Review question
Does culture media containing the growth factor GM-CSF (granulocyte macrophage colony-stimulating factor) improve the chances of a pregnancy and live-born baby, and reduce the risk of miscarriage, twin or triplet pregnancy, premature birth, birth defects, genetic problems in the baby, and stillbirth?
Background
Assisted reproduction includes processes whereby a woman's eggs and a man's sperm are combined to achieve fertilisation outside of the body. Embryos are placed in a solution called culture medium to support the growing embryo until it can be replaced into the woman's uterus. Culture medium supplemented with GM-CSF is widely available in clinics and is often offered as an 'add-on' to an in vitro fertilisation (IVF) cycle in an effort to improve the success rates of treatment. Using GM-CSF-supplemented culture medium can make IVF more expensive.
Study characteristics
The evidence is current to October 2019. We obtained data from three randomised controlled trials (a type of study in which participants are randomly assigned to one of two or more treatment groups) of 1532 infertile women undergoing IVF or intracytoplasmic sperm injection (ICSI), a specialised form of IVF whereby the sperm is injected into the egg. We compared GM-CSF-supplemented culture media versus culture media not supplemented with GM-CSF for those undergoing assisted reproduction.
What the review found
Low-quality evidence reveals that we are uncertain whether GM-CSF-containing culture media makes any difference to the live-birth rate when compared to using culture media not containing GM-CSF. This suggests that if the rate of live birth associated with culture media not containing GM-CSF is 22%, the rate with the use of GM-CSF-containing culture media would be between 21% and 30%. Low-quality evidence also reveals that we are uncertain whether GM-CSF-containing culture media makes any difference to miscarriage when compared to using culture media not containing GM-CSF. This suggests that if the miscarriage rate associated with culture media not containing GM-CSF is 4%, the rate with the use of GM-CSF-containing culture media would be between 2% and 5%. Low-quality evidence for pregnancy, birth defects, and genetic problems with the baby, and very low-quality evidence for twin or triplet pregnancies, and premature birth, reveals that we are uncertain whether GM-CSF-containing culture media makes any difference to these outcomes when compared to culture media not containing GM-CSF. Two studies looked at stillbirth, but as no stillbirths occurred in either study, we were unable to analyse this outcome.
Overall conclusions
Due to the very low to low quality of the evidence, we cannot be certain whether GM-CSF is any more or less effective or harmful than culture media not supplemented with GM-CSF. It is important that independent information on the available evidence is made accessible to those considering using GM-CSF-supplemented culture media. In the meantime, more large studies are needed to increase the certainty of our conclusions.
Due to the very low to low quality of the evidence, we cannot be certain whether GM-CSF is any more or less effective than culture media not supplemented with GM-CSF for clinical outcomes that reflect effectiveness and safety. It is important that independent information on the available evidence is made accessible to those considering using GM-CSF-supplemented culture media. The claims from marketing information that GM-CSF has a positive effect on pregnancy rates are not supported by the available evidence presented here; further well-designed, properly powered RCTs are needed to lend certainty to the evidence.
GM-CSF (granulocyte macrophage colony-stimulating factor) is a growth factor that is used to supplement culture media in an effort to improve clinical outcomes for those undergoing assisted reproduction. It is worth noting that the use of GM-CSF-supplemented culture media often adds a further cost to the price of an in vitro fertilisation (IVF) cycle. The purpose of this review was to assess the available evidence from randomised controlled trials (RCTs) on the effectiveness and safety of GM-CSF-supplemented culture media.
To assess the effectiveness and safety of GM-CSF-supplemented human embryo culture media versus culture media not supplemented with GM-CSF, in women or couples undergoing assisted reproduction.
We used standard methodology recommended by Cochrane. We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, LILACS, DARE, OpenGrey, PubMed, Google Scholar, and two trials registers on 15 October 2019, checked references of relevant papers and communicated with experts in the field.
We included RCTs comparing GM-CSF (including G-CSF (granulocyte colony-stimulating factor))-supplemented embryo culture media versus any other non-GM-CSF-supplemented embryo culture media (control) in women undergoing assisted reproduction.
We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live birth and miscarriage rate. The secondary outcomes were clinical pregnancy, multiple gestation, preterm birth, birth defects, aneuploidy, and stillbirth rates. We assessed the quality of the evidence using GRADE methodology. We undertook one comparison, GM-CSF-supplemented culture media versus culture media not supplemented with GM-CSF, for those undergoing assisted reproduction.
We included five studies, the data for three of which (1532 participants) were meta-analysed. We are uncertain whether GM-CSF-supplemented culture media makes any difference to the live-birth rate when compared to using conventional culture media not supplemented with GM-CSF (odds ratio (OR) 1.19, 95% confidence interval (CI) 0.93 to 1.52, 2 RCTs, N = 1432, I2 = 69%, low-quality evidence). The evidence suggests that if the rate of live birth associated with conventional culture media not supplemented with GM-CSF was 22%, the rate with the use of GM-CSF-supplemented culture media would be between 21% and 30%.
We are uncertain whether GM-CSF-supplemented culture media makes any difference to the miscarriage rate when compared to using conventional culture media not supplemented with GM-CSF (OR 0.75, 95% CI 0.41 to 1.36, 2 RCTs, N = 1432, I2 = 0%, low-quality evidence). This evidence suggests that if the miscarriage rate associated with conventional culture media not supplemented with GM-CSF was 4%, the rate with the use of GM-CSF-supplemented culture media would be between 2% and 5%.
Furthermore, we are uncertain whether GM-CSF-supplemented culture media makes any difference to the following outcomes: clinical pregnancy (OR 1.16, 95% CI 0.93 to 1.45, 3 RCTs, N = 1532 women, I2 = 67%, low-quality evidence); multiple gestation (OR 1.24, 95% CI 0.73 to 2.10, 2 RCTs, N = 1432, I2 = 35%, very low-quality evidence); preterm birth (OR 1.20, 95% CI 0.70 to 2.04, 2 RCTs, N = 1432, I2 = 76%, very low-quality evidence); birth defects (OR 1.33, 95% CI 0.59 to 3.01, I2 = 0%, 2 RCTs, N = 1432, low-quality evidence); and aneuploidy (OR 0.34, 95% CI 0.03 to 3.26, I2 = 0%, 2 RCTs, N = 1432, low-quality evidence). We were unable to undertake analysis of stillbirth, as there were no events in either arm of the two studies that assessed this outcome.