Knocked Up Podcast - We answer your questions: part 1
Such great questions! Thank you listeners :)
Questions answered in this episode:
Please explain the difference between egg freezing and and embryo freezing, which is best and why?
Can you please explain the ICSI process
How important is embryology grading in a euploid bastocyst?
When a patient has multiple frozen embryos, how do you select the best one to implant?
Why would a day 2 transfer be recommended if a day 5 blastocyst is more likely to implant
How do you recommend prepping for implantation? Tips for success?
How many embryos do you typically implant in one go?
Is the process of frozen embryo transfer different from fresh? Are pregnancy rates the same?
Can a frozen embryo transfer cycle be successful without progesterone support
Hosted by Dr Raelia Lew and Jordi Morrison
Dr Raelia Lew is a RANZCOG Board Certified CREI Fertility specialist, Gynaecologist and the Director of Women’s Health Melbourne.
Find us on Instagram - @knockeduppodcast
Have a question about women's health? Is there a specific topic you'd like us to cover? Email podcast@womenshealthmelbourne.com.au. We keep all requests anonymous.
TRANSCRIPT
Jordi Morrison:
Hi, it's Jordi here, cohost of the podcast. Before we get into this week's episode, it's your questions, which were just amazing. We wanted to answer them all, which has meant splitting the episode into two. If you don't hear your question in this week's episode, it'll be in the next episode, which will come out in a fortnight's time. Thank you again everyone. We loved your questions.
Hello, and welcome to Knocked Up, the podcast about fertility and women's health. You are joined as always by me, Jordi Morrison, and Dr Raelia Lew, CREI fertility specialist.
Welcome, Raelia.
Dr Raelia Lew:
Hi, Jordi. Great to be here.
Jordi Morrison:
We've got some great questions from our community today, Raelia. You ready to go?
Dr Raelia Lew:
Sure am. Let's fire.
Jordi Morrison:
First question. Please explain the difference between egg freezing and embryo freezing. Which is best and why?
Dr Raelia Lew:
This is a question that lots of people are often confused about. The freezing part is vitrification. That is flash freezing technology that ensures either an egg or an embryo has its best chance of survival when warmed up later to make a baby. That can be tomorrow, next week, next month, next year, or even ten years from now.
The difference is that an egg is a very different biological entity to an embryo. An egg is a single cell belonging to a female that has a chance — if it meets a sperm and does absolutely everything right over the course of the next week of human development — may make an embryo. Lots of eggs, unfortunately, will never make an embryo.
And so when we freeze eggs to give someone the same chance of having a baby as if they freeze an embryo, we have to freeze five eggs for every one embryo. When we do that, the chance of future pregnancy is the same, but we're freezing something very different when we're freezing an embryo.
An embryo is an early form of human life. An egg and sperm have combined to make a zygote, which is a single-cell embryo. And by the time we freeze an embryo, we actually watch it usually for about a week, and it becomes a blastocyst.
Over the course of that week, it has gained about 200 to 250 individual cells that are pluripotent, which means they can become any tissue in the body — embryonic stem cells. And it's just a completely different entity to an egg.
So when it comes to fertility preservation, the message is that if you're freezing eggs, it's a great solution. They're not embryos yet, and many of them will never be. So we have to freeze a lot of eggs to have the same chance of success when compared to embryos.
And that's why your fertility doctor, when talking to you about egg freezing, should — and usually I would expect will — explain that not every egg will be successful, and you have to freeze quite a few. Most women will be advised when considering egg freezing to undertake more than one treatment so that, serially, they can have more eggs in the freezer.
Jordi Morrison:
Can you please explain the ICSI process?
Dr Raelia Lew:
Sure. ICSI — the cute little word ICSI — stands for intracytoplasmic sperm injection. In other words, it is injecting a sperm into an egg to artificially fertilize that egg. It's a process that is used in many different circumstances.
The most common is when there is male factor infertility and the sperm simply can't do the job by itself. Another context is when we are warming frozen eggs. One issue that we see when we do freeze and warm eggs is the egg shell, the zona pellucida, artificially hardens. And in order to make sure the egg has the best chance of fertilizing in that circumstance, we choose to inject the egg with a sperm rather than dollop the sperm on the outside of the egg in the more natural way.
We also use ICSI in some other contexts, like, for example, when we genetically test embryos for tiny little mutations that can cause serious disease in children. We have to be very certain that the sperm and egg DNA is not contaminated by the DNA from other sperm to give us a confusing test result. And so in that circumstance, even when we know that the sperm looks okay, we will use ICSI.
The actual process of ICSI — remembering that an egg is about a thousand times smaller than a poppy seed — is done through a microinjector apparatus using a very high power microscope. Scientists train for a very long time to become competent at performing ICSI. It's not easy, and technique is important. There are many different varieties and little tricks that scientists can use to finesse the ICSI process, and we hope that with ICSI, somewhere between 60–70% of mature eggs will fertilize successfully and have a chance to go on and make a blastocyst.
Some eggs, which are vulnerable and fragile, may not do well with the ICSI process, and a risk of ICSI is egg degeneration. So we don't use it unless we have to. We know also that there are some birth defects in babies that are more common with ICSI, and so we do try and avoid it if it's unnecessary.
We also have an episode on ICSI, which we'll link to in the show notes that goes into much more detail.
Jordi Morrison:
Next question, Raelia. How important is embryology grading in a euploid blastocyst?
Dr Raelia Lew:
We're getting some really technical questions today, which is great. Euploid means a blastocyst that has, on a macro level, the right number of chromosomes to make a baby — that's 23 chromosome pairs. In terms of what it takes to make a baby, having the right DNA roadmap is very important.
However, it's not the only important thing. We also need the embryo to be metabolically competent and physically robust. So it must have the right DNA. It must have the right physical characteristics, and it has to have the right metabolism. And then on top of that, it has to do the right thing without making any errors.
The embryo grading is important, but it also isn't everything. Embryos change rapidly. They can look much better the day after they are graded in some circumstances than the day that they were graded. And they can look different when they're warmed from having been frozen compared to before they were frozen.
The process of freezing embryos subjects them to the risk of some trauma and damage, and some embryos do lose some of their cells in that process, unfortunately and unavoidably. So you may actually have a better chance of a pregnancy, paradoxically, in an embryo with a lower grade if it has better self-survival on warming compared to an embryo of a higher grade before it was frozen.
I would say that to reassure anyone who's listening who has frozen embryos — IVF laboratories in the modern way we practice only freeze embryos of good grade. So if an embryo has been frozen, then we're splitting hairs whether its Gardner grading scale has A’s or B’s.
Jordi Morrison:
Leading on from that question, when a patient has multiple frozen embryos, how do you select which one to implant?
Dr Raelia Lew:
It's a little bit like how we select the pupil to be school captain. We select the embryo that has put in the best performance to date, is well presented, and sometimes it's a matter of choosing between several excellent and almost identical candidates.
There are different ways that we score embryos. Sometimes they have a grading like the Gardner grading scale — I think that's almost universal. And then we can also give them other indices based on things like how they've behaved while they've been monitored, like the RI score.
Jordi Morrison:
Why would a day two transfer be recommended if a day five blastocyst is more likely to implant?
Dr Raelia Lew:
This is a great question. When we transfer embryos, as individuals, a day two embryo does not actually have a lower potential than a day five embryo. Each of us — you and I and every human being on this earth — was once a day five embryo. We were also once a day two embryo.
Sometimes, and in some patients, there’s rationale to transfer an embryo earlier than day five. In fact, every IVF baby in the whole world that was born before about the year 2000 was transferred as a day two or three cleavage stage embryo because that’s what we used to do all the time.
The rationale for culturing embryos in parallel to day five is really about embryo selection. It’s not that the embryo has a higher chance intrinsically. It’s that there’ll be observations possible to rule out certain embryos from transfer. So transferring an embryo on day five means that we may have a better chance of ruling out some embryos that were never going to make it. And statistically, that means that we end up with reporting a higher pregnancy rate per embryo transfer.
There are several embryos that might have looked great on day two or three, and we might have given an opportunity to make a baby — maybe ruled out in the lab. In terms of whether those embryos might have done better in the body, we’ll never know. And it’s important to recognize that the IVF lab is doing its best to simulate the ideal conditions of the human body. It’s never quite as good.
And the rationale for transplanting an embryo earlier — in someone particularly who is having difficulty creating good looking embryos in a lab environment — is that their gametes and their early embryos may have a better chance in the body. So as an individual, that can be true.
We also sometimes transfer embryos earlier than day five for logistical reasons — like, for example, laboratory planning and the ability to work around staff availability. There’s nothing wrong with transferring an embryo back early or later, and we take these techniques on board to individualise care to different people.
I’ve had patients over the years who’ve been able to get pregnant with an early transfer, where they’ve never been able to get pregnant with a blastocyst transfer due to inability of their embryos to make it to the blastocyst stage in the artificial laboratory environment. So it is something that I do from time to time, for logistical and individualized care reasons.
Jordi Morrison:
How do you recommend prepping for implantation? What tips for success can you recommend?
Dr Raelia Lew:
The most important thing to optimize the condition of your body to successfully have a pregnancy is to be healthy globally. A lot of people under-recognize the importance of the embryo in successful implantation. There will be some circumstances where the uterine environment can be hostile to implantation — such as when the patient has chronic endometritis or inflammation of the lining — and that’s important to recognize. Recognizing that is part of a workup in IVF, and it can be a condition that develops.
So if somebody’s had serial embryo transfers and they haven’t become pregnant, one thing that I often do is pause and have a look inside the uterus with a camera called a hysteroscopy. So adequately investigating for underlying health conditions that can be optimized is important. Controlling any diabetes or insulin resistance, optimizing BMI.
We know from many studies that, unfortunately, being overweight — and particularly having a BMI over 35, even more exaggerated at higher BMIs — is associated with the failure to implant of normal chromosomally euploid embryos. And it also is associated with a higher rate of miscarriage of normal pregnancies.
When it comes to optimizing weight, diet, and lifestyle, doing the work preconception can improve your chance of pregnancy. It also pays to optimize any anatomical concerns of the uterus. Sometimes there are issues like fibroids or polyps that need to be treated and removed before an embryo goes back.
In terms of being healthy — having a good diet, being nutritionally replete, optimizing exercise, weight, sleep — all of these things are important. At Women's Health Melbourne, we pride ourselves on having a holistic approach to preparing our patients to achieve their optimal chance of success. And we can involve as many members of our team to guide patients as they would like involved in their care, from nutritional advice, acupuncture, therapy to reduce stress, and improve the patient's quality of life during the embryo transfer process, to specialist assessment by CREI subspecialist to ensure that all bases have been adequately covered.
We have endocrinology support to ensure conditions that might be causing underlying disturbance — like thyroid disease — is optimally controlled. Other conditions like insulin resistance and diabetes are optimally controlled. All of these things contribute to improved implantation success in an IVF context and naturally as well.
It’s really important to recognize that the embryo is often to blame when implantation doesn’t happen — either due to DNA error or due to just making a developmental mistake. And often, what you need to do differently next time is try again with a different embryo, which has a different combination of DNA from you and your partner and also has a different chance to run a successful race in making a baby.
Jordi Morrison:
How many embryos do you typically implant in one go?
Dr Raelia Lew:
This is a topic in its own right, and I think we do have another episode about single versus double embryo transfer. So I'll answer it in brief and direct our listeners to have a listen to that older episode of Knocked Up.
It is in the IVF world considered best practice in modern standards to transfer a single embryo at a time. The reason for this is that it gives the best probability of having a baby at full term without medical problems for the mother or the child. When we transfer multiple embryos, we incur a burden of multiple pregnancy risk, and that increases both the baby's and the mother's risks of serious medical problems due to multiple gestation.
Jordi Morrison:
Is the process of frozen embryo transfer different from fresh, and are pregnancy rates the same?
Dr Raelia Lew:
The process of frozen embryo transfer is very, very different to the process of fresh embryo transfer, and the pregnancy rates are not the same. The pregnancy rates for frozen embryo transfer are superior to the pregnancy rates for fresh embryo transfer for multiple reasons.
The process of fresh embryo transfer references the transfer of an embryo in the same IVF cycle in which eggs are collected. It’s important to note that it is not suitable for safety reasons for patients at risk of ovarian hyperstimulation syndrome. And some patients will be denied the opportunity of a fresh embryo transfer in their best interest for that reason.
A fresh embryo transfer can be undertaken when a reasonable number of eggs — ideally between ten and fifteen — have been collected or fewer. And when an embryo goes back in that stimulated cycle context, it is performed on day five after egg collection. It can be performed earlier on day two to three after egg collection in certain circumstances, as we mentioned earlier.
The ovaries have been stimulated in an IVF cycle to create multiple eggs, and this results in significant hormonal dysregulation compared to a natural cycle. Estrogen levels run much higher, as do progesterone levels initially, and this can cause the endometrial lining to be suboptimally prepared when it comes to implantation. It is a more hostile environment for the embryo to navigate. But the embryo does have the advantage of having not being frozen and has not had the opportunity to sustain any cryo injury.
In a frozen transfer context, we have the opportunity to prepare the endometrium in a much more physiologically natural and a lot more sympathetic way. And so when we put a frozen embryo back in that environment, one of the advantages the embryo has is environmental — a better implantation environment.
We also have other reasons that frozen embryos do better. One is the fact that they were suitable for being frozen in the first place. So when we are transferring a frozen embryo from the beginning of the cycle, we know we have a good embryo to transfer. Our criteria for freezing embryos are more stringent than our criteria for allowing a fresh embryo to be transferred.
When we have a fresh embryo and it is of poor quality, we may decide — if it's the only embryo we have — to still give it a chance, even if it is a fundamentally very low chance. So for example, if you have an embryo with a CC grading that would never be frozen, it might have between a 2 and 5 percent probability of birth if we transfer it. It’s a very low chance, but it is still a chance. And fundamentally, we miss a hundred percent of the chances we don’t take.
So you can say that fresh embryo transfer may have a higher utilization rate than frozen embryo transfer, and part of the benefit of frozen transfer may be selective.
When we bank embryos for freezing, it’s often with more than just the current pregnancy in mind. And certainly, our cumulative live birth rate — as well as our embryo transfer-related live birth rate — is higher with frozen embryos when we’ve banked embryos for a person and a family.
So quite often, my approach in IVF with my patients who are suitable candidates — and it’s not possible for everybody — is: if they would like more than one child, we talk about it and we strategize to freeze embryos for them. Ideally so that when they’ve had a baby and they come back and see me a little bit older with a few more barriers, with poorer egg quality — unfortunately, it happens to all of us — we have a resource of embryos for later that gives them a better chance of success.
Not everyone with embryos banked will succeed, but in the majority of cases, if we’ve prepared well, we can set someone up for success longitudinally to have the number of children they ultimately want in their family. And so sometimes the strategy is not necessarily just about the here and now — it’s about the big picture.
Jordi Morrison:
Can a frozen embryo transfer cycle be successful without progesterone support?
Dr Raelia Lew:
I'm going to answer this question in a facetious way. And the answer is: no, it can't. However, progesterone support can come from your own ovary.
So to answer the question in another way: the progesterone you make yourself in a natural cycle may be adequate to support the embryo, but progesterone support as a concept is critical. That’s why sometimes with the natural cycle — and actually this is my practice 99% of the time — doctors will support with a bit of extra progesterone artificially just to make sure that the progesterone made by the ovary is ideal. We're not just looking for “sufficient”; we're looking to improve the chance of pregnancy.
It’s important to recognize that the embryo was not made from the follicle that released an egg and ovulated in the natural cycle. That follicle is what is supporting the pregnancy.
It's also important to point out that not every follicle and not every corpus luteum is equal, even in the same person. You can buy a bunch of roses and critically analyze each one — you'll see that some roses are more perfect than others. Appreciate also that not every follicle is as perfect as every other follicle, and not every follicle and every cycle will make the exact same amount of progesterone hormone.
Progesterone hormone is very aptly named: pro — in favor of — gest, pregnancy. So it is the pregnancy-supporting hormone. You cannot overdose on progesterone. You can have not enough. And if you have not enough, a good embryo may fail.
So when your doctor prescribes you additional progesterone to support your luteal phase in the context of frozen embryo transfer, what they're trying to do for you is improve your chance that that embryo will succeed.
Jordi Morrison:
Why would someone be asking that question?
Dr Raelia Lew:
Someone might be asking that question because progesterone as a supplement is often given in different ways that can be unpleasant — like vaginal gels or tablets or capulets. And it can cause a bit of irritation and it could cause a bit of discharge — and it’s nobody’s favorite thing.
It can also be given in injections. That's unusual in the natural cycle. We don't generally need as much as all that, although in an artificial cycle or a hormone-supported cycle, injections are quite common as a way to give progesterone into the system.
You can take progesterone orally, but unfortunately, it has a lot of side effects when you take it orally, and that's why it's generally avoided. I sometimes do give a progesterone dose orally to my patients at night.
The main side effect people are concerned about with oral progesterone is it makes you very, very sleepy. So people can be foggy or find it difficult to function.
Other progesterone side effects are things like breast tenderness and bloating, and sometimes exacerbation of impulses of hunger. It's important also to note that these are all symptoms of early pregnancy as well.
Jordi Morrison:
To support Knocked Up, leave us a review or recommend us to a friend. Join us on Instagram at @knockeduppodcast, and join Raelia at @drraelialew, and email us your questions to podcast@womenshealthmelbourne.com.au.
Thank you for listening!