Pregnancy and metabolic health: Hormone changes and gestational diabetes

Metabolic health researcher Azure Grant, PhD, talks about the connections between metabolic health and a healthy pregnancy


Article highlights

  • Good metabolic health before pregnancy, by losing excess weight and controlling insulin resistance, improves fertility and reduces complications like gestational diabetes.
  • Insulin resistance naturally increases during pregnancy to support growth, reaching a peak in the third trimester when the body relies more on fat stores.
  • Continuous glucose monitoring could enable early diagnosis of gestational diabetes by tracking abnormal glucose patterns that emerge weeks before current testing.
  • Gestational diabetes puts mothers at high risk for developing Type 2 diabetes and babies at risk for complications like hypoglycemia and obesity later in life.
  • More diverse research studying continuous biomarker data across ethnicities and geographies is needed to understand healthy pregnancy patterns and improve outcomes.

Metabolic Health as the Foundation for a Healthy Pregnancy

Ben Grynol: Let’s start off with family planning. People are becoming more aware that pregnancy doesn’t just start when you are pregnant. There’s so much that goes into creating a solid foundation for having good health, and good metabolic health, which increases your chances of getting pregnant and of having a healthy pregnancy.

This is something that exists for both men and women. We are learning much more about sperm quality, egg quality—all these things come into consideration. What can people do,  from a health and wellness perspective, to prepare for family planning?

Azure Grant: That’s a big old question. Most of the time, in our daily work, we think about preparing from a metabolic health perspective: getting weight into a healthy range, getting blood glucose into a healthy range. We’re approaching a statistic of around three quarters of people in the US who are overweight or obese, and that means that is the first big bucket you can approach to try to get yourself ready to start a family.

Ben Grynol: What happens for both women and men, from a metabolic perspective? Why is it important for people to take their metabolic health into consideration as they think about family planning?

Azure Grant: When there’s 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. Insulin resistance can directly contribute to increases in testosterone in women, leading to ovulatory dysfunction.

One of the key ways to address that is to work on the insulin resistance. Then hopefully you’ll get to the point where you can have a healthy ovulatory cycle. It’s natural to have some fluctuation in insulin sensitivity across the course of a female ovulatory cycle. And it’s normal to have a little bit more insulin resistance after ovulation than before ovulation. But once you have too much excess weight, you can prevent ovulation altogether. And that leads to these decreases in fertility that we see in people with PCOS.

Ben Grynol: How many women today are facing challenges in their pregnancies?

Azure Grant: It’s a difficult question. We’re dealing with two issues that contribute to, in particular, female difficulties in getting pregnant and staying pregnant. One is that being overweight or obese are so common and decrease fertility rate.

Another one is simply that people are now having kids at an older age. That negatively impacts sperm quality, with a paternal age over 40. For women, anything over 35 is considered geriatric pregnancy.

This is part of a multi-decade trend. Ever since the ’80s, the rate of pregnancies in the latter half of the 30s has been going up, and with that an increased risk of metabolic problems and an increased risk of pregnancy complications.

I don’t actually know the combined rate of pregnancy complications across all those different factors, but usually age and metabolic function interact to negatively impact pregnancy outcomes.

How the Body Changes Before, During, and After Pregnancy

Ben Grynol: Different biomarkers—cortisol, glucose, insulin—contribute to the health of a pregnancy, as well as things like sperm quality. As soon as we take all these biomarkers into account, you start to realize the importance of creating this foundation and building it up.

It’s not, snap your fingers, flip the switch, and all of a sudden it’s easy to get pregnant or have a healthy pregnancy. Good-quality sleep, exercise, eating well—all of these factors contribute to healthy biomarker levels.

You almost have to train to have a healthy pregnancy. You almost have to set this foundation and say, “What lifestyle choices do I need to make to maximize the probability of having a healthy pregnancy?”

What happens in women’s bodies right before getting pregnant?

Azure Grant: There’s a part of the ovulatory cycle called the fertile window. When a group of follicles has developed, one follicle has been selected as the winter egg. Then there’s a brief amount of time—maybe a week, maybe a little bit shorter—where you have an egg that is about ready to be released or ovulated from the ovary. That egg can stay alive for a couple days after it’s released and potentially be fertilized, or it will just degrade.

If a person is having healthy regular ovulations, they have an opportunity to get pregnant for about a week each cycle. If they are lucky enough to get a fertilized egg and start a family, then they get a large rise in progesterone, even larger than the typical post-ovulatory rise in progesterone. It’s where the hormone gets its name.

That contributes to very early rises in body temperature and heart rate, and to very early decreases in heart rate variability. Even from early on in the pregnancy—as little as a few days to a week—a unique signal says the body is gearing up to grow and allow that fertilized egg to implant.

At the same time, we have one thing we know and one thing we’re kind of guessing about, which we should absolutely be studying. It’s already known that the most common pattern for blood glucose after ovulation is for it to rise.

Normally, blood glucose would fall a little bit across the follicular phase or the preovulatory time of the cycle and then rise afterward due to a bit of increased insulin resistance. And it may be the case that if an egg was actually fertilized, that signal would actually be a little stronger, and you might even get a bit of a larger relative increase in glucose and insulin resistance. But that’s just a hypothesis, and something I think would be awesome for us to test.

If you look at trends for blood glucose or insulin across pregnancy, they’ll probably start with data around eight weeks into a pregnancy. This is part of a general challenge where people often don’t know they’re pregnant until quite a ways into the pregnancy. 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, if a pregnancy is starting, you might get a more extreme version of the metabolic changes that would accompany that part of the cycle. This accompanies those changes in the autonomic cardiovascular system that happen to an extreme degree after ovulation when you have a fertilized egg.

Ben Grynol: It’s interesting how everything changes and oscillates so much as you go through each trimester, and then even into postpartum. You’ve said before how it’s almost like a musical orchestra, all these things dancing together.

How do things change during each trimester and why is it important for women to be aware of what these changes are and what they can do about them to make sure their biomarkers aren’t getting to levels that are outside of the window you want them in?

Azure Grant: Let’s do it. We’re going to say a lot of times how we need to get more information to know about what the healthy ranges and patterns should look like at all.

Pretty much every system in the body has to adapt to a pregnancy. We talked a little bit about how, at the very beginning of a pregnancy, or even in the latter part of a cycle, you’re seeing changes not just in hormones, but also in autonomic metrics, cardiovascular metrics, heart rate, heart rate variability, and thermal regulation. You’re seeing changes across the body. When a pregnancy really gets going—in the first trimester—those changes continue and become a little bit more extreme.

By the end of the pregnancy, the mom is going to have about 50% more blood in her body, which is amazing. You’re not just growing the baby, you’re growing your blood supply, you’re growing your placenta. The concentrations of many key hormones of the body are going to be near lifetime high levels. It’s not just the normal kind of fluctuation you would get in an ovulatory cycle. It’s a really big growth in the concentration of several hormones.

Those include cortisol, your stress hormone. If you’ve used a continuous glucose monitor, you probably know that cortisol tends to drive up blood glucose. You can keep that in the back of your head as one of the contributing factors to higher blood glucose during pregnancy.

You also get lifetime high levels of estrogen and progesterone. The estrogen-progesterone combo is something that in a natural, normal ovulatory cycle would maybe be contributing to higher blood glucose. That pattern would continue.

And you also get high levels of things like oxytocin and placental lactogen. All those hormonal changes create these changes in blood glucose and insulin. These in turn combine to contribute to the changes that raise heart rate, core body temperature, and even skin temperature. That’s the end state.

A lot of the summary information out there will show you a relatively straight line in many of these hormones from the beginning of the pregnancy all the way to the end, and then a steep drop-off after delivery. But there’s probably a lot more to that picture. 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 suggesting everything gets really high across the pregnancy.

The Relationship Between Pregnancy, Insulin Resistance, and Glucose Response

Ben Grynol: Being pregnant is a naturally insulin-resistant state. There’s this misconception that you can eat whatever you want: You’ve got to feed the baby. It’s like no matter what you do, you’re going to put yourself into a state where you’re going through these big oscillations of glucose spikes, which then affects how much insulin is released.

All of these things happen, which can contribute to someone feeling even sicker. There’s this dichotomy between knowing your body is changing and knowing you have to eat differently.

What are some of the considerations around this idea of dynamic insulin resistance and how it changes?

Azure Grant: You absolutely have higher energetic needs. And we’ll talk about those. But, culturally, we think that because you have higher energetic needs, you should be eating as much as possible, or you have a free rein to eat lots of foods that were not evolutionarily available all the time—very sugary foods. That’s not a good connection to make. But the increase in the need for food and the way your body is trying to build mass and feed the baby—that’s very real.

First: insulin resistance. Just because pregnancy is a naturally insulin-resistant state 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.

Insulin resistance is when the cells, muscles, fat, and the liver aren’t responding as well to insulin; they don’t as easily take up glucose from the blood. We said pregnancy is a naturally insulin-resistant state, but it’s actually a progression. By the end of pregnancy, you’re about half as insulin sensitive as you were at the beginning.

This is all about growth. Insulin helps the placenta grow. It helps breast tissue grow in preparation for lactation. It helps make sure that the mom has enough energy for the very demanding processes by increasing her body’s inclination to store fat. 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 and grows more readily, and fat stores reach a peak toward the end of that second trimester. This is called adipocyte hyperplasia, or increased adipose tissue lipogenesis.

You’re making more fat, but you then get an interesting switch. The metabolism switches to a catabolic state around midgestation. That means you’re increasing adipose tissue and fatty acid turnover; you’re increasing lipolysis. That’s the point where you start creating more insulin resistance.

One of the hormones that increases across pregnancy is called HPL, or human placental lactogen, which really starts picking up around 20 weeks. It’s physiologic, meaning it’s the opposite of pathologic. 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. When you get this increase in HPL, and you start driving up insulin resistance, you increase the rate of lipolysis.

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. 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.”

You start going to lipolysis and breaking down that fat. You’re using some of those maternal fat stores that accumulated in early pregnancy. You’re also, by means of that more general insulin resistance, reducing your glucose uptake into maternal tissues.

Those things together all help make sure that you have the maximum nutrients available to the developing baby. 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 this process is supposed to happen.

Ben Grynol: I’m curious about this idea of fat utilization. It sounds like insulin resistance is kind of a good thing during pregnancy, because it’s helping your body biologically adapt to the state you’re in. You’re trying to grow a baby inside of you.

Is this why fat utilization goes when you’re pregnant? Is it because your body’s adapting to everything going on?

Azure Grant: Exactly. If you think of it as a unilateral thing—fat utilization going up or down—you’re actually getting both processes. 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 around that time—you’re upping that utilization of fat by around 200% by the end.

Ben Grynol: Glucose dips after conception around 20 weeks, but then starts to increase again as mothers reach full term. What’s happening there?

Azure Grant: Let’s break that down. If you’re not pregnant, you might have noticed how your glucose changes by your phase of ovulatory cycle, but hopefully those changes aren’t too big, maybe five to 10 milligrams per deciliter max.

What is it during pregnancy? You mentioned this dip. A lot of these charts start at about eight weeks. I mentioned how it’s kind of hard to study people who are pregnant very early in pregnancy if they don’t know they’re pregnant. A lot of the numbers for early pregnancy glucose levels start around eight weeks. But generally, around that time, they’re a bit high. Then they kind of decrease to the bottom of a saddle at around 20ish weeks. Then they rise for the rest of the pregnancy.

This 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. Overall, glucose is actually trending down during that time.

Then, when you switch to wanting to be insulin resistant, in part to allow more nutrient availability for the baby and to utilize fat stores, you get higher levels of blood glucose that climb for the rest of pregnancy.

There are a couple things that are really interesting about that. One is that a lot of the reports of glucose during pregnancy show you these very sparse markers. You see maybe a week-by-week picture; you don’t see the continuous picture. But you do see some interesting things show up in the numbers that would indicate there’s something really interesting going on in the continuous glucose signal during pregnancy.

The time blood sugar is high goes from just over an hour per day to an average of five or six hours per day during the month before term. That’s a really big difference, especially since the average change across the pregnancy is only 10 to 15 milligrams. This U-shape isn’t super tall on average, but the amount of hyperglycemic time is high. On top of that, the individual standard deviation or variability of that hyperglycemic time almost triples. In a lot of these older studies, we’re not seeing that full picture, but we could make a guess that it seems like glucose is not only going up, but it’s also getting a lot more variable.

My guess would be that if we were looking at continuous glucose all the way across pregnancy, we’d be seeing a lot more spikes in the latter part of pregnancy, probably some taller amplitude daily rhythms. 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 do something to help someone be diagnosed early for risk of something like gestational diabetes.

Ben Grynol: That is interesting. Let’s use an example: Someone has lunch. They have this lunch every day. They go to the small café and they have the quinoa and sweet potato bowl. They’re not pregnant, and maybe they’re hyperglycemic for an hour. When they’re pregnant, they might see that hyperglycemia for a period of four or five hours. The spike might not be huge, but it’s a long rolling hill, and it takes them longer to come back down.

Is that what leads to some of these symptoms like lethargy? Is it within a woman’s control if she thinks through what she’s eating and how it might impact the way she physically feels? There’s so much happening, and you want to make sure people have the right insight and toolkits at their disposal to understand what choices they’re making and how it might make them feel throughout the pregnancy.

Azure Grant: It’s a hard question because 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 them avoid those big spikes? We particularly want to help people avoid those really long spikes, and those seem to make people feel tired, and so they should manage those completely.

I want to be careful saying that about pregnancy. There’s no reason someone should be eating a giant quinoa bowl with lots of sweet potato, and definitely no reason to eat processed food or something with a lot of added sugar. That’s a very safe one to cut out. But that fatigue is probably going to be in part because of the spike, but fatigue is also very common and normal. It would not be good to put all the responsibility on the person saying, “If you control your spikes, you’re not going to feel that fatigue,” because we don’t know that yet.

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 extreme carb restriction or keto diets do not seem to be super safe for pregnancy. It’s a balancing act.

If someone’s eating a meal that’s processed or sugary and they don’t feel well afterwards during pregnancy, it’s great to know you are going to be extra responsive to that, and that it’s probably worth restricting more during this extra sensitive state.

But also, if you’re generally eating very healthy foods and focusing on mixed macros, it’s okay, or at least normal. We have a lot more to learn about what amount of those spikes you can tolerate and what number and duration of those kinds of spikes are optimal for creating a healthy baby.

The question you’re asking is exactly why it is so important to study using 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. That could do a lot to define what the body can tolerate to lead to a healthy baby. It can help us see the difference between what’s normal or common, which includes a lot of pathology, and what’s healthy, even if healthy sometimes feels uncomfortable.

Ben Grynol: Pam only wore a CGM during the last pregnancy. But there was a noticeable difference. All pregnancies are different. The three prior ones differed from each other in their own way, shape, and form, as far as the way she felt.

When she could see what was happening to her glucose levels based on exercise, sleep, and what she was eating, and see how she could stabilize her glucose though that, she wasn’t seeing drastic peaks and valleys over and over again. She felt better that her pregnancy was healthy. It was great.

Being able to have that insight for herself and say, “This is what I am in control of right now” was helpful for her. She didn’t have any morning sickness, which she had with the previous three. Whether that’s related to understanding the choices she’s making, or whether it was a point in time, we’ll never know. But it did make a difference for her. It was eye-opening, especially because she had worn a CGM prior to being pregnant. She sort of already had a baseline.

Azure Grant: That’s really cool. Did she notice if her spikes were a lot bigger or more volatile compared to her non-pregnant self?

Ben Grynol: Different variability. Previously, she would see those longer spikes. They weren’t super high all the time. We were eating things humans eat, like pizza. It doesn’t mean we were eating this stuff all the time, but when we did, she would see a glucose spike.

We’re all so different in what impacts our blood glucose. Pam can generally handle potatoes a lot better than I can. She was seeing longer durations of her spikes from things like potatoes. It was interesting to see that and be able to think, “When I’m not pregnant, my body metabolizes these foods differently than when I am pregnant.” Even just seeing that data was an interesting insight for both of us. Things really do change drastically.

Azure Grant: That’s pretty amazing. Even if it is just an n-equals-one, that’s a very powerful n-equals-one. It’s likely that spike management as a strategy during pregnancy could be really helpful. The clinical practice surrounding things like weight gain during pregnancy have changed immensely. Women who were having babies in the ’60s, say, were actually put on diets during pregnancy to minimize weight gain.

If you think about a woman who’s very small, maybe around 5’5″, she might only be allowed to gain something like 15 pounds during pregnancy. Nowadays the recommendation would be something like double that.

That volatility in part indicates just how adaptable the body is; 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. 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.

In the last 60 years or so, we’ve seen the full range of how 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. It’s really interesting.

It would be amazing to see more curves like Pam’s. I’m looking at an example right now where you can find more data about glucose during pregnancy, or glucose during the development of diabetes. I’m looking at an old paper that looked at continuous glucose and body temperature as the researchers induced the development of diabetes. When you look at not just those single time points, but 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 the glucose spike is getting elongated. The spikes are getting bigger; the daily amplitude is getting bigger.

There’s even an interesting relationship where, as glucose goes up, temperature goes down. You talked at the beginning about this thing that I like to say, and a lot of people like to say, about the rhythms of our hormones and metabolites and nervous system acting like an orchestra.

There’s a lot of that information to be found within the context of developing diabetes and watching a pregnancy progress as well. If you had slapped a temperature sensor on Pam, as her spikes got bigger and as her daily range of blood glucose got higher, you might have watched her temperature go down.

Frequency of measurement should be the next thing studied by the field, and there are already some really cool grants that are going to focus on that.

Levels Member Experience:

The Short- and Long-Term Effects of Gestational Diabetes

Ben Grynol: You brought up weight gain and this misconception around it, which is wild, because it happens even outside of pregnancy. In the world in general, we see a certain body shape or type and we make an assumption—this is just our irrational minds talking—where we’ll say, “That’s a healthy person,” which is totally ridiculous because somebody could be tall and skinny and very insulin resistant.

But what happens with gestational diabetes? What are things women should be aware of?

Azure Grant: Let’s talk first about gestational diabetes. Excess weight and obesity are absolutely related to this. We like to talk about Gerry Schulman‘s work a lot. A young thin person can be insulin resistant, but it is kind of just a matter of time.

For a lot of people, if insulin resistance is developing, even if you can stave off that weight gain, or even if you can compartmentalize that change to specific fat accumulation in the viscera around the middle, that is absolutely something that is unhealthy and going to contribute to diabetes risk.

There’s a lot of wonderful work going on with gestational diabetes that incorporates CGM right now. Teresa Hillier over at Kaiser recently put out a really good review on this. Basically, gestational diabetes results from changes to glucose metabolism, those changes that start in the second half of pregnancy we talked about. That’s when insulin resistance is increasing to accommodate the fetus.

Normally, in a healthy pregnancy, to accommodate that change, the pancreas would pump out more insulin to compensate for the insulin resistance and to help regulate glucose levels. We talked about how Pam saw 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, your blood sugar can get really high and you can start developing other problems.

They now think gestational diabetes might be a mix of different phenotypes. You could have insulin-resistant gestational diabetes, insulin-deficient gestational diabetes, or both, where you’re both really insulin resistant and you’re not pumping out enough insulin to overcome it.

What happens and what are the risks here? Those short-term complications of things like being overweight or obese do contribute to greater risk for gestational diabetes and hypertension. They often go together, and getting gestational diabetes once makes you much more likely to get it again later. The recurrence risk is thought to be as high as 80-plus percent. This is not only affecting the mom, but is likely to make the kid bigger. Macrosomia is when babies are large for their gestational age.

If the baby’s growing up in an extremely nutrient-rich environment, it could be big enough that it’s actually going to have trouble getting out. This makes the birth itself more likely to be complicated. That obviously impacts the mom, too: it can make her recovery longer, and make it more difficult to breastfeed.

Stillbirth is still a problem in the diabetic population in the 21st century. Placental abnormalities are more common. The risk of stillbirth is about five times greater if you have gestational diabetes.

Infant hypoglycemia also comes up. You can think of it as a withdrawal. If diabetes is underdiagnosed or not managed within pregnancy, the newborn baby can become hypoglycemic. In the diabetic pregnancy, the placental-to-fetal glucose transfer would increase even more than it normally would in a healthy pregnancy. The baby would be exposed to really high levels of glucose. Once it gets out into the 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 match what that uterine environment was.

For the mom, you’re looking at birth complications, postpartum complications, and increased risk of having diabetes again. You’re looking at increased risk of her actually developing diabetes outside the context of gestation. About half of those women are going to go on to develop Type 2 diabetes within five years of their pregnancy.

For the baby, you’re setting them up with a pretty big disadvantage. They are at risk during those more complicated deliveries, and if they’re really big, they are at metabolic risk if they’re hypoglycemic when they’re really young. They’re also more likely to have metabolic problems down the line and become metabolically dysfunctional adults themselves.

Metabolic health impacts the cycle of life. It’s a very important thing, and early intervention and early detection could make a huge difference, not just for the mom, but for the health of subsequent generations.

Ben Grynol: That statistic that 50% of women who develop gestational diabetes developing Type 2 down the road is mind-boggling. That number is astronomically high.

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

Ben Grynol: 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’s happening? There is some interval—maybe every 12 hours—where the baby gets tested in the hospital to see what the glucose levels are. What are they looking for?

Azure Grant: They want to make sure the baby doesn’t go hypoglycemic. It’s part of helping the baby stay warm, making sure their energetic needs are taken care of. After that baby is delivered, it’s in this window where you want the baby to get skin-to-skin contact with mom,  and to get breastfed quite soon.

It’s also part of this risk-mitigation cycle, where if you’ve had a child born in a complicated delivery, or the mom was under anesthesia, or even if she took things like Pitocin, all of these interventions can interfere with the immediate process of bonding with the baby and then, later on, with being able to feed the baby adequately.

Postpartum Hormone Levels and the Need for More Data

Ben Grynol: What is happening with biomarkers postpartum? Many biomarkers are oscillating, but in general, hormones are going up and up, and all of a sudden the baby’s born and there’s a cliff. All the hormones that were going up over the course of three trimesters are now at a completely different baseline. And there’s one marker, oxytocin, for which we still see a lot of oscillation.

What is happening there, and how does that tie into the way women are feeling?

Azure Grant: 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 hormone changes during pregnancy.

As you said, you get up to these lifetime-high levels. You get a steep drop off with delivery. With oxytocin and prolactin, you get these nice oscillations that accompany breastfeeding episodes. Those hormones get nice and high, and they go up and down regularly. It’s very common to have these oscillations happen every hour or two, and then to get a little bit slower as you get further away from the delivery itself.

A lot of our members, actually, are curious about the relationship between breastfeeding episodes and glucose, and have been logging these episodes. That relationship 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.

It seems like, at least from published evidence so far, there’s a little bit of a mixed bag about how closely coordinated a change in glucose is with a change in oxytocin and prolactin. But it’s a really cool question.

Alongside that, in the postpartum period, you have suppression of ovulation specifically by the act of maintaining breastfeeding. 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 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? How does that relate to how well they’re able to breastfeed? How does that relate to appetite or symptoms like postpartum depression?”

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. The fourth trimester is often forgotten about or left to be studied until later. There are a lot of open questions there, because we should be able to say a lot more about glucose patterns during this period.

Ben Grynol: When we talk about getting larger data sets and seeing what’s happening across multiple populations—thinking about ethnicity, geography, and many other factors that can impact pregnancy—why would it be beneficial to have some of these studies? Why do  we need more studies of pregnancy as it relates to what’s happening across all these different biomarkers?

Azure Grant: It has to do with both the behavioral impacts on the people who are in the studies and then who would be using the tools down the line. It also has to do with the research that generates the features for what is pathological and what is healthy.

If we think about the kind of advice we give to people who use Levels, 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 or in large numbers of people or that has not been studied to this extent. We’re kind of trying to learn and advise in a general way as we go, and it’s really difficult.

You can imagine applying that same strategy to pregnancy. We know gestational diabetes is a huge problem. We know overweight and obesity are present in way more than the majority of people now, and that this problem is probably only going to get worse. The current way we test for this is by looking at your risk factors: Are you already overweight? Are you Asian, Hispanic, or Middle Eastern? Are you older?

Then we prescribe an oral glucose tolerance test, which is super unpleasant to do, and we put you in a risk category and give you a diagnosis or not. Then we offer you some general lifestyle advice or some medication options. That’s a very core screen approach to dealing with this problem.

Imagine if, instead, when someone became pregnant, they put on a CGM and could watch that saddle shape of glucose. They could watch week over week as their spikes change. If you could compare that to a normal range of trajectories—not just for what the level should be or what the oral glucose tolerance test response should be at one time point—you could say, “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 resistance is growing a lot more quickly than a normal individual’s, and you’re having an increased number of larger spikes than we would expect.” That could offer an opportunity for earlier behavioral intervention. By 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.

It’s a combination of giving people the data and helping them understand the general principles so they can hopefully better guide their actions. At the same time, it’s collecting and annotating that data and studying it for patterns across people. This will allow you to know what’s healthy, what’s happening on average that may or may not be healthy, and where the dividing line is to pathological. Then, for the next set of people who wear CGM when they’re pregnant, you’ll be able to give even more specific advice and have earlier markers of dysfunction.

As I said, there are some grants happening right now and some studies trying to work on this: that group from Kaiser, Denise Scholtens. These groups are studying glucose patterns during pregnancy, and the studies take a long time. It’s super important. It’s going on right now, but we’re definitely not studying it to the extent I think we ought to.

Socioeconomic Factors, Key Takeaways, and CGM as a Powerful Learning Tool

Ben Grynol: Do different ethnicities affect rates of gestational diabetes or produce differences in pregnancy outcomes? Does it have to do with geography?

Azure Grant: Asian, Hispanic, and Middle Eastern moms are at greater risk of insulin resistance generally. That ups their risk for gestational diabetes. We’ve also talked about the 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.

The reasons for those differences—what genes are involved, food availability, socioeconomic status, cultural eating practices—are complicated and difficult, but there are definitely ethnic backgrounds that put you at greater risk for this particular kind of dysfunction in pregnancy.

As far as pregnancy outcomes overall go, and all the reasons for disparities in pregnancy outcomes—that could be a whole other series. There’s actually a really interesting initiative going on right now at UCSF called the Preterm Birth Initiative. It focuses on African American women in the Bay Area and tries to figure out why they’re at an increased risk for preterm birth. Different story there, but tons of complex contributing factors. Insulin resistance, specifically, is something that seems to vary by ethnic background, as well as by cultural food intake and socioeconomic status and all those things.

Ben Grynol: It’s fascinating. There is so much stuff to dig into. It’s one of those things where you want to absorb it all, because there are so many different paths you can go down to study some of these things that historically we haven’t had as much insight about. Excited for the future ahead with a lot of this research.

If women are pregnant now or wanting to start a family, or maybe they’re postpartum, what are some takeaways they can think through as far as maintaining good or adapted metabolic health?

Azure Grant: I like that term, “adapted metabolic health.” If you’re in the stage of family planning, metabolic health should be very important to you. Whether you have weight to lose or not, insulin resistance can be a sneaky thing. Checking continuous glucose is one thing you can do in the pre-pregnancy planning stage to get an idea of where you’re at, and maybe if you’re more likely to have high insulin resistance later on in your pregnancy. CGM can also help increase the chances of getting pregnant.

During the pregnancy itself, being aware that you’re likely to start your pregnancy with higher blood sugar, to see a decrease for a while, and then to see an inflection around that 20-week mark can probably help you understand what you’re feeling, what you’re craving, and maybe incentivize you to check out your blood sugar during that latter part of pregnancy. You can see if your fatigue, like Pam’s was, is associated with your spikes and glucose crashes.

We didn’t talk too much about oral glucose tolerance today, but 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.

In the postpartum period, that is definitely one we want to learn about. Women are usually at least somewhat aware that there’s going to be a little hormonal crash after delivery and that it will take a while to get back to normal. But that’s the transition to the point where you’re trying to feed your baby and create healthy breast milk.

General awareness of those patterns is a main takeaway I would give people. But there’s one other category of takeaway. We mentioned a handful of different studies going on right now about continuous glucose in pregnancy, which are going to take a while to conduct. But there’s an opportunity—not just for Levels, but for any company retailing CGMs to people—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.”

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—not just in the general health and wellness space, like we’ve been doing, but in these really important use cases as well. 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 the field.

Ben Grynol: Very, very cool. Lots of stuff to learn, lots of things to think about. 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. Always fun to learn from you and hear all of these anecdotes.

Azure Grant: We’re just brand new at this. Thanks for wanting to talk about it, and for sharing some of your dad stories. It’s as informative as any of this stuff.