Abstract
Background
The use of peri‐implantation glucocorticoids has been advocated to improve embryo implantation during assistive reproductive technology (ART) cycles such as in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). It has been proposed that glucocorticoids may improve the intrauterine environment by acting as immunomodulators to reduce the uterine natural killer (NK) cell count and activity, normalising the cytokine expression profile in the endometrium and by suppression of endometrial inflammation.
Objectives
To evaluate the effectiveness and safety of glucocorticoids versus no glucocorticoids administered around the time of anticipated implantation in women undergoing IVF or ICSI.
Search methods
We searched the Cochrane Gynaecology and Fertility (CGF) Group specialised register, CENTRAL (now also containing output from two trial registers and CINAHL), MEDLINE and Embase, on 20 December 2021, together with reference checking, contact with experts in the field and relevant conference proceedings to identify additional studies. This review is an update of the review first published in 2007 and last updated in 2012.
Selection criteria
Randomised controlled trials (RCTs) comparing the efficacy of supplementary systemic administration of glucocorticoids in the peri‐implantation period with a placebo or no glucocorticoids in subfertile women undergoing IVF or ICSI were included.
Data collection and analysis
We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live birth rate and multiple pregnancy.
Main results
We included 16 RCTs (2232 couples analysed). We are uncertain whether glucocorticoids improved live birth rates (odds ratio (OR) 1.37, 95% confidence interval (CI) 0.69 to 2.71; 2 RCTs, n = 366; I2 = 7%; very low‐certainty evidence). This suggests that if the chance of live birth following no glucocorticoids/placebo is assumed to be 9%, the chance following glucocorticoids would be between 6% and 21%. We are also uncertain whether there was a difference between peri‐implantation glucocorticoids on multiple pregnancy rates per couple (OR 0.86, 95% CI 0.33 to 2.20; 4 RCTs, n = 504; I2 = 53%; very low‐certainty evidence). The I2 of 53% may represent moderate statistical heterogeneity and results have to be interpreted with caution. With regard to pregnancy rates, we are uncertain whether there was a difference between ongoing pregnancy rates after glucocorticoids versus no glucocorticoids/placebo (OR 1.19, 95% CI 0.80 to 1.76; 3 RCTs, n = 476; I2 = 0%; very low‐certainty evidence) and clinical pregnancy rates after glucocorticoids versus no glucocorticoids/placebo (OR 1.17, 95% CI 0.95 to 1.44; 13 RCTs, n = 1967; I2 = 0%; low‐certainty evidence). This suggests that if the chance of clinical pregnancy following no glucocorticoids/placebo is assumed to be 25%, the chance following glucocorticoids would be between 24% and 32%. Furthermore, we are also uncertain whether peri‐implantation glucocorticoids influenced miscarriage rates per couple (OR 1.09, 95% CI 0.63 to 1.87; 6 RCTs, n = 821; I2 = 0%; very low‐certainty evidence), the incidence of ectopic pregnancies per couple (OR 2.28, 95% CI 0.33 to 15.62; 3 RCTs, n = 320; I2 = 0%; very low‐certainty evidence) and ovarian hyperstimulation syndrome (OHSS) per couple (OR 1.07, 95% CI 0.60 to 1.90; 3 RCTs, n = 370; I2 = 0%; very low‐certainty evidence) compared to no glucocorticoids/placebo. The evidence was very low to low certainty: the main limitations were serious risk of bias due to poor reporting of study methods, and serious imprecision.
Authors' conclusions
Overall, there was insufficient evidence that administration of peri‐implantation glucocorticoids in IVF/ICSI cycles influenced clinical outcomes. These findings were limited to the routine use of glucocorticoids in subfertile women undergoing IVF or ICSI.
Plain language summary
Peri‐implantation glucocorticoid administration for assisted reproductive technology cycles
Review question
This review investigated whether the administration of glucocorticoids around the time of embryo implantation improved the chance of pregnancy in women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) when compared to no glucocorticoid administration. IVF and ICSI are both treatments to help achieve pregnancy.
Background
Glucocorticoids are a class of medicines that are similar to the steroid hormones that are naturally made in the body. These medicines reduce inflammation and suppress the body's immune system. Glucocorticoids suppress the inflammation of the endometrium (the tissue in the womb where the embryo implants). Therefore, glucocorticoids have been suggested to improve the chance of embryo implantation and pregnancy in women undergoing IVF or ICSI cycles.
Study characteristics
We found 16 randomised controlled trials (studies where treatments are decided at random; these usually give the most reliable evidence about treatment effects) comparing glucocorticoids around the time of embryo implantation versus no glucocorticoids or placebo (dummy treatment), in 2232 couples undergoing IVF/ICSI. The evidence is current to 20 December 2021.
Key results
Considering the quality of evidence, we are uncertain whether there was a difference in live birth rates after glucocorticoids. The evidence suggests that if the chance of live birth following no glucocorticoids or placebo is assumed to be 9%, the chance following glucocorticoids would be between 6% and 21%. We are also uncertain whether there was a difference in multiple pregnancy rates (more than one embryo per pregnancy). With regard to ongoing pregnancy and clinical pregnancy rates, we are also uncertain whether there was a difference between glucocorticoids versus no glucocorticoids or placebo. The evidence suggests that if the chance of clinical pregnancy following no glucocorticoids or placebo is assumed to be 25%, the chance following glucocorticoids would be between 24% and 32%. We are also uncertain whether there was a difference in adverse events such as ectopic pregnancy, ovarian hyperstimulation syndrome (pain and swelling of the ovaries and tummy), but these were poorly and inconsistently reported.
Quality of the evidence
The evidence was very low to low quality. The main limitations were poor reporting of study methods and the small size of included studies. More research is needed to work out the possible role of this therapy in well‐defined patient groups.
Summary of findings
Summary of findings 1. Glucocorticoids compared to no glucocorticoids or placebo for assisted reproductive technology cycles.
| Glucocorticoids compared to no glucocorticoids or placebo for assisted reproductive technology cycles | ||||||
| Patient or population: women receiving assisted reproductive technology cycles Setting: IVF clinics Intervention: glucocorticoids around peri‐implantation period Comparison: no glucocorticoids or placebo | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with no glucocorticoids or placebo | Risk with glucocorticoids | |||||
| Live birth rate per couple | Study population | OR 1.37 (0.69 to 2.71) | 366 (2 RCTs) | ⊕⊝⊝⊝ Very lowa,b | — | |
| 87 per 1000 | 116 per 1000 (62 to 206) | |||||
| Incidence of multiple pregnancies per couple | Study population | OR 0.86 (0.33 to 2.20) | 504 (4 RCTs) | ⊕⊝⊝⊝ Very lowa,b | — | |
| 36 per 1000 | 31 per 1000 (12 to 76) | |||||
| Ongoing pregnancy rate per couple | Study population | OR 1.19 (0.80 to 1.76) | 476 (3 RCTs) | ⊕⊝⊝⊝ Very lowb,c | — | |
| 280 per 1000 | 317 per 1000 (238 to 407) | |||||
| Clinical pregnancy rate per couple –pregnancy rate per couple (primary analysis) | Study population | OR 1.17 (0.95 to 1.44) | 1967 (13 RCTs) | ⊕⊕⊝⊝ Lowc | — | |
| 245 per 1000 | 275 per 1000 (235 to 318) | |||||
| Clinical pregnancy rate per couple – subgroup IVF | Study population | OR 1.44 (1.00 to 2.08) | 724 (5 RCTs) | ⊕⊝⊝⊝ Very lowb,c | — | |
| 202 per 1000 | 267 per 1000 (202 to 345) | |||||
| Clinical pregnancy rate per couple – subgroup ICSI | Study population | OR 1.08 (0.81 to 1.42) | 992 (6 RCTs) | ⊕⊝⊝⊝ Very lowb,c | — | |
| 274 per 1000 | 290 per 1000 (234 to 349) | |||||
| Clinical pregnancy rate per couple: dosage and timing of glucocorticoids – clinical pregnancy rate: lower dose glucocorticoids | Study population | OR 1.20 (0.87 to 1.67) | 780 (6 RCTs) | ⊕⊝⊝⊝ Very lowb,c | — | |
| 265 per 1000 | 302 per 1000 (239 to 376) | |||||
| Clinical pregnancy rate per couple: dosage and timing of glucocorticoids – clinical pregnancy rate: higher dose glucocorticoids | Study population | OR 1.15 (0.87 to 1.50) | 1187 (7 RCTs) | ⊕⊝⊝⊝ Very lowb,c | — | |
| 232 per 1000 | 264 per 1000 (208 to 312) | |||||
| Clinical pregnancy rate per couple: dosage and timing of glucocorticoids – clinical pregnancy rate: glucocorticoids during implantation | Study population | OR 1.17 (0.90 to 1.52) | 1246 (7 RCTs) | ⊕⊝⊝⊝ Very lowb,c | — | |
| 235 per 1000 | 274 per 1000 (216 to 318) | |||||
| Miscarriage rate per couple | Study population | OR 1.09 (0.63 to 1.87) | 821 (6 RCTs) | ⊕⊝⊝⊝ Very lowb,c | — | |
| 66 per 1000 | 72 per 1000 (43 to 117) | |||||
| Incidence of ectopic pregnancies per couple | Study population | OR 2.28 (0.33 to 15.62) | 320 (3 RCTs) | ⊕⊝⊝⊝ Very lowb,c | — | |
| 6 per 1000 | 14 per 1000 (2 to 92) | |||||
| Incidence of OHSS per couple (mild–severe) | Study population | OR 1.07 (0.60 to 1.90) | 370 (3 RCTs) | ⊕⊝⊝⊝ Very lowa,b | — | |
| 156 per 1000 | 165 per 1000 (100 to 260) | |||||
| *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; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilisation; OHSS: ovarian hyperstimulation syndrome; 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. | ||||||
aVery serious risk of bias, downgraded two levels; studies at risk of selection bias due to unclear allocation concealment and at risk of performance bias or attrition bias, or both. bSerious risk for imprecision, downgraded one level; wide confidence intervals. cVery serious risk of bias, downgraded two levels; studies at risk of selection bias due to unclear randomisation or allocation concealment and at risk of performance bias or attrition bias, or both.
Background
This is the second update of a Cochrane Review first published in 2007 (Boomsma 2007), and last updated in 2012 (Boomsma 2012).
Description of the condition
Despite substantial progress in the treatment of subfertile couples since the early 2000s and numerous advances in the field of in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), the live birth rate remains at 20% to 30% per treatment cycle (Banker 2021). When a viable embryo is transferred in the uterus during an IVF cycle, there is a chance of not getting pregnant, which is called implantation failure. The failure of embryo implantation has been a source of psychological trauma for patients and disappointment for clinicians.
Little progress has been made in the development of therapeutic strategies. Multiple aetiologies for implantation failure have been proposed. Focus has been on the embryo factor and the endometrial factor. Therapeutic strategies that improve the embryo factor, such as assisted hatching (artificial disruption of the outer coat of the embryo) (ASRM 2018; Knudtson 2017; Lacey 2021; Magli 1998; Stein 1995), and pre‐implantation genetic testing for aneuploidies (PGT‐A) are not recommended for routine use at present (Cornelisse 2020; Munné 2019; Pehlivan 2002; Pirtea 2021).
In recent years, more attention has also focused on the endometrial factor with the aim of improving endometrial receptivity. It is increasingly recognised that the receptive endometrium denotes a range of functions that may be amenable to testing and therapeutic intervention (Saxtorph 2020). These include the assessment and treatment of embryo‐endometrial asynchrony (Simón 2020), the diagnosis and modification of endometrial microbiota (Molina 2020; Moreno 2016), and the targeted or blind application of intentional injury to the endometrium (also known as endometrial scratching), with the aim of increasing the chance of pregnancy. However, the efficacy of such interventions remains uncertain, and one recent Cochrane Review concluded that current evidence does not support the routine use of endometrial injury for women undergoing IVF (Lensen 2021). A substantial amount of research has focused on the effect of ovarian stimulation protocols on endometrial receptivity. With high oestradiol concentrations and premature progesterone elevation being reported to influence endometrial receptivity, proposed strategies to avoid this include milder stimulation protocols and segmentation by which all embryos are frozen and transferred in a later cycle (Fatemi 2013).
Much interest remains in the concept of peri‐implantation immunomodulation with the aim of reducing inflammation and thus improving the intrauterine environment. Uterine receptivity is in part controlled by locally acting growth factors, cytokines and uterine natural killer (uNK) cells. Research has increased understanding of the embryo‐endometrial cross‐talk and progress is now being made in translating these new insights into clinically meaningful prognostic tests that can provide a rational basis of therapeutical interventions, including peri‐implantation immunomodulation (Craciunas 2019; Mackens 2020; Meisner Hviid 2017; Odendaal 2021). Prednisolone reduces preconceptual uNK cells in women with recurrent miscarriage (Quenby 2005). Moreover, it is now clear that not just numbers of uNK cells identified are important, but also their activity and function (Lédée 2016), and that some women with recurrent implantation failure with immune deregulation may benefit from prednisone (Lédée 2018). Immunomodulation by glucocorticoids may therefore be beneficial in IVF. However, despite evidence pointing to immunosuppression being detrimental in some cases (Robertson 2016), the 'blind' use of glucocorticoids in this context remains widespread.
Description of the intervention
Supplementary systemic administration of glucocorticoids (e.g. dehydrocortisone/prednisolone) is used in the peri‐implantation period (around the time of embryo transfer) in subfertile women undergoing IVF/ICSI, since glucocorticoids are supposed to increase endometrial receptivity and, therefore, may increase the chance of embryo implantation.
How the intervention might work
It has been proposed that glucocorticoids may improve the intrauterine environment by acting as immunomodulators to reduce the uNK cell count to the normal range (Lédée 2016; Quenby 2005), and by suppression of endometrial inflammation and normalisation of the cytokine expression profile in the endometrium. Moreover, there is some evidence that glucocorticoids may also be useful in improving the ovarian response (Fridstrom 1999), and this is the topic of another Cochrane Review (Kalampokas 2017).
Why it is important to do this review
The published trials on glucocorticoids for embryo implantation are insufficiently powered to draw conclusions on their efficacy and the trials reveal inconsistent results. Therefore, it seems appropriate to consider pooling the results from the available randomised controlled trials (RCTs).
Objectives
To evaluate the effectiveness and safety of glucocorticoids versus no glucocorticoids administered around the time of anticipated implantation in women undergoing IVF or ICSI.
Methods
Criteria for considering studies for this review
Types of studies
Inclusion criteria
We considered only truly randomised controlled trials for inclusion in this review.
Exclusion criteria
We excluded non‐randomised or quasi‐randomised controlled trials.
Types of participants
Inclusion criteria
Subfertile people, regardless of the cause of the infertility.
IVF or ICSI treatment.
Exclusion criteria
Other types of assisted reproductive technology (ART) or spontaneous conception.
Specific subgroups of people with suggested immunological disorders such as positive antibodies, or a high number of uNK cells.
Types of interventions
Inclusion criteria
We included trials that compared the efficacy of supplementary systemic administration of glucocorticoids in the peri‐implantation period with a placebo or no glucocorticoids in women undergoing IVF or ICSI.
Exclusion criteria
We excluded trials that limited administration of glucocorticoids to the follicular phase of the cycle as they are the topic of another Cochrane Review investigating the effects on response to ovarian stimulation (Kalampokas 2017).
Types of outcome measures
Primary outcomes
Effectiveness
Live birth rate per couple: number of live births divided by the number of randomised couples.
Safety
Incidence of multiple pregnancies: occurrences per randomised couple.
Secondary outcomes
Effectiveness
Ongoing pregnancy rate per couple: number of couples achieving a clinical pregnancy (evidence of a gestational sac with fetal heart motion at 12 weeks) divided by the number of randomised couples.
Clinical pregnancy rate per couple: number of couples achieving a clinical pregnancy divided by the number of randomised couples, defined as a viable intrauterine pregnancy confirmed by ultrasound.
Safety
Miscarriage rate: miscarriage prior to 24 gestational weeks per randomised couple (confirmed by ultrasound, pregnancy test or histology).
Incidence of ectopic pregnancies: occurrence per randomised couple (confirmed by histology).
Incidence of adverse effects: occurrence per randomised couple (e.g. hypertension, hypernatraemia and water retention, hypokalaemia, diabetes, osteoporosis, psychosis, muscle wasting, peptic ulceration).
Infection rate following oocyte retrieval: occurrence per randomised couple.
Incidence of ovarian hyperstimulation syndrome (OHSS): occurrence per randomised couple
Incidence of fetal abnormalities: occurrence per total number of clinical pregnancies, such as congenital abnormalities or growth restriction
Additional outcomes not appropriate for statistical pooling
Data per cycle, per pregnancy or per embryo transfer (ET) were not appropriate for pooling because of 'unit of analysis' errors. Simple group comparison tests for categorical data require that observations are statistically independent. The use of multiple observations per woman leads to unpredictable bias in the estimate of treatment differences (Vail 2003). However, due to the frequency that this form of data is reported in subfertility research, it has been entered into the table of comparisons for the following outcomes.
Implantation rate, the number of fetal sacs divided by the number of embryos transferred.
Incidence of miscarriage per total number of pregnancies.
Incidence of multiple pregnancies per total number of pregnancies.
Search methods for identification of studies
We searched for all published and unpublished RCTs, without language restriction, in consultation with the CGF Group Information Specialist, on 20 December 2021. We handsearched the European Society of Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM) abstract books. A full description is given in the Group's module on the Cochrane Library (see cgf.cochrane.org).
Electronic searches
We searched the following databases:
the CGF Group's Specialised Register of Controlled Trials, ProCite platform (searched 20 December 2021) (Appendix 1);
CENTRAL, via the Cochrane Register of Studies Online (CRSO) Web platform (CENTRAL now contains output from two trials registers and CINAHL) (2021, Issue 11) (Appendix 2);
MEDLINE Epub Ahead of Print, In‐Process, Ovid platform (searched from 1946 to 20 December 2021) (Appendix 3);
Embase, Ovid platform (searched from 1980 to 20 December 2021) (Appendix 4);
PsycINFO, Ovid platform (searched from 1806 to 20 December 2021) (Appendix 5).
The MEDLINE search was combined with the Cochrane highly sensitive search strategy for identifying randomised trials which appears in the Cochrane Handbook of Systematic Reviews of Interventions (Version 5.1.0; Section 6.4.11). The Embase and PsycINFO searches are combined 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 searched the citation lists of relevant publications, review articles, abstracts of scientific meetings and included studies. We contacted experts in the field for any additional trials. The trial registry search results from the ClinicalTrials.gov database (clinicaltrials.gov/ct2/home) and the World Health Organization International Trials Registry Platform search portal (www.who.int/trialsearch/Default.aspx) were included in the CENTRAL search output.
We also searched the Epistemonikos database (www.epistemonikos.org/), a multilingual database of health evidence (the largest source of systematic reviews and also other scientific evidence).
Data collection and analysis
Selection of studies
For this review update, two review authors (CB and MSK) independently conducted an initial screen of titles and abstracts retrieved by the search. We retrieved the full texts of all potentially eligible studies. Two review authors (CB and MSK) independently examined these full‐text articles for compliance with the inclusion and exclusion criteria and selected the studies eligible for inclusion. If necessary, we sought additional information on trial methodology and original trial data from the authors. We resolved disagreements by discussion. We documented the selection process in a PRISMA flow chart. We extracted study characteristics and data from the included studies and presented them in the Characteristics of included studies table.
Data extraction and management
Two review authors (CB and MSK) independently extracted the data and assessed the quality of the trials.
Assessment of risk of bias in included studies
Two review authors (CB and SDK, and CB and MSK for the current update of the review) independently assessed the risk of bias for each study. Judgements were assigned as recommended in the Cochrane Handbook for Systematic Reviews of Interventions Section 8.5 (Higgins 2011). We resolved disagreements by discussion. We described all judgements fully and presented the conclusions in the risk of bias table, which was incorporated into the interpretation of review findings by means of sensitivity analyses (see below).
Selection bias (random sequence generation and allocation concealment)
Random sequence generation describes the method used to generate the allocation sequence. Biased allocation to interventions would result in a selection bias.
Method of randomisation
Truly randomised (e.g. by computer, random number tables or drawing lots).
Quasi‐randomised (e.g. by hospital number or date of birth): these studies were not included in the meta‐analysis.
Not clear (e.g. stated but not further described).
Allocation concealment describes the method used to conceal the allocation sequence. Biased allocation to interventions due to inadequate concealment of allocations prior to assignment would result in a selection and performance bias.
Good quality of concealment of allocation
Yes (e.g. sealed in opaque envelopes, computerised allocation in a non‐participating centre): low risk of bias.
Unclear (not stated): unclear risk of bias.
No (e.g. open list of random numbers, open envelopes, tables): high risk of bias.
Performance bias (blinding of participants and personnel)
Bias due to knowledge of the allocated interventions by participants and personnel during the study can result in a performance or detection bias.
Detection bias (blinding of outcome assessors)
Bias due to knowledge of the allocated interventions by outcome assessors can result in detection bias. However, the primary and secondary outcomes live birth rate and (ongoing) pregnancy rate, were not susceptible to this type of bias.
Attrition (incomplete outcome data)
Attrition bias is a type of selection bias caused by attrition (loss of participants) and includes dropouts, protocol deviations and withdrawals. We assessed dropout rates (less than 10%), reasons for dropping out, duration of follow‐up and selective loss to follow‐up, the number of and reason for cancelled cycles (less than 10%), and whether or not studies used an intention‐to‐treat analysis.
Reporting (selective reporting)
Within‐study selective reporting bias applies to the failure to report outcomes within studies. This bias was assessed by considering whether individual studies reported all relevant and expected outcomes.
Publication bias is a form of reporting bias referring to the review as a whole rather than individual studies. It refers to the phenomenon by which trials with positive results are more likely to be published (and thus identified) than trials with negative results (Begg 1989). Publication bias is detected by the construction of a funnel plot, plotting sample size versus effects size. In the absence of publication bias, the graph is symmetrical. The number of trials needed to construct a funnel plot is arbitrarily a minimum of 10 studies.
Other sources of bias
We assessed other sources of potential bias such as conflict of interest.
Measures of treatment effect
For dichotomous data (e.g. live birth rates), 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 (CI) for all outcomes.
Unit of analysis issues
The primary analysis was per couple randomised. Per pregnancy data were included for some outcomes (e.g. miscarriage, multiple pregnancy rates) and implantation rate per embryo transferred: these data do not allow valid analysis and are shown but not meta‐analysed.
Dealing with missing data
For included studies, we noted levels of attrition in the Characteristics of included studies tables. We analysed the data on an intention‐to‐treat basis as far as possible.
Assessment of heterogeneity
We examined heterogeneity between the results of different studies by inspecting the scatter in the data points and the overlap in their CIs, and more formally by checking the results of the Chi2 test.
Thresholds for the interpretation of the I2 statistic can be misleading, since the importance of inconsistency depends on several factors. An approximate guide to interpretation in the context of meta‐analyses of RCTs is as follows (Higgins 2021):
0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity;
75% to 100%: considerable heterogeneity.
Clinical heterogeneity in subfertility cannot be avoided because most centres use their own materials and methods, which can differ in several ways. When trials met the inclusion criteria and they had performed the same intervention, we considered it appropriate to pool their results.
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 studies and by being alert for duplication of data. If there were 10 or more studies in an analysis, we used a funnel plot to explore the possibility of publication bias (small‐study effects: a tendency for estimates of the intervention effect to be more beneficial in smaller studies).
Data synthesis
If the studies were sufficiently similar, we combined the data using a fixed‐effect model. We performed statistical analysis using Review Manager 5 (Review Manager 2014).
Subgroup analysis and investigation of heterogeneity
We performed the following subgroup analyses:
including women who underwent IVF and studies including women who underwent ICSI (the effect of glucocorticoids on pregnancy rates might be higher in women undergoing IVF rather than ICSI; in women undergoing ICSI an andrological cause of infertility is more likely, than an intrauterine immune disturbance);
including only women with tubal factor infertility and studies including women with male factor infertility only;
using different dosages (high versus low dose). And timing of glucocorticoid administration: around the time of embryo implantation versus studies providing glucocorticoids around the time of embryo transfer and not during the phase of embryo implantation. The dosages of all prescribed glucocorticoids were converted to an equivalent dosage of prednisolone (Corticosteroid Conversion Calculator – ClinCalc.com; clincalc.com/corticosteroids/).
The following planned analyses were not performed as no studies were identified that met the criteria:
studies including only women with unexplained infertility or recurrent implantation failure, which is usually defined as three or more failed attempts of IVF or ICSI, or implantation failure after the replacement of more than 10 embryos (El‐Toukhy 2006);
studies using different methods of administration (parenteral versus oral).
Sensitivity analysis
If more than five trials for a particular endpoint were included in the meta‐analysis, we performed the following sensitivity analyses to examine stability regarding the direction of outcomes, using:
a random‐effects model in addition to the fixed‐effect model;
studies that used adequate concealment of allocation;
studies reporting the method of randomisation.
Summary of findings and assessment of the certainty of the evidence
We prepared a summary of findings table using GRADEpro GDT and Cochrane methods (GRADEpro GDT; Higgins 2011). This table evaluates the overall certainty of the body of evidence for the main review outcomes (live birth rate, multiple pregnancy rate, ongoing pregnancy rate, clinical pregnancy rate, miscarriage rate, ectopic pregnancy rate and OHSS rate). We assessed the certainty of the evidence using GRADE criteria (risk of bias, consistency of effect, imprecision, indirectness and publication bias). Two review authors independently judged the certainty of the evidence (high, moderate, low or very low), with disagreements resolved by discussion. We justified, documented and incorporated judgements into reporting of results for each outcome.
Results
Description of studies
The included and excluded studies are described in the Characteristics of included studies and Characteristics of excluded studies tables.
Results of the search
The search identified 68 studies which potentially provided data comparing peri‐implantation glucocorticoids versus no glucocorticoids or a placebo in ART. Further evaluation based on the inclusion criteria resulted in 16 studies being eligible for inclusion in this review (Ando 1996; Bider 1996‐1; Bider 1996‐2; Botti 1998; Catt 1994; Duvan 2006; Ezzeldin 2003; Kemeter 1986; Kim 1997; Moffitt 1995; Mohammadi 2018; Mottla 1996; Nanbakhsh 2014; Salah Edeen 2009; Tan 1992; Ubaldi 2002; see Characteristics of included studies table). Full agreement existed between the two review authors concerning inclusion or exclusion of trials. A PRISMA flow chart of the results of the initial and updated search is included (Figure 1). Two of these studies were included in the review, but excluded from the meta‐analysis (Ando 1996; Kim 1997). These studies included more than one cycle per woman. These data are not appropriate for statistical pooling because data per cycle will result in an unit of analysis error.
1.
PRISMA study flow diagram (updated search 2021).
Two other studies are awaiting classification (Beltran 2020; ChiCTR1800018783; see Characteristics of studies awaiting classification table). ChiCTR1800018783 is a study protocol of an RCT comparing prednisone versus placebo in people undergoing frozen thawed embryo transfer after IVF/ICSI. Beltran 2020 is an abstract of an RCT comparing methylprednisolone versus placebo in a subgroup of women with a high risk of OHSS. It is unsure whether these women had an embryo transfer despite their OHSS, and there are no data that are pregnancy related.
Fifty studies did not meet the inclusion criteria for one or more reasons as outlined in the Characteristics of excluded studiestable.
Included studies
Study design and setting
The 16 RCTs were single‐centre studies except for Moffitt 1995. Moffitt 1995 was performed in three centres for reproductive medicine in the USA. One study used of cross‐over design (Ubaldi 2002). However, a preliminary abstract reported outcomes of the first cycle only (Ubaldi 2000). These data have been included in the meta‐analysis.
Participants
The total number of trial participants was 2232. Three studies included women with a variety of causes of infertility (Ando 1996; Duvan 2006; Moffitt 1995). Botti 1998, Mottla 1996, and Nanbakhsh 2014, did not report the cause of infertility. Three studies included women with male factor infertility (Catt 1994; Ezzeldin 2003; Ubaldi 2002). Kemeter 1986 included women with male and tubal factor infertility, whereas Bider 1996‐1 and Bider 1996‐2 included only tubal factor infertility. Tan 1992 and Salah Edeen 2009 only included women with a high risk of OHSS. Mohammadi 2018 and Salah Edeen 2009 only included women with polycystic ovarian syndrome (PCOS).
Two studies were included in the review but excluded from meta‐analysis (Ando 1996; Kim 1997): Kim 1997 included two different populations of women: endometriosis and tubal factor or only tubal factor. Among women with endometriosis and tubal factor, 38.1% had positive titres for autoantibodies. Since this systematic review focused on the routine use of glucocorticoids to improve implantation, only the results of the second group of women with tubal factor infertility were shown. Ando 1996 included data from women who were positive and women who were negative for autoantibodies; data from autoantibody negative women were shown.
Interventions
Studies used a variety of different protocols for glucocorticoid administration. The type of glucocorticoid differed: (methyl)prednisolone (Botti 1998; Catt 1994; Duvan 2006; Ezzeldin 2003; Kemeter 1986; Kim 1997; Mohammadi 2018; Moffitt 1995; Mottla 1996; Nanbakhsh 2014; Salah Edeen 2009; Ubaldi 2002), dexamethasone (Bider 1996‐1; Bider 1996‐2), and hydrocortisone combined with prednisolone (Tan 1992). Ando 1996 prescribed either dexamethasone or prednisolone with no explanation of the basis for choosing which to give.
The dose schedules and length of treatment were also variable. Methylprednisolone was used at a dose of: 16 mg per day (Botti 1998; Catt 1994; Mohammadi 2018) or 4 mg per day (Moffitt 1995). Prednisolone was used in a dose of: 5 mg per day (Ando 1996), 7.5 mg per day (Kemeter 1986), 10 mg per day (Duvan 2006; Ubaldi 2002), 15 mg per day (Ezzeldin 2003), 20 mg per day (Nanbakhsh 2014; Salah Edeen 2009), or 60 mg per day (Mottla 1996). Nanbakhsh 2014 provided prednisolone 20 mg per day in the first seven days and continued with 10 mg per day for the next seven days. Kim 1997 prescribed 10 mg per day during ovarian hyperstimulation and 60 mg per day from oocyte retrieval onwards. Controls and study participants in Ubaldi 2002 also received aspirin for four weeks. Dexamethasone was used at 0.5 mg per day by Ando 1996 and Bider 1996‐2, although Bider 1996‐1 enrolled participants either receiving 0.5 per day or 1 mg per day (cumulative results from both treatment groups were calculated). Tan 1992 administered intravenous hydrocortisone 100 mg after oocyte retrieval and started prednisolone 30 mg per day for five days, 20 mg per day for three days and 10 mg per day for two days. All other studies only used oral regimens.
Glucocorticoids were provided during the luteal phase, follicular phase, or both. They were administered from ovarian hyperstimulation onwards by Ando 1996, Kemeter 1986, Kim 1997, Mohammadi 2018, Ubaldi 2002 (until four days after oocyte retrieval) and Bider 1996‐1 (until one day after embryo transfer). In addition, glucocorticoids were administered from oocyte retrieval onwards by Mottla 1996 and Moffitt 1995 (for four days), Catt 1994 (starting after one day) and Botti 1998 (starting one day earlier) and Tan 1992 (for 10 days) and from ovulation onwards by Bider 1996‐2 (for five days). Salah Edeen 2009 provided prednisolone from human chorionic gonadotropin (hCG) onwards until the day of pregnancy testing. Glucocorticoids were provided from embryo transfer onwards by Duvan 2006, Ezzeldin 2003, and Nanbakhsh 2014 (one day before embryo transfer).
The assisted reproductive technique differed between the included studies. Participants in Duvan 2006, Ezzeldin 2003, Nanbakhsh 2014, and Ubaldi 2002 underwent ICSI; either IVF or ICSI in Botti 1998 and Salah Edeen 2009; and IVF in Ando 1996, Bider 1996‐1, Kemeter 1986, Kim 1997, Moffitt 1995, Mohammadi 2018, Mottla 1996, and Tan 1992. Only one study used subzonal sperm injection (SUZI) (Catt 1994), which involves direct placement of sperm into the space between the zona pellucida and the oocyte. This technique is comparable to, but less invasive for the oocyte than, ICSI. In addition to IVF cycles, Moffitt 1995 also included transfer cycles of frozen‐thawed embryos. Bider 1996‐2 only included transfers of frozen‐thawed embryos obtained after IVF treatment. Kemeter 1986 was an older study which used a different ovarian stimulation protocol, by using clomiphene in combination with gonadotrophins without gonadotropin‐releasing hormone (GnRH) analogue treatment.
Outcomes
Three studies assessed the primary outcome of live birth rate per couple (Ando 1996; Bider 1996‐1; Moffitt 1995). Bider 1996‐2 and Moffitt 1995 only reported preliminary results due to incomplete follow‐up, and we excluded the remaining study from meta‐analysis (Ando 1996). All studies except Salah Edeen 2009 reported the clinical pregnancy rate per couple. However, three studies reported pregnancy rate rather than clinical pregnancy rate (Bider 1996‐1; Bider 1996‐2; Botti 1998). Nine trials reported any of the other considered outcomes of adverse effects, namely multiple pregnancy rate (five RCTs), miscarriage rate (eight RCTs) and the incidence of ectopic pregnancies (four RCTs). Three studies investigated the incidence of OHSS (Mohammadi 2018; Salah Edeen 2009; Tan 1992). Bider 1996‐2, Duvan 2006, and Mottla 1996 described adverse effects of glucocorticoids.
Excluded studies
Fifty studies did not meet the inclusion criteria for one or more reasons as outlined in the Characteristics of excluded studies table. Most excluded trials did not use a random design or did not compare peri‐implantation glucocorticoids versus no glucocorticoid in the target population. Several trials investigated glucocorticoids in combination with aspirin/low molecular weight heparin (LMWH) or compared glucocorticoids in women undergoing ovulation induction/intrauterine insemination (IUI) rather than IVF or ICSI. One study reported only in abstract form without data (Shohayeb 2005). We were unsuccessful in contacting the authors. However, the study was also excluded because all participants were women with anti‐thyroid antibodies. One study with incomplete data due to premature termination was also excluded (Dmowski 1995); shortly after beginning this trial, the team moved out of the institution and the trial was discontinued. Some studies were excluded because they only included women with autoantibodies or a high number of peripheral CD69+ natural killer (NK) cells.
Studies awaiting classification
Two studies are awaiting classification (Beltran 2020; ChiCTR1800018783; Characteristics of studies awaiting classification table).
Ongoing studies
We found no ongoing studies.
Risk of bias in included studies
The risk of bias of the studies is summarised in Figure 2 and Figure 3. As can be concluded from this graph, only a small number of included studies used blinding of the study participants and personnel, only a limited number of studies reported the primary outcome of interest (live birth rate) and only one study addressed the number of dropouts and the handling of these data.
2.
Risk of bias: review authors' judgements about each risk domain presented as percentages across all included studies.
3.
Risk domains: review authors' judgements about each potential risk of bias item for each included study.
Allocation
The risk of selection bias related both to sequence generation and allocation concealment; grades were low risk, unclear or high risk. No studies were at high risk of selection bias.
Eleven studies were at low risk of selection bias related to sequence generation as they used computer randomisation, random numbers table or envelopes (Bider 1996‐1; Bider 1996‐2; Catt 1994; Duvan 2006; Kim 1997; Moffitt 1995; Mohammadi 2018; Mottla 1996; Salah Edeen 2009; Tan 1992; Ubaldi 2002). The other five studies did not describe the exact method used and had an unclear risk of this bias.
Five studies were at low risk of selection bias related to allocation concealment (Catt 1994; Moffitt 1995; Mottla 1996; Salah Edeen 2009; Tan 1992). Mottla 1996 randomised participants to receive identically packaged placebo or glucocorticoids using a table of random numbers. A pharmacist not involved in the allocation encoded identical tablets or placebo in Catt 1994 and Moffitt 1995. Salah Edeen 2009 and Tan 1992 randomised participants by drawing sealed opaque, sequentially numbered envelopes.
Blinding
Three studies comparing corticosteroid use with a placebo blinded participants (Catt 1994; Moffitt 1995; Mottla 1996). All three studies were double blind. Although the outcome pregnancy/live birth is objective, we categorised studies without blinding at high risk of performance bias as it is possible that participants in the control arm could access the corticosteroids from other sources. Moreover, for adverse effects and other subjective secondary outcomes blinding status could potentially affect findings. The remaining studies were not blinded and were at high risk of performance and detection bias.
Incomplete outcome data
Six studies were at high risk of attrition bias (Ando 1996; Bider 1996‐2; Kemeter 1986; Moffitt 1995; Mohammadi 2018; Ubaldi 2002).
Kemeter 1986 and Mohammadi 2018 reported a high rate of cancelled cycles (19 and 14%, respectively). Neither study used an intention‐to‐treat analysis; however, we used an intention to treat principle including the data of Mohammadi 2018 in the meta‐analysis. In Mohammadi 2018, transparency of dealing with dropouts was good; however, 30% of participants did not receive an embryo transfer because of a high risk of OHSS, which also increases risk of bias for our outcome clinical pregnancy. Kemeter 1986 used an atypical method of dealing with dropouts: in 34 participants the IVF treatment was cancelled. Among these participants, 22 did not receive glucocorticoids and 12 did receive glucocorticoids. The authors equalised the difference in the number of dropouts between the two study arms by removing at random an additional 10 participants from the glucocorticoid group. This method, rather than using an intention to treat analysis, resulted in an underestimation of the treatment effect of glucocorticoids. We were unsuccessful in contacting the study authors.
Ubaldi 2002 reported the number of cancelled cycles and the reasons for cancellation. The number of cancelled cycles was greater than 10% (45/360 cycles): 32 cycles had only one embryo transferred, 10 cycles were had poor response, and three cycles had a risk of OHSS. A high risk of bias may have been present since glucocorticoids were provided from controlled ovarian hyperstimulation onwards and may have influenced ovarian stimulation and embryo quality.
Few studies reported data on follow‐up or dropouts.
Bider 1996‐2 and Moffitt 1995 reported data on live birth rates; however, these data were preliminary due to incomplete follow‐up.
Three studies performed a prospective power calculation (Duvan 2006; Moffitt 1995; Tan 1992). Ezzeldin 2003 and Mottla 1996 performed a retrospective power analysis. One study employed analysis on the basis of intention to treat (pregnancy rate per initiated cycle) (Tan 1992).
Selective reporting
A study protocol was available for Mohammadi 2018 and was therefore classified as a low risk of selective reporting. All studies reported the outcomes that they planned to in their methods section. We classified the studies that did not report any adverse events at high risk of selective reporting (Bider 1996‐1; Botti 1998; Duvan 2006; Ezzeldin 2003).Salah Edeen 2009 was at high risk of selective reporting since there were no data on pregnancy or live birth rates, only the risk of OHSS.
Three studies assessed the primary outcome, namely 'live birth rate per couple' (Ando 1996; Bider 1996‐1; Moffitt 1995). However, this primary outcome is often not reported in fertility studies presumably because of the need for long follow‐up.
A funnel plot of precision versus OR showed a suggestion of publication bias for clinical pregnancy rate per couple (Figure 4). Results from the largest and third largest studies showed negative results, suggesting we do not have a fully representative set of studies. Publication bias would result in an overestimation of the effect.
4.
Funnel plot of comparison: Glucocorticoids versus no glucocorticoids or placebo, outcome: 1.5 Pregnancy rate per couple.
Other potential sources of bias
The risk of other biases was unclear in six studies. Regarding baseline comparability, four studies provided no data on maternal age to assess the comparability of the two intervention groups (Bider 1996‐2; Botti 1998; Mottla 1996; Nanbakhsh 2014). Therefore, baseline comparability of other potential prognostic factors, such as prior IVF attempts, cause and length of infertility, semen quality and dose of follicle‐stimulating hormone (FSH), was unclear. Four studies were abstracts that did not describe their methods in detail (Botti 1998; Ezzeldin 2003; Nanbakhsh 2014; Salah Edeen 2009). We found no potential sources of within‐study bias in the other 10 studies.
Use of cross‐over data was a source of potential bias in one study (Ubaldi 2002). However, a preliminary abstract reported outcomes of the first cycle only (Ubaldi 2000). These data have been included in the meta‐analysis.
We examined heterogeneity between the results of different studies by inspecting the scatter in the data points and the overlap in their CIs, and more formally by checking the results of the Chi2 test. The data points and overlap in CIs did not suggest heterogeneity in results. The I2 statistic was 0% in all analyses except for multiple pregnancy per couple (53%). The I2 statistic of 53% may represent moderate statistical heterogeneity. It is essential to consider the extent to which the results of studies are consistent with each other. However, since clinical and methodological diversities always occur in a meta‐analysis, statistical heterogeneity is inevitable. We explored the heterogeneity; however, the number of studies was low, the sample sizes were small and the number of multiple pregnancies was very low. The results among the different studies all crossed the line of no effect. The results of multiple pregnancy rate per couple had to be interpreted with caution though.
Effects of interventions
See: Table 1
The results are summarised in Table 1.
Primary outcomes
1 Live birth rate per couple
We are uncertain whether peri‐implantation glucocorticoids influenced live birth rates compared to no glucocorticoids/placebo (OR 1.37, 95% CI 0.69 to 2.71; 2 RCTs, n = 366; I2 =7%; very low‐certainty evidence; Analysis 1.1; Figure 5) (Bider 1996‐2; Moffitt 1995). This suggests that if the chance of live birth following no glucocorticoids/placebo is assumed to be 9%, the chance following glucocorticoids would be between 6% and 21%. The results from Bider 1996‐2 and Moffitt 1995 were preliminary due to incomplete follow‐up until birth. We included the data in the meta‐analysis, since it is unlikely to affect the relative effect estimates.
1.1. Analysis.
Comparison 1: Glucocorticoids versus no glucocorticoids or placebo, Outcome 1: Live birth rate per couple
5.
Forest plot of comparison: 1 Glucocorticoids versus no glucocorticoids/ placebo, outcome: 1.1 Live birth rate per couple.
2 Incidence of multiple pregnancies per couple or per pregnancy
We are uncertain whether peri‐implantation glucocorticoids influenced the rate of multiple pregnancies per couple compared to no glucocorticoids/placebo (OR 0.86, 95% CI 0.33 to 2.20; 4 RCTs, n = 504; I2 = 53%; very low‐certainty evidence; Analysis 1.2) (Bider 1996‐2; Catt 1994; Mohammadi 2018; Mottla 1996). This suggests that if the chance of a multiple pregnancy per couple following no glucocorticoids/placebo is assumed to be 4%, the chance following glucocorticoids would be between 1% and 8%. The results of multiple pregnancy rate per couple have to be interpreted with caution since an I2 statistic of 53% may represent moderate statistical heterogeneity.
1.2. Analysis.
Comparison 1: Glucocorticoids versus no glucocorticoids or placebo, Outcome 2: Incidence of multiple pregnancies per couple
The results from the multiple pregnancy rate per pregnancy, which were not statistically pooled, showed no difference in both treatment groups (Analysis 1.3).
1.3. Analysis.
Comparison 1: Glucocorticoids versus no glucocorticoids or placebo, Outcome 3: Multiple pregnancy rate per pregnancy
Secondary outcomes
3 Ongoing pregnancy rate per couple
We are uncertain whether peri‐implantation glucocorticoids influenced the ongoing pregnancy rate per couple compared to no glucocorticoids/placebo (OR 1.19, 95% CI 0.80 to 1.76; 3 RCTs, n = 476; I2 = 0%; very low‐certainty evidence; Analysis 1.4) (Moffitt 1995; Mottla 1996; Nanbakhsh 2014). This suggests that if the chance of an ongoing pregnancy following no glucocorticoids/placebo is assumed to be 28%, the chance following glucocorticoids would be between 24% and 41%.
1.4. Analysis.
Comparison 1: Glucocorticoids versus no glucocorticoids or placebo, Outcome 4: Ongoing pregnancy rate per couple
4 Clinical pregnancy rate per couple
Thirteen studies reported clinical pregnancy rates per couple and were included in the meta‐analysis (Bider 1996‐1; Bider 1996‐2; Botti 1998; Catt 1994; Duvan 2006; Ezzeldin 2003; Kemeter 1986; Moffitt 1995; Mohammadi 2018; Mottla 1996; Nanbakhsh 2014; Tan 1992; Ubaldi 2002). We are uncertain whether peri‐implantation glucocorticoids influenced clinical pregnancy rates per couple compared to no glucocorticoids/placebo (OR 1.17, 95% CI 0.95 to 1.44; 13 RCTs, n = 1967; I2 = 0%; low‐certainty evidence; Analysis 1.5; Figure 6). The evidence suggests that if the chance of clinical pregnancy following no glucocorticoids/placebo is assumed to be 25%, the chance following glucocorticoids would be between 24% and 32%.
1.5. Analysis.
Comparison 1: Glucocorticoids versus no glucocorticoids or placebo, Outcome 5: Clinical pregnancy rate per couple
6.
Forest plot of comparison: 1 Glucocorticoids versus no glucocorticoids/ placebo, outcome: 1.3 Clinical pregnancy rate per couple.
Clinical pregnancy rate per couple, subgroup analysis 1: as shown in forest plot. Subgroup of women undergoing IVF versus subgroup of women undergoing ICSI.
Clinical pregnancy rate per couple, subgroup analysis 2: not shown in forest plot. Subgroup of women with tubal infertility only versus couples with male factor infertility only. Tubal factor infertility only: two studies (OR 1.03, 95% CI 0.43 to 2.46; Bider 1996‐1; Bider 1996‐2). Male factor infertility only: three studies (OR 0.97, 95% CI 0.69 to 1.36; Catt 1994; Ezzeldin 2003; Ubaldi 2002).
Sensitivity analyses
We performed a sensitivity analysis of four studies that used adequate concealment of allocation (Catt 1994; Moffitt 1995; Mottla 1996; Tan 1992). There was insufficient evidence to determine whether peri‐implantation glucocorticoids influenced clinical pregnancy rates compared to no glucocorticoids/placebo in this selection of studies (OR 1.23, 95% CI 0.83 to 1.83).
We performed an analysis of nine studies reporting the method of randomisation (Bider 1996‐1; Bider 1996‐2; Catt 1994; Duvan 2006; Moffitt 1995; Mohammadi 2018; Mottla 1996; Tan 1992; Ubaldi 2002). It was unclear whether peri‐implantation glucocorticoids influenced clinical pregnancy rates compared to no glucocorticoids/placebo in this selection of studies (OR 1.14, 95% CI 0.86 to 1.52).
A sensitivity analysis with application of a random‐effects model revealed similar results (OR 1.16, 95% CI 0.94 to 1.43).
Subgroup analyses
IVF versus ICSI
We are uncertain of the effect of glucocorticoids on clinical pregnancy rates in a subgroup of women who underwent IVF rather than ICSI (OR 1.44, 95% CI 1.00 to 2.08; 5 RCTs, n = 724; I2 = 0%; very low‐certainty evidence; Figure 6) (Bider 1996‐1; Kemeter 1986; Moffitt 1995; Mohammadi 2018 with exclusion of cryo‐thawed embryo transfer cycles; Mottla 1996). Application of a random‐effects model revealed similar results (OR 1.43, 95% CI 0.98 to 2.07), as would be expected since the I2 statistic was 0%. We are uncertain whether there was an effect of peri‐implantation glucocorticoid administration on clinical pregnancy rates in a subgroup of women undergoing ICSI or SUZI (OR 1.08, 95% CI 0.81 to 1.42; 6 RCTs, n = 992; I2 = 0%; very low‐certainty evidence; Figure 6) (Catt 1994; Duvan 2006; Ezzeldin 2003; Nanbakhsh 2014; Tan 1992; Ubaldi 2002).
Cause of infertility
We performed a second subgroup analysis for cause of infertility, namely subgroup analyses of studies including women with tubal factor infertility (Bider 1996‐1; Bider 1996‐2), or male factor infertility only (Catt 1994; Ezzeldin 2003; Ubaldi 2002). We are uncertain whether peri‐implantation glucocorticoids influenced clinical pregnancy rates compared to no glucocorticoids/placebo in women with tubal factor infertility or male factor infertility only (tubal factor infertility: OR 1.03, 95% CI 0.43 to 2.46; male factor infertility: OR 0.98, 95% CI 0.70 to 1.38). No other subgroup analyses on cause of infertility could be performed.
Dosage and timing of glucocorticoids
The third subgroup analysis was on the dosage and timing of glucocorticoids. The dosages of all prescribed glucocorticoids were converted to an equivalent dosage of prednisolone (Corticosteroid Conversion Calculator – ClinCalc.com; clincalc.com/corticosteroids/). Studies using prednisolone at more than 10 mg per day during the luteal phase (Botti 1998; Catt 1994; Ezzeldin 2003; Mohammadi 2018; Mottla 1996; Nanbakhsh 2014; Tan 1992), and studies using prednisolone at 10 mg per day or less (Bider 1996‐1; Bider 1996‐2; Duvan 2006; Kemeter 1986; Moffitt 1995; Ubaldi 2002), were analysed separately. We are uncertain whether both a lower dose of prednisolone and a higher dose of prednisolone around the time of implantation influenced clinical pregnancy rates compared to no glucocorticoids/placebo (lower dose prednisolone versus no glucocorticoids/placebo: OR 1.20, 95% CI 0.87 to 1.67; higher dose prednisolone versus no glucocorticoids/placebo: OR 1.15, 95% CI 0.87 to 1.50; both very low‐certainty evidence; Analysis 1.6). Application of a random‐effects model revealed similar results.
1.6. Analysis.
Comparison 1: Glucocorticoids versus no glucocorticoids or placebo, Outcome 6: Clinical pregnancy rate per couple: dosage and timing of glucocorticoids
The anticipated day of embryo implantation was approximately eight to 10 days after ovulation (Wilcox 1999). Seven studies administered glucocorticoids around the time of embryo implantation (Duvan 2006; Ezzeldin 2003; Kemeter 1986; Mohammadi 2018; Nanbakhsh 2014; Tan 1992; Ubaldi 2002), other studies provided glucocorticoids around the time of embryo transfer rather than embryo implantation. We are also uncertain whether glucocorticoids influenced clinical pregnancy rates compared to no glucocorticoids/placebo in a subgroup of studies that administered glucocorticoids around the time of implantation rather than embryo transfer (OR 1.17, 95% CI 0.90 to 1.52; very low‐certainty evidence; Analysis 1.6); application of a random‐effects model revealed similar results.
All subgroup and sensitivity analyses indicated that the results were relatively robust around this variable.
5 Miscarriage rate per couple or per pregnancy
We are uncertain whether peri‐implantation glucocorticoids influenced miscarriage rates per couple compared to no glucocorticoids/placebo (OR 1.09, 95% CI 0.63 to 1.87; 6 RCTs, n = 821; I2 = 0%; very low‐certainty evidence; Analysis 1.7) (Bider 1996‐2; Kemeter 1986; Moffitt 1995; Mottla 1996; Nanbakhsh 2014; Ubaldi 2002). The random‐effects model confirmed this result.
1.7. Analysis.
Comparison 1: Glucocorticoids versus no glucocorticoids or placebo, Outcome 7: Miscarriage rate per couple
Sensitivity analysis
We performed sensitivity analyses of studies that used adequate concealment of allocation (Moffitt 1995; Mottla 1996), and studies reporting the method of randomisation (Bider 1996‐1; Kemeter 1986; Moffitt 1995; Mottla 1996; Ubaldi 2002). We are uncertain whether peri‐implantation glucocorticoids influenced miscarriage rates compared to no glucocorticoids/placebo in these two subgroups (adequate concealment of allocation: OR 1.42, CI 0.69 to 2.94; reporting the method of randomisation: OR 1.28, CI 0.69 to 2.36). The results from the number of miscarriages per total number of pregnancies were not statistically pooled.
6 Incidence of ectopic pregnancies per couple
We are uncertain whether peri‐implantation glucocorticoids influenced the incidence of ectopic pregnancies per couple compared to no glucocorticoids/placebo (OR 2.28, 95% CI 0.33 to 15.62; 3 RCTs; n = 320; I2 = 0%; very low‐certainty evidence; Analysis 1.9) (Bider 1996‐2; Kemeter 1986; Mottla 1996).
1.9. Analysis.
Comparison 1: Glucocorticoids versus no glucocorticoids or placebo, Outcome 9: Incidence of ectopic pregnancies per couple
7 Incidence of adverse effects
Bider 1996‐2, Duvan 2006, and Mottla 1996 described the incidence of adverse effects from glucocorticoids; since there were no documented cases in the control or placebo and glucocorticoid groups, the OR could not be estimated.
8 Infection rate following oocyte retrieval
No studies reported infection rate following oocyte retrieval
9 Incidence of ovarian hyperstimulation syndrome per couple
We are uncertain whether peri‐implantation glucocorticoids influenced the incidence of OHSS per couple compared to no glucocorticoids/placebo (OR 1.07, 95% CI 0.60 to 1.90; 3 RCTs, n = 370; I2 = 0%; very low‐certainty evidence; Analysis 1.10) (Mohammadi 2018; Salah Edeen 2009; Tan 1992).
1.10. Analysis.
Comparison 1: Glucocorticoids versus no glucocorticoids or placebo, Outcome 10: Incidence of ovarian hyperstimulation syndrome per couple (mild‐severe)
10 Incidence of fetal abnormalities.
No studies reported fetal abnormalities.
11 Implantation rate per embryo transferred
Ten studies reported implantation rate per embryo transferred (Ando 1996; Botti 1998; Catt 1994; Duvan 2006; Ezzeldin 2003; Moffitt 1995; Mohammadi 2018; Mottla 1996; Tan 1992; Ubaldi 2002). The results are presented but not statistically pooled. All studies crossed the line of no effect and revealed an OR around 1.0 or showed a moderate trend favouring glucocorticoids. Only Botti 1998 showed a trend that favoured controls.
Discussion
Summary of main results
The aim of this review was to evaluate the effectiveness and safety of glucocorticoids administered around the time of implantation, in women undergoing IVF or ICSI in whom no assessment of endometrial immune status had taken place, when compared to no glucocorticoid or placebo administration. Overall there is insufficient evidence to indicate a beneficial effect of peri‐implantation glucocorticoids on clinical outcomes when used in this way (Table 1). We are uncertain whether there was a difference in the live birth or clinical pregnancy rate after administration of glucocorticoids in women undergoing IVF or ICSI versus no glucocorticoids/placebo. We are also uncertain about the effect of glucocorticoids versus no glucocorticoids/placebo on the clinical pregnancy rate in a subgroup of women who underwent IVF rather than ICSI (OR 1.44, 95% CI 1.00 to 2.08). The results of this subgroup should be interpreted with caution since overall certainty of the evidence was very low. Similarly, we are uncertain whether there is a difference in the multiple pregnancy rate following administration of glucocorticoids versus no glucocorticoids or placebo in women undergoing IVF or ICSI.
Adverse effects were also considered as a secondary outcome. We are uncertain about possible negative effects of glucocorticoids such as adverse effects or OHSS, but these were poorly reported. Only three trials reported the incidence of adverse effects from glucocorticoids and there were no cases documented. No studies reported the incidence of infections or fetal abnormalities.
Overall completeness and applicability of evidence
Live birth rate is the standard primary outcome for RCTs of this nature (Vail 2003). Two trials included in the meta‐analysis reported this outcome and there was insufficient evidence for a beneficial effect of glucocorticoids (Bider 1996‐1; Moffitt 1995). Using clinical pregnancy rate as a surrogate endpoint is of dubious accuracy. Thirteen RCTs included in the meta‐analysis reported clinical pregnancy rate. These results could not easily be extrapolated to live birth rate due to the high rate of multiple pregnancies and subsequent higher rates of perinatal mortality.
These findings are limited to the empirical use of glucocorticoids (routine use in a non‐selected IVF or ICSI population) and cannot be extrapolated to women with unexplained infertility, endometriosis or recurrent implantation failure since we were unable to make subgroups of these women. None of the included studies focused on these patient subgroups. With these underlying conditions, women may have a higher chance of benefiting from peri‐implantation glucocorticoids since an impaired intrauterine environment could be a cause for their infertility and immunomodulation may improve endometrial receptivity.
Our results cannot be extrapolated to women with positive autoantibodies. Geva 2000 and Ando 1996 administered glucocorticoids to women with antinuclear, antidouble‐stranded DNA, anticardiolipin antibodies and lupus anticoagulant in an RCT; there were promising results. Another RCT investigated women with tubal factor infertility and endometriosis, of whom 38% were positive for autoantibodies (Kim 1997); women in this study receiving glucocorticoids showed significantly higher pregnancy rates versus the controls. This was not confirmed by Shohayeb 2005, who investigated glucocorticoids in women with antithyroid antibodies and found no significant differences in pregnancy rates.
Quality of the evidence
Overall, the certainty of the evidence was very low to low. The level of certainty was downgraded using GRAD, mainly because of possible selection bias (unclear method of randomisation and allocation concealment), performance bias (due to lack blinding), attrition bias and serious imprecision (wide CIs due to small sample size and small number of events). The meta‐analysis included only RCTs. No studies were graded at high risk of selection bias related to sequence generation or allocation concealment. Sample sizes were relatively small. However, many fertility trials lack power. A prospective power calculation should always be performed although the calculated sample size in most cases will be prohibitively large.
There are several methodological considerations to be considered when interpreting these results as there was substantial heterogeneity between the 14 trials in the meta‐analysis. Although there was no significant heterogeneity between trials for live birth rate and pregnancy rates, differences in clinical parameters were often considerable (clinical heterogeneity). Clinical heterogeneity cannot be avoided because most centres use their own materials and methods. The underlying assumption when similar trials are pooled is that differences found between the trials are likely to be differences in the extent of treatment effect rather than direction of treatment effect. For example, clinical heterogeneity between the studies may result in different outcomes between the studies but they all show more or less the same trend in treatment effect. Moreover, when all trials find similar results despite differences in clinical parameters, this renders more robust conclusions drawn.
The cause of infertility, type of ART and intervention protocol all varied considerably between the trials. Most importantly, there was no uniformity of dose and timing of the intervention. Subgroup analyses of higher and lower doses of corticosteroids and timing (during or before implantation) revealed no differences in pregnancy rates with glucocorticoid administrations versus controls; there was no apparent dose‐response relationship. However, most trials included a mix of the three factors. As a result, the effect of individual confounders could not be assessed.
Heterogeneity existed between the trials with regards to most aspects of trial methodology. Ezzeldin 2003 was most heavily weighted in the meta‐analysis due to its large sample size (526 participants), but this abstract did not report the method of randomisation and concealment of allocation. Only three studies were double‐blind by using a placebo, which may have introduced bias in the other studies. However, these trials did not show unusual results. In order to investigate the effect of methodological quality on treatment effect, we performed sensitivity analyses on studies with an adequate concealment of allocation and studies in which the method of randomisation was described. These sensitivity analyses did not reveal a change in treatment effect.
The results of multiple pregnancy rate per couple have to be interpreted with caution since an I2 statistic of 53% may represent moderate statistical heterogeneity.
A funnel plot of precision versus OR showed a suggestion of publication bias for the clinical pregnancy rate per couple (Figure 4), which is reason to believe that the set of studies is not fully representative. Publication bias would result in an overestimation of treatment effect. This has to be taken into account when interpreting the results. Even though there is some evidence of publication bias, there was no evidence of significant treatment effects. No studies reported funding streams.
Potential biases in the review process
The search was comprehensive and included clinical trial registries for ongoing trials. However, there is a possibility that some studies may have been missed.
Agreements and disagreements with other studies or reviews
We identified no other review or meta‐analysis that evaluated use of glucocorticoids in the peri‐implantation period in women without any underlying autoimmune disorder who were undergoing ART.
In women with autoimmune conditions undergoing ART, use of corticosteroids alone or in combination with low‐dose aspirin has been reported to improve treatment outcomes (Geva 2000; Revelli 2009). One recent systematic review including three studies reported improvement in clinical pregnancy and live birth rates following glucocorticoids in women with antithyroid antibodies undergoing ART (Zhou 2021).
Authors' conclusions
Implications for practice.
Overall, there was insufficient evidence that administration of peri‐implantation glucocorticoids in in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles influenced the clinical outcome. These findings were limited to the routine use of glucocorticoids in subfertile women undergoing IVF or ICSI, and cannot be extrapolated to women with autoantibodies, unexplained infertility or recurrent implantation failure. Further well‐designed randomised controlled trials (RCTs) are required to elucidate the possible role of this therapy in well‐defined patient groups. Overall, certainty of evidence was very low to low.
Implications for research.
There is a paucity of RCTs investigating the use of glucocorticoids among women with unexplained infertility, and recurrent failure in IVF. Those that exist have assessed the use of glucocorticoids on the assumption that immunosuppression is generally desirable. Future RCTs are more likely to discern the value of such interventions if targeted on those patients with evidence of increased inflammation.
RCTs should follow the CONSORT guidelines; many fertility trials lack adequate reporting of methodology.
Trials should be of sufficient duration to have live birth as their primary outcome and should ideally report all outcomes listed in this review.
What's new
| Date | Event | Description |
|---|---|---|
| 21 June 2022 | New search has been performed | Two new studies included in the meta‐analysis (Mohammadi 2018; Nanbakhsh 2014). Two previously included studies have been excluded from meta‐analysis due to methodological issues (Ando 1996; Kim 1997). Two studies are awaiting classification. |
| 19 January 2022 | New citation required but conclusions have not changed | The addition of two new studies has not changed the conclusions of this review |
History
Protocol first published: Issue 2, 2006 Review first published: Issue 1, 2007
| Date | Event | Description |
|---|---|---|
| 17 January 2012 | New citation required but conclusions have not changed | One study included in the meta‐analysis of the secondary adverse outcome 'incidence of OHSS'. Conclusions have not changed. |
| 17 January 2012 | New search has been performed | One study included in the meta‐analysis of the secondary adverse outcome 'incidence of OHSS'. Conclusions have not changed. |
| 27 July 2009 | New search has been performed | Two additional studies were found. However, both were excluded from the meta‐analysis. |
| 31 August 2008 | Amended | Converted to new review format. |
| 16 November 2006 | New citation required and conclusions have changed | Substantive amendment |
Acknowledgements
The authors would like to thank several people for helping in the construction of this review.
Anita Ballantyne and The Gynaecology and Fertility Information Specialist Marian Showell for searching the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials and M Kosterman (University Medical Center Utrecht, the Netherlands) for her help in handsearching the journals.
Dr F Ubaldi (European Hospital, Rome, Italy), Dr A Mollo (University of Napoli, Italy), Prof WP Dmowski (Rush Medical College, Chicago, USA) and Dr MD Hornstein (Brigham and Women's Hospital, Boston, USA) for responding to the questions about their studies.
Dr T Harada (Tottori University School of Medicine, Yonago, Japan) who kindly translated a Japanese article.
S Mirkov, K Stocking and L Craciunas, referees of the updated review 2022.
Anne Lawson, Copy Editor of this review. Cochrane provided Copy Edit Support.
Appendices
Appendix 1. Cochrane Gynaecology and Fertility Group's specialised register search strategy
ProCite platform
Searched 20 December 2021
Keywords CONTAINS "IUI" or "Intrauterine Insemination" or "insemination" or "IVF" or "in vitro fertilization" or "in‐vitro fertilisation" or "ICSI" or "intracytoplasmic sperm injection" or "Embryo" or "in‐vitro fertilization" or "ART" or "*Ovulation Induction" or "ovarian hyperstimulation syndrome" or "subfertility" or Title CONTAINS "IUI" or "Intrauterine Insemination" or "insemination" or "IVF" or "in vitro fertilization" or "in‐vitro fertilisation" or "ICSI" or "intracytoplasmic sperm injection" or "Embryo" or "in‐vitro fertilization" or "ART" or "*Ovulation Induction" or "OHSS" or "ovarian hyperstimulation syndrome" or "subfertility"
AND
Keywords CONTAINS "adrenocorticosteroids" or "corticosteriods" or "corticosteroids" or "Corticotropin‐Releasing Hormone" or "methylprednisolone" or "prednisolone" or "*Steroids" or "Glucocorticoids" or "ACTH" or "immune response" or "immunosuppressants" or "Immunosuppression" or "immunotherapy" or "prednisone" or "DHEAS" or "DHEA" or "dehydroepiandrosterone" or "dehydrogesterone" or "Dexamethasone" or "Testosterone" or "testosterone cream" or "testosterone gel" or "testosterone patch" or Title CONTAINS "adrenocorticosteroids" or "corticosteriods" or "corticosteroids" or "Corticotropin‐Releasing Hormone" or "methylprednisolone" or "prednisolone" or "*Steroids" or "Glucocorticoids" or "ACTH" or "immune response" or "immunosuppressants" or "Immunosuppression" or "immunotherapy" or "prednisone" or "DHEAS"or "DHEA" or "dehydroepiandrosterone" or "dehydrogesterone" or "Dexamethasone" or "Testosterone"or "testosterone cream" or "testosterone gel" or "testosterone patch"
(443 records)
Appendix 2. CENTRAL via the Cochrane Register of Studies Online (CRSO) search strategy
Web platform
Searched 20 December 2021
#1 recurrent miscarriage* 236
#2 implantation failure* 461
#3 ((poor or low) adj2 responder*) 1043
#4 MESH DESCRIPTOR Reproductive Techniques, Assisted EXPLODE ALL TREES 3154
#5 (assisted reproduct*):TI,AB,KY 1414
#6 (vitro fertilization or vitro fertilisation):TI,AB,KY 3433
#7 (intracytoplasmic sperm injection*):TI,AB,KY 1925
#8 insemination*:TI,AB,KY 1527
#9 IUI:TI,AB,KY 886
#10 (ovulation induction* or superovulation*):TI,AB,KY 2743
#11 (ovar* adj3 stimulat*):TI,AB,KY 2345
#12 (embryo* adj3 implant*):TI,AB,KY 1132
#13 (embryo* adj3 transfer*):TI,AB,KY 4028
#14 (luteal phase*):TI,AB,KY 2044
#15 (IVF or ICSI):TI,AB,KY 6536
#16 MESH DESCRIPTOR Ovarian Hyperstimulation Syndrome EXPLODE ALL TREES 260
#17 (Ovarian Hyperstimulation Syndrome or OHSS):TI,AB,KY 970
#18 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 13298
#19 MESH DESCRIPTOR Glucocorticoids EXPLODE ALL TREES 18979
#20 glucocorticoid*:TI,AB,KY 8200
#21 methylprednisolone*:TI,AB,KY 5139
#22 prednisolone*:TI,AB,KY 6854
#23 Steroid*:TI,AB,KY 28956
#24 corticotropin:TI,AB,KY 1170
#25 deltacortisone:TI,AB,KY 1
#26 dexol*:TI,AB,KY 2
#27 corticosteroid*:TI,AB,KY 19804
#28 MESH DESCRIPTOR Immunotherapy EXPLODE ALL TREES 7879
#29 Immunotherap*:TI,AB,KY 9663
#30 MESH DESCRIPTOR Immunosuppression EXPLODE ALL TREES 2006
#31 Immunosuppress*:TI,AB,KY 13772
#32 (dehydroepiandrosterone or DHEA):TI,AB,KY 1452
#33 (Dexamethasone or testosterone or androgel):TI,AB,KY 18385
#34 prednisone:TI,AB,KY 9243
#35 #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 or #32 or #33 or #34 99874
#36 #18 AND #35 939
Appendix 3. MEDLINE search strategy
Ovid platform
Searched from 1946 to 20 December 2021
1 exp reproductive techniques, assisted/ (74945) 2 assisted reproduct$.tw. (16967) 3 (vitro fertilization or vitro fertilisation).tw. (25239) 4 (intracytoplasmic sperm injection$ or ICSI).tw. (11804) 5 insemination.tw. (16771) 6 (artificial insemination$ or intrauterine insemination$).tw. (9893) 7 IUI.tw. (1936) 8 (ovulation induction$ or superovulation$).tw. (5770) 9 (ovar$ adj3 stimulat$).tw. (8816) 10 (embryo$ adj3 implant$).tw. (8605) 11 (embryo$ adj3 transfer$).tw. (19379) 12 luteal phase$.tw. (11162) 13 IVF.tw. (25841) 14 exp Ovarian Hyperstimulation Syndrome/ (2399) 15 (Ovarian Hyperstimulation or OHSS).tw. (5639) 16 ((poor or low) adj2 responder*).tw. (5379) 17 implantation failure*.tw. (1942) 18 recurrent miscarriage*.tw. (2312) 19 or/1‐18 (125757) 20 exp glucocorticoids/ (200288) 21 (Dexamethasone or testosterone or androgel).tw. (143496) 22 (dehydroepiandrosterone or DHEA).tw. (14005) 23 glucocorticoid$.tw. (72696) 24 methylprednisolone$.tw. (17357) 25 (prednisolone$ or prednisone).tw. (54843) 26 Steroid$.tw. (246575) 27 corticotropin$.tw. (15577) 28 deltacortisone$.tw. (22) 29 dexol$.tw. (5) 30 corticosteroid$.tw. (111169) 31 exp Immunotherapy/ (301938) 32 Immunotherap$.tw. (102817) 33 exp Immunosuppression/ (63494) 34 Immunosuppress$.tw. (160944) 35 or/20‐34 (1079505) 36 randomized controlled trial.pt. (553778) 37 controlled clinical trial.pt. (94614) 38 randomized.ab. (544364) 39 placebo.tw. (230134) 40 clinical trials as topic.sh. (198482) 41 randomly.ab. (372267) 42 trial.ti. (253166) 43 (crossover or cross‐over or cross over).tw. (91639) 44 or/36‐43 (1448046) 45 exp animals/ not humans.sh. (4932094) 46 44 not 45 (1330823) 47 19 and 35 and 46 (662)
Appendix 4. Embase search strategy
Ovid platform
Searched from 1980 to 20 December 2021
1 exp infertility therapy/ (116325) 2 artificial insemination.tw. (6835) 3 assisted reproduct$.tw. (25637) 4 (vitro fertilization or vitro fertilisation).tw. (33223) 5 (intracytoplasmic sperm injection$ or ICSI).tw. (20679) 6 insemination.tw. (18509) 7 IUI.tw. (3562) 8 (ovulation induction$ or superovulation$).tw. (7705) 9 COH.tw. (2724) 10 (ovar$ adj3 stimulat$).tw. (13321) 11 (embryo$ adj3 implant$).tw. (12266) 12 (embryo$ adj3 transfer$).tw. (30543) 13 luteal phase$.tw. (12852) 14 IVF.tw. (44311) 15 exp ovary hyperstimulation/ or exp superovulation/ (13077) 16 (Ovarian Hyperstimulation Syndrome or OHSS).tw. (5017) 17 ((poor or low) adj2 responder*).tw. (7814) 18 implantation failure*.tw. (3718) 19 recurrent miscarriage*.tw. (3903) 20 or/1‐19 (182356) 21 corticosteroid therapy/ or exp glucocorticoid/ (759183) 22 glucocorticoid$.tw. (92641) 23 methylprednisolone$.tw. (27916) 24 (prednisolone$ or prednisone).tw. (89214) 25 (Dexamethasone or testosterone or androgel).tw. (176948) 26 (dehydroepiandrosterone or DHEA).tw. (16234) 27 steroid$.tw. (328280) 28 deltacortisone$.tw. (4) 29 dexol$.tw. (9) 30 corticosteroid$.tw. (159186) 31 Immunotherap$.tw. (156288) 32 exp immunosuppressive treatment/ or exp immunotherapy/ (447554) 33 immunosuppress$.tw. (240282) 34 or/21‐33 (1650841) 35 Clinical Trial/ (1010544) 36 Randomized Controlled Trial/ (683094) 37 exp randomization/ (92454) 38 Single Blind Procedure/ (44551) 39 Double Blind Procedure/ (187477) 40 Crossover Procedure/ (68768) 41 Placebo/ (360978) 42 Randomi?ed controlled trial$.tw. (272269) 43 Rct.tw. (44534) 44 random allocation.tw. (2241) 45 randomly allocated.tw. (39681) 46 allocated randomly.tw. (2715) 47 (allocated adj2 random).tw. (833) 48 Single blind$.tw. (27678) 49 Double blind$.tw. (218592) 50 ((treble or triple) adj blind$).tw. (1439) 51 placebo$.tw. (329443) 52 prospective study/ (731101) 53 or/35‐52 (2442607) 54 case study/ (82516) 55 case report.tw. (459065) 56 abstract report/ or letter/ (1172015) 57 or/54‐56 (1701070) 58 53 not 57 (2383974) 59 20 and 34 and 58 (1866)
Appendix 5. PsycINFO search strategy
Ovid platform
Searched from 1806 to 20 December 2021
1 exp reproductive technology/ (1999) 2 vitro fertili?ation.tw. (821) 3 ivf.tw. (623) 4 icsi.tw. (81) 5 intracytoplasmic sperm injection$.tw. (63) 6 (blastocyst adj2 transfer$).tw. (4) 7 assisted reproduct$.tw. (1104) 8 artificial insemination.tw. (269) 9 iui.tw. (46) 10 intrauterine insemination$.tw. (36) 11 ovulation induc$.tw. (33) 12 (ovari$ adj2 stimulat$).tw. (63) 13 ovarian hyperstimulation.tw. (16) 14 COH.tw. (144) 15 superovulat$.tw. (8) 16 infertil$.tw. (3832) 17 subfertil$.tw. (102) 18 (ovari$ adj2 induction).tw. (8) 19 or/1‐18 (5986) 20 exp glucocorticoids/ (4347) 21 exp Corticotropin/ (2347) 22 glucocorticoid$.tw. (6621) 23 methylprednisolone$.tw. (615) 24 prednisolone$.tw. (416) 25 Steroid$.tw. (10370) 26 deltacortisone$.tw. (0) 27 corticosteroid$.tw. (3239) 28 dexol$.tw. (0) 29 or/20‐28 (22258) 30 random.tw. (63532) 31 control.tw. (475418) 32 double‐blind.tw. (23977) 33 clinical trials/ (12000) 34 placebo/ (6135) 35 exp Treatment/ (1121927) 36 or/30‐35 (1544423) 37 19 and 29 and 36 (31)
Data and analyses
Comparison 1. Glucocorticoids versus no glucocorticoids or placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Live birth rate per couple | 2 | 366 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.37 [0.69, 2.71] |
| 1.2 Incidence of multiple pregnancies per couple | 4 | 504 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.33, 2.20] |
| 1.3 Multiple pregnancy rate per pregnancy | 4 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4 Ongoing pregnancy rate per couple | 3 | 476 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.80, 1.76] |
| 1.5 Clinical pregnancy rate per couple | 13 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.5.1 Clinical pregnancy rate per couple (primary analysis) | 13 | 1967 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.95, 1.44] |
| 1.5.2 Subgroup in vitro fertilisation | 5 | 724 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.44 [1.00, 2.08] |
| 1.5.3 Subgroup intracytoplasmic sperm injection | 6 | 992 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.81, 1.42] |
| 1.6 Clinical pregnancy rate per couple: dosage and timing of glucocorticoids | 13 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.6.1 Clinical pregnancy rate: lower dose glucocorticoids | 6 | 780 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.20 [0.87, 1.67] |
| 1.6.2 Clinical pregnancy rate: higher dose glucocorticoids | 7 | 1187 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.87, 1.50] |
| 1.6.3 Clinical pregnancy rate: glucocorticoids during implantation | 7 | 1246 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.90, 1.52] |
| 1.7 Miscarriage rate per couple | 6 | 821 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.63, 1.87] |
| 1.8 Miscarriage rate per pregnancy | 6 | 255 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.45, 1.50] |
| 1.9 Incidence of ectopic pregnancies per couple | 3 | 320 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.28 [0.33, 15.62] |
| 1.10 Incidence of ovarian hyperstimulation syndrome per couple (mild‐severe) | 3 | 370 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.60, 1.90] |
| 1.11 Implantation rate per embryo transferred | 10 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.11.1 Subcategory | 10 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected |
1.8. Analysis.
Comparison 1: Glucocorticoids versus no glucocorticoids or placebo, Outcome 8: Miscarriage rate per pregnancy
1.11. Analysis.
Comparison 1: Glucocorticoids versus no glucocorticoids or placebo, Outcome 11: Implantation rate per embryo transferred
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Ando 1996.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel Allocation: stated as randomised but no further details Concealment of allocation, blinding, follow‐up, intention‐to‐treat analysis, power calculation: not stated This study included > 1 cycle per woman. These data are not appropriate for statistical pooling because data per cycle will result in an unit of analysis error. |
|
| Participants | 58 participants: A: 23, B: 35 Baseline comparability: good Mean number of cycles: A: 1.26, B: 1.6 (significantly different) Cause of infertility: varied ART: IVF COH: FSH, GnRH analogue. hCG 5000 IU Luteal support: progesterone 25 mg IM for 7 days, 50 mg IM for 8 days |
|
| Interventions | Group A: glucocorticoid: prednisolone 5 mg or dexamethasone 0.5 mg from COH onwards for 4 weeks. No further description of type of glucocorticoid used Group B: no glucocorticoids |
|
| Outcomes | Live birth rate per couple: A: 24.1%, B: 24.6% Clinical pregnancy rate/couple: A: 52.2%, B: 45.7% Clinical abortion rate/couple: A: 17.2%, B: 3.5% Implantation rate/embryo transferred: A: 15.5%, B: 14.6% Number of embryos transferred: A: 3.6 (SD 0.7), B: 3.2 (SD 0.8) |
|
| Notes | Study also included a group of antibody‐positive women. We have not included these results in the analysis. Control women underwent a higher number of cycles per woman; the reason is unclear. We were unsuccessful in contacting the study authors. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Stated as randomised but no further details. |
| Allocation concealment (selection bias) | Unclear risk | Not reported. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding. Open RCT. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Control women underwent a mean number of cycles of 1.6 versus 1.26 for women using glucocorticoids, which is significantly different. Likely direction of bias: towards a lack of effect. |
| Selective reporting (reporting bias) | Low risk | All outcomes planned in methods section were reported. Reported 1 adverse outcome: miscarriage rate. |
| Other bias | Low risk | Baseline comparability no risk of bias. No other potential sources of bias identified. |
Bider 1996‐1.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel Allocation: computer‐generated randomisation Blinding: no Intention‐to‐treat analysis, follow‐up, power calculation: not stated |
|
| Participants | 78 participants: A: 54 (split into 2 groups: A1: 27 receiving 0.5 mg, A2: 27 receiving 1 mg), B: 24 Baseline comparability: only age reported, no differences Cause of infertility: tubal factor ART: IVF COH: 225 IU hMG, GnRH analogue. hCG 10,000 IU Luteal support progesterone 50 mg vaginally twice a day |
|
| Interventions | Group A: glucocorticoid: dexamethasone 0.5 mg (A1) or 1 mg (A2) for 5 days from COH onwards, until 1 day after ET Group B: no glucocorticoids |
|
| Outcomes | Pregnancy rate/couple: A1: 16.7%, A2: 18.5%, A total: 16.7%, B: 16.7% Number of embryos transferred: A1: 3.5 (SD 2.2), A2: 3.3 (SD 3.1), B: 4.0 (SD 2.1) |
|
| Notes | This study had 2 glucocorticoid groups receiving dexamethasone 0.5 mg (A1) or 1 mg (A2). In this analysis, we calculated a cumulative pregnancy rate for both groups. The data from implantation (%) have not been included, since it was unclear whether 'per embryo transferred' could be extracted. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation. |
| Allocation concealment (selection bias) | Unclear risk | Not reported. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding. Open RCT. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Number of dropouts and cancelled cycles was reported and was low. |
| Selective reporting (reporting bias) | High risk | No adverse effects reported. |
| Other bias | Low risk | Baseline comparability no risk of bias. No other potential sources of bias identified. |
Bider 1996‐2.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel Allocation: computer‐generated randomisation Blinding: no Intention‐to‐treat analysis, follow‐up, power calculation: not stated |
|
| Participants | 99 participants: A: 52, B: 47 Baseline comparability: only age reported, no differences Cause of infertility: tubal factor ART: cycles in which cryo‐thawed embryos were transferred. ET 48 hours after presumed ovulation. Embryos obtained after IVF, hMG, GnRH agonist |
|
| Interventions | Group A: glucocorticoid: dexamethasone 0.5 mg for 5 days from ovulation onwards Group B: no glucocorticoids |
|
| Outcomes | Pregnancy rate/couple: A: 13.5%, B: 12.8% Ectopic pregnancy rate per couple: A: 0%, B: 0% Miscarriage rate per couple: A: 1.9%, B: 2.1% Multiple pregnancy rate: A: 0%, B: 0% Live birth rate (preliminary): A: 5.8%, B: 8.5% Incidence adverse effects of corticosteroids: A: 0%, B: 0% Implantation rate: A: 8.1%, B: 7.8% Number of embryos transferred: not available |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation. |
| Allocation concealment (selection bias) | Unclear risk | Not reported. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding. Open RCT. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Live birth data reported; however, preliminary. Incomplete follow‐up. |
| Selective reporting (reporting bias) | Low risk | Adverse effects reported. All outcomes reported that were planned according to the methods. |
| Other bias | Unclear risk | Baseline comparability unclear. |
Botti 1998.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel Allocation: stated as randomised but no further details Concealment of allocation, blinding, follow‐up, intention‐to‐treat analysis, power calculation: not stated |
|
| Participants | 91 participants: A: 39, B: 52 Baseline comparability: only age reported, similar Number of embryos transferred in both groups similar Cause of infertility: not stated ART: IVF and ICSI COH, luteal support: not stated |
|
| Interventions | Group A: glucocorticoid: 16 b‐methylprednisolone 16 mg/day for 4 days from 1 day before oocyte retrieval until 1 day after ET Group B: no glucocorticoids |
|
| Outcomes | Pregnancy rate/couple: A: 33.3%, B: 32.7% Implantation rate/embryo transferred: A: 9.5%, B: 15.2% Number of embryos transferred: A: 3.5 (SE 0.24), B: 3.4 (SE 0.22) |
|
| Notes | Abstract | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Stated as randomised but no further details. |
| Allocation concealment (selection bias) | Unclear risk | Not reported. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding. Open RCT. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Number of dropouts and cancelled cycles was reported and was low. |
| Selective reporting (reporting bias) | High risk | No live birth rates or adverse effects reported. |
| Other bias | Unclear risk | Abstract. Baseline comparability unclear. |
Catt 1994.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel (1 cycle) Allocation: randomised by pharmacist who encoded each course of tablets (placebo or glucocorticoid) Blinding: double‐blind, placebo Cancelled cycles, intention‐to‐treat analysis, follow‐up: not stated |
|
| Participants | 111 participants: A: 56, B: 55 Cause of infertility: male factor Baseline comparability: good ART: SUZI COH, luteal support: not reported Embryo transferred 48 hours after oocyte retrieval |
|
| Interventions | Group A: glucocorticoid: methylprednisolone 16 mg/day for 4 days from 1 day after oocyte retrieval onwards Group B: placebo |
|
| Outcomes | Clinical pregnancy rate per couple: A: 14.3%, B: 10.9% Multiple pregnancy rate per couple: A: 3.6%, B: 0% Implantation rate per embryo transferred: A: 13.2%, B: 9.1% Number of embryos transferred: A: 2.1, B: 2.2 |
|
| Notes | High proportion of women did not have an embryo transferred (45/111 women); however, there was no significant difference between groups. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised by pharmacist who encoded each course of tablets (placebo/glucocorticoid). |
| Allocation concealment (selection bias) | Low risk | Randomised by pharmacist who encoded each course of tablets (placebo/glucocorticoid). |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Double‐blind, participant and clinical staff. Placebo controlled. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Number of dropouts and cancelled cycles not reported. |
| Selective reporting (reporting bias) | Low risk | Adverse effects reported. All outcomes reported that were planned according to the methods. |
| Other bias | Low risk | Baseline comparability no risk of bias. No other potential sources of bias identified. |
Duvan 2006.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel Allocation: randomised by a lottery with envelopes No concealment of allocation, no blinding, no intention‐to‐treat analysis Prospective power calculation performed |
|
| Participants | 90 participants: A: 50, B: 40 Cause of infertility: variety of causes Baseline comparability: good ART: ICSI COH: 225–450 IU/day FSH, GnRH analogue. hCG 10,000 IU Luteal support vaginal progesterone 3 × 200 mg/day |
|
| Interventions | Group A: glucocorticoid prednisolone 10 mg until clinical pregnancy confirmed from ET onwards Group B: no glucocorticoids |
|
| Outcomes | Clinical pregnancy rate per couple: A: 38%, B: 35% Implantation rate/embryo transferred: A: 13.3%, B: 10.9% Adverse effects: not reported Number of embryos transferred: A: 4.0 (SD 1.2), B: 4.3 (SD 1.7) |
|
| Notes | Trial also investigated use of aspirin and a combination of prednisolone and aspirin. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised by a lottery with envelopes. |
| Allocation concealment (selection bias) | Unclear risk | Not reported. It was not stated whether the envelopes were sealed and opaque. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding. Open RCT. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Number of dropouts and cancelled cycles was reported and was low. |
| Selective reporting (reporting bias) | High risk | No adverse effects reported. |
| Other bias | Low risk | Baseline comparability no risk of bias. No other potential sources of bias identified. |
Ezzeldin 2003.
| Study characteristics | ||
| Methods | Single centre Study design: parallel Allocation: stated randomised, no further details Power calculation retrospectively performed |
|
| Participants | 526 participants: A: 267, B: 259 Baseline comparability: good Cause of infertility: male factor ART: ICSI COH: hMG. No further details |
|
| Interventions | Group A: glucocorticoid: prednisolone 15 mg following ET during luteal phase. Exact duration not described Group B: no glucocorticoids |
|
| Outcomes | Clinical pregnancy rate per couple: A: 24.7%, B: 25.1% Implantation rate per embryo transferred: A: 9.46%, B: 10.2% Number of embryos transferred: A: 4.0, B: 3.4 |
|
| Notes | Abstract | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Stated randomised, no further details. |
| Allocation concealment (selection bias) | Unclear risk | Not reported. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding. Open RCT. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Number of dropouts and cancelled cycles not reported. |
| Selective reporting (reporting bias) | High risk | No adverse effects reported. |
| Other bias | Unclear risk | Abstract. |
Kemeter 1986.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel Allocation: randomised by drawing lots Blinding: no High number of cancelled cycles (19%), resulting from abnormal follicle maturation, semen quality or hormonal assays. Together with random partners they were removed from the study. Intention‐to‐treat: not performed Follow‐up, power calculation: not stated |
|
| Participants | 146 participants: A: 73, B: 73 Baseline comparability: good Cause of infertility: male or tubal ART: IVF COH: clomiphene + hMG. hCG 5000 IU. No GnRH agonist |
|
| Interventions | Group A: glucocorticoid: prednisolone 7.5 mg for 4 weeks from COH onwards Group B: no glucocorticoids |
|
| Outcomes | Clinical pregnancy rate per couple: A: 21.9%, B: 8.2% Miscarriage rate per couple: A: 5.5%, B: 4.1% Ectopic pregnancy rate per couple: A: 2.7%, B: 0% Number of embryos transferred: not available |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomised by drawing lots. |
| Allocation concealment (selection bias) | Unclear risk | Not reported. Open RCT. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | High rate of cancelled cycles, atypical method of dealing with dropouts. |
| Selective reporting (reporting bias) | High risk | No adverse effects reported. |
| Other bias | Low risk | Baseline comparability no risk of bias. No other potential sources of bias identified. |
Kim 1997.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel Allocation: randomised by permuted block design Blinding: no Follow‐up, power calculation, drop‐outs: not stated Study included > 1 cycle per woman. These data are not appropriate for statistical pooling because data per cycle will result in an unit of analysis error |
|
| Participants | 87 participants: A: 43, B: 44 Baseline comparability: good Cause of infertility: tubal ART: IVF COH: hMG + hFSH + GnRH agonist. hCG 10,000 IU Embryo transferred 3 days after oocyte retrieval Luteal support progesterone 50 mg |
|
| Interventions | Group A: glucocorticoid: prednisolone 10 mg during COH, from oocyte retrieval onwards 60 mg for 4 days Group B: no glucocorticoids |
|
| Outcomes | Clinical pregnancy rate per couple: A: 76.7%, B: 65.9% Ongoing pregnancy rate per couple: A: 67.4%, B: 59.1% Multiple pregnancy rate per couple: A: 14.0%, B: 6.8% Miscarriage rate per couple: A: 9.3%, B: 6.8% Ectopic pregnancy rate per couple: A: 0%, B: 0% Number of embryos transferred: not available |
|
| Notes | 2 different populations of participants were included: endometriosis and tubal factor or only tubal factor. Among women with endometriosis and tubal factor 38.1% had positive titres for autoantibodies. Only women with tubal factor infertility were presented. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised by permuted block design. |
| Allocation concealment (selection bias) | Unclear risk | Not reported. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding. Open RCT. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Number of dropouts and cancelled cycles was reported and was low. |
| Selective reporting (reporting bias) | Low risk | Adverse effects were reported. All outcomes were reported that were planned according to the methods. |
| Other bias | Low risk | Baseline comparability no risk of bias. No other potential sources of bias identified. |
Moffitt 1995.
| Study characteristics | ||
| Methods | Multicentre Trial design: parallel (1 cycle) Allocation: randomised by pharmacist who equally packaged the tablets/placebo and randomly assigned sequential numbers Prospective power calculation: performed Blinding: double‐blind, placebo Cancelled cycles, intention‐to‐treat analysis, not stated Follow‐up: until live birth; however, article written before all women delivered, therefore live birth rate not included in outcomes |
|
| Participants | IVF: 206 participants: A: 103, B: 103 Cryo‐thawed ET cycle: 61 participants: A: 28, B: 33 Baseline comparability: good Cause of infertility: variety of causes Inclusion criteria: ET without micromanipulation ART: IVF or cryo‐thawed ET cycle (natural/programmed cycle) COH: FSH + hMG, leuprolide acetate long/short protocol. hCG 10,000 IU Luteal support: IM progesterone 50 mg/day for 14 days ET: 2 days after oocyte retrieval. All participants received tetracycline during oocyte retrieval |
|
| Interventions | Group A: glucocorticoid: 6‐alpha‐methylprednisolone 4 mg/day for 4 days from oocyte retrieval from day before the thaw onwards Group B: placebo | |
| Outcomes |
IVF Pregnancy rate/couple: A: 42.7%, B: 40.8% Ongoing pregnancy rate/couple: A: 30.1%, B: 26.2% Clinical pregnancy rate/couple: A: 40.8%, B: 35.9% Clinical abortion rate/couple: A: 10.7%, B: 8.7% Implantation rate/embryo transferred: A: 12.6%, B: 13.0% Live birth rate (preliminary): A: 17.5%, B: 11.7% Cryo‐thawed ET cycle Pregnancy rate/couple: A: 25.0%, B: 30.3% Ongoing pregnancy rate/couple: A: 14.3%, B: 24.2% Clinical pregnancy rate/couple: A: 25.0%, B: 30.3% Clinical abortion rate/couple: A: 10.7%, B: 6.1% Implantation rate/embryo transferred: A: 7.4%, B: 9.9% Live birth rate (preliminary): A: 0%, B: 0% Number of embryos transferred: A: 4.0 (SD 1.2), B: 4.0 (SD 2.1) |
|
| Notes | Study used 2 study groups: IVF, cryo‐thawed ET cycles. In this analysis, we calculated a cumulative pregnancy rate for both groups. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised by pharmacist who equally packaged the tablets/placebo and randomly assigned sequential numbers. |
| Allocation concealment (selection bias) | Low risk | Randomised by pharmacist who equally packaged the tablets/placebo and randomly assigned sequential numbers. |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Double‐blind, placebo controlled. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Live birth data preliminary due to incomplete follow‐up. |
| Selective reporting (reporting bias) | Low risk | Adverse effects are reported. All outcomes were reported that were planned according to the methods. |
| Other bias | Low risk | Baseline comparability no risk of bias. No other potential sources of bias identified. |
Mohammadi 2018.
| Study characteristics | ||
| Methods | Single‐centre Trial design: parallel (1 cycle) Allocation: permuted block randomisation method in blocks of 6 that was generated by a statistician according to a computer‐generated list. The participants' enrolments and assignments to intervention and control groups were done by a research midwife in the clinic. Prospective power calculation: performed Blinding: no blinding Cancelled cycles: high, 14%. Intention‐to‐treat analysis not performed. The data included in the meta‐analysis have been analysed by intention‐to‐treat. In addition, 30% of cycles were included in the study for the primary outcome OHSS. However, these women did not have an ET Follow‐up: not reported. Ultrasound 4 weeks after ET |
|
| Participants | IVF: 219 participants: A: 108, B: 111 Baseline comparability: good Cause of infertility: PCOS only Inclusion criteria: PCOS, aged 18–40 years, BMI < 30, basal FSH < 10 IU/L Exclusion criteria: allergy to methylprednisolone, the presence of hepatic and renal diseases, hypothyroidism, hypertension, peptic ulcer, diabetes, viral diseases, history of convulsion and tuberculosis, current use of any treatments that interacted with corticosteroids ART: IVF COH: long protocol with 150 FSH IU step‐down regimen. uhCG 10,000 IU Luteal support: daily progesterone 400 mg vaginal administration ET: 2 or 3 days after oocyte retrieval. All participants received tetracycline during oocyte retrieval |
|
| Interventions | Group A: glucocorticoid: oral methylprednisolone 16 mg/day from first day of stimulation until 2 weeks after ET, and discontinued gradually within 1 week and IV methylprednisolone 1 g on day of oocyte retrieval and ET Group B: no glucocorticoids |
|
| Outcomes | Clinical pregnancy rate/couple: A: 12.0%, B: 9.9% OHSS rate/couple: A: 16.7%, B: 13.5% Number of embryos transferred: A: 1.41 (SD 1.2), B: 1.6 (SD 1.2) |
|
| Notes | Primary outcome OHSS, 30% of women did not receive an ET. We were unsuccessful in contacting the authors. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Permuted block randomisation method in blocks of 6 that was generated by a statistician according to a computer‐generated list. |
| Allocation concealment (selection bias) | Unclear risk | The participants' enrolments and assignments to intervention and control groups were done by a research midwife in the clinic. Method of allocation not reported. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding. Open RCT. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 14% dropouts. The study did not use an intention‐to‐treat analysis, we have used an intention‐to‐treat analysis on the data included in the review. The transparency for reasons of dropouts was good. However, > 14% dropouts, 66 (30%) participants did not receive an ET due to high risk of OHSS, which is understandable but also a risk of bias for our outcome (clinical pregnancy). |
| Selective reporting (reporting bias) | Low risk | Trial registered prospectively (NCT01014104). |
| Other bias | Low risk | Baseline variables were balanced. Funding source: not mentioned. |
Mottla 1996.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel Allocation: table of random numbers corresponding with identically packaged placebo or glucocorticoids Blinding: double‐blind Intention‐to‐treat analysis, follow‐up not stated Power calculation retrospectively performed |
|
| Participants | 75 participants: A: 39, B: 36 Baseline comparability: only age reported, similar Cause of infertility: not stated Inclusion criteria: aged < 40 years Exclusion criteria: contraindications to corticosteroid therapy/use of other medication besides COH ART: IVF COH: hMG + GnRH agonist. hCG 10,000 IU ET 2 days after oocyte retrieval All participants received doxycycline for 3 days. Luteal support: vaginal progesterone 600 mg/day + IM hCG 3300 IU day 3, 6 and 9 after retrieval |
|
| Interventions | Group A: glucocorticoids: 1.2 dehydrocortisone 60 mg/day for 4 days from oocyte retrieval onwards Group B: placebo |
|
| Outcomes | Ongoing pregnancy rate/couple: A: 30.7%, B: 28.0% Clinical pregnancy rate/couple: A: 43.5%, B: 32.3% Clinical abortion rate/couple: A: 12.8%, B: 5.6% Multiple pregnancy rate/couple: A: 15.4%, B: 11.1% Ectopic pregnancy rate per couple: A: 2.6%, B: 2.8% Implantation rate/embryo transferred: A: 16.0%, B: 11.0% Incidence of adverse effects reported by couple: A: 0%, B: 0% Number of embryos transferred: A: 4.1 (SD 1.2), B: 4.0 (SD 0.9) |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Table of random numbers corresponding with identically packaged placebo or glucocorticoids. |
| Allocation concealment (selection bias) | Low risk | Table of random numbers corresponding with identically packaged placebo or glucocorticoids. |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Double‐blind, placebo controlled. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Number of dropouts and cancelled cycles not reported. |
| Selective reporting (reporting bias) | Low risk | Adverse effects were reported. All outcomes were reported that were planned according to the methods. |
| Other bias | Unclear risk | Baseline comparability unclear (only age reported). |
Nanbakhsh 2014.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel (1 cycle) Allocation: RCT, no details available Prospective power calculation: not stated Blinding, cancelled cycles, intention‐to‐treat analysis, not stated Follow‐up: unclear "positive results were followed on 6 weeks and monthly." |
|
| Participants | 134 participants: A: 67, B: 67 Baseline comparability: not stated Cause of infertility: infertile candidates for ICSI Inclusion criteria: no other criteria stated Exclusion criteria: not stated ART: ICSI. No further details on ICSI protocol |
|
| Interventions | Group A: glucocorticoids, prednisolone started from 1 day before ET, 20 mg/day to 7 days and continued with 10 mg/day for next 7 days Group B: no glucocorticoids |
|
| Outcomes | Pregnancy rate/couple: A: 47.8%, B: 47.8% Clinical pregnancy rate/couple: A: 41.8%, B: 32.8% Clinical abortion rate/couple: A: 5.9%, B: 10.4% Number of embryos transferred: not available |
|
| Notes | Only abstract available, we were unsuccessful in contacting the authors. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not reported. |
| Allocation concealment (selection bias) | Unclear risk | Not reported. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No details available. No blinding. Open RCT. Low risk for detection bias since the primary outcome was objective. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Not reported. It appeared to be analysed by 'intention to treat'. |
| Selective reporting (reporting bias) | Unclear risk | Not reported. No information on trial registration. |
| Other bias | Unclear risk | Only abstract available, we did not succeed in contacting the authors. |
Salah Edeen 2009.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel Allocation: randomised by drawing serially numbered sealed opaque envelopes Prospective power calculation: not performed Blinding: no Intention‐to‐treat analysis: no Follow‐up: 5 days after ovulation trigger for signs of early OHSS Dropouts: 3.5% due to inadequate ovarian response to ovarian stimulation |
|
| Participants | 120 participants: A: 72, B: 48 Baseline comparability: BMI and E2 values reported, no significant differences Cause of infertility: PCOS Inclusion criteria: aged 25–35 years, PCOS according to Rotterdam criteria Exclusion criteria: oophorectomy, immune diseases such as systemic lupus erythematosus, sclerosis and rheumatoid arthritis ART: IVF or ICSI COH: rFSH 200–300 IU/day + GnRH agonist. hCG 10,000 IU. ET: not stated Luteal support: vaginal progesterone 400 mg twice per day and ethinyl oestradiol |
|
| Interventions | Group A: glucocorticoids: prednisolone 10 mg twice day from hCG injection onwards until day of pregnancy test Group B: no glucocorticoids |
|
| Outcomes | Incidence of severe OHSS per couple: A: 12.5%, B: 9.7% Number of embryos transferred: not available |
|
| Notes | Additional information was obtained from the authors. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised by drawing serially numbered sealed opaque envelopes. |
| Allocation concealment (selection bias) | Low risk | Randomised by drawing serially numbered sealed opaque envelopes. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding. Open RCT. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Number of dropouts and cancelled cycles was reported and was low. |
| Selective reporting (reporting bias) | High risk | Pregnancy rates not reported. |
| Other bias | Unclear risk | Abstract. |
Tan 1992.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel Allocation: randomised by drawing serially numbered sealed envelopes Prospective power calculation: performed Blinding: no Intention‐to‐treat analysis used: pregnancy rate per initiated cycle Follow‐up, dropouts: not stated |
|
| Participants | 31 participants: A: 17, B: 14 Inclusion criteria: high risk for OHSS (> 20 follicles, E2 > 10,000) Cause of infertility: tubal, unexplained or male factor Baseline comparability: good ART: ICSI COH: hMG. GnRH agonist. hCG 10,000 IU The embryos were transferred 2 days after oocyte retrieval Luteal support: IM gestone 100 mg |
|
| Interventions | Group A: glucocorticoid: hydrocortisone 100 mg IV after oocyte retrieval. Prednisolone 30 mg for 5 days, 20 mg 3 days, 10 mg 2 days Group B: no glucocorticoids |
|
| Outcomes | Clinical pregnancy rate per couple: A: 41.2%, B: 35.7% Incidence of OHSS per couple: A: 41.2%, B: 42.9% Implantation rate per embryo transferred: A: 20.5%, B: 21.7% Number of embryos transferred: A: 2.7 (SD 0.2), B: 2.8 (SD 0.1) |
|
| Notes | Power calculation showed 15 women were needed in each study group. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised by drawing serially numbered sealed envelopes. |
| Allocation concealment (selection bias) | Low risk | Randomised by drawing serially numbered sealed envelopes. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding. Open RCT. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Number of dropouts and cancelled cycles is not reported. |
| Selective reporting (reporting bias) | Low risk | Adverse effects were reported. All outcomes were reported that were planned according to the methods. |
| Other bias | Low risk | Baseline comparability no risk of bias. No other potential sources of bias identified. |
Ubaldi 2002.
| Study characteristics | ||
| Methods | Single centre Trial design: parallel Allocation: computer‐generated randomisation Blinding: no Follow‐up, power calculation: not stated |
|
| Participants | 100 participants: A: 50, B: 50 Baseline comparability: good Cause of infertility: male factor Inclusion criteria: < 39 years, normal hormonal profile, normal uterine cavity, < 4 previous ICSI attempts ART: ICSI. All participants received aspirin 100 mg/day from COH onwards for 4 weeks COH: (r)FSH 200–225 IU, GNRH agonist. hCG 10,000 IU Luteal support: IM progesterone 50 mg/day |
|
| Interventions | Group A: glucocorticoid: prednisolone 10 mg/day for 4 weeks from COH onwards Group B: no glucocorticoids |
|
| Outcomes | Pregnancy rate/couple: A: 42%, B: 48% Clinical pregnancy rate/couple: A: 38%, B: 42% Clinical abortion rate/couple: A: 2.0%, B: 4.0% Implantation rate/embryo transferred: A: 21.2%, B: 18.5% Number of embryos transferred: A: 2.8 (SD 0.7), B: 2.7 (SD 0.6) |
|
| Notes | This article used a cross‐over design. First cycle data were not available. However, preliminary data from an abstract only included 1 cycle per participant (ESHRE meeting 2000, Ubaldi 2000). These data were included in the meta‐analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation. |
| Allocation concealment (selection bias) | Unclear risk | Not reported. |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding. Open RCT. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Number of dropouts and cancelled cycles reported. Number of cancelled cycles > 10% (45/360 cycles). 32 cycles were excluded since only 1 embryo was transferred. A high risk of bias may be present since glucocorticoids were provided from COH onwards and may influence embryo quality. |
| Selective reporting (reporting bias) | Low risk | Adverse effects were reported. All outcomes were reported that were planned according to the methods. |
| Other bias | Low risk | Baseline comparability no risk of bias. No other potential sources of bias identified. |
ART: assisted reproductive technology; BMI: body mass index; COH: controlled ovarian hyperstimulation; E2: oestradiol; ET: embryo transfer; FSH: follicle‐stimulating hormone; GnRH: gonadotropin‐releasing hormone; hCG: human chorionic gonadotropin; hMG: human menopausal gonadotropin; IM: intramuscular; IU: international units; IV: intravenous; IVF: in vitro fertilisation; OHSS: ovarian hyperstimulation syndrome; PCOS: polycystic ovarian syndrome; RCT: randomised controlled trial; rFSH: recombinant follicle‐stimulating hormone; SD: standard deviation; SE: standard error; SUZI: subzonal sperm injection; uhCG: urinary human chorionic gonadotropin.
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Alhalabi 2011 | Included only women with > 1% peripheral CD69+ NK cells of total lymphocytes after flow cytometry. |
| Al‐Hilli 2019 | RCT of women with idiopathic recurrent miscarriage who conceived spontaneously rather than by IVF. |
| Ashrafi 2007 | Glucocorticoids were only provided during the stimulation (follicular) phase. |
| Basirat 2016 | Dexamethasone and folic acid were continued until the day of oocyte collection. |
| Bedaiwy 2009 | Abstract. Not an RCT. Participants were undergoing ovulation induction instead of IVF/ICSI. Glucocorticoids were administrated during ovulation induction rather than peri‐implantation. |
| Bider 1997 | Participants underwent ovulation induction instead of IVF or ICSI. |
| Bider 1999 | Not an RCT. Participants were women with polycystic ovarian syndrome. |
| Chillik 1995 | RCT. Participants were randomised to a combination of antibiotics and methylprednisolone for 4 days from oocyte punction versus no additional treatment. |
| Cohen 1990 | It is unclear whether this was an RCT. We were unsuccessful in contacting the authors. |
| Colacurci 1991 | Not an RCT. Participants did not undergo IVF or ICSI. |
| Dmowski 1995 | Incomplete data. Study was prematurely terminated. Authors did not have access to the data. |
| Esmaeilzadeh 2011 | Participants were undergoing ovulation induction rather than IVF/ICSI. Dexamethasone was compared to controls in combination with clomiphene citrate. |
| Fan 2016 | Participants with antinuclear antibodies; non‐representative for the whole population. In addition, the RCT compared glucocorticoids plus aspirin versus controls. Medical treatment started 3 months prior to IVF. |
| Farzaneh 2020 | Dexamethasone was provided during the follicular phase only. ART: no IVF was provided, only ovulation induction. |
| Fawzy 2014 | Quasi‐randomised controlled trial. In addition, study compared prednisolone and low molecular weight heparin versus controls in women with 1 or 2 implantation failures in ICSI. |
| Ferreira 2007 | Participants were given aspirin and prednisone or received no treatment. Abstract. |
| Forges 2006 | Not an RCT. Participants were women with ≥ 2 previous IVF failures with antiovarian antibodies. |
| Franken 1985 | Glucocorticoids were administrated in a high dose versus a low dose. Method of randomisation not stated. |
| Fridström 1999 | Glucocorticoids were administrated during ovarian stimulation, until the night of hCG injection. |
| Geva 2000 | Participants with positive non‐organ‐specific antibody levels; non‐representative for the whole population. In addition, the RCT compared glucocorticoids plus aspirin versus controls. |
| Hasegawa 1998 | Not an RCT. |
| Hernandez‐Nieto 2021 | Non‐randomised study. Retrospective study in which methylprednisolone was standard care, which was discontinued as a result of SARS‐CoV‐2 pandemic. |
| Hope 2011 | Abstract. Not an RCT. Study compared glucocorticoids plus aspirin, oestradiol and doxycycline versus controls. |
| Ishihara 2001 | Not an RCT. |
| Kasteren 1998 | This abstract described a trial in which participants with premature ovarian failure were undergoing ovulation induction. They received glucocorticoids during ovarian stimulation. |
| Kaur 2019 | Not an RCT. Participants conceived spontaneously, no IVF/ICSI treatment. Subgroup of women with recurrent miscarriage. |
| Keay 2001 | Glucocorticoids administrated during ovarian stimulation, until the night before oocyte retrieval. |
| Kim 1996 | Participants were undergoing intrauterine inseminations instead of IVF or ICSI. |
| Kim 2002 | Unclear if this was an RCT and until which day the glucocorticoids were administrated. We were unsuccessful contacting the authors. |
| Lee 1994 | Unclear if this was an RCT. We were unsuccessful contacting the authors. |
| Litwicka 2015 | Women with hypothyroidism with antithyroid antibodies. |
| Liu 2018 | Dexamethasone was only provided during the stimulation phase. Participants were a subgroup of women with high progesterone. |
| Mitic 2019 | Corticosteroids and aspirin versus placebo. No comparison of interest. Not an RCT. |
| Mollo 2002 | RCT comparing glucocorticoids plus aspirin versus controls. |
| NCT04701034 | Study protocol. No comparison of interest. Prednisolone and intravenous immunoglobulin versus placebo. |
| Polak de Fried 1993 | Not an RCT. |
| Rein 1996 | Participants undergoing ovulation induction instead of IVF or ICSI. |
| Revelli 2008 | RCT comparing glucocorticoids plus aspirin versus controls. |
| Revelli 2009 | Not an RCT. Study comparing glucocorticoids plus levothyroxine plus aspirin versus levothyroxine alone or no adjuvant treatment in women with antithyroid antibodies. |
| Sakr 2012 | Growth hormone versus corticosteroids in ICSI in potentially low responders. Only provided during the follicular phase. |
| Shohayeb 2005 | Abstract with no data. We were unsuccessful contacting the authors. Women with hypothyroidism with antithyroid antibodies. |
| Siristatidis 2017 | Not an RCT. Low molecular weight heparin plus prednisolone versus low molecular heparin alone in participants with failed IVF/ICSI cycles. |
| Smarr 1988 | Not an RCT. |
| Strehler 2002 | Conference abstract. No details available. Excluded because prednisolone was combined with aspirin. |
| Taiyeb 2017 | Participants were men with immunological male infertility undergoing prednisolone treatment prior to IVF. |
| Taniguchi 2005 | Not an RCT. |
| Turi 2010 | Participants undergoing ovulation induction and intrauterine insemination instead of IVF or ICSI. Participants with antithyroid antibodies. Glucocorticoids were administrated during ovarian induction only. |
| Yano 1996 | Article written in Japanese. Not an RCT. |
| Yari 2010 | Exclusion since ovulation induction was performed rather than IVF and dexamethasone only provided during the follicular phase. |
| Zhong 2016 | Exclusion because prednisolone plus aspirin was compared to controls. Participants were a subgroup of women with autoantibodies. |
ART: assisted reproductive technology; hCG: human chorionic gonadotropin; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilisation; NK: natural killer; RCT: randomised controlled trial.
Characteristics of studies awaiting classification [ordered by study ID]
Beltran 2020.
| Methods | Prospective randomised controlled trial |
| Participants | Subgroup of women with high risk of OHSS. However, it is unsure whether these women have had an embryo transfer despite their OHSS |
| Interventions | Placebo versus methylprednisolone |
| Outcomes | No data on pregnancy, only related to OHSS. Full text is awaited |
| Notes | Conference abstract, no full text available yet. |
ChiCTR1800018783.
| Methods | Prospective, multicentre, randomised, double‐blind, placebo‐controlled trial |
| Participants | Infertile people with recurrent implantation failure who intend to undergo frozen‐thawed embryo transfer after in vitro fertilisation or intracytoplasmic sperm injection or pre‐implantation genetic testing for aneuploidy |
| Interventions | Participants will be given the treatment of prednisone or placebo from the start of endometrial preparation until the end of the first trimester of pregnancy if pregnant |
| Outcomes | Primary outcome: is live birth rate |
| Notes | Study protocol registered in Chinese Clinical Trial Registry, ChiCTR1800018783. We were unable to contact the authors to determine if preliminary data were available. |
OHSS: ovarian hyperstimulation syndrome.
Differences between protocol and review
We made the following changes from the published protocol (Boomsma 2006).
Mohan S Kamath joined the review team for the 2022 update.
At the 2022 update, we changed the outcome 'pregnancy rate' to 'clinical pregnancy rate' as most of the studies reported this.
Contributions of authors
CB has taken the lead in writing the protocol and updated review. She completed the literature search and selected trials for inclusion. She extracted the data and completed the statistical analysis.
MSK was involved in the update of the review in 2022. He also independently selected the relevant trials for the review, extracted data, and performed a risk of bias assessment and quality assessment of the selected trials.
NSM developed the clinical question of the review. He addressed and contributed to the background and discussion sections. He also independently selected the relevant trials for the review.
SDK contributed to the development of the selection criteria, the search strategy and methods section. He independently extracted data and performed a risk of bias and quality assessment of the selected trials in previous version of the review.
Sources of support
Internal sources
University Medical Center Utrecht, Netherlands
External sources
-
CM Boomsma, Netherlands
CB has no conflicts to declare.
-
M Kamath, India
MK has no conflicts to declare.
-
S Keay, UK
SK has no conflicts to declare. Dr Keay was author of the excluded study Keay 2001. He took no part in assessing this study for inclusion in this review.
-
N Macklon, UK
NM has no conflicts to declare.
Declarations of interest
CB: none.
MSK: none.
SDK was lead author of the excluded study (Keay 2001). He took no part in assessing this study for inclusion or exclusion in this review.
NSM: none.
MSK is an editor of Cochrane Gynecology and Fertility. He took no part in the editorial process or decision‐making for this article.
New search for studies and content updated (no change to conclusions)
References
References to studies included in this review
Ando 1996 {published data only}
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References to other published versions of this review
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