In this webinar, Maria Arqué, MD, International Medical Director at Fertty International, is explaining IVF add-on procedures and their impact on the outcome of treatment.
Many optional extras are offered to patients on top of their normal fertility treatment. These are called IVF add-ons. Often those have an additional cost, and some techniques might have shown very promising results, but some haven’t certainly been proven to improve the pregnancy or birth rates or have any tangible benefits in terms of the health of the offspring.
Clinical IVF add-ons
Starting with screening hysteroscopy, there is no evidence that there is any benefit to performing a routine screening with hysteroscopy in women undergoing IVF. It might be necessary or implied and may have a positive effect in patients with prevalent implantation failure, or there is a suspicion that they might have a uterine formation. Otherwise, it doesn’t look like it has any positive effect.
Regarding stimulation regimens, e.g., DHEA, a supplement is sometimes used to improve the levels of androgens. It is usually used for patients with a low ovarian reserve and poor responders, and it has been demonstrated it may have a beneficial effect on this kind of patient.
In most studies, 75 milligrams of DHEA has been used for around 3 months before. However, the patients have to be aware that the current evidence is inconsistent and that randomized controlled trials are needed. Using Testosterone brings similar results, again there might be a possible benefit in poor responders. More trials are needed to reassure us of its benefits.
The growth hormone has been used in some patients as well, but there is a lack of strong evidence to support the use of adjuvant growth hormone in ART except for very specific diseases or patients that might have some hormone defects of this hormone. Aspirin is widely used in contemporary clinical practice, even though there is no proven efficacy for routine use of aspirin in IVF treatment. Current evidence does not exclude the possibility of having adverse effects. Heparing might be beneficial in patients with Recurrent Implantation Failure (RIF) with thrombophilia, however, needs to be carefully considered and balanced against the potential side effects.
When we look at antioxidants for both male and female partner, we need to remember that all tournament record is very low because the studies use different kind of supplements or mixes of supplements, so it is difficult to exactly know which component used is responsible for that effect.
Seminal plasma, according to the Cochrane review, there is no clear evidence of a difference in the live birth rate after its application. PRP (Platelet Rich Plasma) is an option for improving endometrial thickness, especially in a patient with recurrent implantation failures and patients with low ovarian reserve. However, it should also be considered experimental.
Lab IVF add-ons
Hyaluronic acid (HA)
Hyaluronic acid (HA) and adherence compounds, better known as Embryo Glue or other names similar to this. It is the use of a specific medium enriched with glycoprotein hyaluronan. It could have a potentially beneficial effect in enhancing the process of implantation and avoiding embryo explosion. There has been a Cochrane review that included 17 randomized controlled trials that showed moderate quality evidence for an improvement in clinical pregnancy rates and live birth rates, with an associated increased risk of multiple pregnancies when that medium was used. However, further evidence and more randomized controlled trials are needed to evaluate the efficacy of HA aromatic acid as an evidence component when doing an embryo transfer for single embryo transfers and the possibility of reducing multiple pregnancy rates.
Sperm DNA fragmentation
Sperm DNA fragmentation is one of the most frequent DNA anomalies that occur in the male gamete, and it has been associated with poor semen quality. Some other techniques in the lab could be implemented to maximize the chances of pregnancy or possibly justify the use of antioxidants before starting the treatment. The assay includes different kinds of tests (TUNEL, Comet, SCD assay, SCSA 8-OHdG test), all those methods are different, but they do not reliably predict treatment outcomes, and cannot be recommended opportunities for clinical use, this is the recommendations from the American Society for Reproductive Medicine (ASRM). According to the Cochrane review, antioxidant therapy in a male might increase clinical pregnancy rates and live birth rates in patients where spermatozoa are suffering from oxidative stress.
Time-lapse is taking pictures over time and reviewing them as a film. The usefulness of the time-lapse image in human reproduction has been justified by not missing any important events during culture and having more quality control. It can also be used as teaching applications for embryologists, and it gives more information to the patient about their embryos, and possibly increase live birth rates. Cochrane review published in 2019 showed insufficient good-quality evidence of differences in the live birth rate or clinical pregnancy rate, miscarriage and stillbirth with or without embryo selection software, and conventional incubation. Once more, more trials are needed to establish its benefits.
Preimplantation Genetic Testing for aneuploidies (PGT-A)
PGT-A has been actively marketed as it is increasing implantation rates and consequently decreasing the time to pregnancy, recurrent miscarriages and repeated implantation failures. The important thing is to remember that PGT-A doesn’t improve live birth rates in IVF. What does it mean? It means that your overall chances of having a successful live birth depend mainly on the embryo quality. However, it helps to select chromosomally normal embryos. It means there will be a healthy embryo for transfer, and therefore, it will decrease the time to pregnancy because such embryos have higher chances of implanting, and the risk of miscarriage will be lower. The main disadvantage of PGT-A is the cost and the fact that it’s an invasive procedure.
The STAR is one of the most important trials done regarding PGT-A. They were comparing different groups of populations, so patients between 25- 34, 35-40 and then, all ages. They were comparing patients who were having PGT-A and those who didn’t. All had selective embryo transfer, and when they were looking at surveys, there was a difference in the pregnancy rates for the group population between 35 and 40 being higher than for patients who have done the PGT-A. However, they didn’t see any difference in the miscarriage rates, at least, it was not even significant. Not all patients benefit from PGT-A, it’s important to think about the risk, not only the benefits.
Mitochondria DNA load measurement
It has been estimated that metaphase II oocytes contain approx. 105 mitochondrial DNA (mtDNA) copies, but since there’s no replication of the mitochondria DNA until the blastocyst stage of embryonic development, those mtDNA molecules are divided over the cleaving cells. In 2015, two papers were published reporting an association between higher mtDNA levels and lower implantation potential in the blastocyst, pointing out that perhaps the oocyte’s energy provision and metabolic stress in those embryos might have higher mtDNA content.
There is no evidence that selection through mtDNA load measurement increases the live birth rate. The application of this technique for women should, therefore, still be limited to participation in a controlled trial.
Assisted hatching is usually done on days 3, 5 or 6 of embryo development. It is done by making a breach in the zona pellucida to help implantation. Embryologists usually use assisted hatching for patients that are of advanced maternal age, smokers or patients with high FSH or when they are transferring embryos that have been frozen.
Three meta-analyses have found a significant increase in clinical pregnancy rate, but there is no evidence for a difference in the live birth rate. In 2011, it was published that there was found a significant difference in clinical pregnancy rates using frozen-thawed embryos in unselected women and also patients with repeated IVF failure, but no evidence of benefit for subgroups of either older women or those with good prognosis.
NICE (The National Institute of Health and Care Excellence) guidelines from 2013 state that assisted hatching are not recommended because it has not been shown to improve pregnancy rates.
Artificial oocyte activation (AOA)
Artificial oocyte activation (AOA) is a method to avoid total fertilization failure in IVF cycles. There are different methods to artificially induce oocyte activation that have been proposed as a possible treatment for fertilization failure. Systematic reviews of randomized control trials concluded that there is insufficient clinical evidence to recommend its using practice. The process of oocyte activation is thought to automatically influence normal embryo development, epigenetic imprinting and pregnancy outcomes. The HFEA (Human Fertilisation and Embryology Authority) states that oocytes with calcium ionophores may improve fertilization rates in the ICSI cycle where failed fertilization has previously been observed. However, they noted that there are no randomized controlled trials to demonstrate that it’s effective or follow-up studies on the safety of this technique.
Advanced sperm selection techniques
Advanced sperm selection techniques include all those techniques that help select mature and genetically normal sperm for fertilization to try to improve the outcome of traditional IVF or ICSI.
means co-incubation of sperm in hyaluronic acid (HA) to better identify the best sperm for ICSI. Sperm, which expresses the receptors to bind to HA, have better morphology and motility as well as lower rates of sperm DNA fragmentation and better chromatin structure. Nevertheless, according to the Cochrane review, there is little or no effect on live birth rates or clinical pregnancy rates, but it may reduce miscarriage.
, sperm is examined under a very high magnification microscope that helps to identify better the quality of the sperm. The disadvantage of this technique is that it requires much more time for the embryologist to examine and select the spermatozoa. The risk is the same as when using the ICSI procedure. The Cochrane review published that there is no improvement in clinical pregnancy rates, and miscarriage rates with IMSI compared to ICSI.
- Medical treatment and lab techniques are critical for the success of medically assisted reproduction cycles.
- In the search for improvement in outcomes, many innovations have been introduced unfortunately often those innovations that introduced with little evidence of improved outcomes.
- There is a big need for collaboration between clinicians, embryologists and patients to develop priorities develop a rational approach to evaluating innovations that might lead to improved outcomes