Anxiety and Mood Swings Life’s challenges are part of the human condition and yet none are immune from the ravages of existence. They arise for reasons you cannot comprehend and leave you feeling like a wounded bird, with broken wings.⁠ Is anxiety associated with IVF? Does IVF cause anxiety? Are there certain medications that cause anxiety? ALL those answers can be found in our blog post today!

Anxiety and Mood Swings? Stress, pre-existing depression, and anxiety from not being able to fall pregnant, combined with hormone therapy, invasive time-consuming tests and procedures, and complicated medication schedules all contribute to the stress and anxiety we feel undergoing IVF. While there have been numerous studies documenting the psychological burden of fertility treatment, there have only been a few studies specifically investigating the role of hormones during ovulation induction.

Infertility is often a silent struggle. Patients who are struggling to conceive report feelings of depression, anxiety, isolation, and loss of control. Depression levels in patients with infertility have been compared with patients who have been diagnosed with increased cancer risk. It is estimated that 1 in 8 couples (or 12% of married women) have trouble getting pregnant or sustaining a pregnancy.

Despite the prevalence of infertility, the majority of infertile women do not share their stories with family or friends, thus increasing their psychological vulnerability. The inability to reproduce naturally can cause feelings of shame, guilt, and low self-esteem. These negative feelings may lead to varying degrees of depression, anxiety, distress, and a poor quality of life.⁠ There are science backed ways to improve these feelings, and mindfulness and meditation are proven strategies to help!

Patients who undergo assisted reproductive treatment (ART) are at significant risk of experiencing psychiatric disorders and it is important to recognize, acknowledge, and assist our patients as they cope with their infertility diagnosis and treatment.⁠

Gonadotropin-releasing hormone agonists suppress a woman’s menstrual cycle, effectively causing menopause. GnRH agonists have been associated with depression in women who are taking it to treat endometriosis. A more recent study of the effect of GnRH agonists on mood during its use for ovulation induction did not show an increase in depression. In a study of the effect of clomiphene citrate and human menopausal gonadotropin (stimulates follicle growth), both have been shown to be associated with significant mood symptoms.

Despite many efforts to break the silence on infertility and pregnancy loss, fertility and miscarriage remain taboo subjects.⁠
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Those suffering don’t share their experiences with others. Non-members of the infertility-and-loss club don’t know how to react or what to do when they are told of a friend’s struggle. Some honestly are uncomfortable hearing about it at all.⁠
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The stigma is strong. Why? With 1 in 8 couples experiencing infertility– and up to 25 percent of pregnancies ending in miscarriage – why as a society are we so uncomfortable discussing these relatively common life events?⁠
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Most causes of infertility and miscarriage are not under the direct control of a couple. However, even when a person knows this, the nagging feeling that “this is all my fault” pulls at them.⁠
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Shame can only survive in dark corners.⁠
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It’s time we break the silence on infertility (miscarriage!). It’s time we stop feeling ashamed of medical problems over which we have little control.⁠

De-stress

Take care of yourself to lower stress levels, which appears to increase fertility treatment success.⁠

Most forms of self care focus on a healthier body, which directly translates to a healthier reproductive system.⁠

⁠Focus on what you can do. Live. Right now. Every day. Don’t make this all about the wait. Make it about you. ⁠

Anxiety and Mood Swings, Meditation, and other forms of mindfulness are known to stress relievers, and those who practice mindfulness on a regular basis report being more content, balanced, and physically healthier. ⁠

Scheduling a telehealth appointment with a fertility doctor may be easier than ever before. You may be able to explore some deeper queries that may arise such as donor eggs, sperm, using a gestational surrogate.⁠

Shove the journal articles aside, unplug from the treadmill of infertility and fertility treatment research, tips and information – and enjoy something mindless for a change- magazine or novels!⁠

Take a good walk or hike: Researchers have found spending time outdoors – even just 10 to 15 minutes in a green space or with a view of the trees/landscape immediately decreases stress and anxiety and mood swings, revives dulled minds, and boosts the immune system.⁠

You know that exercising keeps you healthy. It makes you strong and helps you stay in shape. But it also improves your mood and your sleep. It reduces stress and anxiety and mood swings. It helps your brain to function better.⁠

Infertility Warriors, of all people, need a functioning brain. For all the reasons listed above. That’s why you need to move your physical body in this period of waiting. Not too much, not too little. ⁠

If you are following the guidance about things that will put your body in its optimum state to get pregnant — your weight, foods to avoid/eat, cut down/stop drinking alcohol and smoking, cut back on caffeine and take vitamins — you may have a hard time finding ways to treat yourself during your journey. ⁠
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Find some small and special treats that won’t throw off your fertility diet goals- a single macaron, a decadent dark chocolate. ⁠
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Spend time with friends that lift you up and spend time together as a couple.⁠
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Although it may feel like infertility has taken over your life, it doesn’t define you or your achievements in life. You are amazing and strong! ⁠
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⁠Struggling with infertility can be an extremely lonely process. A lot of people struggling don’t tell friends or family, but it is so important to get support from somewhere. Infertility can leave you questioning everything — your future, your relationship, and most crucially your mental health.⁠
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Talking through your thoughts with someone who understands will help validate your feelings and make you feel less alone. It will also help you see more clearly to be able to take positive action to change how you feel and increase your chances of getting pregnant.⁠
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Research has found that feelings of depression and anxiety peak around three years post-infertility diagnosis. However, six years post-diagnosis, couples are feeling stronger, and depression and anxiety symptoms lessen.⁠
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Bromelain to Brazil Nuts- IVF Myths 

IVF Myth No. 1: Eating pineapple core for five days after embryo transfer can up one’s chances of conception.⁠

The fruit contains bromelain, an enzyme with anti-inflammatory, anticoagulant and blood-thinning properties. Much of the bromelain is concentrated in the core. There are a lot of stories about pineapple’s effectiveness, but not a lot of data backing it up. Some fertility doctors prescribe low-dose baby aspirin — also a blood thinner — to help improve blood flow to the uterus, so the idea is that pineapples could mimic that effect. ⁠

IVF myth No. 2: Eating Brazil nuts during the two-week wait can lead to a healthy pregnancy.⁠

Brazil nuts are packed with selenium. One study (published in the journal Metallomics) found that selenium helps promote healthy egg follicles in female cows, and that same study also found that levels of GPX-1 (a protein found in selenium) were much higher in women who got pregnant after a single embryo transfer.⁠

However, too much selenium can be toxic, so stay within the recommended daily allowance typically just 55 micrograms, with the highest maximum amount being 400 micrograms daily. ⁠

Gestational Carriers 

What is a gestational carrier? A gestational carrier (GC), is not the same as a surrogate. A surrogate is someone who donates her egg and then subsequently carries the child; she is genetically linked to that baby. Today, such cases of true surrogacy are very rare. In the case of a gestational carrier, the woman carrying the pregnancy is in no way biologically related to the child she is carrying; the eggs and sperm are derived from the “intended parents” (or possibly an egg or sperm donor), through the process of In Vitro Fertilization (IVF). The egg is fertilized in the lab, and then the embryo (or embryos) is placed into the uterus of the gestational carrier.

– Absent uterus, either congenital, which means you were born with, or from surgery.⁠

– Abnormalities of the uterus such as severe intrauterine scarring from Asherman’s syndrome or multiple benign tumors of the uterus called fibroids ⁠

– If carrying a pregnancy is too risky where the woman or baby’s life would be in danger (Turner’s Syndrome, or pulmonary hypertension, for example). ⁠

Other circumstances to use a GC include a single male, or in the LGBTQ population of a gay male couple, or single transgender female. Lastly, there may be a strong consideration for a GC if the woman has undergone multiple uterine surgeries for example, fibroid tumors, and also cesarean sections, where the uterine muscle may be weakened to result in complications near the end of the pregnancy as well as when recurrent miscarriage is unexplained following a thorough evaluation and multiple treatments.⁠

According to the American Society for Reproductive Medicine, 859 surrogacy and gestational carrier cycles were performed in the United States in 2010.

Once the ovarian follicles have achieved an adequate size and stage of development, a trigger injection is given to induce the 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. Mini-STIM, Natural Cycle FET, and Vaginal Progesterone. An egg retrieval procedure is then scheduled for 36 hours following this injection.⁠
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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. ⁠

Have you discussed alternate IVF treatments with your reproductive endocrinologist? ⁠

Mini-IVF (also known as micro or minimal stimulation IVF) is similar to conventional IVF in the procedures used during treatment, but mini-IVF uses weaker medications or lower doses of medications to produce only a few eggs. It may also be done without any ovarian stimulating drugs.⁠

Because lower amounts of fertility drugs are used, the cost per cycle is lower, and the risk of ovarian hyperstimulation syndrome (OHSS) is reduced.⁠

___________⁠

With frozen embryo transfer, it’s crucial that the timing of transfer occur when a woman’s endometrium is receptive, meaning an embryo can implant. The protocols used to prepare the endometrium for embryo transfer vary more than most of us would imagine — there is truly no standardization, and each clinic you visit might approach this in a different way. Patients undergoing FET may not require hormonal supplementation if normal follicular development and ovulation is observed. ⁠

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Mini-STIM, Natural Cycle FET, and Vaginal Progesterone. Doctors usually prescribe progesterone supplementation to start on the day the eggs are harvested. If pregnancy takes place, the doctor may tell you to continue taking progesterone throughout the first trimester. Progesterone can be taken as an intramuscular injection or vaginally (suppositories, gel, or vaginal tablets). There appears to be no difference in the chances of becoming pregnant or continuing a pregnancy if progesterone is given by injection or intravaginally. You should talk to your doctor about which form of progesterone will better fit your needs.⁠

Egg retrieval day is an exciting and anxious time. The success or failure of an IVF cycle depends on this moment. Embryologists know that everything the patient has gone through up to this day; from the first negative pregnancy tests to the infertility diagnoses, every shot, all the stimulation medications, all the financing, and trauma of infertility- all of it has been leading up to this day. The patient has been so INVOLVED up to this point, so seemingly “in control” (even if that is an illusion). But then you arrive at the clinic the morning of the retrieval, and it all out of your hands. It’s even out of your physician’s hands. Your eggs are about to pass through a tiny window, into the hands of scientists you have never met. The IVF lab is under strict lock and key. No one can enter that sterile environment without permission. Not even the physicians.

Pre-Surgery

In pre-covid days, embryologists used to see patients briefly at the bedside pre-surgery, before they become groggy with anesthesia, to confirm your cycle plan with you. We discuss and confirm: How many eggs to be fertilized? How many to be frozen? We are doing PGT? How many embryos do you want biopsied? We are using partner sperm? Donor 257? We could explain to you what to expect on cycle day 0, 1, 3, and 5-7. You could ask us questions. I am hopeful we will go back to that again one day, when it is safe for everyone.

When you get wheeled into the operating room, we do a “time out” through the tiny window that leads to our sterile lab- we confirm your name and date of birth and IVF cycle plan with the physician. Then you will start to go under, as the anesthesiologist puts you “to sleep”. After you are comfortably asleep, the nurses, medical assistants and physician will drape all of your exposed skin with soft sterile towels, so that your human dignity is preserved while you are asleep, and only a small square of your body directly in front of the physician is exposed. Then the vagina is washed and prepped for the ultrasound guided transvaginal oocyte retrieval. The physician positions the gooseneck light, the OR lights are turned down low. And then the retrieval begins!

So what is the egg retrieval like from the embryologist’s perspective?

The Egg Retrieval

The egg retrieval is often the first patient procedure we learn as junior embryologists. Getting “signed off” on retrievals is a HUGE moment for our clinical career. Even after years and years of doing retrievals, they are still exciting for me. It is my job to hunt for every single egg. No matter how obscured by blood, mucus, or epithelial cells they are. No matter how misshapen, dark, abnormal or odd the eggs are (see images below of unusual eggs!). We depend on eggs being surrounded by a nice “cloud” of fluffy, nurturing cumulus cells. But sometimes the stimulation does not go as planned. The cumulus cells are a small tight dark ball. Sometimes they are shot through with capillaries. Sometimes eggs get ripped out of their cumulus cells entirely by the suction of the needle. And it doesn’t matter, we have to find them all.

In general, we know how many eggs to expect. We want to know the number of follicles over 14 mm- that gives us an indication of how many mature eggs will be retrieved. and we want to know the number of “small” follicles too- how many may not be holding a mature egg.

As the tubes of follicular fluid are handed through the window, we take them into a dark, warm, and humid environment. Then, we pour the fluid into a petri dish and start examining it closely under a microscope. As I find eggs, I call to your clinical team; One, Two, Three, and so on, so everyone knows what I’m seeing. Everyone is waiting for the embryologist to find and call the first egg. There is nothing worse than not finding eggs. Sometimes, one tube will go by, then another, than another and still no EGG! That is when I always call in a second set of eyes to double check my work. Usually, by the 5th or 6th tube at the latest, eggs are found. But occasionally, we have a retrieval that yields no eggs. Something went wrong with the stim. Maybe only one egg was expected, but it can’t be found. Maybe the patient didn’t time the trigger correctly or the surgery started late and the patient ovulated. Maybe the trigger didn’t “absorb” properly. Maybe it’s a rare case of empty follicle syndrome. Whatever the cause, “no egg” retrievals are devastating. For the patient first and foremost, but your embryologist care team feels it too.

At the same time as your retrieval is happening, the sperm for your egg insemination is being processed. Maybe it is being thawed, or in the case of fresh samples, it is being separated from the semen of the ejaculate and being prepared so the best most “motile” sperm will be available for later use.

Post Egg Retrieval

Mostly, we get the number of eggs we expect, based on the number of large follicles seen by follicle ultrasound. Occasionally, we get a huge surprise and get more eggs than expected! After the eggs are collected they are washed, and sometimes we let them rest in the cumulus cells in an incubator hoping for any last – or slow maturation to happen, before we process them further. In conventional IVF the eggs stay in the cumulus until they are combined with sperm cells. But if ICSI will be performed, then we “strip” them of the cumulus cells, grade them, and asses the quality. On average, about 80% of the eggs that are retrieved will be mature enough to fertilize. To asses egg maturity and quality we essentially dissolve the cumulus cells from around the eggs with an enzyme (the same one found in nature in the sperm head!). Then we gently swish each egg cell up and down in a tiny pipette, about the width of a sharp pencil lead. In the end we only want to see one single, clean cell- THE EGG!

Then, we grade the maturity and separate them for fertilization. We want to see mature MII oocytes. Mature eggs are referred to as “MII” ie. “meiosis two” ready oocytes. The final meiotic division– where the egg’s chromosomes are split in half one final time, will not happen until the egg is injected via ICSI, or one sperm breaches the “zona pellucida” in conventional IVF.

Besides seeing nice mature MII oocytes, we may see slightly immature eggs, called MI (Meiosis I) or very immature eggs called “GV” (ie geminal vessicle). Unfortunately, sometimes we see eggs that have fractured zonas, or are severely compromised due to vacuoles, dented cyctoplasm, or other abnormalities. I have included several images of abnormal eggs below!

Insemination

Whether you and your physician opt for ICSI or conventional IVF, or if your lab only offers ICSI, your eggs will be combined with your partner or donor sperm in the afternoon of the day of the egg retrieval. This is referred to as “insemination” and it is not the same as fertilization. I will talk about ICSI, what it is and why I love it, in another Embryologist Perspective post!

Just because we put egg cells and sperm cells together doesn’t mean they will fertilize… stay tuned for the next Embryologist Perspective post on Day 1- The Fertilization Check!!

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Oocyte retrieval- Technical Notes

Oocyte retrieval is a particularly sensitive procedure and special attention should be given to temperature and pH as well as efficient and quick handling.

ESHRE Guideline Group on good practice in IVF labs , December 2015

1. An identity check before the oocyte retrieval is mandatory.
2. The time between oocyte retrieval and culture of washed oocytes should be minimal.
3. Prolonged oocyte exposure to follicular fluid is not recommended.
4. Appropriate equipment must be in place to maintain oocytes close to 37°C. Flushing medium, collection tubes and dishes for identifying oocytes should be pre-warmed.
5. Follicular aspirates should be checked for the presence of oocytes using a stereomicroscope and heated stage, usually at 8-60x magnification.
6. Exposure of oocytes to light should be minimized.
7. Timing of retrieval, number of collected oocytes and the operator should be documented.

Additional Embryologist Perspectives

Assisted Hatching: What is it and why does my IVF Clinic do it?

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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:

• impaired heart morphogenesis
• non-compartmentalized heart
• embryonic renal hypoplasia
• impaired diaphragm development.
• bilateral lung hypoplasia

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:

• green leafy vegetables
• dairy products.
• carrots
• sweet potatoes, tomatoes
• red bell peppers
• squash and pumpkin
• essentially any orange colored food!

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:

• oily fish
• red meat
• liver
• egg yolks
• supplements (because it can sometimes be difficult to get sufficient amounts from diet and sunshine). We recommend the BlueBonnet brand available on Amazon.

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 D in fertility” USC Fertility https://uscfertility.org/fertility-treatments/vitamin-d-fertility/
• “How vitamin D affects your fertility” shady grove fertility https://www.shadygrovefertility.com/blog/fertility-health/how-vitamin-d-affects-your-fertility/
• “Foods high in vitamin D” healthline https://www.healthline.com/nutrition/9-foods-high-in-vitamin-d
• “The Role of Vitamin D in Fertility and During Pregnancy and Lactation: A Review of Clinical data” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210343/
• “Vitamin D” nhs https://www.nhs.uk/conditions/vitamins-and-minerals/vitamin-d/
• https://www.focusonreproduction.eu/article/News-in-Reproduction-Vitamin-D

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!

• Sunflower seeds
• Almonds
• Sunflower oil
• Hazelnuts (I’m going to go eat that Ferrer Rocher now!)
• Pine nuts
• Peanuts
• Avocado
• Brazil nuts
• Kiwi

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. 

Common Causes of Infertility in Women and Men, Though you may feel alone, though it may seem you’re the only infertile couple among all your friends, you are not alone in this big world.⁠

One in eight experience fertility problems at some point in their lives. There’s a good chance someone you know has struggled with trying to conceive, but like you, they are keeping it secret about the Common Causes of Infertility in Women and Men.⁠

⁠In Women: ⁠

Blocked fallopian tubes due to pelvic inflammatory disease, endometriosis, or surgery for an ectopic pregnancy.⁠

Physical problems with the uterus.⁠

Uterine fibroids, which are non-cancerous clumps of tissue and muscle on the walls of the uterus.⁠

Ovulation disorders, meaning you ovulate infrequently or not at all, account for infertility in about 1 in 4 infertile couples. Problems with the regulation of reproductive hormones by the hypothalamus or the pituitary gland, or problems in the ovary, can cause ovulation disorders.⁠

Are your periods irregular? Do you have acne on your chin or neckline? Do you have extra long dark hairs growing? ⁠If you answered yes to these, you may need to be screened for PCOS. ⁠
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PCOS is partially genetic: 24% of women with polycystic ovary syndrome had a mother with PCOS and 32% of the women had a sister with the condition⁠.⁠
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Researchers have shown that women with PCOS regardless of their weight (overweight and lean) will experience insulin resistance as compared to women of the same age and weight who do not have PCOS.⁠
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If you have PCOS, multiple bubble-like cysts may form on the surface of one or both of your ovaries as eggs partially mature but are not released. These eggs remain in their follicles, which swell but don’t open. A woman with PCOS may have 25 or more cysts on a single ovary.⁠

In Men:⁠

A varicocele is a swelling of the veins that drain the testicle, which can impact sperm quality. ⁠

Ejaculation disorders include premature ejaculation, anejaculation (the failure to ejaculate), and retrograde ejaculation, which is when semen enters the bladder during orgasm instead of coming out the tip of the penis.⁠

Prior vasectomy, inguinal hernia repairs, scrotal or testicular surgeries, prostate surgeries, and large abdominal surgeries performed for testicular and rectal cancers risk, among others.⁠

Preimplantation genetic testing. We always hear the term PGT testing but what actually happens during the test?? It’s always helpful to understand what exactly happens to an embryo as it progresses through the different stages of IVF. 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. ⁠
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Besides the two possible PGS results we’ve already talked about– euploid and aneuploid– there’s also another: mosaic. A mosaic embryo is comprised of both euploid and aneuploid cells. While mosaicism has existed all along, PGS testing 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.⁠

We can perform up to three types of preimplantation genetic testing on embryos during the ivf process.

• 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. The biopsy removes 3 to 10 cells from the trophectoderm which are the outer layers 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!

No Result Embryos

Did any of your embryos return with a PGT result of “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.⁠
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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. ⁠
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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.⁠

Are you struggling with the question “To Embryo Biopsy or NOT?” ⁠

Preimplantation Genetic Testing (also known as PGT-A, CCS, or PGS) is a diagnostic tool to tell your fertility doctor which embryos are likely to be chromosomally normal and therefore, which to transfer.⁠

As women age, the chance of a chromosomally normal embryo declines. Underage 30, roughly half of the embryos will be normal, and most young women find multiple euploid embryos after testing. Overage 40, 1/3 to 1/2 of all women will not find a viable embryo after PGT-A.⁠

Euploid embryos are most likely to lead to living birth and should be transferred first. Embryos that are mosaic can still lead to living birth, but depending upon the type, do so less often, and carry some risk. Embryos that are aneuploid almost never lead to live birth and if they do, carry a major risk the child will be unhealthy.⁠

PGT typically costs $5,000 can help to avoid:⁠

-FailedFET (each costs $3,000 to the patient)⁠

-Miscarriages (each cost $5,000 to the insurer, which pales in comparison to the emotional pain they cause patients)⁠

-Multiple gestation births from transferring back more than one embryo (twin deliveries cost $100,000 and triplet deliveries cost $500,000)⁠.

Canadian PGT Guidelines

Preimplantation genetic testing for aneuploidy: A Canadian Fertility and Andrology Society Guideline 

1. Maybe offered to patients to assist with the selection of the best embryo for transfer.
2. In patients with two or more blastocysts available for biopsy, PGT-A can improve the likelihood that a transferred embryo will lead to a viable pregnancy.
3. Offering PGT-A with eSET reduces the risk of multiple pregnancies, may improve implantation rates, and may decrease the risk of EPL per embryo transfer in select populations at higher risk of aneuploidy.
4. PGT-A has largely included good-prognosis patients with multiple blastocysts available.5. use of PGT-A in poor-prognosis patients, who may have difficulty producing blastocysts for testing.
6. A paucity of evidence on the effect of PGT-A on the critical outcome of cumulative LBR (CLBR) per cycle started.
7. The current data do not support the universal use of PGT-A for all patients undergoing IVF.
8. Future research should also consider broader issues such as economic costs, patient satisfaction, correlation with prenatal genetic testing, and long-term follow-up studies on the health of children born after PGT.
9. Other technical issues confounding the field include diagnostic inaccuracy and mosaicism.
10. Patient counseling and informed consent before undertaking PGT-A should acknowledge the known limitations of the technology and gaps in knowledge 

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.

If there is one thing I need at least once a day, it’s a good old cup of joe. Who doesn’t love the smell of freshly brewed coffee in the morning? It might get you thinking though, about the effects caffeine has on your fertility. One cup of coffee has 95mg of caffeine. A cup of tea has 27mg and do not get me started on those energy drinks that you might need on those all-nighters. Caffeine is pretty difficult to cut out of our daily diet entirely so let’s explore the effects this energy-boosting goodness has on fertility!

Is there a relationship?

As of now, there is no clear and concise relationship that has been identified between the chances of becoming pregnant and caffeine intake. There is a relationship between caffeine intake during early pregnancy and the risk of experiencing a spontaneous abortion. The risk increased with increasing consumption of caffeine. 

Nevertheless there are some studies that could prove to be of interest. One of them is a report published in 1998 in Reproductive Toxicology. It demonstrated that women who drank between 300 to 700 milligrams of caffeine a day suffered a 12% lower chance of achieving a pregnancy. As caffeine intake increased, the probability of conceiving fell by 37%. In 2008, Dutch researchers announced that in their study of nearly 9,000 women with fertility issues, those who drank four or more cups of coffee, or some other kind of caffeinated drink, on a daily basis were 26% less likely to become pregnant

Another study published in Clinical Epidemiology supported the hypothesis that increased caffeine consumption results in higher chances of spontaneous abortion. There was no relationship established between caffeine consumption and fertility treatment outcomes.

What dosage is recommended?

This one is a little difficult because again, we are still learning about the connection between caffeine intake and fertility. The European Food Safety Authority (EFSA) and World Health Organization (WHO) advise limiting caffeine consumption to a maximum of two to three cups of coffee/200-300mg caffeine per day.

Caffeine and Fertility Treatments

Fertility specialists often recommend not consuming caffeine and alcohol during fertility treatments. The study “Alcohol and Caffeine Consumption and Decreased Fertility,” published in Fertility and Sterility demonstrates just that. More than 100 women were included in the study. Their urine samples were analyzed each day. They were 50% less likely to become pregnant when drinking alcohol. However, alcohol is not our topic of interest here. The caffeine is. The role of the caffeine was interesting. Rather than directly decreasing fertility the caffeine enhanced the detrimental impact of the alcohol on fertility. 

“Couples’ Pre-Pregnancy Caffeine Consumption Linked to Miscarriage Risk,” is another study of interest performed by National Institutes of Health. The study showed that the likelihood of a woman having a miscarriage increases when both her and her partner drink at least two caffeinated drinks a day. This possibly hints that the caffeine intake is not only impacting fertility in women but may influence the fertility in men too. The study also illustrated that if a woman consumed more than two caffeinated beverages a day during her first 7 weeks of pregnancy she is more likely to miscarry.

The takeaway

I don’t think I could give up coffee. It’s the only way I get through my day! However there seems to be some sort of correlation between caffeine intake and fertility though this relationship has not been completely established yet. Make sure you talk to your doctor and let them know about important aspects of your lifestyle (such as caffeine consumption) that could help them help YOU make the best decisions moving forward. Different aspects of our lifestyle can have drastic impacts on fertility. Would you like to see a series of blog posts about the influence of lifestyle on fertility? Let us know!

References:

1. Lyngsø, Julie et al. “Association between coffee or caffeine consumption and fecundity and fertility: a systematic review and dose-response meta-analysis.” Clinical epidemiology vol. 9 699-719. 15 Dec. 2017, doi:10.2147/CLEP.S146496
2. Mehta Rinku, “ The Facts About Alcohol and Caffeine During Fertility Treatment,” Dallas IVF, https://dallasivf.com/alcohol-caffeine-fertility-treatment/#:~:text=of%20becoming%20pregnant.-,Avoid%20alcohol%20and%20caffeine%20during%20fertility%20treatment,and%20caffeine%20during%20fertility%20treatment.
3. “Couples’ pre-pregnancy caffeine consumption linked to miscarriage risk” National Institutes of Health, https://www.nih.gov/news-events/news-releases/couples-pre-pregnancy-caffeine-consumption-linked-miscarriage-risk#:~:text=Because%20their%20study%20found%20caffeine,Buck%20Louis%20said.
4. Hakim RB, Gray RH, Zacur H. Alcohol and caffeine consumption and decreased fertility [published correction appears in Fertil Steril 1999 May;71(5):974]. Fertil Steril. 1998;70(4):632-637. doi:10.1016/s0015-0282(98)00257-x

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 

• Lower circulating insulin levels
• Restore hormonal imbalance 
• Resume ovulation 

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.

2. 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.
3. 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.
4. 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.
5.  “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.
6. “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