How the Endometrium's Interview Process Affects your Fertility: Conversation with Dr. Nick Macklon

You may not have given much thought to the lining of your uterus, aka your endometrium; but it is a super important workhorse when it comes to pregnancy, and one that, it turns out, has a voice. The old story used to be that the endometrium is this passive, patient group of cells waiting to give any embryo it glimpsed a warm, safe harbor to grow. Today's guest shares the updated story: the endometrium as selective screener, interviewing the embryo--by assessing its chemical signals-- accepting and investing in the embryos it thinks are viable, and rejecting the rest.

Nick Macklon's published work can be found here: https://pubmed.ncbi.nlm.nih.gov/?term=nick+macklon&sort=date 

Uterine Selection of Human Embryos at Implantation: https://pmc.ncbi.nlm.nih.gov/articles/PMC3915549/

Dr. Macklon's work at the London Women's Clinic, Kind IVF

Transcript

[00:00:00] 

 You may not have given much thought to the lining of your uterus, a. k. a. your endometrium, but it is a super important workhorse when it comes to pregnancy and one that, it turns out, has a voice. The old story used to be that the endometrium is this passive, patient group of cells waiting to give any embryo a glimpse to warm, safe harbor to grow.

Today's guest shares the updated story. The endometrium as selective screener, interviewing the embryo, by assessing its chemical signals, accepting and investing in the embryos it thinks are viable, and rejecting the rest. Welcome to Making Sense of Pregnancy. This show is a new pregnancy reference. I'm finding and talking with experts doing cutting edge work to better understand what we do and [00:01:00] don't know about pregnancy, and what you can do to better understand your own experience.

Each week, I'll be talking to scientists, Doctors and researchers who are trying to uncover the many mysteries that still exist in reproduction, giving you the most current evidence based way to approach this enormous transition in your life. I hope it will become your go to source for how to make your pregnancy better.

Please enjoy my conversation with Dr. Nick Macklin. 

Today we're lucky to have Nick Macklin, who's an expert in reproductive medicine and fertility research, and has taught in universities in the Netherlands, Denmark, and in England, and is currently Professor and Medical Director of London Women's Clinic in London. Thanks so much for coming on, Dr.

Macklin. 

Thank you. It's great to, great to join you. Thanks for inviting me. 

 You've written widely about a number of different topics in fertility. And to start, I just want to set a context for our conversation, which is how inefficient human reproduction is. In a number [00:02:00] of your papers, you write only 30 percent of conceived pregnancies will progress to live birth, which for me was a stunning statistic.

I hadn't read that anywhere else. Can you talk a little bit about how we got that number and what that means? 

Yeah, it is a stunning statistic, isn't it? And I think it's important , to unpack it a little bit because, it might be quite, disconcerting for people to hear that. , certainly, , when you compare humans to other species, we are very inefficient and people have often wondered why that is.

might be the case. From an evolutionary point of view, it's probably helpful for us not to have too many kids at one time, because they take a lot of effort to, nurture compared with other animals, of course. , and we understand that one of the, things that nature's put in place is an unusually high rate of abnormalities in the embryos that we create.

So only a small proportion of the embryos that we make as a species, compared with others, are capable of producing a [00:03:00] live birth. And that's why we see this reflected in the data. Now, quite interestingly, that this first came to light, I suppose, clinically in the 70s, when some very simple calculations were done about how many babies were being born in England and Wales, and how many episodes of unprotected sexual intercourse were going on.

 Some calculations were made and there seemed to be a big gap between the number of babies they calculated should be being born and those that were actually making it to the birth register. And what really lies behind it as we've been able to elucidate through our work over the years and, and others have too in some very classical studies in the U.

S. particularly. is that the issue with humans is that we have a very high rate of loss of embryos before they've implanted long enough for the woman to know that she has got a pregnancy. So what we mean by that is that there's this very high rate of attrition [00:04:00] between an egg being fertilized in the body.

and a positive pregnancy test occurring. So most of the losses that occur in our species occur in that what we call preclinical phase, in that sort of week or two, just after ovulation, where fertilization might take place, an embryo might be created, , and may even begin the process of implanting, but just doesn't proceed long enough for the woman to miss her period.

or to have a positive pregnancy test. So ultimately, from what we see clinically and what women see clinically, of course, far more than 30 percent will end up as a live birth, much more like 80%, something like that. But we're not taking into account all of those losses, which have evidently occurred prior to that.

So that is why this rather distressing figure of 30 percent emerges, because it's not so much 30 percent of clinical pregnancies, it's 30 percent of [00:05:00] conceptions. And if we define a conception as when an egg has fertilized and produced an embryo, then that is how we arrive at that figure. 

 It's super interesting.

And in one of your papers, I think it's one published in 2013. You talk about the iceberg of pregnancy loss and these preclinical, losses are sort of below the water level. So we don't necessarily see them, which is a cool way to describe it. , and many of us are familiar with, miscarriage once we've gotten a, positive pregnancy test and that's the other 10%.

So it's 60 percent that don't even make it to, I miss my period and I know I'm pregnant. And then 10 percent on top of that. , there's an element of 

estimate in that because we don't yet have a test of conception. We've got a test of implantation, but the data we have from IVF and from other sources suggest it's in that.

Um, 

so that's super interesting. And we're going to get into the different parts of how those things fail and, when they work, maybe why they [00:06:00] work. , but let's talk a little bit about people who are classified as infertile. I was a member of this group at some point. I now have two kids, but we had trouble getting pregnant.

 And when I was going through it, I was told the rate was like 10%. I was 31 at the time, so maybe the fertility rate probably varies by age. , but can you say, is there some overall rate and does it vary other than by age, does it vary by country or anything like that? 

Well, it's age is without doubt the dominant determinant of your chance of conceiving naturally.

 But the figures, , are generally actually pretty encouraging. So although per month, , it doesn't sound great, 10 to 15%, clearly most couples who are trying to conceive. are looking to do so over a period of time, maybe six months, if they're patient a year. , and the data,, for natural conception of an ongoing pregnancy is very good.

I mean, 80 to 90 percent of young women up to the age of 33, 34 would expect to conceive if they're having [00:07:00] regular unprotected well timed intercourse over a year. And that number actually stays up until the 70 percent 70 80 percent right up until the late 30s. , so it's only really after , you're hitting the very end of your 30s into 40s where we start seeing very clinically noticeable impact of age on that number.

 The trouble is that, if you're at 40 and you wait a year, , to conceive, yes, there's a good chance you will, but there's also an increased chance you won't, and by that time, you know, age is beginning to have an impact on the effectiveness of the other ways of conceiving, and that's why, in general, the advice for people will be, up to the age of 35, 36, give it a year, if it hasn't worked, you're possibly in this group that will need help, And if you're older than that, maybe give it six months because although you probably still have a reasonable prognosis of conceiving naturally, clearly as time goes past, the benefit of IVF or other treatments is going to diminish fairly quickly once you get into your 40s.

[00:08:00] Okay. That is a positive story. , and when we talk about infertility or even conception in general, it seems like there's two sides to the story. So one is egg quality, which is, , or embryo quality, which is egg plus sperm. And the other one is endometrium. And you've written a lot about, this uterine lining that acts as a biosensor.

And there's actually a conversation going on between the embryo and the endometrium that we're trying to hone in on right now to understand. How that works, how implantation works, , in the relationship between age and fertility, you have written that the oocyte meiosis, which for people who don't remember their seventh grade science is, , how the sex cells, , divide.

 So this oocyte meiosis is sensitive to external and internal forces. Can you talk about some of what those are? 

Yeah, so just to remind everyone, meiosis is the very important process that happens in eggs and sperm to make sure that they, the egg can receive another load of genetic material, , drops down to half the number of [00:09:00] chromosomes that you and I have, so that it can accept another half from the sperm.

And what we're learning is that the interactions that take place between those chromosomes are affected by changes in the embryo which affect their efficiency. So there are certain binding process proteins and spindles and all of these things which act to coordinate the transmission and coordination of chromosomes moving around, rejoining, reconnecting, forming this new genetic individual.

That can go wrong as the ages, and that's what we think is the primary reason why we see meiosis perhaps not generating, and then subsequently fertilization, what we call normal. Chromosomes in the embryo which balance chromosomes, i. e. the right number, and that's what we call a euploid, And that is thought to be, that process is thought to be the primary mechanism by which aging reduces fertility in women, , through that.

, but, coming back to the [00:10:00] biosensor, what we know is that even in young women, compared with other species, The rate of chromosomal abnormalities in embryos is It's quite high. And by that, I might say 20 to 30 percent of embryos may have some sort of abnormality. Now, we take the view and certainly I believe that many that are not chromosomally perfect, are okay.

They're good enough and they can self correct and they can survive. But what emerged when we were looking at all this, almost 20, 20 years ago now, initially, and 10 years ago in terms of doing real research, was that this problem that women have been presented, possibly, you know, quite frequently, if they're having regular unprotected intercourse with an embryo that is invasive, but is chromosomally not quite right, means that she needs to have an abortion.

a means of deciding whether or not to invest in it. If she's 40, that becomes very important because most of those embryos are probably [00:11:00] going to be chromosomally not perfect. When she's younger, it's less of an issue because more of the embryos will be all right. Since she's being presented with these, she needs to have this biosensor.

And, you know, we discovered this biosensor, as is often the case in science, by chance. I wish I could have said I thought of it, and we went looking for it. , What happened was that one of my PhD students working with me in Utrecht, 

So regrettably the audio got crunched here and we're going to miss the story that Professor Macklin was talking about. But I think he was describing this experiment, which I found in a paper he wrote in 2014. , and this is what I think the experiment was. They had this cell culture, this kind of soup for cells to grow in, in which two kinds of embryos had been developing separately.

In one dish were embryos that went on to become a pregnancy, and The other dish housed embryos that were rejected as candidates for IVF [00:12:00] transfer. And while the two different embryos are in their separate soups, they're dividing, and this process is releasing a certain chemistry.

 And then, taking only the soup from these dishes, they added uterine lining cells that were primed to receive an embryo. So, in the end, they have three dishes. One with uterine lining cells and the soup from the working embryos.

One with uterine lining cells and the soup from non working embryos and a control group which is just uterine lining cells and the soup that's used to grow embryos but no embryos had grown in it. And next, they observed what happens. 

Apologies to Dr. Macklin if I have butchered this description in some way.

and, culturing them and just watching what happened. Basically, , what, how did the uterus respond?

And you've got a good embryo. The endometrial lining gets very excited and upregulates all of these wonderful molecules to say, let's, let's have you, we didn't see that. What we saw was something very different, and that was that. Nothing really happened when there was a good [00:13:00] embryo, the cells were, you know, just got on with life.

But when a poor quality embryo was there, they got very, very stressed. They didn't like it and started down regulating all of these things. And we also saw this in the way in which cells migrate around the embryo. We, we, we did some studies where we looked and showed that cells from the lining of the womb actually migrate around the embryo .

 Helping it embed, but they don't do that if the embryo is abnormal. So this was the sign that we have this. biosensor, which can smell, sniff the embryo and decide whether or not to engage with it. But that was a very convenient finding because we were then able to say, okay, okay, this fits with the data we have showing that there is this problem the mother faces, where she's being confronted with embryos, which are potentially invasive.

Which could establish a pregnancy, but if it was allowed to carry on without a biosensor, would just end in a miscarriage or the birth of babies with genetic abnormalities. So that sort of came together in that way, [00:14:00] yes, this seems to be a key part of human reproduction, by which we're not just requiring the lining of the womb to be receptive and welcoming to an embryo, which of course we do need, but also slightly Tuesday about which Andreas will invest in and we discovered evidence that that is indeed what is happening.

Yeah, that's super cool I saw you saying somewhere that endometrial receptivity is kind of too passive a term It's more like endometrial engagement or something like that. And I'm wondering Given what you're talking about, how the endometrium is kind of noisy when, it gets an embryo that is not quite right.

And it's quiet when it gets an embryo that seems totally normal. Do we know what the endometrium is selecting for? 

Yes. That's a very good. So one of the things we wanted to know is what, what is it, what is it smelling when it's, it's the embryo. And it's interesting you use these terms quiet and noisy [00:15:00] because they've been used in the past to describe embryos metabolically.

And there was, this term called the quiet embryo hypothesis that was, , produced by Henry Lees way back. He's a British scientist, very eminent British scientist who noticed that good quality embryos are not very busy. Metabolically that all they have to do is grow. So they're not producing much.

You can't measure much around them. But, you know, if you look at the fluid they're sitting in and you look to the metabolites, they're producing. It's not very much actually. They're quite quiet metabolically. Whereas when you looked at embryos that were struggling. You know, these are ones that weren't very good quality, they're undergoing processes, perhaps, of repair or survival.

They were very metabolically active and pumping out all these different metabolites. And what we were able to identify through work I was doing with Jan Brosons, was that there is a whole range of these molecules which are being produced, and we identified certain enzymes called proteases, which are being produced.

by these embryos as [00:16:00] being one, at least, of the signals which the endometrium sniffs or tastes, if you want to use that. And that when the embryo is producing too much of these proteases, it causes a change in the response of the cells underneath the very surface. Which the embryo has broken through, it's come through, but at that point it, because these proteases are detected and they, they, they cause a chain of events which ultimately leads to the embryo's rejection.

Now, there probably are many others, and work's being done to actually identify some others that are coming out. And that's very interesting, because it does two things. It means, well, we might be able to use that as a measure of embryo quality, but also potentially. If the endometrium is not responding properly to the embryo, and we'll maybe talk about that in a minute, about what happens when that biosensor goes wrong, you could maybe correct it , by modulating these proteases or other hormones [00:17:00] to calm the endometrium to thinking, oh, this is actually a reasonable embryo, I'll accept it after all.

That's super interesting. And it's clear that for some women, their biosensor is off. So maybe this is a fix for that. And it also is a scary response because you think like. Doesn't the body know whether it should be pregnant or not? 

Yes, and I think we came to the conclusion that sometimes it doesn't.

Okay, that's a good answer. 

Yeah, and there are some women whose biosensor is just not selective enough. So what happens is that that embryo, which is not quite right, , invades the upper layer of the endometrium, the epithelial layer, and starts producing HCG, which is detected as a positive pregnancy test, and delays her menstruation.

, and in most women, that embryo would not pass the test of quality. But there are some women who are [00:18:00] less discerning in their endometrium, and allow that embryo to establish a pregnancy, but because it's not viable. They get presented with a positive pregnancy test, but then a miscarriage, and they suffer knowing that this pregnancy has failed.

Whereas if their biosensor had kicked in, then they would have been blissfully unaware that there had been a conception, they'd just got their period. So , we wondered whether or not, in some women with recurrent miscarriage, this is indeed the case, that they are just not twosy enough. The other spin you can put on that is that, you know, are some women with recurrent miscarriage not actually, the problem is not that they're rejecting their embryos, But they're just being too accepting of embryos, which is a nice spin to put at it.

And I remember when we came out with this work and it got some media attention, I got a lot of emails actually from, from women who suffered, very huge distress of recurrent miscarriage and felt very guilty about it, that actually they found some comfort in acknowledging it, [00:19:00] the knowledge that it might not be that they're being nasty to their embryos, but they're being too nice.

 And I think that is, is probably what's happening, for these women. And what we're learning now, too, is why their biosensor isn't working in some women. And this is, again, work that's been going on, with my collaborator, Jan Brossens, who works in Warwick with his group.

And others have been looking at this, and, and we're beginning to understand how the biosensor works. what goes wrong and how we might be able to correct it. This is still work that's pretty much in the science stage, but I think it does offer a, an interesting route forward for helping women who either have recurrent miscarriage because they're not Tuesday enough, or the other end of this is where you're.

To choose, and it may well be that there are women who suffer from infertility, , simply not, not because they're not producing embryos, but they're just only allowing the A1 top ones to have a shot. [00:20:00] And the rest are just not even making it to a positive pregnancy test. And again, if that is the case, then there may be ways that we can, in the future, turn down that selectivity so that they allow embryos, which are not utterly perfect.

But good enough, as I think, I probably was not perfect as an embryo, but it seems I was good enough to convince my mother to let me implant. And I suspect that applies to most of us, to be honest. 

 That's super interesting. I think you're talking about endometrial diagnostics. Is that what you're talking about?

This, the future of this, where we look at things like microbiome and the population of immune cells that exist in that space. Yes. 

And I think I think this is very important. And, you know, if we think about IVF, we're celebrating what for the first almost 50 years of it soon, , the profound advances that have been made have been in generating and testing embryos, which is vital because they are the primary determinants of [00:21:00] success.

The poor old endometrium has got a little bit left behind, I would say, and it's just beginning to catch up now. So we've got all these remarkable tests of embryo quality, but really not very many of endometrial function. , in fact, if you go to, you know, most, most of us in clinical practice, how do we do it?

We just measure it and we look to see how thick the endometrium is as an ultrasound. That's it. Well, it's very, very crude and it's not very, very predictive. , and that's a sign that we need to, we've got a lot of catching up to do here. 

 Part of why it's interesting for everyone and not just people with fertility issues is that I wonder once we understand this conversation better, whether we can affect the way the placenta invades, which, , even if you do get pregnant, , abnormal placental invasion causes so many problems with preeclampsia and preterm birth and, that's a huge fraction of people who actually do get pregnant.

So, I feel like we're all invested in the outcome of these studies. [00:22:00] 

I think we are, and you're quite right that over the last 10 years or so, there's been an increased understanding that , the basis of these great, complications of pregnancy, which you've just outlined, like preeclampsia and growth retardation, they have their origins right at the beginning.

 And probably, as you say, in, abnormalities in the way in which this is what we call the decidualized endometrium, that's the endometrium that's undergone all these changes under the impact of progesterone hormone to become a nurturing environment, but also to regulate invasion, where that goes wrong.

And either you get excessive invasion or not enough. And it's probably all happening around about this. time shortly after the decision has been made to allow this embryo to continue. So increasingly we see the deciduum as being this early, very, very early pregnancy endometrium as being absolutely key, not to just determining whether or not a pregnancy gets established, but then whether or not it's going to proceed without complication.[00:23:00] 

So what that does is that opens the door to really interrogating that and finding out, okay, what's going wrong and how can we treat it at that early age? Because at the moment, if you ask obstetricians, like me, , what is the treatment for preeclampsia? It's end of pregnancy still, which, that is the primary treatment for it.

We have means of trying to reduce its impact by giving aspirin and things like that. It's very important. , but if we can really get to grips with what is going on in very early pregnancy around about 67 weeks gestation, then we may be able to actually get in early and say, right, let's make sure that invasion is normal because the decision is responding normally to that embryo rather than abnormally.

And I think that is the key. the key issue that we need to focus on in our field. 

, beyond implantation, does the endometrium have an impact, , later into the first trimester or later into the pregnancy? 

Well, I think, [00:24:00] there are other what we've learned is that this very early biosensor is one of a series of checkpoints which nature has put in place to determine whether or not a pregnancy will continue.

 And there probably are other checkpoints later in. in pregnancy around about eight or nine weeks, and we know many pregnancies end, don't they, , where it's not just that the embryo has failed, it's just that one of these checkpoints has kicked in and said, no, this is not going to work. And the endometrial will have a role in that or the corpus luteum, which is what's left over after the ovary, has ovulated.

That follicle then becomes the primary source of that key hormone of early pregnancy called progesterone. , and if it's not functioning normally because that follicle wasn't great and the egg wasn't great, then it, at some point it will stop producing that progesterone. before the placenta has time to take over and we will lose that pregnancy.

So that is one of nature's checkpoints. Once you get full, creation of the placenta and this is, we've had this [00:25:00] establishment of this very close connection between the mother's circulation and the fetal circulation, the lining of the womb has really played its role by then and what happens after that in pregnancy will be determined largely by other factors as long as the invasion is gone.

Is that like eight weeks or how far along is that? 

Yeah, it's 89 weeks. So it's what we call the luteal placental shift where the primary source of progesterone moves from what's left after ovulation, the corpus luteum, to the placentas around about 10 weeks gestation, eight to 10 weeks gestation. 

 So I find all of this Information that you scientists have found just mind blowing in that, it's so complicated and there's so many details going on.

So to parse out exactly what's going on seems to me like magic. In the future, I can imagine that we will wait, OB interest much earlier in the pregnancy than we do now, because right now you [00:26:00] go in maybe at eight weeks to get a HCG test or something, and then you go in much later.

But by eight weeks, so many things have happened that it seems odd to have the pregnant mother on her own at the same time. You know, today we, there's nothing we can do to change the course of that process. 

I agree with you. And I think a good, a good which you're already seeing is in managing miscarriage.

So, for instance, for many years we've, , it's been quite popular amongst clinicians if a woman has got a history of recurrent miscarriage to wait until she's pregnant and then give her progesterone to try and retain the pregnancy. And that has had very, very limited benefit in randomized controlled trials.

And the view that, , I have and others who have been working in this field is that it's because we're going in too late, that possibly we can correct things by giving progesterone, but really, you need to get that in there prior to the decidualization process taking place, whether that be progesterone or some other intervention, to make sure that the [00:27:00] way in which the embryo are interacting in that very crucial early phase is up to, if you wait until The pregnancy test is positive, you've, that that path has probably already been set and it's probably quite difficult to manipulate beyond a very minor effect.

But that, you know, that that's, that's a quite a claim to make. , and in order to sort of organize maternity services in that way, there needs to be a much more robust evidence and a clear clinical pathway to offer, which we're not at that stage yet. , but I think the way we're looking at recurrent miscarriage is changing.

 And that could lead the way to us. you know, then looking into pregnancy as a whole. 

, so on that note, one thing that I've seen you talk about is preconception care. How people can behave in a way that gives them the best chance of getting pregnant. Can you share some of that with us? 

Yes. I mean, this has been an interest of mine for a long time and one of the great pleasures I had professionally was when I went to become professor of R and G in South Hampton was I was [00:28:00] working with a chap called David Barker, who many of my colleagues who don't listen to us, , was still there.

And, I had the chance to meet with him and to talk with him quite a bit. And just to remind people who haven't heard of David Barker, he's an epidemiologist who, in the 70s and 80s, did some very, very seminal work where he looked at some birth record outcomes , and, , birth weight and then looked at , the incidence of diabetes later in life.

And what he found was that there was a sort of a J shaped curve. So in other words, if you're born very big, with a big weight, you had a higher chance, not just of diabetes, but of cardiovascular disease, such as strokes and that kind of thing. But that was also seen if you were born too small. And there was a sort of a Goldilocks area, born just about right, where that risk seemed to be lower.

And what this suggested to him was that these very, during pregnancy, he called it the first thousand days of life, actually starting. at the time of [00:29:00] conception. In fact, we now know several weeks before conception, if you want to influence it, was having an impact on long term health later in life.

 And this remained a hypothesis for many years. It was known as the Barker hypothesis, and you often still hear people hearing about that, but it's moved on hugely from then. And we now understand many of the mechanisms by which that very early Intrauterine environment, right from even the pre implantation phase when the embryo is just swimming around in the uterus waiting to get a foothold, it's already sensing its environment and adapting to it.

And if that environment is not optimal, it will maladapt because it will adapt to a situation in the uterus that it's not going to find when it comes out and it's born. So a good example might be the embryo that finds itself in a very nutritionally poor environment through pregnancy. The classic studies were the Dutch hunger winter in the 1950s, where women who were pregnant just [00:30:00] didn't get sufficient nutrition.

And these babies who were born from that suffered terribly later in life from diabetes and other conditions because they had adapted. in the uterus to a certain environment that they didn't encounter when they came out. So , we've now learned that there are a number of ways in which we can affect that intrauterine environment to affect outcomes.

, and we've also learned of direct mechanisms by which the embryo detects that environment. And there's lots of studies in that that have been done to show how that happens. So it's a very real thing. It's a very real biome. Now, what is the message for us? Was humans just wanting to have a healthy baby?

Well, it, reminds us how important it is to create an environment for that very early embryo, which is optimal for it. And that's what we call preconception care, essentially. There's the element, of course, for making sure the mother will survive the pregnancy, without complications, but also that [00:31:00] that embryo is going to get its best start in life.

Now, when should that start before conception? Well, there's a lot of discussion about that, but if you think that it takes an egg around about three months to mature from being in the ovary fast asleep, waiting for its moment, later in life, to, in a woman's life to, to embark on that journey to ovulate, it takes about three months to do that.

And for sperm, it takes about three months. , roughly, a little bit less than that, to produce a mature sperm. That seems to be a decent period to think about, right? , if we want to have a baby in three months time, let's get cracking now and just create the optimal environment for it. , and, what's that, what is that going to be?

That the key tenants of it are to avoid toxins like smoking, which is the key, , is a dreadful thing, really, to be To do because it affects fertility and all affects the embryo too, as many of us know now and smoking is unfortunately a lot lower than it used to be. But also diet and nutrition is getting the nutritional environment right [00:32:00] now hopefully most of us have a good diet and that's fine.

We don't need to go off and spend thousands of dollars on supplements because we're getting a good diet. But some of us aren't. And that's why if you're planning a pregnancy, thinking about that and just making sure you're getting a good balanced diet. You're getting your vitamins, primarily the most important ones, probably folic acid, vitamin D.

And the essential fats, fatty acids like 6. Now, as it happens, those are well known important contributors to the Mediterranean diet, and that's why we often hear the Mediterranean diet is great. for babies and great for mothers if they're trying to conceive. And there's good evidence from studies including randomized controlled trials that we've been part of that that is the case.

 But I think you can overdo it , if you ask me, I don't think, sometimes I have women who come to see me and think, , can I sort of Have any fun for the next three months, maybe a glass of wine or, occasional bag of French fries or whatever. And , [00:33:00] it's about getting balance and moderation and, , I don't think we all need to turn into, to self denying miserable people because that's probably not a good way to get pregnant either to be honest.

So, you've got to get the balance right. 

 Yeah, I hope it would have given Dr. Barker a feeling of triumph to know that his work has created this actionable thing in the world where you can affect, or potentially affect the, , uterine environment you create.

 That's super cool. So this is my last question for you , what do you hope fertility care will look like in the future? 

Yeah, great question. There are different Ways to approach that question, isn't there? The first one is that it's accessible to many, many more people because we have great fertility care, but very few people can actually access it.

So let's assume that's been dealt, and that people can access it. And, there are many people working on that either by generate producing programs, which are less expensive or using, a lot of hope in [00:34:00] AI and automation, , to bring down the cost of I think that is where we're going to see, , the major change.

You know, the biology is not going to change. What, and I think we're already pretty good, , IVF results are often seen as being disappointing when people look at them. But when you think what we've been discussing earlier in life, , , the relatively low fertility of humans as a species, IVF does pretty well.

Really, to get the outcomes that we do. I don't think we're going to see any huge breakthroughs that suddenly turn your IVF chance from 40 percent to 80 percent in one cycle, unless we can really change how embryos develop or change how change egg quality. And that may happen in the future, but we're somewhere off that at the moment.

So I think in the future that I hope that the main change will be that we will see more automation, which will have two effects. It will become safer because there's [00:35:00] less room for human error. And when mistakes happen in IVF, it's, it's not good for anyone. The stakes are very high, of course. So we'll see fewer of those, and it will be much easier for people to access.

And that I think is going to be the main change we see over the next 15 years. I don't think we're suddenly going to. sole fertility for all unless we can start taking stem cells and creating perfect eggs from them. But that's a long way off. So yeah, that would be my take on it. 

, well, 

that's a great goal. And it is, here in the U S it's exceedingly expensive, so it would be nice to have it, , more generally available. , thanks so much for coming on and talking to us today. 

Okay. Really great. Really enjoyed it. And, thanks for inviting 

me. 

Thanks so much to Dr. Macklin for sharing some of his amazing work. We covered a lot of topics, so here are some takeaways. Based only on the information you might get from social media, [00:36:00] It looks easy to get pregnant. It looks like unprotected sex essentially equals pregnancy. But it's useful, when we think about pregnancy, to have the right frame of reference.

To know that this is not the case. Things have to be quote unquote, just so. A rating that's meted out in part. in the chemical conversation between embryo and endometrium. At least to get to the positive pregnancy test. And, knowing about this chemical checkpoint may explain either why you might experience repeated miscarriage if the endometrium is not selective enough, or if you continue to fail to get pregnant, which might be because the endometrium is too selective.

 It's also useful to know that you have some agency here. Pay attention to healthy habits, exercise, avoid smoking, eating well, which, based on all the papers I saw about diet and fertility, seem to be tilted toward the Mediterranean diet. Do all these things to give your system the best chance of getting and maintaining a [00:37:00] pregnancy.

Thanks for listening. If you like the show, please share it with friends. We'll be back next week with more amazing research about your body and pregnancy.