IVF Archives - Art Compass IO

Oocyte Maturation

In Vitro Maturation (IVM) was developed as an alternative to traditional IVF due to the adverse outcomes of ovarian hyperstimulation syndrome and the costs

associated with the administration of FSH. The treatment also has the potential to overcome other causes of infertility such as male factor, gamete donation and poor response to stimulation, and also has profound benefits for women undergoing oocyte or embryo cryopreservation with an estrogen-sensitive tumor or with a prothrombotic medical condition. IVM consists of collecting immature (ie. Geminal Vesicle or GV) oocytes and applying FSH and HCG in the culture media.

In vitro maturation of immature oocytes from an unstimulated cycle is an emerging technology. One of the safest ways to prevent OHSS is to not stimulate the ovaries. During an in vitro maturation of oocytes cycle, the immature eggs are retrieved from ovaries that are barely stimulated or completely unstimulated. The eggs are maturated in defined culture media for 24 to 48 hours and fertilized through IVF or ICSI. 4 IVM is an experimental technique that consists of the in vitro conversion of oocytes at the GV stage to oocytes at the metaphase II stage. This technology must include nuclear and cytoplasmic maturation of the oocyte and give rise to embryos that have a developmental potential that is similar to embryos obtained from standard IVF or from spontaneously in vivo matured oocytes. A few IVM practitioners advocated for “rescue IVM” in IVF conventional settings to prevent severe OHSS. “Rescue IVM” is when the physician has come to the conclusion that a safe conventional IVF cycle cannot be done so they change the treatment direction to an IVM protocol to the cycle instead. If the aspiration happens prior to the follicle selection, then OHSS risk can be eliminated.

Though IVM shows promising results, it is not a mainstream for fertility treatment. Mainly because there are difficulties retrieving eggs from immature ovaries that are not stimulated, and a lower chance of live births compared to conventional IVF, and there is an increased rate of abnormalities in meiotic spindles and chromosomes from immature eggs.

Sperm Preparation for ART

When sperm is ejaculated it is surrounded by fluid. A typical ejaculate contains cells, debris, dead and damaged sperm, and healthy, motile sperm. Healthy sperm is critical to the success of ART procedures and so we use sperm preparation techniques to separate functional spermatozoa for IUI, IVF, and ART and for cryopreservation. In the IVF lab there are essentially 4 techniques we use commonly; Swim-up, Swim-down, Sucrose and Ficoll-400 density gradient techniques. Each lab finds that one of these techniques will yield more motile, live and normal looking sperm for their procedures.

Companies like ZyMot sell specialty devices for sperm separation that can be very expensive. The idea is that they simulate the cervical and uterine pathways that sperm must navigate to naturally fertilize an egg. By mimicking this natural selection method, sperm can be isolated without the use of chemicals or centrifugation that may damage the sperm. Instead they use microfluidic technology to isolate healthy sperm by laminar flow, which creates gradients through channels. These devices have been tested in randomized controlled trials, which is the gold standard of medical research.

Data shows that up to 25% of semen specimens from men with an undetectable burden of viral RNA (HIV particles in their blood) are HIV positive. Each semen sample must be tested because those results are not consistent. HIV is detected in some samples and not others form the same man, even when HIV is not detected in the blood. SPAR stands for special program of assisted reproduction. They have developed highly sensitive techniques to detect the viral load in semen samples viruses like HIV, CMV, and Hepatitis C, and special procedures to wash the semen samples. This allows the sperm to be used for IVF to decrease or virtually eliminate the risk of transmitting the infection. These specimens can only be used for IVF, they are not appropriate for intrauterine insemination.

ICSI was developed for men with poor sperm quality and quantity. Low sperm count, sperm motility, and abnormal morphology can be indications for ICSI. Abnormal morphology (shape of sperm) has been linked to poor fertilization. Fertilization can now be achieved for men where it previously seemed impossible. It is now used exclusively in some clinics, and it is especially important for couples who want to have their embryos genetically tested. One of the reasons why it is so widely used now, is so that the embryologists can look at the eggs and know the quality and maturation right after the egg retrieval. In conventional IVF, the egg quality and maturity is essentially a mystery because the eggs are surrounded by cells until the day after the fertilization. Fertilization rates are generally higher after ICSI compared to conventional IVF. The more embryos you have the better the chance of pregnancy!

One variation of ICSI is called “PICSI” which stands for physiological ICSI, and uses a specialized dish coated in a substance called hyaluronan. Healthy sperm are attracted to that enzyme and stick to it, they are later used to inject the egg with.

Sperm DNA Fragmentation Testing

DNA fragmentation can be caused by a variety of factors such as infection, chemotherapy, radiotherapy, smoking, drug use, or advanced age. SDF is linked to impaired fertilization, poor embryo quality, increased spontaneous abortion rates and reduced pregnancy rates after assisted reproduction. Currently, there seems to be insufficient evidence to support the routine use of SDF in male factor evaluation nevertheless the importance of DNA fragmentation in spermatozoa has been acknowledged in the latest American Urological Association (AUA) and European Association of Urology (EAU) guidelines on male infertility. Several strategies have been proposed to minimize the influence of abnormal chromatin integrity on ART outcomes. Obesity, smoking, toxins, pollutants, and Bisphenol A (BPA). They include: intake of oral antioxidants, varicocele ligation, frequent ejaculation and sperm sorting.

In vitro gametogenesis (IVG)

A new process called in vitro gametogenesis (IVG) is currently being developed, and if successful, it will completely transform the way humans think about reproduction.

The process of IVG creates sperm and egg cells in a lab from just about any adult cell. IVG uses skin or blood cells to reverse engineer a special type of cells called induced pluripotent stem cells (iPSCs). Essentially, iPSCs are adult cells that have been genetically reprogrammed into an embryonic state, meaning they have the potential to transform into any type of cell: kidney cells, muscle tissue, sperm, or eggs.

IPSCs can be used to create the necessary components for reproduction: eggs and sperm. They’re also at the forefront of all sorts of important research, including disease treatment, transplant science, and cutting-edge drug development.

In the hypothetical human IVG process, an individual would provide a skin biopsy. A lab would then reprogram those skin cells to create induced pluripotent stem cells, which would then be used to create eggs or sperm.

Today, we still need a man and a woman to make a baby. Reproduction still requires testes to make sperm and ovaries to produce eggs.

In 2016, a team of scientists at Tokyo University of Agriculture in Japan helped a female mouse successfully give birth to 26 pups, using eggs created from skin cells.

In 2018, Japanese scientists were able to generate immature human eggs, using induced pluripotent stem cells derived from human blood cells. These incomplete eggs would not be viable for fertilization, but they do represent a major step toward the development of a successful human IVG process.

Oocyte Activation

A small percentage of individuals continue to face repeated fertilization failure, even with normal sperm parameters and a good ovarian response and multiple ICSIs. Normally, when the sperm binds an egg a cascade of events occurs that results in oscillating waves of calcium ions in the egg. This is called egg activation! If this is missing or deficient in a patient it results in zygotes that arrest and cleavage stage defects. Calcium ionophores are the molecules that increase the concentration of calcium ions, and when artificially applied to an egg can activate the egg so that fertilization can occur.

A meta-analysis by Murugesu et al. (2017) included fourteen studies, and found activation with calcium ionophore increased fertilization, embryo cleavage, blastocyst and implantation rates, as well as overall clinical pregnancy rate per embryo transfer (OR=3.48) and live birth rate (OR=3.44). Calcium ionophore treatment may be especially helpful for patients with specific conditions, such as a condition called globozoospermia, which is when the sperm lacks a feature called the acrosome, or if previous, unexplained failed fertilization occurred.

https://www.fertstert.org/article/S0015-0282(17)30488-0/pdf

DHEA – de hydro epi andro sterone.

One of the hottest topics in IVF right now is the use of DHEA to rejuvenate ovarian function, because currently up to 1 in 4 IVF cycles are characterized by poor ovarian response. “Poor responders” suffer from Diminished Ovarian Reserve (DOR) resulting in fewer oocytes and decreased rates of pregnancy. Some studies claim that use of DHEA supplementation improves pregnancy chances in women with Diminished Ovarian Reserve by reducing aneuploidy—chromosome number abnormalities in embryos. DHEA, according to some reports, has been very successful in increasing the number and quality of eggs, reducing the risks of miscarriages and shortening the time to pregnancy.

Endometrial Receptivity Assays

The Endometrium must be prepared with progesterone for the embryo to implant. The typical metric is to look for a think “triple line” pattern. ERA testing determines if the endometrium is “genetically” receptive or not at the time of sampling, by analyzing a few hundred genes that get turned on or off and are known to be important for true endometrial receptivity. When your lining looks ready after but is not expressing the right genes and therefore the right proteins, your “window of implantation” is displaced. ERA testing can find your personalized window of implantation in case of displacement, and will allow a personalized timing for embryo transfer. 3 in every 10 patients have a displaced window of implantation. Use of the ERA test in one study, resulted in a 73% pregnancy rate in patients with previous implantation failure.

https://www.researchgate.net/scientific-contributions/2068756675_M_Ruiz-Alonso

Millions of babies have been born through Assisted Reproductive Technologies (ART), however, only 30% of IVF cycles succeed in a clinical pregnancy. Aside from increasing the success rate, there are other goals for continued improvement across the IVF industry; to simply get patients pregnant faster, reduce treatment dropout, or to reduce embryo wastage. Innovations in Artificial Intelligence (AI) will drive ART that is more reproducible, standardized, efficient, and less costly. Artificial intelligence and big data: Companies are using “big data” and predictive analytics to help fertility doctors recommend the best course of treatment based on what’s worked for patients with similar demographics. Others are using artificial intelligence to predict which embryo will create a viable pregnancy, instead of relying on scientist’s (occasionally) subjective judgment.⁠

Nanotechnology helps sperm swim: Male Infertility issues contribute to about half of all cases of infertility. One major cause is low sperm motility, or the sperm’s inability to swim to the egg. Nano-tech motors can slip over a sperm’s tail to propel it next to an egg.⁠

Creating “Three-person” embryos: The goal of so-called three-person IVF is to create embryos that have nuclear DNA from a woman and her partner but with healthy mitochondrial DNA from an egg donor. Three-person embryos have been created for two reasons, to correct inherited mitochondrial disorders or as an attempt to reverse the biological clock of older women. ⁠

Freeze all Vs. Fresh Transfer

A suggestion originated in the early 2000s that the high hormone levels derived from a stimulated IVF cycle would encourage a non-receptive, out-of-phase endometrium, the concept arose that adopting a freeze-all approach would not only minimize the risk of ovarian hyper response syndrome, but maybe even improve pregnancy rates in the general IVF population.

The latest clinical meta-analysis of fresh vs frozen transfers, now involving 5379 eligible subjects and 11 trials, found eFET associated with a higher live birth rate only in hyper-responders. There was no outcome difference between fresh and frozen in normal responders, nor in the cumulative live birth rate of the two overall groups. Now, here is where it gets complicated.

The CDC described the increase in the number of elective FET cycles between 2007 and 2016 as ‘dramatic’, rising steeply from almost zero to more than 60,000 cycles per year. In its summary of US activity for 2016 the CDC seems unequivocal – at least, based on its observational registry data – that rates of pregnancy and live birth are higher after frozen transfers than after fresh. Yet the (published, peer reviewed or randomized clinical trial) so far has not shown a large difference. It seems to be a case where the clinical trials have not caught up with clinical practice, and because there is clear evidence that for hyper responders outcomes are better, many clinics are now relying on a freeze all strategy to reduce this poor outcome.

Devroey P, Polyzos NP, Blockeel C. An OHSS-free clinic by segmentation of IVF treatment. Hum Reprod 2011; 26: 2593–2597.
Wong KM, Van Wely M, Mol F, et al. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database Syst Rev. 2017 Mar 28;3:CD011184. doi: 10.1002/14651858.CD011184.pub2.
Roque M, Haahr T, Geber S. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update 2019; 25: 2-14.
CDC. Assisted Reproductive Technology: National Summary Report. 2016.

Embryo Retained in Catheter

Thaw Biopsy Revit

Personalized Genomic Medicine

Anticoagulants; Asprin, Lovenox, Heparin

C4M2 mutation is found on the Annexin 5 which keeps the blood thin enough for pregnancy to progress successfully. When mutated, the gene fails to work adequately causing blood clotting, which eventually leads the body to abort the fetus.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by production of antibodies – antiphospholipid antibodies (aPL) – that “attack” the person’s own body, resulting in blood clots and/or pregnancy complications.

For APS patients with a history of pregnancy complications only:

oral low-dose aspirin (LDA), which prevents clots by blocking platelet aggregation.

subcutaneous injections of prophylactic, low-dose heparin (an anticoagulant drug that prevents the clotting ability of the blood).

Prevents the formation of blood clots in the embryo and placenta
Increases the production of cellular substances important to successful embryo implantation in the uterine lining
Increases insulin-like growth at the site of the embryo’s implantation
Increases production of protein assisting in binding the early embryo in the uterine lining
Effects suppression on the immunologic cause of recurrent miscarriage
https://www.ebiomedicine.com/article/S2352-3964(16)30280-8/fulltext

MTHFR

People differ in how much folate or folic acid they need for their health – based on the activity of “the MTHFR gene”. A mutation in this gene causes very low activity of the MTHFR protein in the body. This results into a highly reduced ability of the body to convert folic acid into a usable form and can lead to accumulation of the amino acid homocysteine – which is toxic to the body.

The biggest reason why knowing your MTHFR gene result is because it is involved in creating healthy DNA for both you and your future child. Active folate is directly involved in the synthesis of new DNA. And while we have a constant demand for the production of new and healthy DNA, you can imagine that demand for this hugely increases during pregnancy, when you are growing a new life!

Issues with not enough healthy DNA available for both mother and growing child can result in issues with pregnancy, fetal growth, and general childhood development.

It is also used by the body to prevent levels of a substance in the body called homocysteine from climbing too high, which can be related to blood clots and increased risk of blot clot formation during pregnancy.

It is also important to create molecules called ‘methyl groups’, which act as instruction manuals for your DNA and cells, telling them the correct way to ‘behave’, so they do not do anything unwanted (e.g. cause disease or dysfunction within the body). We need healthy levels of these methyl groups to methylate/instruct your DNA, and without it cells are uncontrolled and can start to cause problems.

Formation of red blood cells, white blood cells, and platelets, which are all vital for both the health of the mother during pregnancy and also for the health of the child during pregnancy and after birth as they begin to rapidly grow and come into contact with bacteria and pathogens to strengthen their immune system.

As you can see, addressing and supporting your MTHFR genes during your preconception phase is the best way to healthily support both your body once you fall pregnant, and the growth and development of your new baby.

Knowing your MTHFR gene result and supporting your folate levels where needed is a key step in preconception, and both should not be undervalued!

As couples navigate through their fertility journey, you will meet with your physician and begin the process for IVF that includes preparation, stimulation, and monitoring.

In the background is the functioning of the IVF laboratory, where what is actually occurring can be a bit of a mystery. It is after all an almost literal black box! A windowless lab that is under strict lock and key and is often a dark, warm humid atmosphere, just like a human fallopian tube which is the site of fertilization inside the body.

The scientist who combines the sperm and egg and helps the resulting embryos to grow in a controlled environment is called an embryologist. Access to the laboratory or embryologists in most clinics is limited.

An embryologist is a fertility specialist that helps to create embryos to either be used in IVF right away or to be frozen for later use. Embryologists aren’t MDs, but we are highly trained medical professionals, usually holding a Masters degree or a PhD due to the specialized nature of our work. Here are ten things we want you to know about IVF!

What is a blastocyst and why is embryo grading relevant?

A blastocyst describes an embryo stage reached usually after about five days of development post-fertilization. It has about 50-150 cells and has started to develop specific regions with different cellular destinies. The blastocyst is working hard; pumping fluids towards its center, creating a fluid-filled center and expanding like a water filled balloon.

Embryo grading is when embryologists grade embryos based on their potential to successfully implant and result in a pregnancy. The criteria varies from clinic to clinic but the goal is always the same-transfer the best embryo!

Embryologists have lots of training in grading embryos and make the best decision they can for you and your embaby! But it’s always possible that things might actually not go as planned. Sometimes an embryo with a lower grade implants successfully and vice versa! Even though science is very logical and precise, that doesn’t mean that there can’t be some surprising ups and downs.

Why are there so many unknowns about “IVF Add-Ons like EmbryoGlue, PGT-A, Assisted Hatching etc?

In my opinion, this is the result of thirty years of political turmoil in the US. research on embryos and IVF has largely been driven out of the public sphere and into the private sector, entirely supported by commercial interests and individual clinics.

A lot of embryos look amazing on Day 3, but do not go on to form blastocysts. Why?

Embryonic gene activation (EGA) is the process by which an embryo begins to transcribe its newly formed genome. Sperm play an essential role in embryonic genome activation and embryonic progression to blastocyst. Embryos often “arrest” at this stage.

All About PGT?

For those new to the terminology, PGT is a genetic test that takes place before embryo transfer, designed to tell you if each embryo is chromosomally healthy. An embryo that is euploid (normal) has 23 pairs of chromosomes and has a better chance at leading to a successful live-birth than an abnormal (aneuploid) embryo.

Aneuploid embryos have missing or extra chromosomes and will typically fail to implant, result in a miscarriage, or lead to the birth of a child with a chromosomal disease. ⁠Aneuploidy (abnormal or incorrect chromosome number) is common in humans and is the leading cause of all human birth defects as well as miscarriage. ⁠We can perform up to three types of preimplantation genetic testing on embryos during the IVF process. Those include:⁠⁠

PGT-A, which screens for an abnormal number of chromosomes.⁠

PGT–M is the test for individual, or monogenic, diseases.⁠

PGT-SR tests for abnormal chromosomal structural rearrangements, like translocation or inversion.⁠

⁠⁠PGT begins with a biopsy of an embryo in the blastocyst stage of development, usually on day 5 or 6 of embryo development. The biopsy removes 3 to 10 cells from the trophectoderm, which is the outer layer of cells that will become the placenta as the embryo develops. The biopsy does not remove any cells from the inner cell mass, which develops into the fetus.⁠

After these cells are removed, the blastocyst is frozen and stored in the lab.⁠

The biopsied cells are sent for laboratory testing. Results are typically returned in a week to 10 days following the biopsy.⁠⁠

Besides the two possible PGT results we’ve already talked about– euploid and aneuploid– there are also two others: mosaic and inconclusive.

A mosaic embryo consists of both euploid and aneuploid cells. While mosaicism has existed all along, PGT has only been able to recognize mosaicism in embryos within the past three years, so there is still a lot of research ongoing about their potential. What we know now is that about 10-15% of all embryos are mosaic.⁠

Embryo biopsy can also yield an “inconclusive’ or “No result”. That means that the trophectoderm biopsy sample was insufficient to be used for PGT or that it did not meet the quality control standards for analysis.⁠

A study by Cimadomo et al. (2018) showed that inconclusive results occur about 1.5-5% of the time because the cell sample is not loaded properly and the tube is actually empty, or that the sample was degraded. ⁠

Inconclusive or no result embryos have a good chance of being “normal”. A large study (Demko et al., 2016) found for women <35 there is about a 60% chance of a blastocyst being euploid (normal) to 30% by age 41. The chance of getting NO euploid (normal) embryos was about 10% for <35 and about 50% by 43.⁠

⁠You have to make a LOT of eggs to have a good cycle.

15 is the optimal number of eggs to retrieve without putting you at risk for OHSS. More eggs often means they are lower quality and higher estrogen levels, which can impair implantation in fresh IVF Cycles.

IVF has a 100% success rate.

The success rate of IVF is about 40% in couples below the age of 35. Also, the success rate of IVF depends on factors such as age, cause of infertility, and biological and hormonal conditions.

IVF is the same thing no matter which clinic you go to.

NOPE! Not all fertility clinics are created equal, so it’s important to do your research to help you make an informed decision. In addition to looking for a clinic with highly-qualified fertility doctors, it’s critical to choose a clinic with a superior IVF lab. You can check out a clinic’s success rates at Society of Assisted Reproductive Technology or the Centers for Disease Control and Prevention website.

Infertility is a female problem.

Most of the practical and emotional infertility support out there is aimed at women. Maybe because we are the ones being stimmed and undergoing the surgeries. But we need to get the men more involved! It’s a common misconception that women are most affected by infertility. In some cultures “male infertility” is literally unheard of, like culturally it does not exist. In fact, men and women are equally affected. In heterosexual couples, 1/3 of infertility cases are attributed to men, 1/3 to women, and 1/3 are unknown. With regard to our healthcare, often we will be the first to approach an infertility doctor, who will then prescribe a standard work up of invasive tests that have become the norm for women who experience problems conceiving: that includes multiple appointments, multiple hormone tests, internal, transvaginal scans to check your womb for fibroids, and an HSG test, where dye is pushed into your fallopian tubes to see if they were blocked. Only then, does the male partner typically obtain a semen analysis. Sometimes, men may need to modify their lifestyle habits quite a bit, but this is often brought up late, if at all. Some providers argue that assessing lifestyle factors and history, or for physical problems like varicocele, is even more important than the traditional semen analysis. Raising awareness male infertility will help us to get more funding, resources, research, and even donations made by male donors.

IVF is only used for individuals/couples struggling with infertility.

Families with a history of genetic disorders can do IVF with pre-implantation genetic testing to screen their embryos for single gene disorders and to prevent the genetic condition from being passed onto their children. Even fertile couples use IVF to have more control over their family building, such as being able to chose the order of the sex of their children or for optimal timing for their lives and careers. Also, IVF is used by moms and dads who are single by choice and for LGBTQ couples to build their families.

EGG, Sperm and Embryo Myths!

We cannot tell “female” (X- bearing) sperm from male (Y-bearing) sperm. There is a persistent myth that X or Y bearing sperm look different from each other or swim at different rates. These myths are not based on good, solid science!

Every egg, sperm and the resulting combination of the two are different. That makes every attempt at IVF using different gametes a different experience. From the embryologist’s point of view, each egg looks different, but we can’t see the DNA with a microscope to select the “good” eggs. Embryologists will care and nurture your gametes, but cannot repair or make an embryo better by culturing it in the laboratory.

Some embryos don’t freeze well or survive the thaw, and are just indicators that there is probably something flawed about them or something we don’t yet understand scientifically speaking. Additionally, each embryo is as different as any child resulting from that embryo would be, but we can’t treat each embryo differently. Adhering strictly to IVF lab culture protocols is what elevated assistant reproductive technologies from being an art into being a reproducible science.

Don’t choose your clinic based solely on insurance coverage. Base your decision on the performance of the individual clinic. Clinics that have higher volumes will naturally have embryologists who get to participate in a lot of procedures. Fertilization rates should be above 70% and 40-50% of fertilized eggs should make it to the blastocyst stage.

Weigh the cost of the treatments with the CDC success rates. Good clinics with high success rates may cost more up front but may get you pregnant faster and at a lower cost in the long run instead of paying for multiple treatments.

Consider inquiring about the technologies the clinic uses. Do they use an EMR? Does it have a patient Portal for easy communication? Is there an electronic consenting process? Does the lab have state of the art cryo-storage monitoring systems? Does the lab use “electronic witnessing”?

How do you choose a fertility clinic? What questions can a lay person ask to begin to understand the quality of an IVF Lab? Quality goes beyond pregnancy success rates to new technologies, inspections and accreditations, staff experience and more! Find out what to ask.

In the industry, we alway say, START with SART! The federal government requires fertility clinics to report IVF treatment cycle success rates, and you can find those statistics on the SART website. It also has a tool that allows prospective patients to search for fertility clinics by ZIP code, state or region; plus, women can plug in information such as their age, height, weight, and how many prior births they’ve had to predict their chances of success with assisted reproductive technology.

Most IVF programs are proud of their results and may list them on their website, however, whatever they are advertising should match the number of cycles and the outcomes reported to SART or found in the CDC Assisted Reproductive Technology Fertility Clinic Success Rates Report.

Look for verified lab accreditation on the CDC report or in the actual facility itself, it will usually be posted in plain site. Find out who the inspecting agency is, the College of American Pathologists? The Joint Commission?

A possible thing to note could be to look at what percentage of their patients are in your age range, or have the same infertility diagnosis as you do.

Consider how the clinic’s staff talk to you, what they say – how professional does the care feel? Use all of your senses. Is the care personalized and professional enough so you feel comfortable?” An example of dehumanizing behavior: some clinics have an application process to decide if you should be treated there.

Failed to call in prescriptions to pharmacy
Lost paperwork
Lost appointments
Failed to call with results
Failed to order appropriate test

Look on Indeed, Glassdoor, or other job sites to get an idea of staff turn over and what staff have to say. Find out how experienced the providers are, how well-trained they are and how long have they been there? As with other fields of medicine, experience matters in reproductive medicine. Providers should be fellowship-trained and board-certified in the field, both of which are the standard. Also inquire how long the medical providers have been at the facility. If there seems to be high staff turnover, there could be leadership and organizational issues at the clinic.

Look for clinics that can offer the latest treatments and protocols. These might include blastocyst transfer, freeze all cycles, mini or low STIM IVF, preimplantation genetic screening of embryos and single embryo transfer, ERA or endometrial receptivity assay testing.

The introduction of intracytoplasmic sperm injection (ICSI) has resulted in a choice of fertilization methods between conventional in vitro fertilization by insemination (IVF) and fertilization by ICSI. Fertilization by insemination relies on the normal healthy functions of the sperm, and those can be bypassed by injection directly into the oocyte. Severe oligospermia (low sperm concentration), asthenozoospermia (low motility) or teratozoospermia (abnormal morphology) are all good reasons to use ICSI. However, many clinics routinely use 100% ICSI no matter what the diagnosis is. In the case of IVF, unexpected complete fertilization failure (CFF) in an individual cycle is a well-known phenomenon and is a risk to the success of IVF cycles.

In the ever-evolving world of IVF lab accreditation and quality management, there are numerous standards and frameworks to choose from, such as from ASRM and ESHRE. However, there’s one accreditation agency that stands out as the optimal choice – the College of American Pathologists (CAP). If you’ve just stumbled upon CAP Accreditation, don’t fret; this comprehensive guide will walk you through the ins and outs, helping you determine if CAP Accreditation is right for your lab and, if so, how to embark on the journey toward excellence.

What is CAP IVF Lab Accreditation?

The CAP Checklist for IVF lab accreditation is a remarkable publication brought to you by the College of American Pathologists. It is more than just a checklist; it’s a meticulously detailed roadmap designed to ensure and enhance quality management in clinical embryology, andrology, and endocrinology labs. Specifically, these standards are meticulously crafted to align with and uphold the USA federal CLIA88 guidelines for clinical laboratories.

Who Needs CAP Accreditation?

CLIA88 isn’t just a suggestion; it’s a legally mandated framework. By law, every clinical laboratory must be in strict compliance with CLIA 88. But what sets CAP Accreditation apart is its capacity to not only meet but exceed these standards. So, whether you’re running an established IVF lab or venturing into this cutting-edge field for the first time, CAP Accreditation is your key to unlocking a world of quality, precision, and excellence.

Staying Ahead of the Curve with CAP Checklist Updates

The College of American Pathologists understands the importance of maintaining consistency and stability in their checklists. While the world of IVF lab accreditation is dynamic, CAP strives not to make major changes to the checklists. This dedication to stability allows IVF labs to maintain their focus on quality assurance without the constant disruption of adapting to significant updates.

For IVF labs, this commitment to minimizing major changes in the checklists is a relief. It allows you to build a strong foundation of quality practices and focus on continuous improvement rather than navigating extensive checklist revisions.

To help you stay informed and up-to-date, we’ve still analyzed the minor changes in recent CAP Checklist updates and compiled them into a convenient reference table for your convenience.

CAP Checklist Update Key Changes & Updates

As a reminder, if you’re looking for a “Turn Key” set of IVF lab Standard Operating Procedures (SOPs), you can find them within the ART Compass IVF Lab Management platform. These SOPs are designed to seamlessly integrate with the latest CAP Checklist updates, making your journey toward CAP Accreditation smoother and more efficient.

Stay with us as we continue to unravel the secrets of CAP IVF Lab Accreditation, equipping you with the knowledge and insights needed to not only meet industry standards but to stand out as a beacon of excellence in the field of IVF.

In the USA, The IVF industry is experiencing a pressing, double-edged problem: it struggles to fill new embryologist positions, an estimated 5% of the existing workforce is already beyond retirement age (65-67 years old)—and an estimated additional 20-40% will reach retirement age within the next 7 years. Embryologists are the core of the IVF supply chain, and a shocking “grey” rhino (an obvious yet ignored threat) is in the room. We cannot make more embryos without more embryologists. By all predictions, the IVF industry is on track to grow astoundingly in the next ten years as millennials who have put off childbearing for career begin to seek age-related infertility care. We are so focused on growing good embryos, but how do we grow (attract) new embryologists?

An ASRM practice document [1]“Minimum standards for practices offering assisted reproductive technologies: a committee opinion” states that:

“There should be a contingency plan in place for all personnel essential to a program in case of illness, absence, or departure of an individual from the program. The purpose of the contingency plan is to ensure that critical operations within the laboratory and practice are covered without interruption.”

Our entire field is in dire need of a contingency plan.

40% of our current workforce is attributed to the “Baby Boomer” generation. The oldest Baby Boomers are 75 years old, and the youngest are now 58. I would wager to guess that the vast majority of 67-75 year olds have already retired. Just think of the IVF lab directors and embryologists you know who will retire in the next 5-7 years (i.e. the 58-65 year olds). Each one likely directs numerous offsite laboratories. And new IVF laboratories open every day. Are enough new HCLD certificates being granted to ensure that IVF labs can continue to function at high levels of patient care and quality after this looming tsunami of retirements?

As a result of this human capital conundrum, it has become even more important that IVF clinics ensure knowledge transfer, retention, and upskilling occur.

Knowledge Transfer

Campbell et al. note in “The in vitro fertilization laboratory: teamwork and teaming”[2] that “Knowledge sharing is vital among an IVF laboratory team to build on the knowledge base and enable succession and development. Clinical case review, journal-based learning, and research opportunities all facilitate such sharing and knowledge building.” Embryologists who are struggling to simply complete the expected clinical laboratory work of the day may not be able to fulfill these ideals, as well as train and supervise junior team members.

The model of meeting for scientific congresses, where this type of knowledge transfer typically occurs, was briefly derailed during the global coronavirus pandemic. Scientific congresses can only serve a fraction of embryologists. The long overdue International IVF Initiative (I3) rose, modernizing the age-old practice of knowledge transfer with the added benefit of democratizing access for embryologists worldwide. Alternate approaches to further modernize the concept of “knowledge transfer” in embryology and the ARTs are so important. Chocair et al [3] proposed a robust roadmap to modernize knowledge transfer that includes multiple digital methods; online self-assessment programs, digital technology integration through blogs, podcasts, and influential videos, an online platform education management platform to report training logbooks, including a “knowledge assessment passport” among other action items. The Y and Z generations of workers are digital natives (digital “junkies” even..) they cannot live without their mobile devices. Investment in and support for “digital first” knowledge transfer technologies is essential. (Full disclosure, I am the inventor of one such unsupported technology, the ART Compass mobile app, so it goes without saying, these opinions are biased).

Embryologist Retention

There is a childcare crisis in the USA. The majority of embryologists are women of childbearing years. These two things are essentially incompatible.

Embryologist schedules are unpredictable (consider the odd 100 egg retrieval or 6 hour TESE) and can start well before a school day begins and stretch until well after a school day ends. Additional childcare considerations must be made for holidays and weekend shifts. That doesn’t even take into consideration the mental anguish of missing significant family related events or milestones. An added consideration is that families rarely reside in multi-generational households (or even in the same city) and Baby Boomers are no longer retiring in a timely fashion due to a combination of economic fragility brought on by multiple successive economic failures and longer life-spans. Even when they do retire, they don’t necessarily want to watch little ones. They have already raised their own children and are ready for travel, adventure, and leisure. Many embryologists are confronted with a very simple calculus: “Do I make enough in one hour to cover one hour of childcare?” With the skyrocketing cost of childcare as well as the scarcity of available childcare providers, too often that answer is “no”.

One action item for the field at large is to train more male embryologists. Diversifying the workforce will have numerous benefits; including, greater insulation from multiple maternity leaves of absence. However, an even more pressing need is to fix the culture of IVF practices to be less rigid, less demanding, and more flexible for those with families or even without, recognizing that work life balance will drive the decisions of Gen Z and Gen Y. And to do that, we must support the elevation of our female embryologists to the highest ranks (PhD/HCLD). It stands to reason that if 80% of embryologists are female, 80% of lab directors should also be female. However, we see the opposite is true. It is clear that when men do become embryologists, they quickly ascend the ranks to become lab directors, or presumptuously, I think they must leave the field because they won’t stand for the intense hours/ low pay/ holidays and weekends. So modulating the intense, unpredictable “culture” of IVF labs should have the impact of retaining both genders equally.

Upskilling

In the USA, we have few formal “embryologist” education, training, or placement programs. The bulk of all new embryologist training falls to the senior embryologists. This dearth, coupled with high embryologist demand has led to the rise of a number of commercialized and privatized training programs to fill the void. Currently, these programs have stellar reputations. But what is to stop predatory programs from also springing up? Generally, consumers of education programs have some level of assurance and transparency because there is oversite and regulation of higher education. Results are measurable and formally assessed and documented, sources of capital and cash flow are understood, the quality of training and/or placement is guaranteed. One action item for the field could be a standardized and digital education management platform to report training logbooks, that includes the “knowledge assessment passport” mentioned above. One example, and in response to the COVID-19 pandemic, the American Center for Reproductive Medicine (ACRM) transitioned its annual training to a fully online modules included manual semen analysis, sperm morphology and ancillary semen tests (testing for leukocytospermia, sperm vitality, and anti-sperm antibody screening)[4].

Conclusion

Within higher education, abundant models exist for hands on biotech training at the “associate degree” open enrollment level, but grow scarcer at the BS / BA level. Advocacy associations for the ART industry might focus lobbying efforts at State legislature levels that acknowledge that without an appropriately skilled workforce, it is impossible to grow this highly-regulated industry. Local ART education programs should eliminate barriers to ART careers by providing access to expensive equipment, space, and real-life education through hands-on learning opportunities, learning FDA, CLIA and other regulatory requirements that result in highly employable, and valuable technical careers in ART. An intriguing new study, Clinical Laboratory Workforce: Understanding the Challenges to Meeting Current and Future Needs [5] suggests further innovative ways to improve workforce recruitment and retention, including; financial incentives to encourage professional development and job satisfaction; and flexible schedules, benefits, tuition incentives, and sign-on bonuses.

Acknowledgment

Unpublished Online survey by the educational platform International IVF Initiative.

Palmer GA, Tully B, Angle M, Sadruddin S, Howles C, Nagy ZP, et al. Occupational Demand & Resultant Stress of reproductive scientists: Outcomes from an International survey.

References

Practice Committee of the American Society for Reproductive Medicine, P.C.o.t.S.f.A.R.T., B. Practice Committee of the Society of Reproductive, and a.a.o. Technologists. Electronic address, Minimum standards for practices offering assisted reproductive technologies: a committee opinion. Fertil Steril, 2021. 115(3): p. 578-582.
Campbell, A., et al., The in vitro fertilization laboratory: teamwork and teaming. Fertil Steril, 2022. 117(1): p. 27-32.
Choucair, F., N. Younis, and A. Hourani, The value of the modern embryologist to a successful IVF system: revisiting an age-old question. Middle East Fertility Society Journal, 2021. 26(1): p. 15.
Agarwal, A., et al., A Web-Based Global Educational Model for Training in Semen Analysis during the COVID-19 Pandemic. World J Mens Health, 2021. 39(4): p. 804-817.
Edna C. Garcia, M., M. Iman Kundu, and P. and Melissa A. Kelly, Clinical Laboratory Workforce: Understanding the Challenges to Meeting Current and Future Needs. . 2021.

March’s Quality Audit from the ARTC Digital Lab Playbook focuses on documenting general IVF lab CAP inspection preparations. This set of guidelines developed by the College of American Pathologists for quality laboratory environments ensures safety, precision, and accuracy!

Reach your quality improvement goals and higher standards of care for your patients, meet your regulatory requirements, and manage your laboratory more efficiently with ART Compass.

IVF labs are busier than ever. This month, we present you with a smart checklist of important and easily missed quality control items to ensure your lab is inspection ready. The ART Compass platform provides a digital method to track and control many of these items.

IVF lab CAP Inspection Preparation

Preparing an IVF lab for inspection requires attention to detail, ensuring compliance with regulatory standards. Essential steps include verifying the presence of certificates such as CAP, CLIA, FDA, and tissue bank permits, prominently displayed for inspection. Quality control (QC) records are meticulously reviewed to confirm that no parameters have fallen out of range during patient service, with corrective actions duly noted for any deviations. It’s imperative to ensure that all instruments and tests are in control, with the director’s sign-off on QC activities. CAP flyers should be visibly posted, and certificates of analysis for product shipments must be checked for validity, marked “ok to use,” and securely stored for reference, potentially in ART Compass for easy retrieval.

Additionally, documenting MEA and sperm motility assays, especially for products not tested by the manufacturer, is crucial for quality assurance. Records of these assays can be efficiently maintained in ART Compass, ensuring compliance and facilitating inspection procedures. Furthermore, items certified by NIST should be appropriately calibrated to guarantee accuracy and reliability in laboratory operations. By adhering to this checklist and maintaining meticulous records, IVF labs can confidently prepare for inspections and uphold the highest standards of quality and compliance.

Top 4 MOST Cited IVF Lab Deficiencies.

Liquid Nitrogen Levels; The laboratory has a written procedure to monitor and maintain adequate liquid nitrogen (LN2) levels and temperatures for all critical storage containers.

Competency Assessment of Embryology Personnel; The competency of each person performing embryology procedures, including micromanipulation and other assisted reproductive technology techniques is assessed.

Alarm Monitoring; Alarms are monitored 24 hours/day (either remote or in the laboratory) and there is a written procedure for responding to alarms.

Monthly QC Review; Quality control data are reviewed and assessed at least monthly by the laboratory director or designee.

We hope you enjoy our reminder to prepare these ahead of your CAP inspections!

Make some time to ensure:

New CAP, CLIA, FDA, and tissue bank licenses are posted
QC records are reviewed
Nothing was out of range on any day of patient service
Corrective actions are noted for any out-of-control instrument or test
Ranges are revised for appropriateness
Director has signed off on all QC
CAP flyers are posted (do you need to order a new poster?)
Check certificates of analysis exist for all relevant product shipments are marked “ok to use” (store them in ART Compass!)
MEA and sperm motility assays are documented for certain products that are not tested by the manufacturer (again, you can record these in ART Compass by making an “MEA” patient”)
NIST-certified items are appropriately calibrated.

Addressing QC issues is important in identifying and communicating potential errors with IVF lab operations. Running a well-controlled IVF lab sure requires a lot of attention to the details, which makes regular QC inspections imperative!

September	FDA Audit
October	Staff Audit
November	Patient Satisfaction and Security
December	Space and Supplies
January	PMs, Air Quality, and Deep Clean
February	Biennial P&P Updates, Review, and Sign Off
March	Grab bag! General Lab CAP Inspection Preparations
April
May
June
July
August

IVF Lab Digital Playbook

DEI practices can also improve health outcomes for patients.

Assisted reproductive technology (ART) has transformed the landscape of infertility treatment, providing a ray of hope to countless couples trying to conceive. In-vitro fertilization (IVF) is one of the most commonly used ART methods, accounting for over 99% of all ART cycles performed in the United States. However, despite the progress made in this field, disparities in IVF outcomes and access persist, and racial factors play a significant role in exacerbating these disparities.

What is DEI?

Diversity, equity, and inclusion (DEI) are crucial components of any healthcare system, including IVF clinics. DEI practices help ensure that all patients are treated equitably, regardless of their race, ethnicity, gender, sexual orientation, or socioeconomic status. By adopting DEI practices, IVF clinics can better serve and advocate for patients and their loved ones, leading to better outcomes and a higher quality of life.

One of the key benefits of DEI practices is that they promote patient-centered care. Patient-centered care is an approach to healthcare that places the patient at the center of their care experience. This approach emphasizes listening to patients’ needs and preferences, involving them in decision-making, and providing care that is respectful of their values, beliefs, and cultural background. When IVF clinics adopt DEI practices, they create an environment that is welcoming and supportive of all patients, which can improve patient satisfaction and outcomes.

Cultural sensitivity is another important aspect of DEI practices in IVF clinics. Cultural sensitivity refers to the ability to understand and appreciate the cultural backgrounds of patients and how these backgrounds may affect their healthcare experiences. For example, a patient from a different cultural background may have different beliefs about fertility treatment, and IVF clinics that are culturally sensitive can adapt their services to better meet these patients’ needs.

In addition to promoting patient-centered and culturally sensitive care, DEI practices can also improve health outcomes for patients. Studies have shown that patients who receive care that is culturally sensitive and responsive have better health outcomes than those who do not. For example, a study of African American women undergoing infertility treatment found that those who received culturally sensitive care had higher pregnancy rates than those who did not.

Finally, DEI practices can help IVF clinics attract and retain a diverse and talented workforce. When IVF clinics prioritize DEI, they create an environment that is welcoming and supportive of all employees, regardless of their background. This can help attract and retain employees who are representative of the communities they serve, which can improve the quality of care and outcomes for patients.

There are several reasons why racial disparities in IVF outcomes and access exist. One of the most significant factors is the cost of treatment. IVF is an expensive procedure that can cost tens of thousands of dollars per cycle, making it out of reach for many individuals and families, especially those without insurance coverage. Unfortunately, insurance coverage for infertility treatment is not mandated in most states, and even in states where it is mandated, the scope and extent of coverage may vary significantly. This lack of access to affordable IVF treatment disproportionately affects low-income individuals and people of color, who are more likely to be uninsured or underinsured.

Another factor contributing to disparities in IVF outcomes is the quality of care. Studies have shown that Black women have lower success rates with IVF, even after controlling for age, infertility diagnosis, and other confounding factors. This disparity may be due in part to differences in the quality of care provided to Black women. For example, Black women may be less likely to receive appropriate preconception counseling, have longer wait times for appointments, and receive lower-quality care during the IVF process.

Finally, there is a significant lack of diversity in the field of reproductive medicine. Black individuals and other people of color are significantly underrepresented in the field, both as patients and as practitioners. This lack of diversity may contribute to the disparities in care and outcomes seen in IVF treatment. For example, a study found that Black women who received care from Black physicians were more likely to have successful IVF outcomes than those who received care from non-Black physicians.

Disparities in IVF outcomes and access are complex and multifactorial, with racial factors playing a significant role. Addressing these disparities will require a comprehensive approach that includes addressing the cost of treatment, improving the quality of care provided, and increasing diversity in the field of reproductive medicine. Legislation such as the ACA presents an opportunity to expand coverage for infertility treatment and improve disparities in fertility prevention, but more needs to be done to ensure that all individuals have access to the care they need to build their families.

DEI and Inclusive and Accurate Medical Language

The use of medical language has a significant impact on the way we think about and understand health conditions. Historically, medical language has been focused on gender, with certain conditions and symptoms being attributed exclusively to either male or female bodies. However, this approach can be problematic as it ignores the fact that gender is not binary and fails to account for individuals whose gender identity does not align with their biological sex.

As such, a more inclusive and accurate approach to medical language would be to shift the focus from gender to anatomy, conditions, and symptoms. This means using language that describes specific body parts and functions, rather than assuming that certain conditions or symptoms are exclusive to one gender or another.

For example, instead of using terms like “male infertility” or “female infertility,” medical professionals can use terms like “sperm count” or “ovulation problems” to describe specific conditions or symptoms. Similarly, rather than using gendered terms like “menstrual cramps” medical professionals can use more specific language like “dysmenorrhea” to describe the symptoms.

By shifting the focus of medical language from gender to anatomy, conditions, and symptoms, we can ensure that all individuals receive accurate and inclusive healthcare. This approach also acknowledges that individuals may have a range of gender identities and expressions, and that these identities do not necessarily correspond to their biological sex.

It is important to note that shifts in medical language are not just a matter of political correctness, but rather a crucial step in providing equitable healthcare. Inaccurate or exclusionary medical language can lead to misdiagnosis, delayed treatment, and a lack of access to appropriate care for marginalized communities. In contrast, more inclusive and accurate medical language can help ensure that all individuals receive the care and support they need to maintain their health and well-being.

DEI and LGBTQIA+

Diversity, equity, and inclusion (DEI) practices can greatly improve fertility outcomes and create a more welcoming environment for LGBTQIA patients in several ways:

Access to Care: DEI practices ensure that all patients have equal access to fertility care, regardless of their gender identity or sexual orientation. This includes providing education and resources to LGBTQIA patients about their fertility options, as well as making fertility services more affordable and accessible.

Culturally Sensitive Care: Fertility clinics that adopt DEI practices can provide culturally sensitive care to LGBTQIA patients. This involves understanding the unique challenges that LGBTQIA individuals face when seeking fertility treatment and developing care plans that are tailored to their specific needs.

Inclusive Language: Fertility clinics that use inclusive language can create a more welcoming environment for LGBTQIA patients. This involves using gender-neutral language and avoiding assumptions about gender and sexual orientation.

Provider Diversity: DEI practices promote provider diversity, which is essential in creating a more welcoming and inclusive environment for LGBTQIA patients. Clinics should strive to hire providers who are representative of the diverse patient population they serve.

Patient Advocacy: Fertility clinics can serve as patient advocates by advocating for policies that promote DEI in healthcare. This includes supporting legislation that protects the rights of LGBTQIA patients, as well as advocating for insurance coverage for fertility treatments.

The table below gives a sample DEI plan, and provides space to record a point person on the executive team, DEI group members who might participate, and a strategy to include staff from the whole company.

DEI Initiative by Department	Activities	Executive Staff	DEI Group Members	Strategy to include all staff
Human Resources	Recruiting – all levels
	Talent Pipeline – Bridging the gap to local schools and Universities
	Diversity Survey: What is does the diverse make-up of your company look like? • Race • Gender More than two options (MANY options) • Religion • Age • Sexual orientation • Parental status • Marital status • Position • Disability (physical or otherwise) Equity: • Salary equity • Equitable promotions and raises • Diversity in leadership positions? Inclusion: Understanding the employee experience. • “I can voice a contrary opinion without fear of negative consequences” • “people from all backgrounds have equal opportunities to succeed ” • “perspectives like mine are included in the decision-making at my company”
Marketing	Analyze your social media feeds for each clinic. Does your social media feed display a range of skin tones? A range of relationships? A spectrum of genders?
	Your ads and creative content should show diversity. Captions and posts should use inclusive language.
	Amplify publications related to disparity in outcomes, eduction, or access. Show you care about these issues.
	“Like,” follow, and occasionally share (amplify) the content of diverse creators.
	Ask physicians and scientists to participate in diverse infertility events and share. Ask them to use inclusive language in social media posts. Educate them on inclusive language.
	Can you create sections on the IVF Clinic website that speaks to the lived experience of BIPOC, LGBTQI+. Can you use inclusive language whenever possible “Pregnant persons” People with a uterus” “Birthing person” “Chest Feeder”?
Clinical	Change all paper or electronic forms to use inclusive language (LGBTQ, race, and ethnicities). Patient and Partner (instead of female and male)
	Increase visual representation in waiting rooms, magazines, pictures, baby pictures
	Attendance at Men Having Babies or other diverse conferences or symposia
	Can you parse your SART data or EMRs and strategize for one abstract / publication a year on a topic related to diversity? What are the IVF success rates of BIPOC at your IVF clinic? What are the ethnic backgrounds of the internal donor egg banks? (Can you recruit more diverse backgrounds?) Do the patients reflect the diversity of the area surrounding your IVF clinic? Does your patient satisfaction surveys have queries for culturally sensitive and competent, or LGBTQI+ specific care?
IVF Laboratory	Seminar on lab handling of HIV+ sperm and embryos. Education about SPAR processing.
	Changes in lab protocols to accommodate egg donor splits for male:male couples.
	Coordinate with clinic for abstracts and papers related to DEI
Internal Network	Mission, Vision, Contract with executive team
	DEI newsletter, 2x per year posted on HR staff management platform and emailed to staff

A Sample DEI action plan for IVF Clinics

Artificial Intelligence for Embryo Selection is here!

Embryo Selection has been proposed as one of the top Infertility research priorities. Healthcare professionals, people with fertility problems and infertility researchers (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process resulting in an article that was published in Human Reproduction in November 2020 outlining the top future infertility-related research priorities. The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions.

The top 10 infertility research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. These top ten research priorities in each topic area outline the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, to assist research funding organizations and researchers to develop their future research agenda.

This post discusses research priority #4: What is the optimal method of embryo selection in IVF cycles?

An article was published in Human Reproduction in November 2020 outlining the top future infertility-related research priorities. The top ten ART research priorities are;
What are the causes of implantation failure?
What is the optimal treatment for women undergoing IVF who are poor responders to increase live birth rates?
What is the optimal method of sperm selection in IVF cycles?
In couples with unexplained infertility, does IUI increase live birth rates when compared with other ARTs, including IVF?
In couples with unexplained infertility, what is the optimal number of IUI cycles before moving to IVF?
What is the optimal method of embryo selection in IVF cycles?
What are the factors that affect cycle to cycle variability in the number and quality of oocytes produced in an IVF cycle?
What is the optimal time interval between ovulation and IUI?
What is the emotional and psychological impact on children born using donor gametes?
What is the emotional and psychological impact of repeated fertility treatment failure?

Why is Embryo Selection a research priority?
- The primary goal of embryo selection is to produce a live birth from a single embryo transfer and to minimize detrimental outcomes, like implantation failure, miscarriage, or birth defects.
Noninvasive imaging (microscopy) systems for gametes and embryos is the primary grading and selection method
- Common:

There are three techniques for imaging live, transparent specimens.

Phase contrast passes light through the sample, so the image is light and dark based on the DENSITY of the sample. HMC (Hofmann Modulation Contrast) and DIC are very similar- both are rendering an image based on the rate of change in the optical path- the slope. However, they do it different ways. In HMC a filter is used to amplify certain signals- in this case, the signal is light that has refracted as it passed through the sample. In DIC light is split into parallel beams and directed at the specimen, then they are further affected as they pass through the specimen, then recombined and analyzed on the other side. DIC relies on waves of light interfering (or not) with each other. The major problem with phase contrast is that it produces “halos” of light. The major problem with DIC is that orientation of the sample matters a lot (so swimming sperm- as they change their orientation- would not be good to view with it). Additionally, you must use glass coverslips/ slides or plates with the same refractive index – whereas with HMC you can use a plastic dish, PVP etc all having different refractive indices than the sample.

Rare:
- - Polscope. Visualize meiotic spindle placement and formation with polarized light. Now we predict the position of the spindle by positioning the 1st polar body at 12 on the clock when we do our ICSI injections. But the spindle is not always there, and we can damage the chromosome apparatus during the injection causing the second polar body to not be able to extrude from the egg, and failed fertilization. If the spindle has not formed when we inject the egg usually dies. So the method we have now works for 90% of eggs. We don’t usually have access to this specialized microscope.
  - MSOME and IMSI. Expensive experimental systems that require extended handling of the sperm, potential to cause more oxidative damage, lack of agreement on what marker of any indicates sperm DNA damage (vacuoles, cytoplasmic droplet)
  - Time lapse monitoring. Expensive and most labs do not have it. Incubation system where the embryos are placed and grown continuously and monitored. Right now, we take embryos from their little culture chamber and inspect them at set time points. Usually at fertilization, day 3, and then 5/6/7. Time lapse can record things we miss in between those checks. Positive selection criteria include the positioning of the pronuclei and a small organelle called the nucleoli inside them, number of blastomeres, the absence of multinucleation, early cleavage to the two-cell stage, and a low percentage of cell fragments in embryos.
Genetic screening selection techniques like PGT-A are peaking in several countries
New controversy: polygenic trait selection of embryos
- There have been and continue to be many many controversies in genetic testing of embryos: namely, mosaic embryos and “segmental aneuploidy” embryos can self correct and make healthy pregnancies 30% of the time.
Algorithmic and artificial intelligence scoring generated by computers is gradually enhancing our selection process, these are becoming more widely used.
EMA by AiVF is a multi-module integrated platform that combines AI, computer vision, and big data to improve the success rates in patients undergoing IVF treatment. Its genetic evaluation tool can determine if the given embryo is genetically suitable for transfer by avoiding an invasive biopsy. AiVF has the largest embryo database in the world and the platform offers objective and automatic tools. One groundbreaking study from AiVF, tested the effectiveness of EMATM, AiVF’s multi-module integrated platform, which combines AI, computer vision, and big data. According to the study, EMATM detected significant differences between aneuploid and euploid embryos during the first five days of embryonic development. This was based on a retrospective study involving 2,500 embryos with PGT-A results – 1,000 euploid (genetically normal) embryos and 1,500 aneuploid (genetically abnormal) embryos. Aneuploid embryos were significantly more likely to reach each specific embryo developmental event later than euploid embryos and the time gaps between developmental milestones were also statistically longer in aneuploid embryos.
- In general, lack of video imaging systems for continuous monitoring and single step embryo culture systems, as well as lack of data handling methodologies, are holding these back from widespread deployment.
The race has been on to find metabolomic markers for embryo selection
- What is the embryo using for energy and growth, and what are its waste products?
- The metabolomic profiling of embryo culture media has been performed through proton nuclear magnetic resonance (1H NMR). Researchers have discovered that the metabolomics profile is correlated with embryo reproductive potential. From the proton NMR spectrum, alanine, pyruvate, and glucose levels were reduced in the culture media of embryos that resulted in pregnancy. Glutamate levels were found to be higher compared to embryos that failed to implant, possibly due to its generation from α-ketoglutarate and ammonium, thereby lowering the potentially toxic ammonium to developing embryos. A sensitivity ― the ability to identify true implantations/pregnancies ― of 88.2 percent and a specificity ― the ability to correctly predict no implantations/pregnancies ― of 88.2 percent was achieved through 1H NMR
Protein markers from the embryo culture medium
- Not too many have been discovered, but surely there are more. Healthy embryos will be producing characteristic proteins as they go about their work growing.
- In one study by Noci et al., soluble human leukocyte antigen-G (sHLA-G) was isolated and considered as a possible protein marker of embryo reproductive potential. The presence of sHLA-G shows no correlation with embryo morphology, and the lack of sHLA-G in culture media has a negative predictive value. In another study in which sHLA-G-positive embryos were transferred, implantation and pregnancy rates were 44 percent and 75 percent, respectively, compared to 14 percent and 23 percent of transferred sHLA-G-negative embryos.
- A protein biomarker that has been found to be upregulated and increased during embryo maturation into the blastocyst stage is a Day 5 secretome ― a set of proteins secreted from the cell ― resembling ubiquitin. Ubiquitin has been implicated in the turnover of key signaling molecules during implantation
Other non-embryonic genomic markers (cumulus cells) have potential
- The cumulus cells (CCs) that surround the oocyte from fertilization until implantation have been analyzed and gene-profiled to gauge embryo potential: the likelihood of an embryo to implant and lead to a successful pregnancy. Several genes expressed in CCs have been correlated with predicting pregnancy, including cyclooxygenase 2 (COX2), steroidogenic acute regulatory protein (STAR), and pentraxin 3 (PTX3). Two upregulated biomarkers have been identified in the CCs of successful pregnancies, BCL2L11 and PCK1, which are involved in apoptosis of abnormal cells and gluconeogenesis.

Written with contributions from Mercedes Randhahn, Natasha Matta, and Dr. Carol Lynn Curchoe, PhD, HCLD

The Supreme Court of the United States issued the landmark Dobbs v Jackson decision, imminently affecting more than half of the country’s population. Dobbs officially overturned the 1973 Roe v. Wade decision, thereby abandoning the principle of stare decisis, or former legal precedent. Roe v. Wade was formative in establishing the right to privacy, and granting pregnant persons the Constitutionally protected right to exercise autonomy in seeking an abortion. The decision paved the way for feminists across the world to rally for further rights, including; contraception accessibility, same-sex marriage, equal pay rights, and basic protection from discrimination on the basis of sex.

Right now, many people have been left dumbfounded and horrified as to what overturning Roe means for the future of essential rights to privacy. As of June 30, 2022, 6 states have banned abortion, 5 states have heavily restricted abortion, and 11 more states have pending legislation to severely limit abortion access. Such legislation that aims to hinder abortion availability falls under the category of “personhood laws”, which define personhood as beginning at the moment of fertilization. Now that stare decisis has been formally abandoned, other rulings like those that legalized same-sex marriage, birth control and gay marriage are without a doubt, also in danger. Abortion is healthcare. Will other reproductive medical procedures become illegal or highly restricted? There have already been reports of pharmacists refusing to fulfill orders for needed medications and physicians refusing to place IUDs.

One of the biggest risks of equating a fertilized egg to having the same rights as a living, breathing child concerns assisted reproductive technology (ART). ART is most frequently used to assist infertile people in their journey toward reproduction. The most well known facet of ART is in vitro fertilization (IVF). In vitro fertilization consists of removing eggs from a consenting person’s ovaries, fertilizing the eggs with sperm from a partner or donor, and freezing the resulting embryos or gametes for later use. Although the process is scientifically sound, personhood laws threaten to disrupt IVF by criminalizing the act of making, freezing, or discarding embryos.

In fact, prominent fertility physicians have been raising alarms about the threat of this court to ART since at least Amy Coney Barrett’s Supreme Court nomination. During her confirmation hearing, Barrett evaded questions about her views on IVF and whether she would overturn Roe v. Wade. When asked whether criminalizing IVF would be constitutional, she replied that she couldn’t “answer questions in the abstract.” She has previously been associated with extremist anti abortion, “life begins at fertilization” groups who have been openly hostile toward IVF.

One area of concern is the legal status of a fertilized embryo. If legislation uses language like “life begins at conception” or “any stage of human development,” would eggs fertilized in vitro be considered alive? Human? Some states might consider them property while others might confer them the legal rights of an adult citizen. Will egg and sperm donation continue to be legal? What if those tissues are being donated to a single person or LGBTQ family? (or anyone else that activist politicians and judges don’t agree with the lifestyle of?).

What will happen to frozen embryos? People choose to have their embryos frozen for many different reasons. Some freeze embryos to maintain their integrity while taking a biopsy and testing them for genetically inherited diseases or an abnormal number of chromosomes. Many undergoing IVF freeze unused embryos for future cycles if an embryo does not implant successfully or to have more children down the line. Additionally, some people choose to freeze their embryos before undergoing intense medical treatments like chemotherapy, which can cause temporary or permanent infertility.

If embryos are awarded legal rights, would people be allowed to have their embryos frozen or would that be considered abuse? Would destroying unused embryos be considered manslaughter? If it is considered murder to place a 5 year old child in a freezer, is it also illegal to do the same to an embryo? Can the two be rationally considered identical in terms of biological characteristics and rights?

Overturning Roe v. Wade may have unwittingly (or worse, perhaps knowingly…) impeded people’s ability to choose what is done with eggs, sperm, and embryos in assisted reproduction. Oftentimes during the IVF process, embryos can be discarded under standard of care due to the potential risk of miscarriage or development of chromosomal abnormalities that could pose extreme risk to the mother and child.

Additionally, the legality of other procedures like selective reduction (terminating some fetuses to decrease the risk for the birthing person and their baby). For instance, this process is utilized if a mother is found to have three viable embryos, or triplets, but would likely not be able to carry all three babies to term without risking developmental setbacks or medical risks. A few of the embryos would then be terminated if needed. This is most often only performed when the risk of carrying multiple fetuses outweighs the additional risks that the reduction procedure brings to the pregnancy.

Under personhood laws, it would be criminal to dispose of an embryo just as it would be deemed manslaughter to do the same to a child. Preimplantation genetic testing, or biopsy of a few cells from an embryo to diagnose inherited genetic diseases or mutations, for example, that cause conditions like breast cancer or Huntington’s disease) could change. But as a society, how can we expect all women to deliver babies with known abnormalities into a country with minimal resources to support people with such disabilities? Without the protections of Roe v. Wade, pregnant people will be forced to carry high-risk pregnancies that compromise themselves and their babies.

The fall of Roe v. Wade signals that IVF along with any other medical procedure that politicians disagree with, could become illegal or severely restricted, leading to higher costs, less accessibility, and lower chances of successful, safe pregnancies. ART recognizes each person’s individual choice to pursue reproduction and intends to support those people with fertility disadvantages that may obstruct the likelihood of conception and safe delivery. On that same note, we recognize that not each person wants to reproduce and we support all people in their right to discern which reproductive journey is right for them. Therefore, our industry is a target for this activist Court.

The government must take steps to mitigate this heinous decision, and codify into law the right to choose what people do with their own bodies.

ART Compass shares the concerns of the infertility community in the USA as the shocking overturn of 50 years of reproductive healthcare certainty leaves more questions than answers. The infertility community already faces many barriers to family building. This vital healthcare is inaccessible, unaffordable, under-diagnosed, under-treated and impacted by complex social and psychological factors like fear, shame, misinformation, stigma, and trauma.
Undoubtedly, IVF accessibility, safety, and success are now in peril in many states. Over the years, there have been 100+ “personhood” bills proposed in the United States to give full personhood status rights to fertilized eggs.
With fertilized eggs considered full humans under the law, anything putting those cells at risk could be a criminal violation for fertility doctors, embryologists, and families. This is an enormous and concerning problem for IVF patients.
Can you perform surgery (biopsy and genetic testing) on a person so without their consent? Will IVF clinics be able to make more than one embryo at a time? What happens to aneuploid embryos? Will we be forced to transfer every embryo or pay to keep them frozen forever? Will unused embryos have to be adopted rather than discarded? Will freezing embryos even be legal? Can you freeze a person? Will PGT testing itself be outlawed in certain states, as it is used to avoid the transfer of unviable embryos?
Already roughly 18 million women lack fertility care in the USA, and insurance coverage is inadequate, preventing families from being able to obtain life-changing IVF care to treat their medical conditions.
Our top priority remains our clients and providing best-in-class fertility support to their patients through our artificial intelligence IVF products.
At ART Compass we pledge to:
Denounce the decision of Dobbs V Jackson Women’s Health Organization. This decision will cause patient harm, and further marginalization, stigma, and inaccessibility in the infertility community.
Support family building journeys for all people.
Develop technologies that advance infertility and IVF healthcare, and reduce the risk of transferring unhealthy embryos. We deliver world class artificial intelligence based embryo selection (noninvasive biopsy) technology to support elective single embryo transfer to the ASRM standard of care, to all clinics regardless of location, and to democratize and expand access to the highest standards of infertility care.
Support medical institutions, like the American Society for Reproductive Medicine – ASRM and the American College of Obstetricians and Gynecologists (ACOG) positions on abortion as essential healthcare.
Lead innovations in the infertility and IVF health space, with a passionate team, and be an outstanding partner to IVF companies doing critical work.
Advocate and support infertility and IVF health innovators and researchers who have already faced a lack of resources, funding and attention. Progress and research in infertility will be negatively impacted by these changes.
Reject and denounce any policy decisions that increase existing inequalities when it comes to accessing reproductive medicine, or restrictions that make accessing IVF more expensive, limit the number of embryos made or implanted, lead to lower chances of successful pregnancy, more IVF cycles, and greater costs.

References & Resources to Learn More

https://reproductiverights.org/maps/what-if-roe-fell/

https://www.plannedparenthoodaction.org/issues/abortion/roe-v-wade

https://www.pbs.org/newshour/health/how-overturning-roe-v-wade-could-affect-ivf

https://www.npr.org/2022/05/05/1096732347/roe-v-wade-implications-beyond-abortion

https://nwlc.org/wp-content/uploads/2018/08/Even-More-Than-Abortion-1.pdf

https://www.plannedparenthoodaction.org/blog/the-womens-health-protection-act-critical-to-help-keep-abortion-legal-throughout-the-u-s