Navigating the Costs and Considerations of Louise Wegmann Assisted Reproductive Technologies

The world of assisted reproductive technologies (ART) has advanced rapidly since 1978, when Louise Brown was the first child born as a result of in vitro fertilisation (IVF). ART offers a chance to start a family for people who can't get pregnant on their own for a number of reasons, including infertility, same-sex relationships, single women, and surrogacy. ART, often known as a "cycle," is a step-by-step procedure. It entails a number of steps, from ovarian stimulation and oocyte collection to gamete mixing, culture, and embryo quality assessment, and finally embryo transfer into the woman's uterus. The effectiveness of ART is the result of all cycle components, owing in part to the capacity to culture human embryos in vitro using culture media that can support the developing embryo.

The Static Success Rates of IVF and the Rise of 'Add-Ons'

Over the past decade, the success rates of IVF, measured as the live birth of a baby, have remained relatively static. In an attempt to improve the success rates, a series of medical and non‐medical adjuncts to an IVF cycle have been developed. These are often referred to as 'add‐ons' and are sometimes novel interventions or therapies that have shown some promise in initial studies, or they may have been around for many years, but have not yet been proven to be effective through randomised controlled trials (RCTs).

GM-CSF: A Growth Factor in ART

GM‐CSF is a growth factor and we understand that pregnancy is supported through secretion and modulation of cytokines and growth factors which play a vital role in cell division, growth, and differentiation. Many different growth factors have been evaluated as supplements to human IVF culture media; however, GM‐CSF‐supplemented culture media is known to be one of the better studied supplements in RCTs. Culture media are available as both sequential preparations and single‐step preparations in some parts of the world. There are many different culture media available that do not contain GM‐CSF. Modern culture media contain up to 80 components including nutrients, vitamins, and growth factors. Most companies disclose the components, but concentrations are rarely disclosed due to commercial competition. For this review, any culture media contain GM‐CSF can be compared in an RCT against any culture media not containing GM‐CSF. This review will address the efficacy and safety of GM‐CSF‐supplemented culture media when compared to culture media not containing GM‐CSF.

The Role of GM-CSF in Reproduction

GM‐CSF (also known as colony stimulating factor (CSF)‐2) and granulocyte colony‐stimulating factor (G‐CSF or CSF‐3) belong to the CSF family. They are a group of cytokines that are known for their role in haemopoietic cell proliferation, differentiation, and activation, as well as being an apoptosis suppressor. Their involvement in reproduction was initially investigated in the 1970s in human placenta‐conditioned media. Among the CSF group, GM‐CSF has been most widely studied and its extensive research on ART has led to the development of new embryo culture media supplemented with human recombinant GM‐CSF. GM‐CSF is a cytokine that is produced by the oestrogen‐primed epithelial cells in the female reproductive tract. It is maximally expressed at the luminal and glandular epithelial cells of the endometrium in the secretory phase, and in the lining of the fallopian tube during the late proliferative and early mid secretory phases of the menstrual cycle. Later during implantation, GM‐CSF is produced by the chorionic villi cells and the maternal decidua.

GM-CSF Deficiency and its Impact on Pregnancy

The control of the immunological environment during early pregnancy involves a series of autocrine and paracrine signalling between the maternal fetal interface. Several studies have suggested an association between recurrent pregnancy loss and infertility and the dysregulation of growth factors and cytokines. In studies of genetically GM‐CSF‐deficient mice, there was a reduced inner cell mass observed which resulted in delayed blastocyst formation, increased fetal resorption in late gestation, decreased fetal size, and greater postnatal mortality.

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Growth Factor Supplementation in Culture Media

The initial studies of growth factor supplementation of culture media are limited mostly to animal models, but have largely revealed improved blastocyst development rates, increased implantation, and birth rates. The use of growth factor supplementation in human culture media has been limited as it is costly to produce and there are concerns about adverse effects. Most growth factors are anti‐apoptotic, that is, they inhibit programmed cell death. If not controlled, adverse effects may occur as apoptosis is a crucial phenomenon in embryogenesis. Early studies on human embryos revealed that those cultured in GM‐CS‐supplemented culture media had more viable inner cell mass and reduced apoptosis. This could potentially contribute to improved fetal viability. Supplementation of culture media with GM‐CSF is reported to be safe for human embryos, there are no increases or changes in ploidy rates or embryonic chromosomes. Furthermore, initial RCTs in women have revealed an improvement in the clinical pregnancy and live birth rates in those randomised to culture of their embryos in GM‐CSF supplemented culture media.

The Cost of Using GM-CSF in IVF

Using GM‐CSF can carry an additional cost to women undergoing IVF. GM‐CSF‐supplemented culture media is widely commercially available and is being offered to women undergoing ART worldwide. It is often considered an 'add‐on' or supplementary therapy given alongside standard IVF in an attempt to improve success rates. There is currently no up to date systematic review of RCTs on this topic, and the one published systematic review relied on non‐randomised studies, and studies where oocytes rather than women were randomised. The available RCTs were small with differing results and did not offer certainty on what should be done in practice.

Review of RCTs on GM-CSF

We will include all published and unpublished RCTs. We will include cross‐over studies for completeness, but pool only data from the first phase in meta‐analyses because this design of study is not valid in the context of infertility trials. We will exclude quasi and pseudo‐randomised trials. Women undergoing IVF or intracytoplasmic sperm injection (ICSI), for any cause of infertility, using autologous or donor oocytes. Miscarriage per woman randomised. Where possible, the definition we will use is miscarriage of clinical pregnancy. Clinical pregnancy per woman randomised, defined as presence on ultrasound scan of one or more gestational sacs, or definitive signs of clinical pregnancy. It includes ectopic pregnancy.

Search Strategies for Databases

We will design search strategies for the following databases: the Gynaecology and Fertility Group Specialised Register of Controlled Trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, and CINAHL EBSCO. The MEDLINE search will be combined with the Cochrane highly sensitive search strategy for identifying randomised trials which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019; Section 4.3.1). trial registers for ongoing and registered trials: ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Trials Registry Platform search portal (apps.who.int/trialsearch/Default.aspx). DARE (Database of Abstracts of Reviews of Effects) on the Cochrane Library (onlinelibrary.wiley.com/o/cochrane/cochranecldarearticles_fs.htm). Web of Knowledge (wokinfo.com). OpenGrey (www.opengrey.eu/) for unpublished literature from Europe. LILACS database (lilacs.bvsalud.org/en/). PubMed and Google Scholar (for recent trials not yet indexed in the major databases).

Independent Assessment of Studies

Two review authors will independently assess eligibility of all studies identified by the search utilising Covidence (Covidence). We will retrieve the full‐test publications of potentially eligible studies. We will screen the full texts to identify studies for inclusion and record reasons for exclusion in the 'Characteristics of excluded studies' table. Two review authors will independently extract data on study characteristics and primary and secondary outcomes from eligible studies using a data extraction form designed and piloted by the review authors. We will resolve any disagreements or discrepancies by discussion. Where studies have multiple publications, we will use the main trial report as the reference and obtain additional details from secondary papers which will appear as subreferences. We will correspond with study investigators for further information on study methods and results, as required.

Methodological Quality and Data Extraction

Two review authors will independently assess the included studies for methodological quality and undertake data extraction according to the Cochrane 'Risk of bias' assessment tool (Higgins 2011). We will assess selection bias (random sequence generation and allocation concealment), attrition bias (incomplete outcome data), reporting bias (selective reporting), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessors), and other biases (other problems that could put a trial at high risk of bias). We will present and describe all our judgements in the 'Risk of bias' table.

Statistical Analysis

We will summarise the effects and adverse events related to the intervention as odds ratios (ORs) using a fixed‐effect model. We will present 95% confidence intervals (CIs) for all outcomes to evaluate the precision of the estimate. Will consider the clinical relevance of the results from the meta‐analysis of each comparison, taking into account the precision of the estimate. When adding data from individual studies to comparisons, we will consider whether the rates of events in both the intervention and control arm reflect current practice. The denominator for all outcomes will be the number of women randomised. We will count multiple births (e.g.

Intention-to-Treat Analysis

We will analyse the data on an intention‐to‐treat basis and attempt to obtain missing data from the primary investigators. We will assume that participants who drop out after randomisation (e.g. because of cycle cancellation), or who were lost to follow‐up or withdrew, did not achieve clinical pregnancy or live birth. We will consider whether the clinical and methodological characteristics of the included studies are sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We will assess statistical heterogeneity using the I2 statistic and consider an I2 statistic greater than 50% to indicate substantial heterogeneity (Higgins 2019).

Addressing Bias

We will reduce the potential impact of publication and reporting bias by performing a comprehensive search for eligible studies and looking for duplication of data. We will construct a funnel plot to explore the possibility of small‐study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies) if there are 10 or more studies included in an analysis. When possible, we will use published protocols and prospective trial registration webpages for included studies to investigate selective reporting (i.e.

Meta-Analyses and Sensitivity Analyses

We will perform meta‐analyses, as appropriate, where data are available from multiple studies investigating the same treatment, and where the outcome has been measured in a standard way between the studies. We will use a fixed‐effect model. If we detect substantial heterogeneity, we will explore possible explanations in subgroup analyses. We will conduct sensitivity analyses for the primary outcomes to determine whether the conclusions are robust to arbitrary decisions made regarding the eligibility and analysis.

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Summary of Findings and GRADE Criteria

We will prepare a 'Summary of findings' table to evaluate the overall quality of the body of evidence for the main review outcomes (live birth, miscarriage, clinical pregnancy) using GRADE criteria (study limitations (i.e. risk of bias), consistency of effect, imprecision, indirectness, and publication bias) (GRADEpro GDT). We will justify and document judgements about evidence quality (high, moderate, low, and very low) and incorporate this into reporting of the results for each outcome.

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