Overview

In vitro fertilisation (IVF) has become increasingly popular as it has revolutionised fertility outcomes and provided hope to couples facing infertility around the world. IVF is one of the many techniques available to help those who are unable to conceive naturally and has resulted in the birth of over 9 million children globally.¹ 

The IVF process includes:

• Suppressing the menstrual cycle and taking follicle-stimulating hormone (FSH) to stimulate the ovaries to produce several eggs
• The collection of mature eggs from the ovaries is then fertilised with sperm. If successful, the embryos develop for 2-6 days
• The best-graded embryo is returned to the womb to grow and develop

In the UK, a birth rate of 33% was noted for patients aged 18-34 who underwent IVF in 2021, highlighting its low success rate. 

New advancements, known as IVF add-on treatments, consist of medications or procedures used in addition to IVF to try and boost success rates.¹ They are currently offered to the general public in licensed fertility clinics across the UK, providing that they have published studies that demonstrate the chances of having a baby are improved. These treatments are typically self-funded.² 

IVF add-ons have received widespread attention from the medical community and infertile couples who are willing to try various procedures that may help improve their chances of having a baby. However, these treatments are often not supported by high-quality evidence to show their clinical use is effective or necessary, and is subject to ongoing research and debate. 

Types of IVF add-ons

Preimplantation genetic testing (PGT)

PGT can be performed for aneuploidies (PGT-A), monogenic disorders (PGT-M) and structural rearrangements (PGT-SR). 

PGT-A assesses embryos for abnormalities in the number of chromosomes (structures made up of DNA material and genetic information) they contain. Embryos with extra or missing chromosomes are known as aneuploid embryos and have a lower chance of developing into a baby or may result in the baby being born with genetic abnormalities.³ 

PGT-M involves checking the genes or chromosomes of the embryos for particular genetic conditions. PGT-M may be used to check for almost any genetic condition that has been approved by the Authority.³ 

PGT-SR checks the chromosome structure to find portions that may be duplicated, deleted or inverted as they can disrupt embryo development and cause developmental defects in babies.³ 

PGT is performed by taking a biopsy (removing and testing cells) from the IVF embryos to determine chromosomal abnormalities or genetic alterations. Embryos found to have no chromosomal or genetic abnormalities are transferred back into the womb. 

PGT may be offered to patients who have: ⁴

• Increased age over 37 as they have an increased chance of having eggs with an abnormal number of chromosomes
• A family history of abnormal chromosomes or genetic conditions
• Failed IVF attempts 
• History of miscarriages
• A child with a genetic condition
• Ended prior pregnancies due to genetic conditions

Assisted hatching (AH)

Before an embryo can be implanted in the womb, it must hatch out from its zona pellucida (ZP). The ZP is a thick layer of proteins that surround the egg and early embryo. However, some people may have abnormalities in the ZP that cause failure for the embryo to hatch and thus implant. AH can enhance implantation where embryologists use acid lasers to make an opening in the ZP and help the embryo hatch.⁵ 

AH may be useful to:

• Patients over the age of 37 
• Those with a history of IVF failure

Intracytoplasmic sperm injection (ICSI)

ICSI is a surgical procedure that involves selecting the best quality sperm and injecting them directly into the egg. The selection method is called intracytoplasmic morphologically selected sperm injection (IMSI) and uses a microscope to assess detailed images of the sperm under an ultra-high magnification between 6000x - 10,000x.⁶

ICSI may be recommended for:

• Low sperm count
• Abnormal shape and movement of sperm
• Previous IVF patients who have none or few fertilised eggs
• Embryo testing for a genetic condition is being carried out 

Physiological intracytoplasmic sperm injection (PICSI)

PICSI involves placing sperm with hyaluronic acid (HA) and is a technique associated with ICSI. Sperms that can bind to HA have been found to have a higher level of maturity, activity and lower aneuploidies. PICSI is thought to improve pregnancy outcomes as mature sperms are chosen for injection over immature sperm which are more likely to exhibit abnormalities.⁷

Time-lapse imaging and incubation

During IVF, developing embryos are removed from the incubator for a brief period to be assessed under a microscope, thereby changing their environment. This allows for the selection and transfer of embryos that are most likely to result in pregnancy. 

Time-lapse and imaging incubation provide stable culture conditions, continuous viewing and documentation of the embryo without removal from the incubator which may affect its development.⁸ It may aid optimal embryo selection as continuous monitoring can detect minute changes that may not have been identified.⁹ 

Hyaluronate enriched media

Some studies have shown that enriching culture media with a substance called hyaluronan may improve implantation of the embryo in the womb and pregnancy outcomes. This may be attributed to an increase in hyaluronan in the reproductive tract that increases at the time of implantation.

An example includes EmbryoGlue, which is added to the solution in which the embryos are kept in the culture dish before being transferred back into the patient. A study conducted with EmbryoGlue demonstrated improved implantation in those who previously suffered from implantation failure and an increase in birth rates. However, further studies have noted no significant difference in these parameters.⁹

Immunological treatments 

Sometimes, infertility may be due to an overactive immune system where natural killer (NK) cells react abnormally to an implanting embryo and signal an immune response to attack it. This can cause problems with achieving and maintaining pregnancy or recurrent miscarriages.¹⁰

Some treatments may be offered to help regulate NK cells and allow the embryo to implant, such as:

• Intravenous immunoglobulin (IVIG), involving antibodies purified from blood of donors
• Intralipids, which are fat emulsions consisting of soyabean oil and water, provide patients with additional nutrients
• Steroids, such as glucocorticoids, reduce inflammation and suppress the immune system 

Endometrial scratching (ES)

ES refers to the “scratching” of the endometrium (lining of the womb) carried out prior to IVF. During the procedure, a sterile plastic tube is used to scrape the endometrium, causing a mild endometrial injury to trigger the body to repair this site. Some research has shown that the procedure causes the body to release hormones and cytokines which allow the lining of the womb to be more receptive to implantation.¹¹ 

Are IVF add-on treatments effective?

Due to safety concerns, the Human Fertilisation & Embryology Authority (HFEA) has developed a traffic light system that provides information on the current state of research and evidence for IVF add-ons:

There are currently no add-on treatments with a green rating, which would indicate an improvement in treatment outcomes.² 

Risks and considerations of IVF add-on treatments 

Despite over 70% of UK IVF patients including add-ons in their treatment, they lack robust evidence of their efficacy and are associated with risks.¹²

Medical risks

Medical risks include: ⁹

• Procedures involving the handling of embryos, such as PGT and AH may cause embryo damage, chromosomal changes and unsuccessful implantation
• Increased risk of multiples and pregnancy complications
• Infections caused by ES, intralipid infusions or IVIG transfusions
• Steroid use weakens the immune system putting you at risk of infections alongside side effects such as mood swings, high blood pressure and weight gain

Financial and emotional risks

Financial and emotional burdens could involve:¹

• Most IVF treatment is carried out privately rather than on the NHS, where add-on treatments significantly increase the overall cost. This can affect patients emotionally as they feel they must try all available treatments to have a successful outcome
• With inconclusive evidence, some add-on treatments such as PGT and time-lapse imaging and incubation may seem beneficial but do not justify their high costs, causing stress and anxiety 

Ethics associated with IVF add-ons

Some ethical considerations about IVF add-ons include:¹

• No clear regulation of introducing add-on treatments into practice despite their lack of effectiveness
• Many clinics offer and advertise add-ons without declaring their lack of evidence-based benefits for financial gain
• The use of misleading or inaccurate claims and marketing on IVF clinic websites which offer patients false hope
• Procedures such as PGT raise questions about the ethics of embryo selection to favour genetics, such as discrimination against embryos that may exhibit disabilities and the discarding of healthy embryos if test results are inaccurate

Summary

• IVF add-on treatments are typically used alongside the IVF procedure to boost treatment success rates
• Common types include preimplantation genetic testing, assisted hatching, intracytoplasmic sperm injection, time-lapse imaging and incubation, hyaluronate enriched media, endometrial scratching, and immunological treatments
• Their efficacy is subject to ongoing debate, where the HFEA have deduced that current add-on treatments are either unclear, proven to have no effect or known to reduce success rates due to a lack of or conflicting high quality evidence
• They lack robust efficacy and are associated with medical, financial and emotional risks
• There is controversy regarding the ethics of embryo selection in PGT and clinics not declaring their lack of evidence and using misleading claims for financial gain
• It is recommended to undertake thorough research, understanding and discussion with your doctor before undertaking any add-on treatments