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.

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.

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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 strategy: 

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.