had data on the primary outcome measure, live birth rate. To be able to show a difference of 5% compared to a standard live birth rate of 17%, one would require to include at least 1970 couples. Six of the included studies had data on the ovarian hyperstimulation syndrome rate. The evidence is generally applicable to women undergoing the conventional stimulation regimens in GnRH analogue downregulated IVF/ICSI cycles.
The sample size for the subgroup analysis in women with poor ovarian response and in women of advanced age was small, therefore there is insufficient evidence to make a conclusive judgement of any beneficial effect of rLH combined with rFSH in IVF or ICSI cycles compared to rFSH alone in these women.
Quality of the evidence
The overall quality of the evidence was very low for live birth, low for ovarian hyperstimulation syndrome and moderate for ongoing pregnancy and miscarriage. The main limitations in the evidence for the primary outcome live birth rate and for the secondary outcome miscarriage was imprecision, due to the small amount of data. We downgraded the quality of evidence of ovarian hyperstimulation syndrome and ongoing pregnancy because there was risk of bias associated with poor reporting of study methods.
Only seven of the 36 studies (19%) clearly stated that they were funded by government or research institutes. Six (17%) were funded by pharmaceutical companies and the rest (64%) did not state their source of funding.
Potential biases in the review process
The review authors minimised the risk of bias by conducting a search that was systematic and thorough and by having two review authors independently perform the data extraction, risk of bias assessment, and GRADE evaluation.
Agreements and disagreements with other studies or reviews
Our results are in agreement with those of a previous systematic review and meta‐analysis, comparing rLH combined with rFSH to rFSH alone in GnRH antagonist in downregulated IVF/ICSI cycles (Xiong 2014). This review identified four of the 11 studies that we included, and included one other study (Sauer 2004). We excluded Sauer 2004, since they randomized between using GnRH agonists (leuprolide) combined with rFSH versus using GnRH antagonists (cetrorelix) with or without rLH.
Our results were also in line with the results of another systematic review and meta‐analysis that compared the combination of rLH and rFSH to rFSH alone in women of advanced reproductive age undergoing IVF/ICSI (Hill 2012). This review identified the same studies that we identified.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 rLH plus rFSH versus rFSH alone for OS in IVF or ICSI treatment cycles, outcome: 1.1 Live birth rate.
Funnel plot of comparison: 1 rLH plus rFSH versus rFSH alone for ovarian stimulation in IVF or ICSI treatment cycles, outcome: 1.8 Clinical pregnancy.
Funnel plot of comparison: 1 rLH plus rFSH versus rFSH alone for OS in IVF or ICSI treatment cycles, outcome: 1.10 Adverse events (cancellation due to low response).
Comparison 1 Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone for ovarian stimulation in in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles, Outcome 1 Live birth rate.
Comparison 1 Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone for ovarian stimulation in in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles, Outcome 2 Subgroup analysis: Live birth by ovarian response.
Comparison 1 Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone for ovarian stimulation in in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles, Outcome 3 Subgroup analysis: Live birth by advanced age.
Comparison 1 Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone for ovarian stimulation in in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles, Outcome 4 OHSS.
Comparison 1 Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone for ovarian stimulation in in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles, Outcome 5 Ongoing pregnancy.
Comparison 1 Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone for ovarian stimulation in in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles, Outcome 6 Subgroup analysis: ongoing pregnancy by ovarian response.
Comparison 1 Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone for ovarian stimulation in in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles, Outcome 7 Subgroup analysis: ongoing pregnancy by advanced age.
Comparison 1 Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone for ovarian stimulation in in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles, Outcome 8 Clinical pregnancy.
Comparison 1 Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone for ovarian stimulation in in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles, Outcome 9 Miscarriage rate.
Comparison 1 Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone for ovarian stimulation in in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles, Outcome 10 Adverse events (cancellation due to low response).
Comparison 1 Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone for ovarian stimulation in in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles, Outcome 11 Adverse events (cancellation due to imminent OHSS).
| Recombinant luteinizing hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) compared to rFSH alone | ||||||
| Population: women undergoing ovarian stimulation in IVF or ICSI treatment cycles | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| rFSH alone | rLH plus rFSH | |||||
| Live birth rate | 173 per 1000 | 217 per 1000 | OR 1.32 | 499 | ⊕⊕⊝⊝ | |
| OHSS incidence | 13 per 1000 | 5 per 1000 | OR 0.38 | 2178 | ⊕⊕⊝⊝ | |
| Ongoing pregnancy rate | 206 per 1000 | 237 per 1000 | OR 1.20 | 3129 | ⊕⊕⊝⊝ | |
| Miscarriage rate | 70 per 1000 | 65 per 1000 (45 to 93) | OR 0.93 (0.63 to 1.36) | 1711 (13 studies) | ⊕⊕⊝⊝ moderate1 | |
| Cancellation rate for low response | 67 per 1000 | 52 per 1000 (37 to 73) | OR 0.77 (0.54 to 1.10) | 2251 (11 studies) | ⊕⊕⊝⊝ | |
| Cancellation rate for imminent OHSS | 44 per 1000 | 27 per 1000 (18 to 40) | OR 0.60 (0.40 to 0.89) | 2976 (8 studies) | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to imprecision: effect estimate with wide confidence interval (wider than the interval 0.75 to 1.25) or low event rate. 4 Downgraded one level due to inconsistency (I2 >50%) 5Downgraded one level due to imprecision: findings are sensitive to choice of statistical model and are not statistically significant with use of a random effects model (OR 0.82, 95% CI 0.34 to 1.97) | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Live birth rate Show forest plot | 4 | 499 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.32 [0.85, 2.06] |
| 1.1 GnRH agonist | 3 | 259 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.73 [0.95, 3.16] |
| 1.2 GnRH antagonist | 1 | 240 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.48, 1.85] |
| 2 Subgroup analysis: Live birth by ovarian response Show forest plot | 4 | 499 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.32 [0.85, 2.06] |
| 2.1 Studies restricted to women with low response | 1 | 43 | Odds Ratio (M‐H, Fixed, 95% CI) | 9.33 [1.03, 84.20] |
| 2.2 Studies not restricted to women with low response | 3 | 456 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.72, 1.83] |
| 3 Subgroup analysis: Live birth by advanced age Show forest plot | 4 | 499 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.32 [0.85, 2.06] |
| 3.1 Studies restricted to women of advanced age | 1 | 240 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.48, 1.85] |
| 3.2 Studies not restricted to women of advanced age | 3 | 259 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.73 [0.95, 3.16] |
| 4 OHSS Show forest plot | 6 | 2178 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.14, 1.01] |
| 4.1 GnRH agonist | 4 | 1418 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.16 [0.03, 0.88] |
| 4.2 GnRH antagonist | 2 | 760 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.21, 3.00] |
| 5 Ongoing pregnancy Show forest plot | 19 | 3129 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.20 [1.01, 1.42] |
| 5.1 GnRH agonist | 12 | 1980 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.27 [1.02, 1.57] |
| 5.2 GnRH antagonist | 7 | 1149 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.82, 1.43] |
| 6 Subgroup analysis: ongoing pregnancy by ovarian response Show forest plot | 19 | 3129 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.20 [1.01, 1.42] |
| 6.1 Studies restricted to women with low response | 3 | 276 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.06 [1.20, 3.53] |
| 6.2 Studies not restricted to women with low response | 16 | 2853 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.94, 1.35] |
| 7 Subgroup analysis: ongoing pregnancy by advanced age Show forest plot | 19 | 3129 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.20 [1.01, 1.42] |
| 7.1 Studies restricted to women of advanced age | 5 | 1170 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.84, 1.48] |
| 7.2 Studies not restricted to women of advanced age | 14 | 1959 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.24 [1.00, 1.54] |
| 8 Clinical pregnancy Show forest plot | 23 | 5071 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.18 [1.03, 1.34] |
| 9 Miscarriage rate Show forest plot | 13 | 1711 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.63, 1.36] |
| 10 Adverse events (cancellation due to low response) Show forest plot | 11 | 2251 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.54, 1.10] |
| 11 Adverse events (cancellation due to imminent OHSS) Show forest plot | 8 | 2976 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.40, 0.89] |
