IVF Add-Ons: What Are They and How Do I Know if They’re Right for Me?
By Melissa Gokhman, RN, BSN, Fertility Coach for Fertility Outreach and Angel Thomas, RN, BSN, Fertility Coach for Fertility Outreach
The views and opinions expressed are those of the authors and should not be considered medical advice. Always consult your doctor, or a mental health professional, for the most appropriate treatment.
You might have heard of in vitro fertilization (IVF) add-ons from your healthcare provider throughout your fertility treatment and care. These may have been referred to as “additional” or “adjunct” therapies. But you may still be wondering what is an IVF add-on, should you consider any, and do they improve your chances of success?
These relatively new treatment add-on therapies within assisted reproductive technology may have promising outlooks. Some small to medium studies have shown potential with add-ons. But extensive, large-scale, high-quality research is still needed. Systematic reviews of science and evidence-based literature concludes that there is not enough current data to make these therapies “routine” in IVF cycles. Randomized controlled trials (RCTs) are needed to know definitively if IVF add-ons do or do not increase the chances of IVF success.
This means that some fertility specialists (reproductive endocrinologists or RE’s) may suggest add-ons where others may not. If your clinician has recommended any add-ons for your protocol, or they haven’t but you are curious about them, ask for further discussion to get the clarity you need to decide.
Examples of IVF Add-Ons
ICSI (Intracytoplasmic Sperm Injection)
ICSI occurs after an egg retrieval, when one sperm is injected directly into the center of an egg in hopes of fertilization. There is evidence supporting the use of ICSI with male factor infertility. Other factors in which ICSI may be recommended are: unexplained infertility, when prior fertilization using conventional insemination has failed, and when attempting fertilization after in vitro maturation (IVM).
ICSI may be routinely used for fertilization of previously frozen eggs, however, there is very limited data on fertilization and live birth rates compared to conventional fertilization of frozen eggs that have been thawed.
The other method used for potential fertilization is known as conventional fertilization. This is when sperm is put in a petri dish with an egg to allow a sperm to potentially fertilize an egg. Like ICSI, there is no guarantee of fertilization when using this method. There is limited to no evidence supporting increased live birth rates or fertilization using ICSI for advanced maternal age, low egg quantity, or quality. Even so, it may be recommended by your fertility clinic, so it is essential to discuss its use if it is part of your protocol.
PGT-A (Preimplantation Genetic Testing for Aneuploidy)
PGT-A is genetic testing of an embryo to determine if there is a normal amount of chromosomes (euploid) or an abnormal amount (aneuploid). Aneuploid embryos have extra or less than normal chromosomes. Risk of chromosomally abnormal embryos increases with age, so PGT-A may be recommended over the age of 35. PGT-A may also be a recommended option for unexplained recurrent pregnancy loss.
Genetic testing of embryos is not without risk. Some examples are false positive results or damage to embryos during the testing process. Embryos may also result as “mosaic,” meaning they have proportions of both abnormal and normal chromosomes (a mix of euploid and aneuploid). Low-mosaic embryos have a higher number of normal chromosomes and lower abnormal, whereas high-mosaic embryos have higher number abnormal than normal. Talk to your RE about their policy on mosaic embryos, as recommended transfer of mosaic embryos can vary as much more research is needed on what this means for pregnancy, genetically affected fetuses, and live birth rates.
Note: PGT-M (for monogenic disorders) is recommended when there is an increased risk of passing an inherited genetic disorder to a child. For example, if you and your partner or sperm donor are both carriers for Cystic Fibrosis, PGT-M can screen embryos for this specific genetic mutation.
Endometrial Scratch (Endometrial Biopsy)
An endometrial biopsy is a procedure that involves taking a small tissue sample from the lining of the uterus (endometrium) for examination. This procedure is typically done in the doctor’s office by inserting a small pipelle (tube) through the cervix into the uterus. This sample is then tested to determine if the cells are consistent with a “receptive” endometrium, so that an RE may recommend an appropriate time to transfer an embryo.
Endometrium receptivity refers to the ability of the endometrial lining of the uterus to allow an embryo to implant in hopes of establishing a successful pregnancy. This period, known as the “window of implantation,” is typically a specific timeframe within the menstrual cycle when the endometrium undergoes changes to support embryo attachment.
An endometrial biopsy may be recommended by an RE when there has been a history of recurrent implantation failures. Hormones, such as progesterone, play a vital role in receptivity. Assessing and testing the endometrial receptivity with a biopsy may help improve the chances of successful implantation and pregnancy.
An endometrial scratch (same procedure as an endometrial biopsy, except the sample is not taken for examination or testing), is used to purposefully cause injury to the uterine lining. Performing this scratch may trigger the release of certain factors in the endometrium that may positively affect implantation. Many studies have been performed on the use of endometrial scratches, including a high quality RCT, and research does not support any benefits to reproductive outcomes for women with recurrent implantation failures. More research is needed to conclude if performing an endometrial scratch prior to a transfer truly does increase the chances of implantation or live birth rates.
Assisted Hatching
Assisted hatching is a technique used by an embryologist in the laboratory to make a small hole in the outer shell of the embryo (zona pellucida) by a laser pulse to help, or assist, it in hatching and subsequently implanting into the uterine wall. The hatching of an embryo is an essential step to result in implantation. If the embryo fails to hatch, this may lead to one of the several factors restricting pregnancy from occurring.
Assisted hatching may help increase the chances of pregnancy in those patients who have failed to get pregnant in previous IVF cycles and those with a poor prognosis (who are not likely to conceive). Assisted hatching also is performed with PGT testing of the embryo.
The procedure may damage the embryo and the embryo’s viability, making the embryo unusable for transfer. Manipulating the zona pellucida artificially also carries the increased risk of monozygotic twinning.
There is insufficient data to make a recommendation for assisted hatching to be performed on an embryo prior to transfer. Studies have shown there to be no evidence for a difference in live birth rates.
Embryo Glue
Embryo glue is an adherence compound, such as hyaluronan, added inside the uterine cavity prior to an embryo transfer that may help the embryo(s) attach to the uterine lining more effectively. Adding such substances allows for a higher viscosity uterine environment.
Embryo glues may be recommended for a transfer of all embryo developmental stages, and in particular for those with recurrent implantation failure. A Cochrane review of 3898 participants from 17 randomized control trials demonstrated moderate-quality evidence supporting improvement in clinical pregnancy rates and live birth rates. Also noted was an increase in multiple pregnancy rates when the transfer medium was supplemented with an embryo glue. The published evidence suggests that embryo glues may be beneficial.
More research is needed in several areas to fully understand the efficacy and safety of using embryo glue. Certain key areas for further research and investigation include its mechanisms of action and how it enhances implantation, as well as potential side effects and risks on both mother and embryo, and possible long-term outcomes for children born following the usage of embryo glue, including any potential developmental or health issues that may result from it’s usage.
Time-Lapse Imaging or Incubation (TLI)
Time-lapse imaging or incubation is a method used to monitor the development of an embryo in the lab. This method involves obtaining continuous images of an embryo on set time intervals, for example every 5 or 10 minutes, throughout the early development stage. Conventionally, embryologists assess an embryo’s development under a microscope about once a day.
As time-lapse imaging cameras are within an embryo incubator, embryos do not need to be removed to be viewed, which is a possible benefit for the embryo to develop without external environment changes.
Time-lapse imaging may help an embryologist predict early patterns that are associated with mosaicism or aneuploidy, or may be coupled with AI (artificial intelligence) to look for these patterns. As selecting the highest quality embryo for transfer is a basic goal of using TLI and of an embryologist, this technology may be an additional cost and time-efficient add on to embryo grading and selection.
Note: in terms of add-on success rates, most research defines success as live birth rates, not pregnancy rates.
Key Takeaways When Considering IVF Add-Ons
Risks
It is essential to discuss risks versus benefits with your fertility specialist, particularly if there is limited data regarding if an add-on may improve chances of success with your specific factors. Add-ons may carry a risk of damaging eggs, sperm, or embryos to certain IVF patients.
Other add-ons
This article reviewed just a few of the emerging and most common IVF add-ons. There may be additional therapies that your RE or IVF clinic recommends for your protocol. This may include other technologies or medications such as: heparin, aspirin, steroids, antioxidants, intralipids, immunoglobulins, granulocyte colony-stimulating factor (G-CSF), dehydroepiandrosterone (DHEA), growth hormone (GH), and artificial oocyte activation (AOA), as well as traditionally Eastern interventions like acupuncture or ayurveda. Similarly to the therapies reviewed in this article, always discuss benefits versus risks and evidence-based recommendations with your RE.
Financial well-being
Compared to an IVF cycle without add-ons, an IVF cycle with add-ons may require more effort, experience, technology and time from your embryologist, RE, clinic, and care team. This may increase the complexity and cost of an IVF cycle.
Tip: Consider discussing costs with your clinic’s billing manager, and confirming if your insurance covers the add-ons that might be recommended for you. Be sure to confirm with your insurance if certain criteria need to be met for coverage.
Emotional well-being
IVF add-ons may add emotional challenges for patients due to several factors and the complexity of their processes. It is essential to have a discussion with your RE about these factors, and how a recommended add-on may or may not benefit your IVF cycle. Make sure to maintain open and honest communication with your partner to ensure mutual understanding and support. Lean on your trusted friends or loved ones as you consider your next steps, and consider reaching out to your fertility coach for support and guidance.
It’s essential to remember that what may have “worked” for someone else may not be recommended or make sense for you. Private social media groups may be helpful for emotional support, however, they may present stories of success based purely on anecdotal factors, which can be confusing. This may lead to comparison and increased stresses or feelings of overwhelm; remember that everyone’s factors, cycles, outcomes, and paths to pregnancy are unique. Consider reflecting on whether a group is truly beneficial to you, or if it may be causing additional stress on your journey.
Tip: Allow yourself ample time to consider all IVF add-on options without feeling rushed to avoid making decisions under pressure or in a highly emotional state. Also, whether pursuing your IVF treatment cycle with or without any additional add-ons, practicing self-care routines to manage stress is essential for your overall and emotional well-being.
There are several IVF add-ons that may be available to you or offered for your IVF cycle. Due to limited data and scientific evidence (specifically, randomized control trials) many add-ons may not be considered standard or routine, but may be recommended based on your cycle needs. It is also important to acknowledge that no IVF add-on guarantees success, and being prepared for various outcomes may help avoid unrealistic hopes and possible disappointment. It is essential to discuss with your RE what evidence-based add-ons might be appropriate for YOU and your factors.
