Artificial Intelligence
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?

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.

ASRM2021 Edition 🗼Reproduction Reimagined
ASRM2021 Edition 🗼Reproduction Reimagined

There are so many exciting talks at ASRM2021, Reproduction Reimagined! We are super excited about these IVF Lab focused talks as well as quite a few others!

Title Speakers
O-199 – COULD THE EMA ARTIFICIAL NEURAL NETWORK GRADE BLASTOCYSTS AS AN EMBRYOLOGIST?Lorena Bori, Ph.D1., Daniella Gilboa, MSc2, Ron Maor, BSc.2, Thamara Viloria, PhD3, Ilya Kottel, BSc.2, Daniel S Seidman, MD4 and Marcos Meseguer, Ph.D.1, (1)IVIRMA Global; IVI Foundation, Valencia, Spain, (2)AiVF, Tel Aviv, Israel, (3)IVIRMA Global, Valencia, Spain, (4)AiVF; Sackler Faculty of Medicine, Israel
 RTM32 Ready, Set, Go! How to Skyrocket Your ART Lab Professional Career.Liesl Nel-Themaat, Ph.D., HCLD, University of Colorado Anschutz Medical Campus, Aurora, CO
 RTT27 Emerging Bioengineering Technologies in the ART LabsT. Arthur Chang, PhD, HCLD, ELD, University of Texas Health Science Center, San Antonio, TX
RTT28 “Be a Scientist, Not a Robot”. Is That a Lost ART?”Mitchel C. Schiewe, MS, PhD, Ovation Fertility, Newport Beach, CA
 RTT29 The Ideal Cryopreservation Storage System – Characteristics and Equipment.Kimball O. Pomeroy, Ph.D., The World Egg Bank, Phoenix, AZ
INT03 To ICSI ALL or NOT to ICSI ALL: That’s the Question!Mitchel C. Schiewe, MS, PhD, Ovation Fertility, Newport Beach, CA, David H McCulloh, PhD, NYU Grossman School of Medicine, New York, NY, Caroline McCaffrey, PhD, NYU Langone School of Medicine, New York, NY, Bill Venier, MSc, ELD (ABB), San Diego Fertility Center, San Diego, CA and Liesl Nel-Themaat, Ph.D., HCLD, Univ of Colorado
RTW21 Looking Past the Hype: Realistic Expectations for AI-Based Embryo Selection.Dean E Morbeck, Ph.D., M.B.A., Fertility Associates, Auckland, New Zealand
RTW22 Lab Disaster Management: Prepare Today be Ready TomorrowSangita K Jindal, Ph.D., Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY
RTW23 New Lab Equipment: Better Outcomes?Anthony R Anderson, D.HSc, EmbryoDirector.com, San Antonio, TX
SYW06 Crises Management: What We Have Learned from Catastrophic EventsRoman Pyrzak, Ph.D., Kimball O. Pomeroy, Ph.D., The World Egg Bank, Phoenix, AZ and Sangita K Jindal, Ph.D., Albert Einstein College of Medicine / Montefiore Medical Center, Hartsdale, NY
SYW07 ON-DEMAND ONLY SESSION: The Environment: It Affects More Than the Ice Caps!Patricia Hunt, Ph.D.1, Dean E Morbeck, Ph.D., M.B.A.2 and Linda C Giudice, MD, PhD1, (1)Washington State University(2)Fertility Associates, Auckland, New Zealand
PLE05 Herbert H. Thomas Plenary Lecture: Applications of Nuclear Transplantation in Reproductive MedicineShoukhrat Mitalipov, PhD, Oregon Health & Science University, Portland, OR
PLE06 Past and Future of IVFEli Y Adashi, MD, The Warren Alpert Medical School, Brown University, Providence, RI
INM08 Snap, Tweet, Tok! Reimagining Patient Education with the Use of Social MediaNatalie M Crawford, MD, MSCR, Fora Fertility, Austin, TX, Jasmine Danielle Johnson, MD, IU Health – Indiana University School of Medicine, Carmel, IN and Temeka Zore, MD, Spring Fertility, San Francisco, CA
SYT07 Artificial Intelligence (AI) in the IVF LaboratoryAlan B Copperman, MD, Sema4, Stamford, CT, Richard Slifkin, BA, TS(ABB), CLT(NYS), Reproductive Medicine Associates of New York, New York, NY and Danielle Soltesz, MBA, MPH, RMA of New York, New York, NY
YM04 PGT Yesterday, Today, and TomorrowJames A Grifo, MD, PhD, New York University, New York, NY, Mike Large, Ph.D., CooperSurgical, Houston, TX and Mark Hughes, Ph.D., COOPERGENOMICS
RTM22 What the IVF Doctor Needs to Know about the IVF LaboratoryEric J. Forman, M.D., Columbia University Fertility Center, New York, NY
RTM08 Polygenic Risk Scores and Embryo Selection: Should We?Amber Gamma, MS, CGC, Northwell Health Division of Medical Genetics, Great Neck, NY
 SYM10 SART-CORS Registry: The State of the ARTJennifer F Kawwass, MD, Emory University School of Medicine, Division of Reproductive Endocrinology and Infertility, Atlanta, GA, Stacey A Missmer, Sc.D., College of Human Medicine, Michigan State University, Grand Rapids, MI and Amanda Nicole Kallen, MD, Yale School of Medicine, New Haven, CT
INT02 Chat with Journal Editors: Good Scientific Publication, Manuscript Review, and Editorial ProcessAlexander M. Quaas, MD, PhD, University of California San Diego, San Diego, CA, Richard J Paulson, MD, MS, University of Southern California, Los Angeles, CA, Denny Sakkas, PhD, Boston IVF, Waltham, MA and David F Albertini, PhD, M.S., Bedford Research Foundation, Salisbury, MA
Vitamins and Infertility - Dietary sources of vitamins A, D, and E!
Vitamins and Infertility – Dietary sources of vitamins A, D, and E!

Can vitamins impact infertility? Certain vitamins are essential in maintaining fertility and we have included sources where you can find these vitamins to incorporate into your diet.

Vitamin A

Vitamin A is crucial for the functioning of various body systems and organs. One of these systems is the reproductive system.

Spermatogenesis  is quite dependent on vitamin a. It is what helps keep structures such as the epididymis and seminal vesicle functioning. without it, instead of finding those structures you might find “stratified squamous keratinizing epithelium.”

In females the problems could be found in ovulation. A study on vitamin A deficient rats showed that the rats were unable to ovulate and form corpora lutea routinely. researchers were also not able to see blastogenesis occur. vitamin A could play a crucial role even after fertilization! it has been shown that a mother’s vitamin A keeps the placenta in good condition.

In studies performed on pigs, it was observed that a lack of vitamin A resulted in several birth defects including cleft palate, lack of eye development etc. embryos observed during days 12.5-20.5 demonstrated a range of defects in vision related structures such as the retina and iris.

The nervous system also uses vitamin A for functions such as neural differentiation. Vitamin A deficient (vad) quail embryos have been observed to have underdeveloped hindbrains. They also did not have many spinal cord neurons. Some other problems were observed in vad rat embryos; these included:

There are many more conditions that can develop in embryos. however, making sure that you include sufficient amounts of vitamin A in your diet prevents such birth defects. It is important to keep in mind that eating healthy is very important during early pregnancy and even pre-pregnancy. It is often stressed by health professionals to get your vitamins from food rather than supplements, and the same is true for vitamins and infertility. Vitamin A can be found in variety of foods including:

References:

1. Clagett-Dame et al. “Vitamin A in Reproduction and Development” Nutrients. Mar 29 2011

2. “Vitamin A” Harvard T.H. Chan School of Public Health

Vitamin D

Scientists are still not completely sure whether vitamin d deficiency is associated with IVF outcomes. The authors of one study did conclude, however, that vitamin D does not affect pregnancy, live birth, and miscarriage rates. They found reason to believe vitamin D is involved in folliculogenesis, oogenesis and endometrial receptivity. Studies are split between whether vitamin D deficiency is a serious issue for individuals who plan on using ART. Certain fertility clinics screen patients for vitamin d deficiency prior to beginning treatment. A good level of vitamin D for fertility treatments is often considered to be 30 ng/ml. It is important to be able to maintain this level even throughout a pregnancy as studies have shown vitamin D deficiency may induce preeclampsia, gestational diabetes and other conditions. The reason for this may be that vitamin D is known to be involved in the embryo implantation process. It controls the genes that generate estrogen and also helps to shift around immune cells in the uterus to fight off infections. Some good sources of vitamin D include:

Serum Vitamin D status is associated with increased blastocyst development rate in women undergoing IVF.
• Strong relationship was observed between blastocyst development and VitD sufficiency- linking vitamins and infertility.

• For every single increase in a blastocyst generated or embryo cryopreserved, the likelihood of VitD sufficiency increased by 32%. 

•  There was no association between VitD and clinical pregnancy or live birth outcomes.

• Larger studies should investigate whether the effect on blastocyst development may affect subsequent clinical pregnancy and live birth rates.


Nikita L. Walz et al., RBMO 2020

References:

Vitamin E 

It is clear that micronutrients, vitamins and infertility go hand-in-hand. Researchers from another study were able to determine an association between recurring abortion and low plasma vitamin e levels and increased lipid peroxidation levels in women. Regarding fetus/embryo growth, it’s important to bring up the study of in vitro matured and fertilized bovine oocytes. The zygotes derived from them when cultured in vitamin E, vitamin C, and EDTA were more likely to enter the blastocyst stage than the control medium. Current studies indicate there is still more we need to know about vitamin E! The University of Rochester is currently conducting trials involving 48 infertile men and 20 fertile men on how vitamin E affects sperm fragmentation. DNA fragmentation occurs due to oxidative stress. Because vitamin E is an antioxidant, it can combat such oxidative stress. It leaves us questioning if vitamin E deficiency perhaps leads to DNA fragmentation? Want to try and incorporate more vitamin E into your diet? Here’s some foods that Healthline listed, which you should eat!

References:

1. Mutalip et al. “Vitamin E as an Antioxidant in Female Reproductive Health” Antioxidants. Feb 2018. 

2. Vitamin E and Male Fertility study on ClinicalTrials.gov

3. Olson et al. “Culture of in vitro-produced bovine embryos with Vitamin E improves development in vitro and after transfer to recipients.” Biol Reproduction. Feb 2000. 

Freeze all Embryos or 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 Freeze all Embryos or Fresh Transfer strategy was initially a ‘rescue’ strategy for women at high risk of ovarian hyperstimulation syndrome; however, this approach has been extended to other indications as a scheduled strategy to improve implantation rates.

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 Embryos or Fresh Transfer strategy to reduce this poor outcome. 

Are you a good candidate for “Freeze all”?

Mathilde Bourdon et al., (RBMO, 2021) recently summarized the evidence in The freeze-all strategy after IVF: which indications? 

The use of this strategy is steadily increasing in ART cycles with various indications 

1. To counter the risk of late pregnancy- induced ovarian hyperstimulation syndrome (OHSS) in patients who experienced an excessive ovarian response to stimulation 

2. The existence of endometrial anomalies, e.g. thin endometrium, polyps, associated metrorrhagia, submucosal leiomyomas and endometritis, or elevated progesterone levels on the last day of stimulation. 

3. The aim was to limit the risk of implantation failure or was used as a ‘scheduled’ strategy before the beginning of ovarian stimulation in various indications, including preimplantation genetic testing (PGT). 

4. Ovarian stimulation with IVF and intracytoplasmic sperm injection (ICSI) cycles could have a negative effect on endometrial receptivity, generalization of the freeze-all strategy to the overall IVF/ICSI population has since been implemented in a number of centers.

5. A recent meta-analysis, the transfer of day-5 blastocysts was associated with significantly higher pregnancy rates compared with the transfer of day-6 blastocysts as the intrinsic embryo implantation potential in day-6 blastocysts is impaired (Bourdon et al., 2020a), an asynchrony between the endometrium and day-6 blastocysts is also a possibility, reported significantly lower live birth rates in fresh day-6 compared with fresh day5 blastocyst transfers, whereas this difference was not found with frozen embryo transfer 

6. It may also be caused by a failed implantation process, possibly related to the endometrial changes that impair endometrial receptivity in fresh autologous IVF/ICSI cycles  

7. Freeze-all strategy increase the chances of a live birth in women with repeated IVF/ ICSI failures, women with at least one failed fresh blastocyst transfer have a significantly greater probability of a live birth with the ‘freeze-all’ and subsequent thawed approach than with another fresh cycle 

8. IVF is associated with an increased risk of thromboembolic diseases (pulmonary embolism and venous thrombosis), with a doubling of risks during pregnancies resulting from ART.

Image by Michele Krozser

Cutting Carbs is notorious for its ability to speed up weight loss. This is because carbohydrates are our primary source of energy. This means that if we find ourselves suddenly running, we’re going to grab energy from the carbohydrates if they are available, rather than from our fat storage. When we do not burn the fats from our bodies, we are essentially not losing any weight. It is why keto diets are a popular choice these days. They are high in healthy fats and low in carbohydrates. So let’s dive in to see if there is any sort of correlation that might be of use to those who are trying to conceive.

A certain study showed that fewer carbohydrates can 

All of those increase pregnancy rates in comparison to a western diet (McGrice et al. 2017). Another study involved women taking meal replacements (Tsagareli et al. 2006). The oocyte levels of the six participating women were measured at the time of IVF before and after taking the replacements. The women possessed fewer oocytes after the consumption of the meal replacements when compared to not having taken them, despite having lost weight. 

All in all, the growing popularity of this “western diet” that is saturated in carbohydrates is proving to be detrimental towards the quality of a woman’s eggs. A recent US trial on 120 women undergoing IVF split them into two groups, depending on the balance of protein and carbohydrate in their diet. In total, 58 per cent of those in the “low carb” group (meaning at least one quarter of their diet was protein) went on to have a baby.⁠ In the “high carb” group, where less than a quarter of daily energy came from protein, just 11 percent achieved success, the study by the Delaware Institute for Reproductive Medicine (DIRM) in Newark found.⁠

Some experts are suggesting that women who are TTC should limit carbs to one portion a day and cut out all white bread, pasta and breakfast cereal, since doing so greatly increases the chance of conceiving.⁠
⁠
If you’re overweight or have a history of polycystic ovarian syndrome (PCOS), your body produces more androgen hormones (a.k.a., testosterone), which can lead to irregular periods or anovulation (where you don’t ovulate).⁠
⁠
Women with PCOS produce more insulin. When you eat lots of carbs, the body has to produce even more insulin, which increases androgen production. And that decreases ovulation.⁠ However, there is not too much data available on the population suffering from PCOS related infertility. PCOS is often known for the resultant weight gain but there is still further research required to establish a relationship between carbohydrate intake and fertility. Some of the data available from “The effect of dietary carbohydrates in women with polycystic ovary syndrome: a systematic review.” shows that a diet lower in carbohydrates may  improve fertility, endocrine and metabolic activity in the body, “weight loss and satiety in women with PCOS” (Frary et al. 2020). 

Side effects of such a diet

Carbohydrates are our primary source of energy. With that being said, a severe lack of carbohydrates could certainly take a toll on the body or take some getting used to. Mayo Clinic suggests individuals using the ketogenic diet might experience “constipation, headaches and bad breath” among other side effects. Additionally, with certain foods not being consumed anymore, there are certain micronutrient levels that might be dangerously low.

The Mayo Clinic also posed concern for heart health when using a keto diet. The CDC states that about 655,000 people die from heart disease each year which approximates to 1 in every 4 deaths (CDC).  Ketogenic diets focus on the intake of fats which might possibly lead to an unhealthy consumption of unhealthy saturated fats which are responsible for heart disease. 

Lastly, an individual might return to their original diet after following through with their initial diet plan. This could lead to weight regain (Hession et al. 2009).

 Our final thoughts

Cutting carbs does not necessarily mean going on a highly restrictive ketogenic diet. Diet is important for fertility, and ensuring that you are providing yourself with all the nutrients you require is essential for your wellbeing, including your reproductive health. Every diet is not for everyone. If your desire to start a diet has risen from reproductive concerns, confide in your doctor and find out if your current diet needs an upgrade or if you are good to go!

References:

  1. McGrice, Melanie, and Judi Porter. “The Effect of Low Carbohydrate Diets on Fertility Hormones and Outcomes in Overweight and Obese Women: A Systematic Review.” Nutrients vol. 9,3 204. 27 Feb. 2017, doi:10.3390/nu9030204 Accessed 30 Sep. 2020.
  1. Frary JM, Bjerre KP, Glintborg D, Ravn P. The effect of dietary carbohydrates in women with polycystic ovary syndrome: a systematic review. Minerva Endocrinol. 2016 Mar;41(1):57-69. Epub 2014 Jun 10. PMID: 24914605. Accessed 30 Sep. 2020.
  2. Tsagareli V., Noakes M., Norman R.J. Effect of a very-low-calorie diet on in vitro fertilization outcomes. Fertil. Steril. 2006;86:227–229. doi: 10.1016/j.fertnstert.2005.12.041. Accessed 30 Sep. 2020.
  3. Hession M., Rolland C., Kulkarni U., Wise A., Broom J. Systematic review of randomized controlled trials of low-carbohydrate vs. Low-fat/low-calorie diets in the management of obesity and its comorbidities. Obes. Rev. 2009;10:36–50. doi: 10.1111/j.1467-789X.2008.00518.x. Accessed 30 Sep. 2020.
  4.  “The truth behind the most popular diet trends of the moment ….” https://www.mayoclinic.org/healthy-lifestyle/weight-loss/in-depth/the-truth-behind-the-most-popular-diet-trends-of-the-moment/art-20390062. Accessed 30 Sep. 2020.
  5. “Heart Disease Facts | cdc.gov.” 8 Sep. 2020, https://www.cdc.gov/heartdisease/facts.htm. Accessed 30 Sep. 2020.

“The truth behind the most popular diet trends of the moment ….” https://www.mayoclinic.org/healthy-lifestyle/weight-loss/in-depth/the-truth-behind-the-most-popular-diet-trends-of-the-moment/art-20390062. Accessed 30 Sep. 2020.

What is it?

Have you heard of this term and not really understood what it meant? Had it mistaken for a “gardener”? Don’t worry, you’re not the only one. The Gardner grading system is a grading system for blastocysts based on their morphology (the shape, size, and appearance). The system was created by D. K. Gardner and W. B. Schoolcraft back in 1999. It is now used by many IVF laboratories as a tool to help measure blastocyst growth and the quality of the inner cell mass and trophectoderm. 

A collection of parameters are graded. One of these is the embryo cavity size, how far the embryo has come, hatching and emerging from the zona pellucida (membrane around the embryo). This is the numerical grades that goes from 1-6 unlike the grading system for the inner cell mass, and trophectoderm, which use alphabetical grades. 1 is used for the smallest blastocysts (and cavities, called blastocoel) and 6 is used for an embryo that has fully escaped its zona. 

The quantity and quality of individual cells is also graded using alphabetical designation (A-C), the inner cell mass and trophectoderm are each given a letter grade. Embryologists are looking for a lot of small, evenly sized cell that are clear and tightly linked together. The ICM should be a good size with a tight border, and the trophectoderm should resemble a quilt. 

Grading limitations

As useful as the Gardner and Schoolcraft system is, there are certain important areas that it does not cover according to “The Blastocyst,” by Thorir Hardarson, Gayle Jones, and Lisbet Van Landuyt. These areas certainly aid in selecting the best embryos for transplantation. These include the generation of cytoplasmic strings that can help keep cells together. Additionally, the perivitelline space and blastocyst cavity are two regions that are home to certain structures. 

Additionally, beautiful “perfect grade” blastocysts can easily be genetically abnormal. 

Final thoughts

Embryo grading systems such as the Gardner system play an essential role in deciding which embryo should be transferred into the womb first. We once again want to reiterate what is often said about embryo grading. While it is a great tool in deciding which embryos are likely to have the best fate in the womb, even the best guesses may sometimes not yield the expected results. In other words, a highly graded embryo may not do well in the womb while a poorly graded embryo actually does.

At the end of the day, they are tools to help embryologists to make the most well-informed decision that can. Embryologists train heavily for this purpose. The ART Compass app helps in optimizing lab performance and ensuring all embryologists are grading embryos similarly, from the most junior staff to the most senior. They are the most qualified people to perform the job and the embryos are always in good hands. 

References:

Thorir Hardarson, Lisbet Van Landuyt, Gayle Jones, The blastocyst, Human Reproduction, Volume 27, Issue suppl_1, August 2012, Pages i72–i91, https://doi.org/10.1093/humrep/des230

We hear the names of these three hormones quite often but what do they even do? Why are they important? Understanding how our bodies work and what goes on inside them can help us navigate our fertility better. There is a lot of difficult and complicated terminology involved so today we’re here to help you understand the significance of FSH, AMH, and TSH!

There are three hormones that can indicate ovarian reserve: AMH (Anti-mullerian hormone), FSH (follicle stimulating hormone), and E2 (estradiol).⁠

FSH, AMH, and TSH! As part of a basic fertility workup, your doctor will likely order blood work to check your FSH levels. Sometimes called the day 3 FSH test, this is a simple blood test meant to measure the amount of follicle-stimulating hormone (FSH) in your bloodstream.⁠

Studies show AMH is the best indicator of ovarian reserve. AMH levels (low, normal, high) directly correlate to the number of eggs remaining. FSH can also detect ovarian reserve, but it’s important to check E2 along with it because high E2 levels can suppress FSH. Meaning, if your FSH levels are suppressed by E2, this FSH measurement may not accurately represent your ovarian reserve. ⁠

Thyroid Stimulating Hormone: Average TSH levels in infertile women are reportedly higher than those in normal fertile women. And elevated serum TSH levels are associated with diminished ovarian reserve in infertile patients. ⁠

Endometriosis 

Endometriosis can be a debilitating disease Ie. painful periods, bleeding and pain during ovulation, uncomfortable intercourse, heavy bleeding and chronic pelvic pain.

Endometriosis can impact fertility in several different ways. Scar tissue and adhesions can block the fallopian tubes and uterus, making the uterus inhospitable to an embryo and damaging egg quality. 

What we call Endometriosis is probably several different diseases lumped together, not just “one” thing. We suspect it is caused by multiple factors but much more research is needed!! 

The most alarming part of this disease is that there is an average delay of four to 11 years from the onset of symptoms to diagnosis. 

Women who are unaware of their diagnosis (obvi) can’t get it treated!! 

During the time you go untreated, the symptoms can get worse and multiply, increasing pain and further negatively impacting your fertility. 

One reason for this delay is that endometriosis needs to be diagnosed through an invasive laparoscopy, a surgical procedure performed in the abdomen or pelvis. You have to CONVINCE your doctor that the pain is not just “normal” period cramps. 

The Trigger Shot 

Once the ovarian follicles have achieved an adequate size and stage of development, a trigger injection is given to induce final maturation of the eggs. The timing of this injection is very important to the outcomes of your in vitro fertilization (IVF) cycle and needs to be precise. An egg retrieval procedure is then scheduled for 36 hours following this injection.⁠

When the hCG trigger is administered too early or too late, or too low a dosage of hCG is administered the result can be an increase in the percentage of immature (M-I) or mature M-II (but aneuploid), eggs at retrieval. ⁠

Image by Sam Jotham Sutharson

Pollution BPA and toxins- something we don’t often hear about when speaking about fertility! That doesn’t mean there aren’t some things to be aware of regarding air pollution and toxins in certain everyday materials! Scroll down to find out why you need to learn about the relationship between pollution and fertility. And while we’re at it, let’s try and keep our amazing planet CLEAN for the generations to come! We must fight to keep our home healthy as it is OUR responsibility.

Pollution BPA and toxins: There is a growing body of evidence that suggests air pollution can have a negative impact on fertility.⁠ Women exposed to increased concentrations of nitrogen dioxide, carbon monoxide, and ambient particulate matter had lower rates of conception following fertility treatment and higher chances of early pregnancy loss compared with women exposed to lower concentrations of these pollutants.⁠ Men living in areas with higher air pollution are also more likely to have a higher proportion of abnormally shaped sperm. ⁠Ultimately, there is a limit to how much individuals can control their own air pollution exposures. Outdoor pollution is one of those problems we can only address through collective action.

BPA: Bisphenol A, known as “BPA” is an industrial chemical that has been used to make certain plastics and resins since the 1960s. In recent years, science has shown that exposure to BPA can result in reproductive endocrine disorders and neurobehavioral problems. Many manufacturers have started to use other chemicals as substitutes for BPA. Products containing these substitutes are sometimes marketed as “BPA-Free.” ⁠Plastics that do not contain bisphenol, however, may not necessarily be any safer than those that do. Be weary of marking claims!

Toxins: “Natural” does not always mean safe, especially when you are trying to conceive or are pregnant. Proceed with caution and care when using even the most natural of “Nature’s Remedies”. Try to minimize your overall exposure to toxins. ⁠

A few quick tips-⁠

OHSS: the dreaded ovarian hyperstimulation syndrome, a rare but significant side effect of IVF.

Today’s post is all about ovarian hyperstimulation syndrome! It is one of the hurdles one might face when undergoing an IVF cycle so we want to help clear up what the risk factors are and what might help reduce the risk of developing it! 

OHSS occurs in 1-10% of IVF patients. Risk factors for OHSS include:

The risk of OHSS is smaller when using GnRH antagonist protocol instead of GnRH agonist protocol for suppression of ovulation during ovarian hyperstimulation. The underlying mechanism is that, with the GnRH antagonist protocol, initial follicular recruitment and selection is undertaken by endogenous endocrine factors prior to starting the exogenous hyperstimulation, resulting in a smaller number of growing follicles when compared with the standard long GnRH agonist protocol. Have more questions about OHSS?

Did you see the recent report that correlated embryo freezing with increased cancer risk? The headline reads “Landmark 16-year Danish IVF Study Points To Babies Born From Frozen Embryos Being 2-3x More Prone to cancer”⁠

Should you worry? Tl;Dr No! Correlation does not equal “causation”.⁠

1. Frozen transfers yield higher results and decrease the time to pregnancy compared to fresh transfers. ⁠

2. This conclusion is based on 14 cases of cancer in babies conceived by frozen embryo transfer. A very small number! ⁠

3. The incidence of increased cancer risk in these patients is less than half the incidence of cancer in all US children conceived by any means. ⁠

4. The study population was mostly the slow freeze method, which is currently obsolete in most high-quality centers. vitrification is now used almost exclusively. ⁠

5. The statistical difference in percentages in this study was a 0.0444% incidence of childhood cancer vs. 0.0177%, so still extremely rare.⁠

The study can be found here. ⁠

⁠https://www.thesun.co.uk/news/10526200/frozen-embryos-ivf-treatment-cancer-diseases/⁠

The Risks of Advanced Paternal Age

This specific post focuses on The Risks of Advanced Paternal Age. This field of research still requires a lot more work and there is a lot that is unknown to scientists right now.

Recent research indicates that Risks of Advanced Paternal Age is significantly correlated with first trimester miscarriage.

Ten studies so far have addressed the theory that advanced paternal age contributes to the incidence of spontaneous miscarriage following natural or ART conception. These studies were included in the meta-analysis because their link between paternal age and spontaneous miscarriage was adjusted for maternal age in order to negate the co-linearity between paternal and maternal age.

However, these studies did not use the same definition of miscarriage with regard to gestational age, prompting the authors to perform two separate analyses putting the threshold for spontaneous fetal demise first at 20 weeks (nine studies) and then at 13 weeks (four studies) of pregnancy. Thus, fathers between 40-44 years of age were 23% more likely to contribute to the incidence of spontaneous miscarriage before 20 weeks of gestation than their younger peers. Similarly, when The Risks of Advanced Paternal Age were over 45 years the risk for pregnancy loss before 20 weeks was increased by 43% and before 13 weeks by 74%. 

Link to: https://www.focusonreproduction.eu/article/News-in-Reproduction-Miscarriage-2

Defects in the development of the skull, limbs, and heart is also another risk of paternal age over 40. Lastly, another possibility is the child developing autism, schizophrenia, and child acute lymphoblastic leukemia. It is believed that many of these conditions may be the result of genetic mutations in the sperm as a result of old age. If you are considering having a child above the age of 40, consult your physician and strategize with them so they can help guide you on your fertility journey. ⁠

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 and PICSI, What are they? 

Before a man’s sperm can fertilize a woman’s egg, the head of the sperm must attach to the outside of the egg. Once attached, the sperm pushes through the outer layer to the inside of the egg (cytoplasm), where fertilization takes place.

Sometimes the sperm cannot penetrate the outer layer, for a variety of reasons. The egg’s outer layer may be thick or hard to penetrate or the sperm may be unable to swim. In these cases, a procedure called intracytoplasmic sperm injection (ICSI) can be done along with in vitro fertilization (IVF) to help fertilize the egg. During ICSI, a single sperm is injected directly into the cytoplasm of the egg.

Why would I need ICSI?

ICSI helps to overcome fertility problems, such as:

-The male partner produces too few sperm to do artificial insemination (intrauterine insemination [IUI]) or IVF.

-The sperm may not move in a normal fashion.

-The sperm may have trouble attaching to the egg.

-A blockage in the male reproductive tract may keep sperm from getting out.

-Eggs that did not fertilize by traditional IVF, regardless of the condition of the sperm.

–In vitro matured eggs are being used.

-Previously frozen eggs are being used.

Will ICSI work?

ICSI fertilizes 50% to 80% of eggs. But the following problems may occur during or after the ICSI process:

Some or all of the eggs may be damaged.

The egg might not grow into an embryo even after it is injected with sperm.

The embryo may stop growing.

Once fertilization takes place, a couple’s chance of giving birth to a single baby, twins, or triplets is the same if they have IVF with or without ICSI.

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. 

What if your IVF Lab does ICSI, But you want to try conventional IVF? 

It’s in your best interest to do what the clinic does 99% of the time and not try to be one successful person on a procedure they do 1% of the time. Clinics have switched to ICSI for very very good reasons. It increases our patients success rates. It decreases chances of contaminating DNA from sperm during PGT. The embryologist will be able to examine and inject the nicest looking sperm. Think about it this way, you are preparing for the “Olympics” of baby making. We want to do anything in our power to shave 1 second off your timing so you can WIN the gold. A take home baby as quickly as possible. 

Veering from the established standard of care for a lab (any lab) introduces another possibility to the mix; one of them making an error. 

Why are you hesitating? Some people want it to be as natural as possible, but that’s not a good reason. Everything about the lab environment is not natural. Yes, fertilization failures do happen. This is not the thing to leave to chance, as you will get more than enough of that after the embryo is transferred back to your uterus. Allow the lab to do the procedures that give the highest success rates.

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. 

Endometrial Receptivity Assays 

The endometrium must be prepared with progesterone for the embryo to implant. The typical metric is to look for a thick “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

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

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.

DHEA – de hydro epiandrosterone. 

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. 

Vitamins and Infertility 

It’s our vitamins and fertility post: ALL. THINGS. VITAMINS.

Find out why certain vitamins are essential in maintaining fertility and sources where you can find these vitamins to incorporate into your diet.

Vitamin A

Vitamin A is crucial for the functioning of various body systems and organs. One of these systems is the reproductive system.

Spermatogenesis  is quite dependent on vitamin a. It is what helps keep structures such as the epididymis and seminal vesicle functioning. without it, instead of finding those structures you might find “stratified squamous keratinizing epithelium.”

In females the problems could be found in ovulation. A study on vitamin A deficient rats showed that the rats were unable to ovulate and form corpora lutea routinely. researchers were also not able to see blastogenesis occur. vitamin A could play a crucial role even after fertilization! it has been shown that a mother’s vitamin A keeps the placenta in good condition.

In studies performed on pigs, it was observed that a lack of vitamin A resulted in several birth defects including cleft palate, lack of eye development etc. embryos observed during days 12.5-20.5 demonstrated a range of defects in vision related structures such as the retina and iris.

The nervous system also uses vitamin a for functions such as neural differentiation. vitamin a deficient (vad) quail embryos have been seen to have underdeveloped hindbrains. they also did not have many spinal cord neurons. Some other problems were observed in vad rat embryos. these included:

There are many more conditions that can develop in embryos. however, making sure that you include sufficient amounts of vitamin A in your diet prevents such birth defects. it is important to keep in mind that eating healthy is very important during early pregnancy and even pre-pregnancy. It is often stressed to get your vitamins from food rather than supplements. vitamin a can be found in variety of foods including:

References:

1. Clagett-Dame et al. “Vitamin A in Reproduction and Development” Nutrients. Mar 29 2011

2. “Vitamin A” Harvard T.H. Chan School of Public Health

Vitamin D

Scientists are still not completely sure whether vitamin d deficiency is associated with IVF outcomes. The authors of a study did conclude, however, that vitamin D does not affect pregnancy, live birth, and miscarriage rates. They were also able to find reason to believe vitamin D is involved in folliculogenesis, oogenesis and endometrial receptivity. Studies are split between whether vitamin D deficiency is a serious issue for individuals who plan on using art. certain fertility clinics screen patients for vitamin d deficiency prior to beginning treatment.

A good level of vitamin D for fertility treatments is often considered to be 30 ng/ml. It is important to be able to maintain this level even throughout a pregnancy as studies have shown vitamin D deficiency may induce preeclampsia, gestational diabetes, and other conditions. The reason for this may be that vitamin D is known to be involved in the embryo implantation process. It controls the genes that generate estrogen and also helps to shift around immune cells in the uterus to fight off infections. Some good sources of vitamin D include:

References:

Vitamin E 

Researchers from another study were able to determine an association between recurring abortion and low plasma vitamin e levels and increased lipid peroxidation levels in women. Regarding fetus/embryo growth, it’s important to bring up the study of in vitro matured and fertilized bovine oocytes. The zygotes derived from them when cultured in vitamin E, vitamin C, and edta were more likely to enter the blastocyst stage than the control medium.

Current studies indicate there is still more we need to know about vitamin E! The University of Rochester is currently conducting trials involving 48 infertile men and 20 fertile men on how vitamin E affects sperm fragmentation. DNA fragmentation occurs due to oxidative stress. because vitamin E is an antioxidant, it can combat such oxidative stress. It leaves us questioning if vitamin E deficiency perhaps leads to DNA fragmentation? Want to try and incorporate more vitamin E into your diet? Here’s some foods that Healthline listed which you should eat!

References:

1. Mutalip et al. “Vitamin E as an Antioxidant in Female Reprosuctive Health” Antioxidants. Feb 2018. 

2. Vitamin E and Male Fertility study on ClinicalTrials.gov

3. Olson et al. “Culture of in vitro-produced bovine embryos with Vitamin E improves development in vitro and after transfer to recipients.” Biol Reproduction. Feb 2000.