Review question
To assess the safety and usefulness of giving granulocyte-colony stimulating factor (G-CSF) in women undergoing in vitro fertilisation (IVF).
Background
It has been suggested that in women who have persistent thin endometrium (inner lining of the womb) or who have experienced multiple failed IVF, giving G-CSF during treatment may improve IVF outcomes. G-CSF is a type of growth factor that stimulates bone marrow to produce certain types of white blood cells. In the endometrium, G-CSF promotes regenerative activity of the cells and helps in increasing the blood supply. It is proposed that G-CSF may increase IVF success by helping to improve embryo implantation (adherence to the lining of the womb) and facilitating continuation of pregnancy. It can be given either by injecting it inside the uterus (womb) with the help of a syringe around the time of embryo transfer or subcutaneously (under the skin) after embryo transfer.
Study characteristics
We found 13 trials (1070 women) comparing G-CSF with placebo or no treatment. Nine trials evaluated the role of G-CSF in women undergoing IVF, with a majority of trials including those women with two or more failed attempts. The remaining four trials investigated the role of G-CSF in women with thin endometrium undergoing IVF. The evidence is current to February 2019.
Key results
We are uncertain whether giving G-CSF in women undergoing IVF improves chances of ongoing pregnancy or overall clinical pregnancy rates or reduces miscarriage rate compared to placebo or no treatment. For a typical clinic with 16% ongoing pregnancy rate, G-CSF administration would be expected to result in ongoing pregnancy rates between 14% and 50%. No study reported on multiple pregnancy rate. Only four trials reported adverse events as an outcome, and none of them reported any major adverse events following either G-CSF administration or placebo/no treatment.
Quality of evidence
We are uncertain whether giving G-CSF improves ongoing pregnancy or reduces miscarriage rates in women undergoing IVF based on very low-quality evidence. The quality of the evidence was reduced because of risk of bias.
In subfertile women undergoing ART, we are uncertain whether the administration of G-CSF improves ongoing pregnancy or overall clinical pregnancy rates or reduces miscarriage rate compared to no treatment or placebo, whether in all women or those with thin endometrium, based on very low-quality evidence. Low-quality evidence suggests that G-CSF administration may improve clinical pregnancy rate in women with two or more IVF failures, but the included studies had unclear allocation concealment or were at high risk of performance bias.
Granulocyte-colony stimulating factor (G-CSF) seems to play an important role in the process of embryo implantation and continuation of pregnancy. It has been used during in vitro fertilisation (IVF) treatment for subfertile women with chronically thin endometrium and those with previous multiple IVF failures. It is currently unknown whether G-CSF is effective in improving results following assisted reproductive technology (ART).
To evaluate the effectiveness and safety of G-CSF in women undergoing ART.
We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform in February 2019. We searched reference lists of relevant articles and handsearched relevant conference proceedings.
Randomised controlled trials (RCTs) comparing G-CSF administration versus no treatment or placebo in subfertile women undergoing IVF treatment.
Two review authors independently screened studies, extracted data, and assessed risk of bias. The primary outcomes were live-birth rate and miscarriage rate following G-CSF administration. We have reported ongoing pregnancy rate in cases where studies did not report live birth but reported ongoing pregnancy. Secondary outcomes were clinical pregnancy rate, multiple pregnancy rate, adverse events, ectopic pregnancy rate, small for gestational age at birth, abnormally adherent placenta, and congenital anomaly rate. We analysed data using risk ratio (RR), Peto odds ratio and a fixed-effect model. We assessed the quality of the evidence using the GRADE criteria.
We included 13 trials involving 522 women who received G-CSF and 528 women who received placebo or no additional treatment during IVF. The main limitations in the quality of the evidence were inadequate reporting of study methods and high risk of performance bias due to lack of blinding. We assessed only two of the 13 included trials as at a low risk of bias. None of the trials reported the primary effectiveness outcome of live-birth rate.
We are uncertain whether G-CSF administration improves ongoing pregnancy rate compared to control in subfertile women undergoing ART (RR 1.62, 95% confidence interval (CI) 0.86 to 3.08; 1 RCT; participants = 150; very low-quality evidence). For a typical clinic with 16% ongoing pregnancy rate, G-CSF administration would be expected to result in ongoing pregnancy rates between 14% and 50%. We are uncertain whether G-CSF administration reduces miscarriage rate (Peto odds ratio 0.40, 95% CI 0.09 to 1.77; 2 RCTs; participants = 291; I² = 0%; very low-quality evidence) compared to the control group in subfertile women undergoing ART.
We are uncertain whether G-CSF administration improves overall clinical pregnancy rate compared to control in subfertile women undergoing ART (RR 1.65, 95% CI 1.32 to 2.06; 12 RCTs; participants = 1050; I² = 19%; very low-quality evidence). For a typical clinic with 18% clinical pregnancy rate, G-CSF administration would be expected to result in clinical pregnancy rates between 23% and 37%. In the unselected IVF population, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.12, 95% CI 0.75 to 1.68; 2 RCTs; participants = 291; I² = 32%; low-quality evidence).
Sensitivity analysis restricted to studies at low-risk of bias suggests no evidence of difference in clinical pregnancy after G-CSF administration versus control group in an unselected IVF population ( RR 1.46, 95% CI 0.81 to 2.65; 1 RCT; participants = 150).
G-CSF administration may improve clinical pregnancy rate in women with two or more previous IVF failures compared to the control group (RR 2.10, 95% CI 1.53 to 2.89; 6 RCTs; participants = 553; I² = 0%; low-quality evidence). However, sensitivity analysis restricted to studies at low-risk of selection bias suggests that there is no evidence of difference in clinical pregnancy rate after G-CSF administration versus control group in women with two or more IVF failures (RR 2.00, 95% CI 0.75 to 5.33; 1 RCT; participants =100). In subfertile women with thin endometrium undergoing ART, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.58, 95% CI 0.95 to 2.63; 4 RCTs; participants = 206; I² = 30%; low-quality evidence). No studies in this subgroup remained in a sensitivity analysis restricted to studies at low-risk of selection bias.
No study reported on multiple pregnancy rate. Only four trials reported adverse events as an outcome, and none of them reported any major adverse events following either G-CSF administration or placebo/no treatment.