IVF Add-Ons: What’s the verdict?
Should we be adding these additional services to improve our chances of success?
In-Vitro Fertilisation add-ons. What are they?
They are additional services that can be included with your conventional IVF treatment in the hope to increase chances of success. The Human Fertilisation and Embryology Authority (HFEA) have looked at Randomised Controlled Trials (RCT's) on each of the most commonly offered fertility treatment add-ons in IVF centers and investigated the effectiveness and safety of those treatments.
What are Randomized Controlled Trials?
A study design that can reliably determine the effectiveness of a treatment. It randomly assigns a person to either the treatment group (having the add-on) versus the control group (not having any add-on treatment during IVF) and looks at the results. The best studies will have a high number of participants to give more strength to the results and will follow up on the participants for long term study follow up. Again, adding more strength and value to the study, determining whether something is really effective or not.
Thankfully, the HFEA have done all of the hard work and they have come up with a comprehensive colour coded classification system to guide the public.
Red
Insufficient evidence to support the treatment is effective or safe
Amber
There is a small or conflicting body of evidence, which means further research is still required and the technique cannot be recommended for routine use
Green
Sufficient evidence present to support its efficacy and safety
So here they are.......
1. Assisted Hatching
The egg and embryo are surrounded by a layer called the zona pellucida. Once it hatches from this layer it can implant in the uterus. Assisted hatching is thought to help the embryo in this process. Using acid or other tools such as laser, this layer can be thinned to help the embryo hatch.
NICE guidelines recommend further research on the effectiveness of this add-on. Some clinics believe that it could help women with thicker zona pellucida however it has not been proven.
HFEA Verdict: RED
2. Reproductive Immunology Testing & Treatment
This is an area looking at a woman's immune system and how it changes when she becomes pregnant. The immune system adapts to a foreign embryo (with a different genetic make-up to the mother), allowing it to implant in the uterus unlike the response it has when invaded by a foreign cell, like an infection for example. Some researchers believe that miscarriage is due to the mother's immune system failing to accept the embryo because of differences in their genetic codes. Immunology treatments are used to suppress the body's natural immunity with hopes of increasing embryo implantation.
Steroids, Intravenous Immunoglobulin (IVIg), TNF-a blocking agents (Infliximab), Intralipids all fall under this category however all have potential side affects. Side affects can include high blood pressure, kidney failure, blood clots, infections, allergic reactions, headaches and dizziness. For more information on these drugs and their potential side affects refer to the HFEA website.
HFEA Verdict: RED
3. PGT-A (Preimplantation-Genetic Testing for Aneuploidy) or 'PGS' Day 3
PGS or PGT-A is a test used to check an embryo for abnormal chromosomal numbers as embryos with abnormal chromosomes have less chance of developing into a baby. Abnormal embryos are called Aneuploid embryos. This test involves a biopsy of the embryo on day 3 of development, removing one or several cells and then testing for any chromosomal abnormalities. When done correctly, the embryo can safely go on to develop after this biopsy.
Risks: Wrong results. Removing the cell may damage it or may cause damage to development in the embryo later on. Mosaicism (when the piece biopsied does not reflect the genetic make up of the embryo correctly). Some embryos can have a mixture of abnormal and normal cells at this early stage of development (day 3) and the embryo can self-correct and become a healthy embryo. If however the abnormal cells are the ones biopsied, the result will indicate abnormal. These embryos will then be discarded when in fact they are normal and could have resulted in a pregnancy.
It is advised to do this testing later in the embryo development (day 5) to get a better picture of the genetic make-up of the embryo (below).
HFEA Verdict: RED
4. PGT-A (Preimplantation-Genetic Testing for Aneuploidy) or 'PGS' Day 5
As mentioned above, this is the test done to assess the chromosomal numbers in the embryo. By day 5 of development the embryo has reached >100 cells. By removing a few cells, the embryo is not as compromised and will provide a more accurate result and reflection of the overall genetic make-up of the embryo, than a day 3 biopsied embryo.
The HFEA recommend that PGT-A is done on day 5 of embryo development.
Why?
Some research has shown that PGS carried out at a later stage, at the blastocyst stage on day five or six, might be helpful in selecting a viable embryo to transfer in younger patients who are typically under 37 with no history of miscarriage or failed IVF cycles. It is important to understand that PGS will not increase your overall chances of having a baby. It may help to reduce the likelihood of having a miscarriage, but more evidence is needed to confirm these findings. When considering whether to have PGS, you should also think about the cost as it is usually very expensive (HFEA).
HFEA Verdict: AMBER
5. Artificial Egg Activation
When a sperm penetrates an egg, it causes egg activation and fertilisation. In cases of no fertilization, a chemical called Calcium Ionophore can be used to promote this process. It is believed to increase fertilisation rates however it could also affect the number of chromosomes in the embryo, possibly resulting in miscarriage.
Insight: No RCTs have been done on the use of Calcium Ionophore for egg activation
HFEA Verdict: AMBER
3. Elective Freeze All Cycles
Usually in an IVF cycle, one or two embryos will be transferred back to the uterus about 3-5 days after fertilisation, and the rest frozen (if suitable). In a freeze all cycle no embryos are transferred back and instead, all of them are frozen. One or two are then transferred back to the uterus in a subsequent cycle.
There is some evidence that the body’s hormonal response to fertility drugs can affect the lining of the womb, which makes it more difficult for the embryos to implant. Freezing the embryos means they can be transferred back into the woman when the womb lining is well developed.
It’s also thought by having all their embryos frozen, women are at lower risk of suffering from ovarian hyperstimulation syndrome (OHSS), an overreaction to fertility drugs. This is because OHSS is more common and more severe when it occurs during a pregnancy.
HFEA Verdict: AMBER
4. Embryo Glue
This is 'glue' like substance that contains hyaluronan, which may improve the chance of the embryo implanting in the womb. It is added to the solution in the petri-dish in which the embryos are kept before being transferred to the woman.
A recent piece of research from the Cochrane review shows that embryo glue containing hyaluronan increases pregnancy and live birth rates by around 10%.
One high quality study in this review showed that the use of embryo glue improved pregnancy and live birth rates, other studies in the review however were of moderate quality. We need more high quality studies before doctors can be confident of the benefits of embryo glue. Listen to our podcast - ‘The Fertility Talk’ where I speak to Embryologist and Lab Director Christiana Antoniadou to learn more about embryo glue and IVF Add-Ons.
HFEA Verdict: AMBER
5. Endometrial Scratching
For a successful pregnancy we need a viable embryo and a receptive 'welcoming' endometrium (lining of the womb). Embryo implantation requires the right synchrony between the embryo and the lining of the womb. Most often the reason for no implantation is due to poor embryo development or a mismatch with this embryo-endometrium synchrony. An embryo needs the right environment for growth and development. Endometrial scratching is carried out before IVF. during the procedure the lining of the womb (the endometrium) is ‘scratched’ using a small sterile plastic tube.
The theory is that this causes two reactions in the body.
It triggers the body to repair the site of the scratch, releasing chemicals and hormones that make the womb lining more receptive to an embryo implanting.
The treatment may also activate genes that make the womb lining more receptive to an embryo implanting.
There have only been a small number of quality studies on the effectiveness of endometrial scratching.
Three larger clinical trials are currently looking into endometrial scratching and the early findings suggest that the benefits of using this procedure may be less certain than initially thought. Once the results are published we will be sharing these findings with you.
HFEA Verdict: AMBER
6. Time Lapse Imaging for Embryos
This uses time-lapse imaging (taking thousand of images) to select the best embryos most likely to develop into a baby. It allows the embryologist to continuously view the development of the embryo without removing them from the incubator. The embryologist can assess the progress and growth of the embryo stage by stage. This is different to conventional IVF where the embryos are checked once per day and requires removing them from the incubator for a brief period.
Numerous studies have tried to see if time-lapse imaging can improve birth rates. Initial research has shown some promise, but it’s still very early days. Keeping the embryos undisturbed while they grow may improve the quality of the embryos but there’s certainly not enough evidence to show that time-lapse imaging improves birth rates. Hence the amber verdict.
HFEA Verdict: AMBER
The Take Home Message
Have any add-ons been give the green light?
To date, none of the mentioned add-on treatments discussed have been given the green classification
For more information on IVF add-ons you can check out the HFEA's website where they thoroughly review the studies that have been released investigating the efficacy and safety of these additional services, advocating for the public.
Do your research. Speak to your doctor about the potential benefits versus the risk factors associated with each additional treatment that is being offered. You are not a cash machine, and these add-ons can be costly. If they have little to no evidence of adding any improvement to your overall chances of success then please do re-consider your reasons for doing them.
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