Treatment Add-ons

What is assisted hatching?

The egg and early embryo are surrounded by a thick layer of special proteins called the zona pellucida. Before an embryo can implant in the womb it has to break out or ‘hatch’ from its zona pellucida. Some people think that assisted hatching - using acid, lasers or other tools to thin or make a hole in the zona pellucida - helps the embryo to ‘hatch’.

What’s the evidence for assisted hatching?

The National Institute for Clinical Excellence (NICE) is the national body advising doctors on treatments. It says: “Assisted hatching is not recommended because it has not been shown to improve pregnancy rates.” NICE also says that further research is needed to find out whether assisted hatching influences birth rates and to examine the consequences for children born as a result of this procedure.

Some clinics believe assisted hatching can lead to higher birth rates in specific subgroups of patients. There is however no high-quality evidence to support the use of assisted hatching for any patient.

Is this treatment add-on safe?

Assisted hatching does not carry any known additional risks for the person undergoing fertility treatment. However, there is always some risk of damaging embryos with these types of procedures.

If you have any questions about the safety and risks, your clinic will be able to discuss whether a treatment add-on would be safe for you to use considering your specific medical history and circumstances.

Reference- https://www.hfea.gov.uk/treatments/treatment-add-ons/assisted-hatching/

What is an elective freeze all cycle?

In a normal IVF cycle, one to two fresh embryos are transferred a few days after the egg collection and any remaining suitable embryos are frozen. Elective freeze all cycles involve creating embryos using IVF or ICSI and then choosing to freeze them all so no embryos are transferred in the ‘fresh’ cycle. The embryos are thawed a few months later and transferred to the patient’s womb as part of a frozen embryo transfer (FET) cycle.

Elective freeze all cycles can be used routinely to reduce a patient’s chances of developing ovarian hyperstimulation syndrome (OHSS). However, on this page we are considering the evidence for offering this treatment to patients for the outcome of increasing their chances of having a baby.

What’s the evidence for freeze all cycles?

Research into freeze all cycles is progressing quickly. 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 patient when the womb lining is well developed.

There is also evidence that while the birthweight of babies born from normal fresh IVF cycles is lower, from FET cycles it is higher, closer to naturally conceived babies. Since birthweight is associated with risk of disease in later life, freeze all cycles may be safer for the baby. Some research suggests that the chances of having a baby are increased by using frozen embryo transfers (FETs) rather than fresh transfers. Currently, doctors don’t know with enough confidence whether freeze all cycles are more effective than conventional IVF or ICSI at increasing your chances of having a baby. However, there is no evidence that freeze all cycles decrease your chances of having a baby.

The use of freeze all cycles is for specific medical reasons

Add-ons may be offered for reasons other than to improve the chances of having a baby and in some specific circumstances there may be a justifiable medical reason for using the add-on as part of fertility treatment.

Freeze all cycles are proven to be effective at reducing ovarian hyperstimulation syndrome (OHSS). Therefore, it could be used appropriately for specific clinical cases after careful discussion with a clinician.

Is this treatment add-on safe?

Elective freeze all cycles do not carry any known risks for the person undergoing fertility treatment. However, there’s always a risk that one or more embryos may not survive.

If you have any questions about the safety and risks, your clinic will be able to discuss whether a treatment add-on would be safe for you to use considering your specific medical history and circumstances.

Reference- https://www.hfea.gov.uk/treatments/treatment-add-ons/elective-freeze-all-cycles/

What is endometrial receptivity array?

Endometrial receptivity array (ERA) is a test that claims to find the optimal time for an embryo to be transferred into a woman’s uterus for the embryo to implant, known as the window of implantation. ERA involves taking a biopsy of the endometrial lining of the uterus and testing the tissue to see which genes are expressed. When combined with a computational predictor these results indicate when the endometrium may be most receptive to an embryo implanting. The endometrium will be categorised as either receptive, pre-receptive, or post-receptive.

In subsequent cycles of treatment, the patient will then have what is termed a ‘personalised embryo transfer’, taking place at the optimal time for her specific window of implantation. This would theoretically increase the chances of the embryo implanting successfully and the patient having a baby. However, there is a question over whether a patient has the same window of implantation for each of their cycles of treatment.

Is this treatment add-on safe?

As this procedure requires obtaining a biopsy of the endometrium patients can experience cramping and there is a small risk of infection and bleeding. There is also a very small chance of uterine perforation. The biopsy may need to be repeated in the rare event that either the results are inconclusive, or the biopsy fails to obtain a sufficient quantity or quality of tissue for testing.

ERA requires patients to undergo a freeze-all cycle which carries a small risk that any frozen embryos would not survive the thawing process. ERA does not carry any additional known risks for the child born as a result of fertility treatment.

If you have any questions about the safety and risks, your clinic will be able to discuss whether a treatment add-on would be safe for you to use considering your specific medical history and circumstances.

Reference- https://www.hfea.gov.uk/treatments/treatment-add-ons/endometrial-receptivity-array-era/

What is endometrial scratching?

In order to have a successful pregnancy, an embryo needs to ‘implant’ in the womb; if it doesn’t, the patient will need to start their cycle again.

Most embryos don’t implant because they’ve been unable to develop fully to the implantation stage or because of a developmental mismatch between the stage of the embryo and the lining of the womb.

However, in a small number of cases an embryo won’t implant because the lining of the womb isn’t providing them with the right environment.

Endometrial scratching, also known as endometrial injury, 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 procedure 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. Some also suggest the treatment may activate genes that make the womb lining more receptive to an embryo implanting.

What’s the evidence for endometrial scratching?

Earlier studies were of poor quality and showed conflicting results. The current evidence base includes some quality studies and has shown that there could be a 0 - 5% improvement in live birth rate. However, due to conflicting results from other recent studies further evidence is needed before the benefits of endometrial scratching can be confirmed.

Is this treatment add-on safe?

Although this is an intrusive procedure, with some patients experiencing pain and blood loss, it is not common for patients to have an infection after the scratch. There is a small risk that if you have an infection within your cervix before ‘scratching’, this may cause the infection to spread into the uterus. Your clinic can treat this if necessary. Endometrial scratching does not carry any additional known risks for the child born as a result of fertility treatment.

If you have any questions about the safety and risks, your clinic will be able to discuss whether a treatment add-on would be safe for you to use considering your specific medical history and circumstances.

Reference- https://www.hfea.gov.uk/treatments/treatment-add-ons/endometrial-scratching/

Hyaluronate enriched medium contains a substance called hyaluronan, which may improve the chance of the embryo implanting in the womb. It is added to the solution in the dish in which the embryos are kept before being transferred to the patient. EmbryoGlue is an example of a hyaluronate enriched medium

What’s the evidence for Hyaluronate enriched medium?

There is one high quality study in this review which shows that the use of hyaluronate enriched medium may be effective at improving your chances of having a baby, other studies in the review were of moderate quality. Further high-quality studies are needed before doctors can be confident of the benefits of hyaluronate enriched medium.

Is this treatment add-on safe?

Hyaluronate enriched medium does not carry any additional known risks for the person undergoing fertility treatment or the child born as a result of fertility treatment.

If you have any questions about the safety and risks, your clinic will be able to discuss whether a treatment add-on would be safe for you to use considering your specific medical history and circumstances.

For many patients experiencing fertility problems, no underlying causes are found (a condition known as unexplained infertility). Due to this inability to explain why a successful pregnancy does not occur, one widely shared theory is that the cause may be that the patient’s immune system is rejecting the foetus, and that it therefore needs to be supressed to successfully carry a baby. 

There is a particular type of immune cell, the uterine Natural Killer (NK) cell, that has been proposed as the root cause of a foetus being rejected. The NK cells in the womb or uterus were given this name as they are related to NK cells circulating in our blood. Blood NK cells are essential in the early stage of viral infections, when they kill infected cells. 

NK cells are naturally present in the uterus, but the placenta is always a physical barrier between the patient’s immune cells and their baby. Thus, despite their name, these uterine NK cells are never in contact with the foetus and thus do not attack the embryo. Indeed, it is now becoming clear that they are beneficial for pregnancy, and work in cooperation with the placenta so that the embryo can successfully become established in the uterus. Because there is no evidence that any immune cells, including uterine NK cells, ever do prevent a pregnancy, there is no reason for any patient without a known immunological disease to take these therapies. 

Despite the lack of any evidence that immune therapies are beneficial during pregnancy, they are nevertheless offered by many clinics. Many patients are also offered blood tests first, in which the number and activity of blood NK cells are measured. However, because these tests are looking at NK cells in the blood and not the special NK cells in the uterus, they offer no useful information in relation to pregnancy outcomes. 

A range of treatments may be offered, that potentially have a profound and serious impact on the patient’s immune system. The main ones used are steroids, intravenous immunoglobulins (IVIG), Humira (TNF blockers) and Intralipid. None of these treatments are harmless and some of their side-effects are serious.

Tests to study the endometrium are invasive, and frequent biopsies are needed. Because of all the uncertainties involved, biopsies to assess the state of the endometrium should only be offered in a research setting. 

There is no convincing evidence that any maternal immune cells cause pregnancy failure. However, suppressing the immune system of a pregnant patient exposes the patient and baby to considerable risks, including potentially life-threatening infections. 

For more information on each individual test and treatments and their risks see the HFEA link below.

Reference- https://www.hfea.gov.uk/treatments/treatment-add-ons/immunological-tests-and-treatments-for-fertility/

Intracytoplasmic morphologically selected sperm injection (IMSI) is a sperm selection method used in intracytoplasmic sperm injection (ICSI). The technique involves using a microscope to view sperm under very high magnification (over x6000). This allows clinics to view detailed images of sperm.

What’s the evidence for IMSI?

Systematic reviews suggest that IMSI could be beneficial in specific situations such as previously failed ICSI attempts. The research that has been carried out does not support the use of IMSI over standard ICSI. One small study found that IMSI had improved pregnancy outcomes in older patients, however this study was carried out with a small number of participants and the link, if any, between IMSI and older eggs is not fully understood.

Is this treatment add-on safe?

IMSI is a non-invasive test performed on a semen sample as an additional step in the ICSI process. The risks associated with the use of ICSI also apply to IMSI. However, IMSI does not carry any additional known risks for the person undergoing fertility treatment or the child born as a result of fertility treatment.

If you have any questions about the safety and risks, your clinic will be able to discuss whether a treatment add-on would be safe for you to use considering your specific medical history and circumstances.

Reference- https://www.hfea.gov.uk/treatments/treatment-add-ons/intracytoplasmic-morphologic-sperm-injection-imsi/

During a conventional IVF cycle, eggs are fertilised and allowed to develop in a special culture fluid inside an incubator. Intrauterine culture differs in that it allows the early stages of embryo development to take place within the patient’s womb.

As with conventional IVF, eggs and sperm are collected and prepared. The eggs are fertilised and placed in an intrauterine culture device, which is inserted into the patient’s womb.

The device stays in place for several hours during the initial stages of embryo development. When the device is removed, the embryos are put in an incubator until they are ready to be transferred back to the womb or frozen for use in future treatment.

Of note, the womb is not the place in the body where the embryo would normally develop at this stage so is only able to mimic the natural environment to some extent. Normally the embryo would be developing in the ‘fallopian’ tube which connects the ovary to the womb.

What’s the evidence for intrauterine culture?

There’s currently no evidence to show that intrauterine culture is effective at improving your chances of having a baby. This is something you may wish to consider if you are offered intrauterine culture.

Is this treatment add-on safe?

Intrauterine culture does not carry any additional known risks for the person undergoing fertility treatment or the child born as a result of fertility treatment. However, there is very little research available into these possible risks.

If you have any questions about the safety and risks, your clinic will be able to discuss whether a treatment add-on would be safe for you to use considering your specific medical history and circumstances.

Reference- https://www.hfea.gov.uk/treatments/treatment-add-ons/

What is PGT-A?

PGT-A (previously known as preimplantation genetic screening or PGS) involves checking embryos for abnormalities in the number of chromosomes. embryos with an abnormal number of chromosomes (known as aneuploid embryos) have less chance of developing into a baby or, less commonly, may result in a baby being born with a genetic condition. PGT-A identifies aneuploid embryos that are unsuitable for fertility treatment.

To do PGT-A, embryologists remove a cell, or if at a later stage, several cells, from the embryo, which is then tested for any chromosomal abnormalities. The embryo can still develop with fewer cells, if the removal of cells is done carefully.

What’s the evidence for PGT-A?

PGT-A is traditionally offered to women over 37, patients who have had several miscarriages or failed IVF cycles, people with a family history of chromosome problems, and men whose sperm may carry abnormal chromosomes.

PGT-A is now mostly carried out at the blastocyst stage on day five or six. There is no evidence from research that PGT-A carried out at this stage is effective at improving your chances of having a baby for most patients undergoing IVF. It appears possible that reduced availability of embryos for transfer following PGT-A may counter any benefit of embryo selection.

There is some evidence that suggests PGT-A may be beneficial for certain categories of women, particularly older women, in relation to a potential reduction in miscarriage. It is important to keep in mind that this reduction in the rate of miscarriage does not increase the chances of having a baby. It is likely that, with PGT-A, embryos that express a chromosomal abnormality that could lead to a miscarriage are not selected for embryo transfer. This means that although the patient does not have a miscarriage, she also does not become pregnant because the embryo transfer did not take place.

It is important to discuss your individual circumstances with your doctor.

Is this treatment add-on safe?

PGT-A does not carry any additional known risks for the person undergoing fertility treatment. However, PGT-A is known to carry some risks for the embryo: Although current PGT-A techniques are mostly very accurate, the test may give the wrong result (it may miss an abnormality or detect one that isn’t there).

Using PGT-A may mean you have fewer embryos to use in treatment, or for freezing to use in treatment later. If any healthy embryos are erroneously discarded in this process, you may have fewer chances to transfer an embryo which could develop into a healthy baby.

Removing a cell from the embryo may damage it and prevent it from successfully developing once it’s been transferred to the womb. Removing part of the embryo may cause changes in later growth in the womb, which may cause problems in later life.

In some cases, cells within the same embryo are not chromosomally identical (known as ‘mosaic’), which means that PGT-A may show that the embryo has chromosome abnormalities when in fact it’s capable of producing a normal pregnancy or vice versa. In some clinics, mosaic embryos are considered for transfer, even though they show some chromosomal abnormality.

If you have any questions about the safety and risks, your clinic will be able to discuss whether a treatment add-on would be safe for you to use considering your specific medical history and circumstances.

Reference- https://www.hfea.gov.uk/treatments/treatment-add-ons/pre-implantation-genetic-testing-for-aneuploidy-pgt-a/

What is PICSI?

Physiological intracytoplasmic sperm injection (PICSI) is a technique used to select sperm to use in Intracytoplasmic sperm injection (ICSI) treatment. It involves placing sperm with hyaluronic acid (HA), a natural compound found in the body. PICSI identifies sperm that can bind to HA and these sperm are selected for use in treatment.

What’s the evidence for PICSI?

There have been several studies comparing PICSI with standard ICSI, but there is very little evidence to suggest any benefit of using it. A large study was recently carried out which showed that using PICSI did not increase the chances of having a baby.

The results of this large study did suggest that PICSI may be beneficial in relation to a potential reduction in miscarriage however it is important to discuss your individual circumstances with your doctor.

Is this treatment add-on safe?

PICSI is a non-invasive test performed on a semen sample as an additional step in the ICSI process. The risks associated with the use of ICSI also apply to PICSI. However, PICSI does not carry any additional known risks for the person undergoing fertility treatment or the child born as a result of fertility treatment.

If you have any questions about the safety and risks, your clinic will be able to discuss whether a treatment add-on would be safe for you to use considering your specific medical history and circumstances.

Reference- https://www.hfea.gov.uk/treatments/treatment-add-ons/physiological-intracytoplasmic-sperm-injection-picsi/

What is time-lapse incubation and imaging?

In IVF, time-lapse incubation and imaging is used to help select the embryos most likely to develop into a baby.

In conventional IVF, the embryologist will check the developing embryos each day under a microscope, which involves removing them from the incubator for a brief period.

Time-lapse incubation and imaging allow the embryologist to take thousands of images of the embryos as they grow without disturbing them. Not only does this mean the embryos do not have to be removed from the incubator, it also allows the embryologist to get a continuous view of each embryo as it develops, rather than just viewing them once a day.

The embryologist can then choose a specific embryo for implantation based on criteria such as rate of development and the number and appearance of cells.

What's the evidence for time-lapse imaging?

There have been various studies to try and see if time-lapse incubation and imaging can be effective at improving your chances of having a baby. Initial research has shown some promise, but it’s still very early days.

Indeed, being undisturbed while they grow may improve the quality of the embryos but there’s certainly not enough evidence to show that time-lapse incubation and imaging is effective at improving your chance of having a baby, which is something you may want to consider if it’s being offered to you at an extra cost.

Is this treatment add-on safe?

Time-lapse imaging and incubation do not carry any additional known risks for the person undergoing fertility treatment or any child born as a result of fertility treatment.

If you have any questions about the safety and risks, your clinic will be able to discuss whether a treatment add-on would be safe for you to use considering your specific medical history and circumstances.

Reference- https://www.hfea.gov.uk/treatments/treatment-add-ons/time-lapse-imaging/