Does Neupogen® (G-CSF) increase IVF success?
IVF success is live birth
Equating clinical pregnancy to live birth requires a leap of faith
Ms. Johnson comes to inquire about the benefits of Neupogen® (or G-CSF, granulocyte colony stimulating factor). One of her friends recently used it and conceived after multiple IVF failures.
I told her that Neupogen®, administered by injection or uterine flushing, is not ready for day-to-day clinical practice yet. It is best used in clinical trials because its benefits on IVF success (i.e., live birth) have not been established. My answer is based on two recent meta-analyses.
Clinical trial to determine the efficacy of COVID-19 vaccine was a classic example to show how the efficacy of an intervention is determined. Two comparable groups of volunteers are randomly assigned to receive vaccine or saline. They went about their lives for a predetermined time (and potentially be in contact with those infected with COVID). The number (or percentages) of volunteers infected by COVID were then compared. This is called a prospective randomized controlled trial (RCT). In COVID vaccine’s case, about 30,000 volunteers are recruited.
A literature search using “G-CSF and IVF” shows hundreds of papers. Most of the papers analyzed fewer than 50 patients and did not use live birth as the endpoint. The few papers based on RCTs showed conflicting results and, due to the small number of patients analyzed, had questionable validity.
Luckily, some researchers combined data from RCTs and analyzed the pooled data. This is called meta-analysis. Combining multiple RCTs makes the results more valid because the results are derived from more patients. Given the constraints mentioned above, meta-analysis is the best source to get the answer about the effects of G-CSF. Two recent meta-analyses are available. The first one analyzed patient who had recurrent implantation failure. The send one analyzed patient who had recurrent implantation failure, thin endometrium, and a third group which have neither (the ”general IVF” group).
The first meta-analysis includes publications up to October 2020. It pooled data from nine RCTs with 976 patients. All of them had recurrent implantation failure (Reprod Biol Endocrinol 2021, 19:125 https://doi.org/10.1186/s12958-021-00810-4). The second meta-analysis searched all published reports till Dec 2021. It includes 1966 patients from 552 studies, 20 RCTs (Reprod Biol Endocrinol 2023, 21:34 https://doi.org/10.1186/s12958-023-01063-z). It is worth pointing out that the patients analyzed by the two reports may overlap with each other.
The first report says G-CSF increased clinical pregnancy regardless of fresh or frozen embryo transfer or how it was administered. Whereas G-CSF increased biochemical pregnancy, it had no impact on miscarriage or live birth.
The second report says G-CSF increased clinical pregnancy only in patients with recurrent implantation failure or thin endometrium, but not in patients of the “general IVF” group. Furthermore, G-CSF had no impact on live birth or miscarriage.
One explanation for not seeing G-CSF's positive impact on live birth in the above analyses is insufficient patient number (i.e., inadequate power). Close to 2,000 IVF patients have been included in reports concerning the use of G-CSF thus far. We have the live birth information on fewer than 400. More research/data is needed.
In conclusion, it is good to see positive impacts on clinical pregnancy, but equating clinical pregnancy to live birth takes a leap of faith. For now, using G-CSF in IVF belongs to clinical trial. It is not ready for day-to-day clinical practice yet.