#210 – Pregnancy & metabolic health: Hormone changes & gestational diabetes | Azure Grant & Ben Grynol

How does pregnancy affect your metabolic health at each trimester, from conception to postpartum lactation? Levels Research Design Lead Azure Grant talks with Ben Grynol about the different phases of pregnancy and how it affects hormones and things you can do to reduce the risk of gestational diabetes.

Azure Grant (00:00:06):

That diabetes is underdiagnosed or not managed within pregnancy, the newborn baby can become hypoglycemic. So I would say that for the mom, you’re looking at increased risk of having diabetes again, you’re looking at birth complications and postpartum complications. You’re looking at increased risk of her actually developing diabetes outside the context of gestation. And then for the baby, you’re looking at setting them up with a pretty big disadvantage. So not only are they at risk during those more complicated deliveries, if they’re really big, not only are they at metabolic risk if they’re going hypo when they’re really young, but they’re more likely to have metabolic problems down the line and become metabolically dysfunctional adults themselves.

Ben Grynol (00:00:58):

I’m Ben Grynol, part of the early startup team here at Levels. We’re building tech that helps people to understand their metabolic health. And along the way, we have conversations with thought leaders about research backed information so you can take your health into your own hands. This is a whole new level.

(00:01:27):

When women are thinking about family planning, there are all of these different things that happen over the course of a pregnancy. There’s pre-planning if you are interested in fertility and thinking about that stage of life, then there’s the idea of being pregnant and there’s postpartum. Well, what happens to the body as it relates to metabolic health? We all know the answer colloquially is a lot. There’s a lot going on hormonally, but how does that impact metabolic health? What does that mean for the gestation of the baby?

(00:01:59):

Well, naturally, women become more insulin resistant when they’re pregnant, and that’s why we hear about all of these different things like gestational diabetes and some of the other things that come with pregnancy, hypertension and other health considerations. And so Azure Grant, part of our product team and a deep researcher in the space of women’s health, specifically in fertility, she and I sat down and discussed this idea of pregnancy as it relates to metabolic health. How can women through all the different phases of fertility, think about the different stages?

(00:02:30):

What are some of the considerations up to pregnancy when women are in the phase of pre-planning, how can they think about optimizing some of their biomarkers leading into pregnancy? What are things that they should consider and how does this impact the health of their pregnancy and the entire term? What happens during pregnancy and what are some of the considerations postpartum? Anyway, no need to wait. Here’s a conversation with Azure.

(00:02:58):

Okay, so we’re going to dive into this topic around pregnancy as it relates to metabolic health or metabolic health as it relates to pregnancy. They’re very much a bidirectional relationship and lots of considerations around it. But let’s go through three buckets. So the first is family planning, pre-pregnancy, then there’s pregnancy and then there’s postpartum. And there are so many things that change with the body and change as it relates to metabolic health that it’d be interesting to talk through what some of those insights and ideas are, things that you’ve come across through your research or things that we’ve learned through our data set with Levels.

(00:03:38):

And then just talk through what happens with the changes women go through with their bodies at all these different stages of becoming a parent. So let’s start off with family planning. So I think this is something that people are becoming more and more aware of, that pregnancy doesn’t just start when all of a sudden you are pregnant. There’s so much that goes into creating a solid foundation for having good health or good metabolic health, which increase your chances of getting pregnant and increases your chances of having a healthy pregnancy. And this is something that exists for both men and women, which we are learning much more about with sperm quality, with egg quality, with all of these things that come into consideration. So let’s start, what can people do to prepare as they think about family planning from a health and wellness perspective?

Azure Grant (00:04:32):

All right, that’s a big old question. The part of it that we think about most of the time in our daily work is preparing from a metabolic health perspective. So getting weight into a healthy range and similar but a little bit different, getting blood glucose into a healthy range. So I think right now something around approaching three quarters of people in the US are overweight or obese, and that means that that is the first big bucket that you can approach to try to get yourself ready to start a family.

Ben Grynol (00:05:08):

And so what happens for both women and men from a metabolic state perspective? So leading into when you’re thinking about family planning, what happens when people have insulin resistance or have oscillating metabolic health and maybe aren’t aware of it? What are some of the things that people should consider or why is it important for them to take their metabolic health into consideration as they think about family planning?

Azure Grant (00:05:35):

So when there’s too much excess weight or when insulin resistance gets severe, particularly in women, it can contribute to polycystic ovarian syndrome or PCOS, which is one of the leading causes of female infertility right now, and we’ve talked about this before on the podcast, but insulin resistance can directly contribute to increases in testosterone in women leading to ovulatory dysfunction.

(00:06:05):

So one of the key ways to address that is to start with working on the insulin resistance and then hopefully get to the point where you can have a healthy ovulatory cycle. So it’s natural to have some fluctuations in insulin sensitivity across the course of a female ovulatory cycle and after ovulation to have a little bit more insulin resistance than before ovulation. But once you get on a track where you have too much excess, then you can prevent ovulation altogether. And that leads to these decreases in fertility that we see in people with PCOS.

Ben Grynol (00:06:44):

And right now when we talk about pregnancy and fertility, how many women are facing challenges in their pregnancies leading into them as far as miscarriages go and as far as having healthy pregnancies?

Azure Grant (00:07:00):

So it’s a difficult question in part. So we’re dealing with two issues that contribute to, in particular, female difficulties in getting pregnant and staying pregnant. And one is that overweight and obesity, it is so common and does decrease fertility rate. Another one is simply that people are having kids at an older age now and that both negatively impacts sperm quality, thinking paternal age over 40. And then for women, geriatric pregnancy is considered anything over 35.

(00:07:36):

So this is part of a multi-decade trend, but ever since around the ’80s, the rate of pregnancies in the latter half of the 30s has been going up and up and up and along with that increased risk of metabolic problems and increased risk of pregnancy complications generally. So as far as how many people does this impact, I don’t actually know the combined rate of pregnancy complications across all those different factors, but I think of usually age and metabolic function as interacting to negatively impact pregnancy outcomes.

Ben Grynol (00:08:18):

And we know that different biomarkers do contribute to the health of a pregnancy, health of things like sperm quality, things like cortisol make a big impact, things like glucose, things like insulin. As soon as we take all these biomarkers into account, you start to realize the importance of creating this foundation and building it up as you’re thinking through family planning.

(00:08:42):

It’s not like snap your fingers, flip the switch, and all of a sudden it’s easy to get pregnant or to have a healthy pregnancy. If somebody isn’t getting high sleep quality, as one factor, or getting enough exercise or eating well, all of these factors contribute to having biomarkers that might be out of fluctuation from where you would want to have a steady state as far as a benchmark goes. So it’s one of those things where it’s almost like if you are in a state where you are wanting to start a family or maybe you’ve already got a family, you want to have another child.

(00:09:16):

The idea of setting that foundation and working at it, you almost have to train to get to have a healthy pregnancy for men and women. You almost have to set this foundation and say, what do I need to do as far as making certain lifestyle choices to maximize the probability of having a healthy pregnancy? And these are things where from a hormonal standpoint, why don’t we get into what happens in women’s bodies as they’re going through right before getting pregnant? What happens with things like estrogen, luteinizing hormone, progesterone, and then as that relates to glucose and insulin levels?

Azure Grant (00:09:51):

Sure. So there’s a part of the ovulatory cycle, it’s called the fertile window that has to do with when a group of follicles have developed, one follicle has been selected as kind of the winter egg, and then there’s a brief amount of time. It’s thought to be maybe a week at the outside, but maybe a little bit shorter, so people kind of think five to seven days wherein you have an egg that is about ready to be released or ovulated from the ovary, and that egg can stay alive for a couple days after it’s released and potentially be fertilized or it will just degrade. So if a person is having healthy regular ovulations, they have an opportunity to get pregnant for maybe about a week each cycle, and if they are lucky enough to get a fertilized egg and start a family, then you get a large rise in progesterone, even larger than the typical post ovulatory rise in progesterone.

(00:10:53):

It’s where the hormone gets its name. And that contributes to very early rises in body temperature, in heart rate, very early decreases in heart rate variability that it seems like even from very early on in the pregnancy as little as a few days to a week in create a unique signal that says the body is gearing up to grow and to allow that fertilized egg to implant. And at the same time, we have one thing that we know and then one thing that we’re kind of guessing and that we should absolutely be studying. So it’s already known that the most common pattern for blood glucose after ovulation is for it to rise. So normally blood glucose would fall a little bit across the follicular phase or the pre ovulatory time of cycle and then rise after due to a little bit of increased insulin resistance.

(00:11:46):

And it may be the case that if an egg was actually fertilized, that that signal would actually be a little stronger and you might get even a bit of a larger relative increase in glucose and insulin resistance. But that’s just a hypothesis and something that I think would be awesome for us to test. And the reason that this isn’t known about yet, most of the time you’ll look online and if you look at trends for blood glucose or insulin across pregnancy, they’ll probably start with data around eight weeks into a pregnancy.

(00:12:16):

And this is part of a general challenge where people often don’t know that they’re pregnant until quite a ways into the pregnancy. And so there’s a big scientific gap in what all of these patterns look like very early on and how to best support a healthy pregnancy from the very beginning. But the guess would be that accompanying those changes in the autonomic cardiovascular system that happen to kind of an extreme degree after ovulation when you have a fertilized egg, that you might get a more extreme version of the metabolic changes that would accompany that part of the cycle too if a pregnancy is starting.

Ben Grynol (00:12:51):

And so in that first trimester, what happens from the first trimester to the third with all the different biomarkers, but specifically, why don’t we start with glucose because it’s so interesting how everything changes and oscillates so much as you go through each trimester and then even into postpartum? All of the biomarkers are continuously in this… I think you’ve said it before, it’s almost like this musical orchestra, this orchestration of all of these things dancing together in some in unison, some have an inverse correlation as far as one can be up and the other can be down.

(00:13:28):

But why don’t we talk through how things change through each trimester and why it’s important that women are aware of what these changes are and what they can do about it to make sure that the markers aren’t getting to levels that are outside of the window or outside of the threshold that you want them to be in to be having a healthy pregnancy.

Azure Grant (00:13:50):

Okay, let’s do it. And we’re going to say a lot of times about how we need to get more information to know about what the healthy ranges and patterns should be like at all. But I guess to step back a little bit, so pretty much every system in the body has to adapt in response to pregnancy. So we talked a little bit just now about at the very, very beginning of a pregnancy or even just in the latter part of a cycle, you’re seeing changes in not just hormones, but also in autonomic metrics, cardiovascular metrics, heart rate, heart rate variability and thermal regulation. So body temperature. So you’re seeing changes across the body and when a pregnancy really gets going, so in the first trimester, those changes continue and they get to be a little bit more extreme. So I’m going to describe the end state that she’ll get to at the end of pregnancy and then kind of tell you how you get there.

(00:14:45):

So by the end of the pregnancy, one of the most amazing things is the mom is going to have about 50% more blood in her body. So you’re not just growing the baby, you’re growing your blood supply, you’re growing your placenta, and the concentrations of many key hormones of the body are going to be near lifetime high levels. So it’s not just the normal kind of fluctuation that you would get in an ovulatory cycle. It’s a really big growth in the concentration of several hormones. So those include cortisol, your stress hormone, and if you’ve ever seen a stress spike in your continuous glucose levels, you probably know that cort tends to drive up blood glucose. So you can keep that in the back of your head as one of the contributing factors to higher blood glucose during pregnancy. You get lifetime high levels of estrogen and progesterone.

(00:15:36):

So remember also that estrogen, progesterone combo is something that in a natural, normal ovulatory cycle would be maybe contributing in part to higher blood glucose. So that pattern would continue. And you also get high levels of things like oxytocin, placental lactogen, that we’ll talk a little bit more, and those all together create these changes in blood glucose and insulin. And we’ll talk a lot about elevated insulin and pregnancy and when that happens, and together those combined to contribute to those changes that raise heart rate, raise core body temperature, and even in combination raise skin temperature as well.

(00:16:15):

So that’s the end state. And if you look at what’s known so far about how you get from that beginning state to the end state, a lot of the summary information will kind of show you a relatively straight line in a lot of these hormones from the beginning of the pregnancy going all the way to the end, and then a steep drop-off after delivery. But there’s probably a lot more to that picture. And I think the changes that happen specifically in insulin and glucose can provide a nice example of how much more complex those changes are and that it’s not really just a straight line of everything gets really high across the pregnancy.

Ben Grynol (00:16:55):

And how does insulin resistance change over the course of a pregnancy? We know being pregnant is this naturally insulin resistant state, but I guess a couple questions. What are some of the considerations? What are some of the things that women should be thinking about is a question, but also this comment that I always revert back to thinking about Pam. So Pam, my wife, we’ve got four kids, and so she has been through many pregnancies and one of which she wore a CGM for, and saw very different results.

(00:17:27):

Also thinking through how some of the food was impacting her metabolic state because of insulin resistance. But there’s this misconception, I think that’s eat whatever you want and it’s good. You got to feed the baby. And so people think if they’re either feeling some sense of morning sickness or they’ve eaten all these things late, let’s say the typical eating the whole tub of ice cream late at night or getting up in the morning and feeling hungry, and you eat that bagel, it’s like no matter what you do, you’re going to put yourself into a state where you’re going through these heavy oscillations for glucose spikes and then how much insulin’s being released.

(00:18:04):

So all of these things happen, which can contribute to you feeling even more sick. So it’s this dichotomy between knowing that your body is changing, knowing that you do have to eat differently, but what are some of the things to think about,, if there’s women that are going through pregnancy now or thinking about it in the future or have gone through it, what are some of the considerations around this idea of dynamic insulin resistance and how it changes?

Azure Grant (00:18:32):

You said this well, that you absolutely have higher energetic needs, and we’ll talk about those, but the jump in culturally what we think about of you have higher energetic needs, therefore you should be eating as much as possible, or you have a free for all to eat lots of foods that were not evolutionarily available all the time. So very sugary foods. That’s not a good connection to make, but the energetic increase in need for food and the way that your body is trying to build mass and be able to feed the baby, that’s very real. So first, insulin resistance. This thing about pregnancy being a naturally insulin resistant state, that doesn’t mean it’s a bad state. These changes in insulin sensitivity are dynamically coordinated across the pregnancy for the purposes of putting on mass and then being able to provide a stable, abundant, energetic environment for the baby.

(00:19:29):

So insulin resistance is when the cells and muscles, fat and liver aren’t responding as well to insulin, they don’t as easily take up glucose from the blood. We said that it’s a naturally insulin resistant state in pregnancy, but that is actually a progression. So by the end of pregnancy, you’re about half as insulin sensitive as at the beginning, and this is all about growth. So insulin helps the placenta grow, it helps breast tissue grow in preparation for lactation, helps make sure that the mom has enough energy for the very demanding processes by increasing her body’s inclination to store fat. So how does this happen early in pregnancy? Early in pregnancy, you increase the number of insulin receptors in fat tissue, the maternal fat tissue grows, grows more readily, and fat stores increase to a peak towards the end of that second trimester. So this is called adipocyte hyperplasia or increased adipose tissue lipogenesis.

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So you’re making more fat, but you then get an interesting switch. So the metabolism switches to a catabolic state around midgestation. So that means you’re increasing adipose tissue, fatty acid turnover, you’re increasing lipolysis. So that’s the point where you start creating more insulin resistance. So we talked a little bit ago about one of the hormones that increases across pregnancy is called HPL or human placental lactogen, which really starts picking up around 20 weeks. And it’s a physiologic, meaning opposite of pathologic, so it’s a natural antagonist to insulin, kind of similar to cortisol, and it contributes to naturally increasing insulin resistance around that time by affecting the insulin receptor. So what happens is when you get this increase in this hormone, HPL, and you start driving up more insulin resistance, you increase the rate of lipolysis.

(00:21:31):

So to back up a little bit, normally insulin would be a storage hormone, so you wouldn’t be wanting to break down your fat if you were trying to store as much as possible. So by driving the switch to insulin resistance in the fat at this point, you actually turn off the listening to the signal that would say, hey, store, store, store. And you start going to lipolysis and breaking down that fat so that you’re using some of that maternal fat stores that accumulated in early pregnancy. And you’re also, by means of that more general insulin resistance, reducing your glucose uptake into maternal tissues, and those things kind of put together all help you make sure that you have maximum nutrients available to the developing baby. So it sounds like a bad thing and it’s a bad thing when it gets out of control or when it’s out of balance, but it is this process that’s supposed to happen. So we could also talk a little bit about blood glucose if you want, or what’s kind of the thought to be the normal amount of how much this is supposed to change.

Ben Grynol (00:22:37):

Yeah, the thing I’m curious about is this idea of fat utilization. So insulin resistance, to break down to a foundational level, it sounds like insulin resistance is kind of a good thing during pregnancy to a degree because it’s helping your body biologically change to adapt to the state that you’re in. You’re trying to grow a baby inside of you, but is this why fat utilization goes up by 200% throughout the state of being pregnant is because your body’s adapting to everything that’s going on?

Azure Grant (00:23:13):

Exactly. If you think of it as a unilateral thing and you’re like, well, it’s fat utilization going up or down, you’re actually getting both processes happening. First you’re in a state where you’re trying to accumulate and store, and then later after around 20 weeks, and we’ll see another interesting change happens around that time, but later you’re switching then to start utilizing and yeah, exactly as you say, you’re upping that utilization of fat by around 200% by the end.

Ben Grynol (00:23:45):

And so then what is it at 20 weeks, we know that there’s a glucose dip that happens after conception around 20 weeks, but then it starts to increase again as mothers reach full term. What’s happening there?

Azure Grant (00:24:03):

Yeah, let’s break that down and kind of visualize it for whoever is listening. So what happens to glucose during pregnancy if you’re not pregnant, you might have noticed this little pattern of your glucose changing by your phase of ovulatory cycle, but hopefully those changes aren’t too big, just maybe five to 10 milligrams per deciliter max. What is it during pregnancy?

(00:24:25):

So you mentioned this dip. So early in pregnancy, and a lot of these charts start out about eight weeks for that reason that I mentioned about it’s kind of hard to study people that are pregnant very early in pregnancy if they don’t know that they’re pregnant, hard to recruit all of this. And so a lot of the numbers for early pregnancy glucose levels start around about eight weeks, but generally around that time they’re a bit high and then they kind of decrease down to this bottom of a saddle around 20ish weeks and then rise for the rest of the pregnancy.

(00:25:01):

So this kind of makes sense if we think about insulin sensitivity being higher in that trimester where you’re trying to build and build and store and store, you want to be sensitive and allow your tissues to respond to insulin to increase those fat stores. So glucose is actually in range overall trending down during that time. And then when you get that switch to wanting to be insulin resistant in part to allow more nutrient availability for the baby and utilize fat stores, you get higher levels of blood glucose that climb for the rest of pregnancy.

(00:25:34):

So there are a couple things that I think are really interesting about that. One is that a lot of the reports of glucose during pregnancy show you these very sparse markers. So you kind of see maybe a week by week picture at its most dense. You don’t see the continuous picture, but you do see some interesting things show up in the numbers that would indicate that there’s something really interesting going on in the continuous glucose signal during that pregnancy.

(00:26:01):

And I’d be curious if you remember Pam seeing something like this, but hyperglycemic time. So the time that blood sugar is high goes from just over an hour per day to an average of five or six hours per day by a month before term. So that’s a really big difference, and it’s a pretty big difference when you look at the average change across the pregnancy being only 10 to 15 milligrams. So that whole saddle that we’re talking about or this U-shape isn’t super tall on average, but the amount of hyperglycemic time being so high. And then on top of that, the individual standard deviation or variability of that hyperglycemic time almost triples. So even though in a lot of these older studies we’re not seeing that full picture, we could make a guess that it seems like glucose is not only going up, but it’s also getting a lot more variable.

(00:26:52):

And I have kind of a little story about that from some animal studies that I could describe to you about how this changes. But my guess would be that if we were looking at continuous glucose all the way across pregnancy, we’d probably be seeing a lot more spikes in the latter part of pregnancy, probably some taller amplitude daily rhythms. And the usual guess is that once we could see that information continuously, we might be able to then detect earlier signs of anomalies by looking at the shape of that change over time. That could maybe do something like help someone be diagnosed early for risk or actual development of something like gestational diabetes.

Ben Grynol (00:27:31):

That is interesting. So let’s use an example. So someone has a lunch, they have this lunch every day, they go to small cafe and they have the quinoa and sweet potato bowl. They’re not pregnant and maybe they’re hyperglycemic for an hour, roughly an hour is what you’re saying. And when they’re pregnant, they might see that hyperglycemia for a period of four or five hours.

(00:28:04):

Even if the spike isn’t huge, but it’s just like a long rolling hill and it takes them longer to come back down, is that what leads to some of these things like lethargy where people are saying, oh my gosh, I feel so tired and I know there’s lots going on biologically [inaudible 00:28:18] in the body, but is that one of those things that is within women’s control to think through what they are eating and how it might impact the way they physically feel like when they’re talking about, oh my gosh, I’m really tired, or these things are happening because there’s so much happening and you want to make sure that people have the insight and the toolkit at their disposal, at their fingertips to understand what choices they’re making and how it might make them feel throughout the pregnancy?

Azure Grant (00:28:46):

Yeah, it’s a hard question because I think the immediate inclination is to say, why don’t we just apply the advice that we give to the general person where we say we want to help you avoid those big spikes. We particularly want to help you avoid those really long spikes, and those seem to make people feel tired, and so you should manage those completely. I want to be careful saying that about pregnancy because I think although if someone’s going and having a giant quinoa with lots of sweet potato, and definitely if they’re eating processed food or something with a lot of added sugar, there’s no reason to be doing that. That’s a very safe one to cut out. But that fatigue that is experienced, yes, it’s probably going to be in part because of the spike, but fatigue is also very common and normal. And I don’t think it would be good to put all the responsibility on the person saying, if you control your spikes, you’re going to not feel that fatigue because we don’t know that yet.

(00:29:41):

And because it’s a naturally insulin resistant state, there’s probably going to be a relative increase in the number and the duration of things like glucose spikes alongside fatigue no matter what you do. And things like the more extreme carb restriction or keto diets, those do not seem to be super safe for pregnancy. So I think it’s a balancing act. If someone’s eating a meal that’s processed or sugary and they don’t feel good afterwards during pregnancy, it’s great to know that you are going to be extra responsive to that, and that that is something that is probably worth restricting more during this extra sensitive state.

(00:30:18):

But also that if you’re generally eating very healthy foods and focusing on mixed macros, it’s okay or at least normal, and we have a lot more that we need to learn about what amount of those spikes you can tolerate and what number and duration of those kind of spikes are optimal for creating a healthy baby. The question that you’re asking is exactly why I think this is so important to study in a continuous manner, not just one CGM every six or eight weeks or so, but if possible, a CGM across an entire series of really healthy pregnancies I think could do a lot to define what can the body tolerate that leads to a healthy baby and help us see that difference between what’s normal or what’s common, which includes a lot of pathology and what’s healthy, even if healthy sometimes feels uncomfortable.

Ben Grynol (00:31:13):

Yeah, n-of-1 in the sense that Pam only wore a CGM once during, it was the last pregnancy, which was 2021. I hope I’m getting that right. But there was a noticeable difference. So all pregnancies are different. The three prior ones were from each other in their own way, shape, and form as far as the way she felt. And I think irrationally we’re all going to say, oh, well, we eat the same things because we are creatures of habit being human beings, so we tend to consume similar things, but there’s so many other factors and environmental factors and sleep and exercise and all these things are planned.

(00:31:52):

So we’ll leave that out. But anecdotally, when she had that feedback loop of seeing what was happening to her glucose levels based on exercise, based on sleep, based on what she was eating and seeing how she could stabilize her glucose to the though that she wasn’t seeing drastic peaks and valleys, peaks and valleys over and over again, anecdotally she felt better that her pregnancy was healthy, it was great.

(00:32:20):

But it was one of those things where I think being able to have that closed feedback loop where it’s like, oh, this is what’s happening to me based on what I am eating and being able to make those choices, I think in probably a more thoughtful way, instead of throwing a dart and saying, I hope I feel great, because as you mentioned, somebody might eat a spinach salad and they put dressing on it that is full of added sugar that they aren’t aware of, and then that is causing them to feel a certain way.

(00:32:46):

So just being able to see that insight for herself and say, hey, this is what I am in control of right now. It was helpful for her, and she didn’t have any morning sickness, which she had with the previous three. So whether that’s related to understanding the choices she’s making, whether it’s point in time, we’ll never know, but again, anecdotal and it did make a difference for her. So I think it was eye-opening to see, especially because she had worn a CGM prior to being pregnant. So she sort of already had a baseline and yeah, really interesting.

Azure Grant (00:33:18):

That’s really cool. So do you recall if she noticed compared to her non-pregnant self her spikes were a lot bigger or at least felt a lot more volatile?

Ben Grynol (00:33:33):

Different variability. So let’s say she wouldn’t have a ton of variability. Previously she would see those longer spikes. They weren’t super high all the time. It’s hard too because it wasn’t, oh my gosh, we’re in this utopian state where it’s like she would have pizza or something, we were eating things that humans eat, it doesn’t mean you’re eating this stuff all the time, but you’re going to get a glucose spike. So she would see that.

(00:33:58):

And I’m trying to think back of things that certain foods that would make larger impacts, but again, we’re all so different in what makes an impact for us. So I think potatoes or something, she can generally handle potatoes a lot better than I can. And I think she was seeing longer durations of her spikes from things like potatoes where it’s like, oh, that’s interesting that when I’m not pregnant, my body metabolizes these foods differently than when I am pregnant. So just even seeing that data was an interesting insight I think for both of us to go like, wow, things really do change drastically.

Azure Grant (00:34:36):

That’s pretty amazing. I think even if it is just an n equals one, that’s a very powerful n equals one. And I think it’s quite likely that spike management as a strategy during pregnancy could be really helpful. I think it’s also worth thinking about, I don’t know if you have your mom or your grandma or if you’ve heard pregnancy stories from older generations, but clinical practice surrounding things like weight gain during pregnancy have changed immensely. Women who are having babies, say in the ’60s, they were actually put on diets during pregnancy to minimize weight gains.

(00:35:12):

So if you think about a woman who’s maybe something very small, maybe around 5’5″, she might be only allowed to gain something like 15 pounds during pregnancy, and nowadays the recommendation would be something like double that. So I think it’s also worth knowing that that volatility in part indicates just how adaptable the body is, and these changes are happening to allow a person to give birth to a healthy baby under very different nutritional conditions and very different nutrient availability.

(00:35:47):

Part of why you build up these fat stores early in pregnancy and then focus on using them up through the rest of it is in case you don’t have enough food around. So I think we’ve seen in the last, call it 60 years the full range of how do you adapt to a pregnancy when there’s not a lot of food around, and then what happens to a pregnancy when there’s way too much food around? So it’s really interesting.

(00:36:16):

I think it would be amazing to see more curves like Pam’s. I’m looking at an example right now where you can find more of data of glucose during pregnancy or glucose during say the development of diabetes. And I’m looking at an old [inaudible 00:36:32] paper that looked at continuous glucose and body temperature while they induce the development of diabetes. And when you look at not just those single time points, but when you look at the whole curve, you see some really cool things happen along the way, which is not just that glucose is going up, but that the shape of glucose is getting elongated.

(00:36:51):

So the spikes are getting bigger, the daily amplitude is getting bigger. And there’s even an interesting relationship where as glucose goes up, temperature goes down. So you talked at the beginning about this thing that I like to say sometimes, and a lot of people like to say about the rhythms of our hormones and metabolites and nervous system acting like an orchestra playing together.

(00:37:14):

And I think that there’s a lot of that information to be found within the context of developing diabetes and watching a pregnancy progress as well. And this is just one example where I think if you had slapped a temperature sensor on Pam, you might have seen that as her spikes got bigger, as her maybe daily range of blood glucose got higher, you might have watched her temperature going down as well and kind of tracking at the same time, but in an opposite direction. So yeah, I think that frequency of measurement should be the next thing that is focused on in the field, and there are actually already some really cool grants that are going on to focus on that.

Ben Grynol (00:37:57):

Very cool. Well, let’s hop into, you brought up weight gain and this misconception around it, which is wild because it happens even outside of pregnancy. Just in the world in general, we see a certain body shape or type and we make an assumption this is just our irrational minds and these heuristics that we have where we’ll say, oh, that’s a healthy person, which is totally ridiculous because somebody could be highly insulin resistant and they could be tall and skinny and very insulin resistant. But what happens with gestational diabetes as far as what are things that women should be aware of, we talk about weight gain, and that might not be tied into this idea of insulin resistance in developing gestational diabetes, but let’s go into how it happens and then why it is of concern as far as downstream implications, things like macrosomia and get into the whole suite of it.

Azure Grant (00:38:54):

Yeah, let’s do it. So let’s talk first about gestational diabetes. And I want to say that over excess weight and obesity are absolutely related to this. And I think when we think about the fact that a young thin person, we like to talk about Jerry Schulman’s work a lot, a young, thin person can be insulin resistant, but it is kind of just a matter of time.

(00:39:16):

For a lot of people, if insulin resistance is developing, even if you can stave off that weight gain, or even if you can let’s say compartmentalize that change to specific fat accumulation in viscera around the middle, that is absolutely something that is unhealthy and going to contribute to diabetes risk. And so let’s talk about gestational diabetes just with that as a starter. There’s a lot of pretty wonderful work going on with gestational diabetes that incorporates CGM right now.

(00:39:46):

Some of them are actually pretty close by, think of Teresa Hilly over at Kaiser. They actually put out a really good review on this recently. But basically gestational diabetes results from changes to glucose metabolism, those changes that start in the second half of pregnancy that we already talked about. So that’s when insulin resistance is increasing to accommodate the fetus.

(00:40:09):

And normally in a healthy pregnancy, something that would accompany that change is that the pancreas would pump out more insulin to compensate for the insulin resistance and to help regulate glucose levels. So we talked about how you’re seeing in Pam, larger glucose swings, her insulin swings were also probably going crazy some of that time to help keep her glucose as regulated as it was. But in gestational diabetes, if you have insufficient pancreatic function to overcome the increased insulin resistance, then your blood sugar can get really high and you can start developing other problems.

(00:40:45):

So they actually think now that gestational diabetes might be a mix of different phenotypes. So you could have insulin resistant gestational diabetes, insulin deficient gestational diabetes, or both, where you’re both really insulin resistance and you’re not pumping out enough insulin to overcome it. So what happens and what are the risks here? Those short-term complications of things like overweight and obesity do contribute to greater risk for gestational diabetes and hypertension.

(00:41:17):

They often go together, and getting gestational diabetes once makes you much more likely to get it again later. So the recurrence risks are thought to be as high as like 80 plus percent for if you’ve had it once you can get it again. And for the kid, this is not only affecting the mom, but this is likely to make the kid bigger. So you talked about macrosomia, so that’s babies who are large for gestational age.

(00:41:44):

This totally makes sense. If the baby’s growing up in a extremely nutrient rich environment, it could be big enough that it’s actually going to have trouble getting out. So this makes the birth itself more likely to be complicated. So that obviously impacts the mom too, can make her recovery longer, can make it more difficult to breastfeed. Stillbirth is still a problem in the diabetic population in the 21st century.

(00:42:10):

Placental abnormalities are more common. I believe, let’s see, for stillbirth, it’s in the 20s out of a thousand risk if you have gestational diabetes and infant hypoglycemia is also a thing that comes up and almost you can think of it as a withdrawal. So if diabetes is underdiagnosed or not managed within pregnancy, the newborn baby can become hypoglycemic. So in the diabetic pregnancy, the placental to fetal glucose transfer would increase even more than it normally does in a healthy pregnancy.

(00:42:49):

And so the baby would be exposed to really high levels of glucose. And then once it gets out into the normal world, they have an absence of that overly high signal. It’s not something that breast milk is recapitulating. It’s not like you have sweet enough breast milk to overcome or to match what that in uterine environment was. And the baby can become very hypo.

(00:43:14):

Long-term for that kid, it looks like increased risk for metabolic dysfunction. And this has even been studied to the extent of looking at adolescents overweight and obesity rates. So I guess altogether, I would say that for the mom, you’re looking at increased risk of having diabetes again, you’re looking at birth complications and postpartum complications. You’re looking at increased risk of her actually developing diabetes outside the context of gestation. So I think about half of those women are going to go on to develop type two within five years of their pregnancy.

(00:43:48):

And then for the baby, you’re looking at setting them up with a pretty big disadvantage. So not only are they at risk during those more complicated deliveries, if they’re really big, not only are they at metabolic risk if they’re going hypo when they’re really young, but they’re more likely to have metabolic problems down the line and become metabolically dysfunctional adults themselves. So it’s metabolic health impacting the cycle of life, and a very important thing where early intervention and early detection could make a huge difference, not just for the mom, but for the health of subsequent generations.

Ben Grynol (00:44:23):

That statistic around 50% of women who develop gestational diabetes have a higher chance of developing type two postpartum is mind-boggling. Not immediately postpartum, but a few years down the road. It is mind-boggling. That number is astronomically high.

Azure Grant (00:44:41):

Yeah, it’s pretty crazy. And you think about the environment that the kid grows up in, that it’s not just their metabolic predisposition to diabetes, but it’s the parental and the familial environment. And if you have parents or a mom who’s at higher risk of diabetes and is kind of on this downward slope of metabolic health, behaviorally, that’s going to make it a lot more harder to create a healthy environment for that kid to grow up in. So yeah, it’s really hard and I think it’s quite sad.

Ben Grynol (00:45:17):

And so if a baby has a higher chance of having hypoglycemic episodes, is that why immediately out of the womb they’re doing tests to check blood sugar to see what is happening? I can’t remember the period, it might be every 12 hours, there is some interval that the baby gets tested regularly when in the hospital to see what the glucose levels are. What’s happening there? What are they looking for?

Azure Grant (00:45:46):

Yeah, I think that’s what they’re looking for is to make sure that baby doesn’t go hypoglycemic. It’s part of helping the baby stay warm, making sure their energetic needs are taken care of. And especially since after that baby is delivered, it’s in this window where you want to get that baby on having skin to skin contact with mom and breastfeeding quite soon. And it’s, I think, also part of this risk mitigation cycle where if you’ve had a child that was born in a complicated delivery or the mom was under anesthesia or even things like took Pitocin, all of these interventions can interfere with the immediate process of bonding with the baby and then going on to be able to feed the baby adequately.

Ben Grynol (00:46:35):

And so why don’t we go into postpartum what is happening across a number of biomarkers? There’s a visual that you reference often where everything is everything. I’m using this loosely, but a number of biomarkers are oscillating, but in general, hormones are going up and up and up and up and up, and all of a sudden the baby’s born and there’s like a cliff. It is literally like a cliff drop off where all the hormones that we’re going up over the course of three trimesters are now at a completely different baseline.

(00:47:08):

And there’s one marker, which is oxytocin, which we still see a lot of oscillation, these peaks and valleys. So why don’t we go through what is happening there and then how does that tie into the way women are feeling? All of the things that have to do with mood and getting back to a state where they’ve got their baseline when they’re not pregnant because the body has to go through a state of repair.

Azure Grant (00:47:30):

Yeah. And I guess also for anyone who wants to go look it up, there’s a cool paper called Neurophysiological and Cognitive Changes in Pregnancy by Dave Grattan and Sharon Ladyman that shows this nice graphical image of the [inaudible 00:47:46] changes of hormones over pregnancy. But as you said, yeah, you get up to these lifetime high levels, you get a steep drop off with delivery, and then with oxytocin and prolactin, you get these nice oscillations that accompany breastfeeding episodes. So those hormones get nice and high and they go up and down regularly. And as you know, it’s very common to have these oscillations happen every hour or two and then get a little bit slower as you get further away from the delivery itself. So that’s another really interesting question that actually a lot of our members log about is the relationship between breastfeeding episodes and glucose.

(00:48:29):

And I think that would be a really cool one to come back to once we take a look at the data. But we have many, many instances of moms recording their breastfeeding episodes. And it seems like, at least from published evidence so far, that there’s a little bit of a mixed bag about how closely coordinated you could see a change in glucose in with a change in oxytocin and prolactin. But I think it’s a really cool question. So alongside that, in the postpartum period, you have suppression of ovulation actually specifically by the act of maintaining breastfeeding. So you’re not having those regular oscillations of estrogen and progesterone. It’s generally a much lower hormone state. And glucose should start to come down pretty rapidly after this. But I think it’s a pretty open field in a lot of ways to say, what is the variability of women’s glucose coming back down after pregnancy?

(00:49:28):

How does that relate to how well they’re able to breastfeed? How does that relate to appetite or symptoms like postpartum depression? And I think there is a need for a continuous picture of glucose across healthy and diabetic pregnancies, there’s also a big need to do the same thing postpartum. And I think that fourth trimester is often forgotten or left to be studied till later. But yeah, I think there’s a lot of open questions there because we should be able to say a lot more than glucose goes down and it doesn’t fluctuate with an ovulatory cycle for a while because there isn’t one, and then eventually it will come back to normal.

Ben Grynol (00:50:07):

Why is it that we need more studies of pregnancy as it relates to what’s happening across all these different biomarkers? There are some studies that go on as far as observational studies, but when we talk about getting deeper into the population to get larger data sets and see what’s happening across multiple populations, as far as ethnicity goes, geography goes, we know there are lots of factors that can impact pregnancy, but why would it be beneficial to have some of these studies?

Azure Grant (00:50:41):

I think it has to do with both behavioral impacts on the people who are in the studies and then who would be using the tools down the line. And I think it also has to do with the research that generates the features for what is pathological and what is healthy. So if we think about the kind of advice that we give to people who use levels, no matter who they’re right now, there’s a lot that we don’t know. We’re looking at a signal that has not been interpreted in all of the different contexts and large numbers of people and study to this extent. And so we’re kind of trying to learn and advise in a general way as we go, and it’s really difficult. So if you imagine applying that same strategy to pregnancy, you can say, we know that gestational diabetes is a huge problem, that overweight and obesity is way more than the majority of people now, and that this problem is probably only going to get worse.

(00:51:37):

Yet, the current way that we test for this is we look at your risk factors. Are you already overweight? Are you Asian, Hispanic or Middle Eastern? Are you older? And then we say, all right, come back and do an oral glucose tolerance test, and we could talk a little bit about what those are as well. But come back and do this one or maybe two time test that’s super unpleasant to do, and we’ll put you in a risk category and then we’ll give you a diagnosis or not, and then offer you some general lifestyle advice or some medication options. And that’s a very core screen approach to dealing with this problem. And you can imagine if instead when someone became pregnant, they put on a CGM and they could, for instance, watch that saddle shape of glucose, they could watch week over week as their spikes change.

(00:52:30):

If you could compare that to a normal range of trajectories, not just for what maybe should the level be or what should the oral glucose tolerance test response kind of be at one time point, but you could say, hey, actually I noticed five, six weeks earlier you’re having some anomalous glucose excursions or it seems like once you hit that 20 week point, your insulin’s resistance is actually growing a lot faster than a normal individuals, and you’re having a lot more larger spikes than we would expect someone to see that could offer an opportunity for earlier behavioral intervention. Maybe even you could by means of helping the person stay aware and keep that closed feedback loop with what their glucose is doing across the first and second trimesters, you might even be able to preempt some of that development of insulin resistance that’s out of range.

(00:53:21):

So it’s a combination of giving people the data and helping them understand the general principles so that they can hopefully guide their actions better. And then at the same time, collecting and annotating that data and studying it for patterns across people that will allow you to know what’s healthy, what’s happening on average that may or may not be healthy, and then where is the dividing line to pathological that could then allow you for the next set of people who wear CGM when they’re pregnant to have even more specific advice and allow you to have hopefully earlier markers of dysfunction. And as I said, there are definitely some grants happening right now and some studies to try to work on this. So that group that I mentioned from Kaiser, [inaudible 00:54:12] to, let’s see who else, Denise Shulton, these groups are studying glucose patterns during pregnancy and the studies take a long time. So that’s something where it’s super important. It’s kind of going on right now, but we’re definitely not studying it to the extent that I think we ought to.

Ben Grynol (00:54:30):

Is there anything that you know of as it relates to different ethnicities and rates of gestational diabetes or differences in pregnancy outcomes, instances of having healthy pregnancies? Is there any research that you’ve come across that… It’s hard because correlation does not equal causation, and does it have to do with geography? Does it have to do with ethnicity? We can parse this into so many different things that need to be studied. And it sounds like the research is at such a foundational level, especially as it relates to things like CGM and being able to have objective data. And as you mentioned, the studies take a long time. You can’t snap your fingers and go fast study. There is a certain amount of time that is needed to get that data and to follow pre and post as far as pregnancies go. So is there anything you’ve come across as it relates to different ethnicities and outcomes for pregnancy or some of the research that’s been done?

Azure Grant (00:55:32):

Yeah, if we keep it on GDM, Asian, Hispanic and Middle Eastern moms are at greater risk of insulin resistance generally, and so that ups their risk for gestational diabetes. I think we’ve also talked about relative likelihood of having PCOS in Middle Eastern and Indian populations. The risk of that insulin resistance driving ovulatory dysfunction is thought to be higher. And the reasons for those differences, what genes are involved, how much it has to do with food availability, socioeconomic status, cultural eating practices. Yeah, it’s super complicated and difficult, but there are definitely ethnic backgrounds that put you at greater risk for this particular kind of dysfunction in pregnancy.

(00:56:25):

And then as far as pregnancy outcomes overall go, that could be a whole nother series of episodes on all the reasons for disparities in pregnancy outcome. There’s actually a really interesting initiative going on right now, I think it’s still going on, it might have finished up, but at UCSF called the Preterm Birth Initiative that I think specifically focuses on African American women in the Bay Area and tries to figure out why they’re at an increased risk for preterm birth. So different story there, but tons of complex contributing factors. And insulin resistance specifically is something that seems to vary by ethnic background as well as cultural food intake and SES and all those things.

Ben Grynol (00:57:12):

It’s fascinating. There is so much stuff to dig into it. It is very cool. It’s just one of those things where you want to absorb it all because there’s so many different paths and avenues that you can go down to study some of these things that we haven’t had as much insight about historically. So excited for the future ahead with a lot of this research. But why don’t we bring it home with some takeaways? So if women are either pregnant now or they’re wanting to start a family, or maybe they’re in a postpartum term, what are some takeaways that they can think through as far as maintaining good/adapted metabolic health?

Azure Grant (00:57:52):

I like that term, adapted metabolic health. So I think the first thing would be that if you’re in the stage of family planning, that metabolic health should be very important for you. And whether you know that you have weight to lose or not, like you’re talking about, insulin resistance can kind of be a sneaky thing. So checking continuous glucose is one thing that you can do in the pre-pregnancy planning stage to get an idea of where you’re at, maybe if you’re more likely to be going very high with your insulin resistance when you are later on your pregnancy, and to increase the chances that you can get pregnant in the beginning.

(00:58:34):

So during the pregnancy itself, I think being aware that you’re likely to start that pregnancy with relatively higher blood sugar to see a decrease for a while, and then to see an inflection around that 20 week mark, that can probably help you conceptually understand what you’re feeling, what you’re craving, maybe incentivize you to check out your blood sugar, if not with a CGM, with some finger pricks during that latter part of pregnancy and see if your fatigue, like Pam’s was, is associated with your spikes and glucose crashes.

(00:59:09):

And then I think as far as bringing that information to your clinician, we didn’t talk too much about oral glucose tolerance today, but I think if someone is able to be very proactive and keep good track of their glucose on their own, that could help them interact with their doctor about assessing risk for gestational diabetes. And then in the postpartum period, I think that is definitely one to one to learn. I think women are usually at least somewhat aware that everything’s going to do a little hormonal crash after delivery and then take a while to get back to normal.

(00:59:45):

But that’s the transition to the point where you’re literally trying to feed your baby and create healthy breast milk. So I think general awareness of those patterns is a main takeaway that I would give people here. But there’s one other category of takeaway, which I would say that we mentioned a handful of different studies that are going on right now and that are going to take a while to conduct that are about continuous glucose in pregnancy. But there’s, I think, an opportunity, not just for Levels, but for any company that is retailing CGMs to people, and almost like a responsibility to say, hey, we’re already collecting this data that is taking millions of dollars of federal funding to collect in much smaller and less frequent numbers by these academic institutions.

(01:00:34):

And therefore we kind of have a responsibility to the health world and to our users to spread awareness about these issues, to find a way to share that data and learn from it as quickly as possible. So not just in the general health and wellness case, like we’ve been doing, but in these really important use cases as well. So maybe that would be a final take home is if someone is pregnant and using a CGM through Levels, know that if you want that data to be used for research or if you’re opting into that study, that’s something that can, will, should be used to advance that field.

Ben Grynol (01:01:17):

Very, very cool. Lots of stuff to learn, lots of things to think about. And yeah, I appreciate you taking the time to inform all of us because you’ve done so much research in the space and it is ongoing. So always fun to learn from you and hear all of these anecdotes that you’ve got.

Azure Grant (01:01:33):

We’re just brand new at this. Thanks for wanting to talk about it and share in some of your dad stories. So [inaudible 01:01:39] as informative as any of this stuff.