Hello, everyone, and welcome to today's session on updates in diabetes and pregnancy. My name is Leslie Alderi, and I'm going to be serving as the moderator for this session. It's my pleasure to introduce today's speaker, Dr. Linda Barber. Dr. Barber is a 10-year professor in endocrinology, metabolism, and diabetes, and maternal fetal medicine with a Master's of Science in Public Health at the University of Colorado School of Medicine. She's a director of the OB Diabetes Clinic at University Hospital. Dr. Barber was recently awarded the Norbert Frankel Award by the ADA for her lifelong teaching clinical and research contributions to the advancement of care of pregnant women with diabetes and metabolic disease. She serves on the editorial board for diabetes care. She's a past chair of the ADA Scientific Planning Committee for Pregnancy, a past president for the North American Society of Obstetric Medicine, and has served on the NIH research panel on gestational diabetes. She's been named among the best doctors in America for over 25 years, has authored around 100 manuscripts, chapters, or textbooks, and her clinical translational research has been funded by several NIH and ADA grants. She served as a research mentor for over 30 junior investigators in the study of the intrauterine environment and fetal programming of childhood obesity and metabolic disease. We're very excited to hear her talk today. I know it's going to be a great lecture and welcome Dr. Barber. Greetings, everyone. I can't wait for the time that we can actually have eye-to-eye contact rather than looking at a laptop camera. But until then, it's wonderful to have you here digitally. I want to thank the organizers and ACE for this invitation. My charge has been to try and give you some highlights of the most important clinical pearls, I think, in the management of type 1 and type 2 diabetes in pregnancy. Since this is an endocrinology audience, we'll really focus on pre-existing diabetes rather than gestational diabetes. Since you'll see a lot more with type 1 and type 2, but I'll certainly refer to GDM and take questions at the end if you have any on that. Let's get started. There's a lot of material and I want to make sure we have a chance for questions. I have no conflict of interest. All my funding is through the NIH, the American Diabetes Association. This is where I'm from, University of Colorado, with the mountains in the far background, and there's actually cars in the parking lot, so this was pre-COVID. In terms of objectives, I think you have them. I'll paraphrase them on this slide. I will be referring a lot to the 2021 guidelines from the American Diabetes Association, as well as the American College of OBGYN practice bulletin, but I have a lot of references for you if you are interested in reading a little bit more. Just to start out with, I want to give you a little bit of background as to why I think it's so important for endocrinologists to be involved in the management of women and their babies with type 1 and type 2 diabetes. It's not just about short-term outcomes for both the mother and the baby, but the developmental origins hypothesis has really demonstrated that the entry to the environment is so critically important in terms of long-term offspring metabolic health. I think we can make a huge difference both in short and long-term and possibly even childhood obesity and diabetes. We'll talk a little bit about that very briefly. Then I just want to underscore that treating diabetes is a whole lot more than just treating the glucose. We'll talk a little bit about the role of obesity is actually the highest risk for maternal morbidity and the role of maternal triglycerides and fetal overgrowth as well. Give you a little bit of a refresher on the importance of insulin resistance and metabolism in pregnancy because this will really be important to how it affects all of our management decisions and discuss a fairly common phenomenon of euglycemic DKA. I'll make a couple of points about how important it is to diagnose pre-existing diabetes in patients who present for the first time with glucose tolerance. They're not all GDM, gestational diabetes, and their prognosis is very similar to type 1 and type 2. We don't want to miss them. Then we're really focused down on the controversies in management of type 1 and type 2 diabetes. Is type 1 higher risk than type 2? Then discuss how we can maybe tailor our management to patient-specific factors and the use of oral meds, including metformin. That's the MITEI trial, the metformin in type 2 trial. Different insulins, non-insulin injectables, ACEs, ARBs, continuous glucose monitors, pumps, and postpartum issues. I apologize ahead of time, we use a whole lot of abbreviations in OB. I'll try and make sure I define those for you. Just very quickly in terms of background, why I think this is so important for endocrinologists and truly such a compelling field, is the entire concept of fetal programming. We know that with diabetes and with obesity, these metabolic factors in the entering environment can have a profound effect on prenatal development after the baby's organs are formed and actually increase the susceptibility for this offspring to have childhood obesity as well as glucose intolerance. In the setting of diabetes and gestational diabetes, I use GDM a lot, we know that that baby responds to all those excess nutrients with very high fetal insulin levels and leptin. It actually changes the fetuses' fat cell development and the number of fat cells, causes enlargement of the pancreas as that fetus is putting out insulin starting at 14 weeks, causes enlargement of the heart, changes in kidney number, and this is all after the organs have formed. So this is in the second and third trimester. We also know that those very high fetal insulin and leptin levels actually affect the appetite regulation in the hypothalamus, and we know this from non-human primate data from mother monkeys that have been fed high-fat diets. And I'll just show you some of the articles you can look up in that because it really is pretty intriguing. We know that if you feed a mother monkey a high-fat diet, they share our placentas, that you actually create what looks like non-alcoholic fatty liver disease in the baby. It affects its mitochondrial function, its appetite, and even its behavior in terms of its serotonergic pathways. And we also know in humans that energy expenditure and mitochondrial oxidative capacity are affected by obesity and impaired glucose tolerance. We have to remember that we inherit our mitochondria from our mother. And one of the most compelling studies that really demonstrates this intrauterine influence is a study done by Kristen Boyle. She presented it to the ADA in 2016 when one of the top 10 abstracts where she showed that the stem cells from the cord of babies born to mothers of obesity preferred to differentiate along the adipocyte pathway rather than skeletal muscle compared to those cord stem cells from babies born to mothers who are normal white. So very early, the intrauterine environment really appears to influence this propensity later on for metabolic disease. And this is just a few of the articles if you're interested in just what can happen if you feed a mother monkey a high-fat diet. Sorry, diet is probably incredibly important. You actually create a NAFLD phenotype in that baby liver. You alter the appetite expression, the palm C expression. You actually create what appears to be a lot more anxiety in the females and more aggression in the males. You change serotonergic pathways. In the skeletal muscle, you actually change mitochondrial content, coupling efficiency, and metabolic flexibility. So really interesting stuff, kind of scary stuff when you think about it. And then lastly, epidemiologically, we know that that intrauterine environment is important because when we look at offspring that are born to a mother with gestational diabetes, and we compare them to a sibling in which the mother did not have gestational diabetes, but shares the same genetics for the most part in the postnatal environment, we find that in the Pima Indian data, in which Pimas obviously have a very high risk of type 2 diabetes, those offspring are seven times more likely to develop type 2 diabetes as an adult if they're exposed to that intrauterine environment compared to a sibling which the mother did not have gestational diabetes yet. And we even know with bariatric surgery, that siblings that are born after the mother had bariatric surgery actually have a lower risk of childhood obesity. So it's not just the postnatal environment or the genetics. So how do we kind of tease out what we really want to target in pregnancy in women with diabetes and with obesity? What are these contributors? Because it turns out that babies that are born with excess fat mass, much more than whether they're large, but actually if they're born with excess fat mass, they have a much higher risk of developing obesity later in life. And we know that the biggest risk is actually overweight and obesity, which is two thirds now of our pregnant population. And of course, we're seeing obesity in our women with gestational diabetes and type 2, and even with type 1, which results in a lot of insulin resistance. One in 10 infants and toddlers are already obese, one in five youth. And when you look at the factors, the intrauterine factors that are associated with a high BMI at two to three years of age, the biggest contributors are maternal obesity and diabetes, which we'll obviously talk about, glucose, but also lipids, the maternal diet, which we alluded to, and being born LGA, that means large for gestational age, greater than the 90th percentile for the gestational age. But even more importantly, we look at body composition. An increased adiposity at birth is probably one of the biggest risk factors. After the baby's delivered, there certainly continue to be risk factors for metabolic disease later on, how quickly that baby gains weight. The last thing you wanna do is take a baby, for instance, that is growth restricted and put them in an obesogenic environment because that rapid weight gain actually markedly increases the risk of childhood obesity, what we call catch-up growth. And so you wanna keep them on the same exposure that they had actually in utero. So a small baby that then is exposed to an obesogenic environment also has an incredibly high risk for obesity and metabolic disease. We know that breastfeeding is protective. It's unclear whether that's the case in type one and type two women, but we certainly recommend it. So lots of influences. I don't wanna pretend they're all just intrauterine, of course, but certainly I think we set the stage early on. And we don't only set the stage for increased subcutaneous fat, but we and others, David Bronbaum is a pediatric gastroenterologist, looked at the offspring, the infants, at two weeks of old of women with gestational diabetes and obesity, and looked at these babies' liver at two weeks of age compared to babies born to mothers who were normal weight. And these babies already had 68% more intrahepatic fat, and that fat actually correlated with mothers' triglycerides. So could this be the first hit for non-alcoholic fatty liver disease like it appears to be in the monkeys? We don't know, but these are all the reasons that for the rest of this talk, we're really gonna try and do whatever we can to normalize that intrauterine environment. And once again, it's not just diabetes that poses the risk. In fact, obesity is the leading cause of maternal and infant morbidity. We and others have shown that women who have obesity, they have much higher 24-hour glucose values, both fasting and postprandially, even though they don't make criteria for gestational diabetes. Their fasting glucose levels are about 10 milligrams per deciliter or higher, as are their postprandial. They also have much higher triglycerides. They have a higher risk of preeclampsia, hypertensive disorders. We and others have shown that they have a very high risk of sleep apnea. We demonstrated that two-thirds of obese women have mild sleep apnea. That results in an increase in their 24-hour glucose profiles and also hepatic insulin resistance that otherwise is not often recognized. They have a higher risk of pulmonary hypertension, C-section, anesthesia complications, higher prematurity rate, but what's really, really sobering is a much higher perinatal mortality rate, and I'll show you that data as well. They also have increased respiratory distress and also an increase for adverse metabolic programming. And we have shown, at least in obesity, it appears that maternal triglycerides may even be a stronger contributor to excess fat in these babies than even glucose. So let's go back and just do a quick refresher on what is going on with the physiology of pregnancy and this insulin resistance that we see that certainly makes diabetes and glucose intolerance worse. Early in pregnancy, you may remember that actually women get more sensitive. It's not quite clear, to tell you the truth, what is mediating that in terms of placental hormones. In some women, there appears to be a slight increase in adiponectin. This often happens somewhere around 12 to 16 weeks. You have to really be careful about this because women with preexisting diabetes, often you have to really decrease their insulin, especially at night, because of this increased sensitivity. And so glucose is going into their muscle, they're packing on fat, probably part of that is for later lactation, and the fetal tissues in the placenta is very small. But at about 16 to 20 weeks, women become incredibly insulin resistant. So this is mediated, we know, by human placental growth hormone, which is very similar to pituitary growth hormone and causes insulin resistance at crazy high levels, even placental lactogen, TNF-alpha. And so we have done muscle biopsies on these pregnant women and they have decreased glucose uptake in their skeletal muscle, and they also have markedly decreased uptake in terms of free fatty acids into their fat. And so instead of storing fat, they become lipolytic very quickly. And this, of course, teleologically, is to meet the huge requirements in now this very big placental fetal unit, which requires up to 150 grams of glucose in the third trimester. So to meet these metabolic demands, especially in times of starvation, mothers became, it was a good thing to become insulin resistant. So these nutrients would actually continue to feed the baby and the placenta and keep the species alive. But we know that in the third trimester, due to this increase in lipolysis where mothers become more insulin resistant, they're breaking down their fat to free fatty acid and ketones, that they have a much higher likelihood to go into starvation ketosis. And this is called the accelerated lipolysis of pregnancy. This is also why diabetic ketoacidosis is more common in pregnancy. We know that there's a lower glucose. We're not gonna see as high a glucose as when they become acidotic because of the increase in their GFR, which can double in pregnancy. So that glucose is being cleared by the kidney. Also, we just talked about those fetal placental demands, which is basically three bags of D5. Pregnant women have a lower buffering capacity because they have a primary respiratory alkalosis from progesterone. That results in a decrease in bicarb. So they have less buffering capacity so they can go into acidosis more easily. And then they have that rapid depletion of their glycogen stores. We talked about those fetal placental glucose demands being up to 150 grams. So if they're not eating, they're throwing up. In 10 hours, they can deplete all their glycogen stores and start switching to lipolysis with increased ketones and free fatty acids. And this is why women who have diabetic ketoacidosis, if they're unable to eat, you should probably be giving them D10, not D5, and just giving them enough insulin because those fetal placental demands are 150 grams just in themselves later in pregnancy. And if you don't give enough adequate glucose, they're gonna stay in lipolysis. So it's very important to check an anion gap, even in women who have a glucose of 200 who you're worried about DKA because they've been vomiting, they're feeling poorly, they've been sick, because they can go into euglycemic ketoacidosis, just kind of like people do on an SGLT2 inhibitor, which also causes glycosuria. We make sure that women have urine and blood ketone strips at home. And unfortunately, especially in the second and third trimester, diabetic ketoacidosis is a very common risk of stillbirth. So we really wanna do everything we can to prevent it. And then just the last thing about diagnosis is we don't want to ever assume that women who have quote unquote, early gestational diabetes are just GDM. A lot of these women probably have type two diabetes that's not recognized. So a study done by Denise Feig showed that in her cohort of women who quote unquote, developed type two diabetes within a year of pregnancy, probably some of them already had it. These women had the same risk of having a baby with congenital anomalies, large for gestational age, RDS is respiratory distress, peritoneal mortality, preterm birth, I'm sorry, is PTB and NICU stays. And they also have a high risk of neonatal hypoglycemia. And it is because probably many of these women actually didn't have GDM, they had type two. So now there's kind of a mandate that we make sure we diagnose women appropriately. Any woman with an A1C of 6.5, anytime in pregnancy, we call them preexisting or overt diabetes because A1Cs actually go down in pregnancy. So if they're that high, they have probably preexisting diabetes. Fasting of 126 or greater or random 200 gives you preexisting diabetes, not GDM. And it's really important to recognize these women because they have the same risk factors as women who come into pregnancy with that diagnosis. So let's cap on kind of the effect of pregnancy on type one and type two diabetes. And then we'll kind of look at the reverse. We already alluded to, because of our pathophysiology, the insulin requirements decrease early in pregnancy. And so you really have to be careful for hypoglycemia, especially in women with type one and especially nocturnally. And then insulin requirements double to triple. The quadruple, I had a woman who had a sixfold increase in her insulin requirements by the end of pregnancy. Couldn't even get all that insulin in a pump. But then they become profoundly sensitive as soon as they deliver. With the cessation of those placental hormones and active weight loss, their pre-pregnancy requirements, I'm sorry, their insulin requirements are even less than their pre-pregnancy requirements. They can almost have a holiday. We know that pregnancy is the perfect storm for proliferative retinopathy to get worse due to the anemia of pregnancy, the hypercoagulable state of pregnancy, the marked increase in growth factors, and then the institution of type control. So it's especially important to get women in remission before they get pregnant. Proteinuria is gonna get worse in pregnancy due to that increased GFR that we talked about. Usually function doesn't deteriorate unless they have moderate to severe renal insufficiency, especially if they get superimposed preeclampsia. But the proteinuria always gets worse and sometimes can become nephrotic. And then you can imagine that pregnancy is really a stress test for coronary artery disease. You have to increase your cardiac output by about 30% and your oxygen demand. So women who have micro-macrovascular disease who might have a cold coronary artery disease, they may present for the first time in pregnancy with MI. And unfortunately, we've had to stamp way too many women in pregnancy because it was unrecognized. So really important to evaluate this before pregnancy. And then with the nausea and vomiting and worsening gastroparesis of pregnancy from progesterone, women who already have gastroparesis have a really, really, really difficult time and are really miserable because of HCG worsening that nausea and the progesterone decreasing that emptying even further. And then lastly, we have to remember that estrogen hugely increases triglycerides. YAB-LDL increased synthesis in a number of different mechanisms. So if women have hyperlipidemia, hypertriglyceridemia, those triglycerides can increase two to three-fold and these women can develop TG-induced periodontitis. Well, what about the reverse? What's the effect of type one and type two on pregnancy outcome? We know that hyperglycemia is a major teratogen and this is why endocrinologists can do much more than a obstetrician can do in terms of preventing malformations because the neural tube in the heart is formed by eight weeks, usually before the woman even knows she's pregnant. So if you have an A1C around 12, that's gonna be a 20 to 25% risk for a major malformation. And again, by the time she knows she's pregnant, it's too late. This is why contraception is so important in women until their A1Cs are normalized. If the A1C is 6.5 or less, the risk for malformation is no less than the normal population. We have to remember that women with gestational diabetes often convert to type two within the next five to 10 years, 50% of them will. And so it's important to screen for that before they get pregnant. Due to all that glucose and triglycerides, we can get a big baby like that one to the right with type two, but due to placental insufficiency, which occurs more often in women with microvascular disease, in type one, you can get a scrawny baby, even though there's high triglycerides and glucose, the nutrients can't get across because the placenta does not form right. And basically what this is, is this manifests as usually preeclampsia. Preeclampsia, the risk is about 15 to 15%, 50% it's a placental disease from abnormal placentation angiogenesis. We see it especially in women with hypertension, renal vascular insufficiency, vascular disease, and it results in preterm delivery. And then one of our biggest fears is an IUFD, intrauterine fetal demise, is what I mean by that, or poorly controlled diabetes. And basically the fetus actually gets hypoxic and acidotic and ischemic. And this is much more common when a baby is overgrown, and then a mother gets some placental insufficiency at term, which often occurs in preeclampsia, and the baby literally outgrows its blood supply and becomes ischemic. And this is much higher in type two diabetes. And then if this baby's been seeing very high glucose, starting at 14 weeks, it starts responding with high fetal insulin. And after the mother's delivered, it's still pointing out all that insulin, and the baby's getting neonatal hypoglycemia, have to stay in the NICU for a couple of days. Those high fetal insulin levels prevent the lungs from maturing and surfactant production, and so they get respiratory distress syndrome, that's RDS. The increased bilirubin is due to the polycythemia and ischemia they get. So they actually have a higher crit due to ischemia, and they can have hypocalcemia. So is type one diabetes worse than type two diabetes? There's actually now data that the risk of type two is at least as high as type one, for all the reasons that we talked about, all the comorbidities associated with obesity, especially as we talked about sleep apnea, hyperlipidemia, hypertension, et cetera. It's interesting that the pregnancy loss in type one is usually due to congenital anomalies. So those major malformations that occur before eight weeks or prematurity, whereas in type two, it's more common with stillbirth, where these babies outgrow their blood supply, or infection, and again, more common with type two. In a cohort in the Netherlands with type two, 20% of the babies were preterm, a third were big, large for gestational age, there was a 5% perinatal fatality. So type two is absolutely as concerning as type one. And if you combine preexisting diabetes with obesity, as I'll show you, then your risk for a stillbirth increases by up to 25 to 34. And that highest risk of stillbirth is about 37 to 39 weeks, where the baby can outgrow its blood supply, and this is why we often deliver early in these women. So stillbirth and diabetes, we know that in terms of other risks for stillbirth, actually stillbirth has decreased in the US except for in diabetes. And we really see the risk increase at about 32 weeks, is when we start doing fetal surveillance, what we call non-stress tests. And then it markedly increases at about 37 weeks. And this is why often we will actually recommend delivery of a baby, depending on comorbidities, glycemic control, and fetal considerations. And the proposed mechanisms are what you kind of expect. They end up, often these women develop placental insufficiency as a manifestation of their microvascular disease from their hypertension, or other things that cause microvascular disease. These babies have been generating a ton of insulin because glucose actually goes across the placenta and diffuses across what we call a placental glucose steel. So as that glucose is going down a concentration gradient, that fetus continues to make more and more insulin, which causes early fetal overgrowth. And then if, once again, this creates an increased oxygen demand for the fetus, ultimately ischemia. And then if, especially if the woman starts developing preeclampsia or placental insufficiency at term, then that higher metabolic demand results in ischemia and sometimes death. And this is just a retrospective series that shows when you look at stillbirth risk, the normal risk is about 15 in 10,000 pregnancies. When you add diabetes to it, you increase that about eightfold. And when you add morbid obesity to it, class three obesity, you increase it by about 15 fold. And at term, that risk is actually 30 fold if you have both the combination of diabetes, type one or type two, and obesity. It's about 25 fold with obesity and 30 fold with class three obesity. So once again, these are the women that we want to deliver early. So we're gonna finish up with treatment. What are our treatment goals? They're not based on randomized control trials, but it's been shown that if you keep the fasting less than 95, one hour and two hour, less than 140 and 120, you can pick either one that you can decrease fetal overgrowth. Now, these are actually higher levels than are normal in pregnancy. We know that post-prandial glucose is markedly exposed that baby to high fetal insulin levels. So we do both pre-prandially and post-prandially. We know that if the A1C is 6.5 or less, these babies are really not at significant risk for major malformations, but we actually try and keep the A1C six or less if we can without hypoglycemia due to the fact that A1Cs do decrease in pregnancy to try and normalize glucose control. But if a woman has severe hypoglycemia or hypoglycemic unawareness, we have to liberalize those goals because of the risk for fetal neonatal hypoglycemia and the mother having a seizure. And obviously babies are not able to make glucose until term, they don't have the gluconeogenesis enzymes. So we wanna make sure that we avoid hypoglycemia. These are the normal glucoses in pregnancy. We and others have shown that in normal pregnancy, fasting glucose of 72 is the usual normal glucose. It's actually lower than outside of pregnancy. In the very large HAPO trial, it was 81. Some of these women were obese and obesity increases your fasting glucose. And then these are the one and two hours in normal pregnancy, it's only 110 and 99. And our goals, as we talked about with treatment, our goal of 140 and 120 for the two hour, 140 for the one hour. And the reason we don't really target those more intense goals is just what we talked about, the concern about severe hypoglycemia. Fastings do go down in pregnancy. Glucoses are actually higher in obese women than they are in normal white women, as we alluded to by about 10 milligrams per deciliter in obese women compared to normal white women, both fasting and post-prandialy. And due to the fact that fasting glucose does go down in pregnancy is that glucose is traversing the placenta to meet those fetal placental demands. The threshold for counter-regulatory hormones is also lower in pregnancy. Severe hypoglycemia can occur to 50% of women with type 1, especially early on, as we talked about when they're sensitive and especially overnight. So we really have to pull back in terms of treatment because these are women that might not wake up the next morning if we're not really, really careful about avoiding this. The fetus has no gluconeogenic capacity until term. So what prolonged type of glycemia does to the baby, we just don't know. If it's short-lived, it's probably fine, but obviously if it's protracted, it's a huge risk to both mother and the baby. So we make sure these women have glucagon intranasal or PINs, glucose tabs, paste, and immediately postpartum, as we alluded to, we reduce their pregnancy doses hugely. So kind of a rule of thumb is whatever they're on in the third trimester, I usually give them about 35 to 40% of that and make sure it's less than their pre-pregnancy doses due to the just abrupt decrease in all those placental hormones. The human placental growth hormone is actually suppressed, pituitary growth hormone, so they don't have that counter-regulatory hormone for a while. Rapid weight loss and breastfeeding all causes them to be incredibly sensitive. So in the last 10 minutes or so, 15 minutes or so, how do we treat these women? Well, there's a lot of controversy on the use of oral agents and gestational diabetes, but not so much for preexisting diabetes. The American Diabetes Association, as well as ACOG, states that oral agents really should not be used to treat diabetes. Number one, they're just not going to work very well with all that insulin resistance. They're gonna require insulin anyway. Both metformin and gliburide, which are the oral agents that have been used in pregnancy cross, metformin much more than gliburide, and metformin core blood levels are at least equal to mothers, and we'll talk about that. And the biggest concern, especially with both of these agents, but especially with metformin, because we followed the kids, there have been studies that followed the kids longer, is that metformin in pregnancy is actually associated with increased weight and fat mass in nine-year-olds in what was called the MIG trial, which was used in a randomized controlled trial, and also in women, in which they were randomized to metformin versus placebo for PCOS. And one of the reasons for this may be all of the different effects of metformin. So metformin is a cation. It's concentrated into mitochondria 1,000-fold. The fetus and the placenta have great cation organic transporters, so that metformin crosses the placenta readily after about 12 weeks. It's probably very safe in the first trimester. The embryo has a low mitochondrial content. It doesn't have these organic cation transporters, and there's very low aerobic metabolism. So if a mother is on metformin or even gliburide, and metformin, I don't stop until about 12 weeks because I don't all of a sudden want her sugars to go higher, but after 12 weeks, I tend to stop it, and the reasons are it's because of its pleiotrophic effects and, again, some of the concerns that we've had about it in terms of long-term effect on childhood obesity. Metformin inhibits mitochondrial complex 1, resulting in a decrease in cyclic AMP. This is one of the reasons it decreases gluconeogenesis. Whether that's good for a fetus, we don't know. It also activates AMP kinase, which signals to mTOR, which results in decreased proliferation, increased cell death, cell cycle arrest. Whether that's good for a fetus, we don't know. It changes gene expression. It has a lot of microbiome effects. In fact, there's a metformin DR that's not absorbed that also decreases glucose that hasn't been utilized yet in pregnancy, decreases inflammation. It does not lower triglycerides, unlike insulin or gliburide, which does lower triglycerides. We have actually, all the Society of Maternal and Fetal Medicine said it was fine to use in gestational diabetes, as well as NICE and some other organizations. We really had some concerns about the use of this drug because of the concern of the effect on fetal growth. mTOR turns out to be the major placental nutrient protein, and if you decrease mTOR, you may end up causing nutrient restriction. And then if you take this nutrient-restricted baby and put them in an obesogenic environment, that, again, is one of the biggest risk factors for obesity. So this is a NICE review by PLOS Medicine, if you're interested, again, looking at all of the follow-up of all the infants that have been exposed to metformin in pregnancy, in which there's been follow-up for 5 to 10 years. And they concluded that despite average lower birth weight, the metformin-exposed children appeared to have accelerated postnatal growth, resulting in heavier infants, higher BMI, by mid-childhood. And so there is a lot of controversy about the use of this in gestational diabetes, but certainly I think for pre-existing diabetes, this is not something that I'm using. But it has been used in a terrific randomized control trial by Denise Feig, which many of you know about, called the MIGHTY trial, metformin in type 2 diabetes. What Denise wanted to do was she randomized a very large number of women who were already on insulin and added metformin versus adding placebo to their insulin. These were their characteristics. They had a BMI of 35, so they were obese. They actually had fairly good control, and they were randomized, excuse me, at 16 and a half weeks. Almost none of these were Hispanic, so we don't know about its risk in Hispanic women, since this was Australia and Canada. And the mean insulin dose going into the pregnancy at 16 and a half weeks was about 66 units. So their major outcome, their fetal composite primary outcome was pregnancy loss, preterm birth, birth injury, respiratory distress syndrome, neonatal hypoglycemia, and NICU admissions. And there was no difference. However, there were some differences in the group that got metformin in terms of secondary outcomes. They had a slightly decreased A1C. They had less of an insulin use. Excuse me, I'm sorry. They had a little bit of less weight gain, about 1.8 kilos, slight decrease in C-section, but not primary C-section, which really makes, is what you wanna study, since if you've had one before, you're probably gonna get another one. There was a decrease in birth weight. Large for gestational age was a different, but very large was 97th percentile, although the upper competence interval almost touched one, same with macrosomia. No difference in the CORD-C peptide, the fetal hyperinsulinemia, but the babies were twice as likely to be small for gestational age. And as we talked about, that's also a risk for later cardiometabolic disease. So there are some people using it, but again, we certainly hope, we're certainly trying to support Denise's attempts to get funding to follow these kids long-term, because that's really the question in terms of what that entry and exposure might do long-term. So that's the MITEI trial. And again, controversial, some people are using it. I tend not to. And then let's finish up with some of the other newer diabetic agents. The GLP-1 agonists that you're all very familiar with, we really don't want to use in pregnancy, even though they're unlikely to cross. Unfortunately, there's some animal data that's a little bit concerning about them. And so they're not approved for pregnancy. The DPP-4 inhibitors probably do have a molecular weight small enough that they would cross. There's minimal human data, but again, it's like they're likely to cross, so they're not recommended. SGLT-2 inhibitors, we already talked about. Pregnancy really is an SGLT-2 inhibitor because of the glycosuria. But these are also agents that are likely to cross, and there's been some concerns about, can you develop it in animal models? And then we don't want to use the PPAR agonists. They're actually insulin sensitizers. They actually promote adipogenesis in animal models. And for stem cells to go along the adipogenic pathway, ROSI is actually embryotoxic, so we really don't use those either. What about insulins? You can use any insulin you like. None of them will cross. Obviously, in type 1, Lyspro and Asparte work really well. You'll see, especially in GDM, a lot of NPH in regular because they're cheap. But with type 1, especially in a lot of type 2, we like these rapid-acting insulins. The Asp is probably fine as well. I've used some of it myself. It's approved in Australia. Glutalysine is not gonna cross. It just isn't a lot of data. Datamir is FDA-approved now, garging less data, but it's also not gonna cross because it has a high affinity to the IGF-1 receptor. I tend to avoid it with proliferative retinopathy. Degludec, again, it's not gonna cross. There's just not a lot of data. Takes longer to adjust. And as we talk about, we'll be adjusting this insulin a whole lot, like every week or two in pregnancy. NPH, believe it or not, we use a fair amount. We use it at night in women in which we push their basal insulins as hard as we can, and they still have fasting hyperglycemia. So if you push their basal insulins any harder, they're gonna get low in the day, but they still have fasting hyperglycemia. NPH has some great characteristics in that if you give a little bit before bedtime, it tends to peak about six to seven hours. And sometimes you can bring down those fastings. We do it a lot in women who are Hispanic because they have a lot of hepatic insulin resistance and they primarily have fasting hyperglycemia. AFREZA, we were going to study it, but COVID came, so there isn't a lot of data. But the most important thing to realize with all of these insulins is the absorption decreases as pregnancy goes on. So the time from the peak insulin concentration increases from 50 minutes early to 80 minutes later in pregnancy. So you really have to tell patients to pre-bolus to avoid a mismatch with insulin. And then we adjust it every couple of weeks. And this is the typical way we treat pregnant women, just like outside. We use a basal insulin, such as guarangine or detemir, and then we give them a bolus insulin, such as Lysopropyl Aspartate, according to usually a carb ratio or a correction factor. And then once in a while, we'll add a little NPH at night if their fastings are still high. But the most important is to pre-treat, especially later in pregnancy. We use more bolus than we do basal because we don't want a lot of long-acting insulin around. They have nausea or vomiting, et cetera. So we're more bolus-heavy in pregnancy. And their insulin requirements change every week or two, so we are literally adjusting their insulin every couple of weeks. And then I just mentioned that Hispanic women tend to have crazy fasting hyperglycemia because they have hepatic insulin resistance. Sometimes if you just give them NPH at night and you bring down their fasting glucose, they really don't have much of a postprandial excursion and you can control them just by NPH at night. I've had a lot of Hispanic women on literally 100 units of NPH at night and then not needing hardly anything else. So they just have a very different physiology. And then in just finishing up, what about continuous glucose monitors? I hear a rumor, I think all of you did, that Medicaid may finally be paying for these in women with type 1 diabetes, which would be truly huge. The concept trial by Denise showed that with continuous glucose monitors were used, although they really didn't improve glucose control by that much, because I think sometimes when you put them on women and they don't look at them, we really don't make that many adjustments. Interestingly, it did decrease large for gestational age by about 50%, decreased their NICU stays, neonatal intensive care unit stays, and also decreased neonatal hypoglycemia by about 50%. And so we're trying to offer it in all type 1 moms, and now if Medicaid is gonna come through, this is gonna be huge. The CG recommendations to the American Diabetes Association, as well as NICE, is to use them with self-monitoring. And I think this, again, is because sometimes if women just put on the CGM and they don't actually notice what their fasting and their postprandials are, they don't really do anything. So I make sure that women are at least marking down or noting what their fasting is. We usually do a two-hour postprandial, because we like to see how well the Lyspro or the Aspart is working, to try and help them achieve their goal. And the combination can really improve macrosomia. And I think that really trying to focus, rather than just fasting in two hours, on time and range for pregnancy is also going to be much more clinically important to decrease fetal overgrowth. And there are studies looking at this now. The ADA defined time and range is 63 to 140 in pregnancy. I would disagree with that because of the risk for neonatal hypoglycemia. I'm sorry, for maternal and fetal hypoglycemia. So we usually target them at 70 to 140, because we want to treat a glucose of 70 before it gets much lower. But that's the range in pregnancy that we try and target. And ACE just updated the recommendations and said that CGM or flash glucose monitoring appears to be superior to self-monitoring blood glucoses from finger sticks. They used a Dexcom or Freestyle Libra. They still had a high incidence of LGA. So again, women have to really pay attention to what their sugars are doing on these continuous measures and make changes rather than thinking that they have one on and you don't really need to do a lot about it. What about pumps? You would think the pumps would be so much better in pregnancy, but in fact, they haven't been shown to be. One of the reasons for this is that when you compare them to multiple daily injections, using carb ratios and corrections and basal bolus insulin, there really hasn't been a clear benefit. I think they absolutely can improve control, especially women with nocturnal hypoglycemia. You can change those overnight rates. They have a dot effect and you can increase it. But I think one of the issues is that if you put pumps on women in pregnancy who are not used to using them, there's a very high failure from a key catheter. And because you only have a rapid acting insulin in that pump, they can go into DKA much more rapidly. So eukalycemic DKA is actually more common on a pump. So it's better to start them preconception if you start them because of the steep learning curve, the inability to really determine their basal rates because you don't want to fast them a long time, and because their insulin resistance is always changing. And basically at this point, there isn't, it's not felt to be necessarily superior to multiple daily injections, but I think they have a huge role, obviously, especially in women who are very sensitive and who have hypoglycemia. In the concept trial, which was not randomized, actually multiple daily injections looked a little bit better than pumps did. There are now hybrid closed-loop pumps. There was one that Helen Murphy helped develop that was reported in the New England Journal about five years ago that seemed to improve glucose control. The two out there now is the Medtronic MiniMed that's being studied by Serit Polsky and her investigators. The problem with this pump, one of the challenges, however, is you cannot target the glucose less than 120. As we talked about overnight, we like to target that glucose more like 90 to 95. The Tandem Control IQ, I've used quite a bit in pregnancy. The Dexcom G6 usually targets the glucose closer to 112. When it's in sleep mode, you get more like 100 to 110. It does give bullets corrections when it's not in sleep mode. It's really great at decreasing or suspending for lows, but data will be forthcoming, I think, on all these hybrid closed-loop pump. They're not perfect for pregnancy, but sometimes they're better than in women who are less able to really get that good control on their own. And then just to finish up, what about ACE inhibitors, ARBs, and what are our goals for them? ACE inhibitors probably don't cause major malformations, but they bottom out the intraclamarular perfusion pressure in the baby's kidneys. And so with continued use in the second and third trimester, they cause renal dysplasia. Babies quit putting out pee, then they get oligo. Babies need to swallow their pee to develop their lungs, so they get pulmonary hypoplasia and growth restriction. So they're probably not major teratogens. If women are actively trying to get pregnant, I stop them and switch them. If they're not and they need it to protect their kidneys, I tell them to do home pregnancy tests, and it's probably fine as long as they stop them early in the first trimester. In terms of target goals, these are all medications, by the way, that we can use in pregnancy. Our target goals for diabetes, we really don't know. We know that if we make them too tight and that placenta becomes insufficient and we decrease the perfusion through that placenta because a woman develops preeclampsia, we could even worsen blood flow to the placenta by too tight a control. But most would recommend targeting about 130 over 80 in pregnancy, especially if they have renal disease or diabetes. What about lipids and other agents? Statins are probably actually not teratogens, but there's really no need to treat an LDL for the short term of pregnancy. We're actually looking at pravastatin because it increases angiogenesis, but right now we don't use statins in pregnancy. There really isn't reason to use them. Women with very high triglycerides, you actually might need to treat in pregnancy because of triglyceride-induced pancreatitis. It's important to put them on a low-fat diet, low simple sugars. We can use high doses of omega-3s like Lavazza, four grams, and we can even use fibrates if necessary. But they have not been shown to be teratogens. Women with very bad polypiped retinopathy, intravitreal anti-VEGF has been used without any adverse effects. And then we get baby aspirin, either 81 to 162 milligrams in the first trimester throughout pregnancy has been shown to modestly decrease the risk for preeclampsia. And then just to finish up in terms of postpartum issues, there is a marked decrease in insulin requirements right after delivery. We talked about that. So the postpartum requirements are about 30 to 40% of their third trimester. We decrease them by about 60 to 65%, make sure they're on even less than what they were prior to pregnancy. We certainly encourage breastfeeding. And this will be another reason you'll have to really decrease the amount of insulin that you're giving. We don't know if it's protective to the baby in type one and type two in terms of metabolic risk, but it's good for many other reasons. So we certainly try and promote that. And then contraception is so critical because endocrinologists I think can do more than anyone to prevent these major malformations by making sure women are on long-acting reversible contraceptive, that's LARC and IUD or Norplant, or even just a low-dose birth control pill. There's no contraindication to using a 20 or 30 microgram birth control pill in a woman with diabetes. Pregnancy is a much greater risk gives them 50-fold higher levels of estrogen unless they either have a blood clot or if they have a really bad hypertriglyceridemia. That's the only time these estrogen-containing birth control pills are truly contraindicated. So I think it's important for endocrinologists to become really comfortable at least prescribing a low-dose combined birth control pill until you can get someone in and discuss more long-acting reversible contraception in these women. You can use Depo as well if they have a complete contraindication to estrogen. So in summary, kind of the highlights is that the ADA came out with recommendations for preconception counseling. There's a really nice table, but just kind of in a nutshell, they're all that we talked about. Trying to get the A1C less than 6.5, remembering the insulin requirements decreased in the first trimester and then cranked up like crazy in the second and the third. Fibroiding metformin is okay in the first trimester. I don't usually pull the metformin off until later because I don't want the sugars to go up, but I tend to pull it off later because of the reasons that we talked about. Consider coronary artery disease testing, functional testing for high-risk patients. We don't want them to have their first event in pregnancy. Make sure their proliferative retinopathy is in remission. Evaluate their lipid status. Stop the statins. You want to make sure that you check their TSH. 5% of women with diabetes, especially type 1, have subclinical hypothyroidism. You want to treat that. Optimize their blood pressure. Avoid ACE inhibitors in ARBs if they're actively trying to get pregnant. Make sure you think about other things, their diet, their exercise, folic acid, et cetera. And then contraception, contraception. You know, we are hormone doctors. So prescribing a low-dose estrogen-containing birth control pill, unless they have blood clots or really crazy high triglycerides, so much safer for them getting pregnant and then having a baby with a major malformations. And refer them to family planning for LARC or IUD implants if they don't want to get pregnant or you're wanting to get their glucose under better control. And then baby aspirin in the first trimester. These are just a couple of my favorite agents or low-dose oral, I'm sorry, low-dose estrogen-containing contraceptives. Anything is fine. Drosperinone is just a really great progestin with very few side effects. And then very last slide, that organogenesis is complete by eight weeks. So as endocrinologists, we want to make sure these women are in good control or on contraception before they get pregnant if they're not yet, if they're not yet in good control. Preconception counseling, more than 50% of pregnancies are unplanned. Type 2 has a similar risk to type 1, maybe even higher. In terms of mortality rate, you want to make sure they don't already have sleep apnea and treat them with CPAP. If they do, address their hypertension, their lipids, see if you can get them to lose some weight. We talked about the goals of glucose in pregnancy, but then hypoglycemia is dangerous. Want to start that baby aspirin by the end of the first trimester. We tend to use flexible insulin regimens, metformin, Zopain in the first trimester. Pumps are equivalent to multi-dose injections for now. And then we talked about the insulin requirements markedly decreasing in the first, only to wrap up like crazy in the second and third, and then plummet immediately postpartum. Had a number of women who've had postpartum seizures because people forgot to decrease their insulin after they delivered to less than pre-pregnancy levels. And then we talked about DKA occurring at lower glucose levels. Make sure you use ketone strips. And then postpartum, weight loss, breastfeeding, and contraception. And this is just a picture of the youngest child to ever develop type 2 diabetes. She was three years old. Just again, reinforcing the importance of that intrauterine environment. And we know it was type 2 diabetes because once she lost weight, her diabetes went away. So thank you very much, and hopefully you have time for questions. Thank you, Dr. Barber, for that really informative talk. And now we have a few minutes for questions. And I'm gonna go ahead and start us off with questions, and then we have a few more in the chat. So you mentioned earlier in the talk how important it is to identify women who have pre-existing or pre-gestational type 2 diabetes. So I wanted to ask what you recommend as far as screening for women who are known to have pre-diabetes or PCOS during pregnancy. And then just as a follow-up to that, we haven't really thought much about triglycerides in pregnancy, or maybe searched for it or counseled heavily on diet. So if you could just talk about what you recommend as far as screening, should it be routine, are there certain patients, and how you would counsel those patients as far as nutrition is concerned. Yes, thank you, Leslie, for asking those questions. They're both, they're all dear to my heart. In terms of screening, there is a tremendous amount of controversy depending on IADPSG versus ACOG. But I think practically, certainly women with pre-diabetes as well as PCOS have a very high likelihood of being diagnosed with quote unquote gestational diabetes. It's just basically the glucose intolerance in pregnancy, but many of them may have already converted to type 2 diabetes. And the reason it's so critical in those women to get an A1C as soon as they come into prenatal care is if their A1C is 6.5 or greater, they actually meet criteria in pregnancy for type 2 diabetes, or a fasting of 126 or a random of 200. It's critical because if you meet any of those criteria, that baby is now at increased risk for major malformations. If you catch those women prior to eight weeks, then you can possibly do something about that. But if it's after that time, at least you can look with a good anatomy scan, get a fetal echo, et cetera. And then in terms of women who have not been diagnosed yet with PCOS or prediabetes, I think any women with risk factors for type 2 diabetes, according to ACOG, should be screened. So obese women should be screened early, women with a history of a GDM pregnancy, women with a macrosomic fetus in the past, advanced maternal age, there are a number of different risk factors. And I would have a very low threshold in those women to screen them early and then get an A1C if they screen at all positive because they're also increased risk. And then just real briefly in terms of the triglycerides, this is actually an area where our research group has done a lot of studies. And we actually just got two studies, one R01 funded to evaluate the role of triglycerides in fetal overgrowth and actually also deposition of fat in the liver of the baby. And we have found that in obese women, fasting and postprandial triglycerides, especially postprandial triglycerides early in pregnancy actually are correlated much higher than glucose for increased adiposity at birth. And we really wanna look at baby fat, not birth weight, because birth weight, you may have a big baby, but it may be just a baby who has a lot of lean muscle mass. But we have found that fasting and postprandial triglycerides, especially in obesity seem more correlated, especially in women who have fasting starting at about 120 milligrams per deciliter. Triglycerides go up by 50% to almost 100% in pregnancy. So we have an R01 that's really going to try and tease out early versus late, fasting versus postprandial, the role of glucose as a moderator. And we've also been funded to do a pilot randomized control trial targeting triglycerides using a point of care triglyceride meter, just like a glucometer and treating randomizing women to high doses of omega-3 fatty acids, four grams a day versus sunflower oil in identical placebo capsules. So we'll hopefully have some more data on that. And then your last question was a GDM diet. We just finished a randomized control trial of diet in gestational diabetes, where we gave the women all of their meals for the entirety of pregnancy. And that data is going to be released soon. We looked at a lower carb diet, 40% carb which was one of the recommendations versus a 60% complex carb diet. So one was low carb, higher fat. And the other one was higher complex carb, lower fat. And we adjusted the fat and the carb by 20%, kept the protein identical. We kept the saturated, monounsaturated, polyunsaturated fats identical. It kept the simple carbs identical. They were euglycemic. And we randomized women to those two diets. And what we found out in looking at adiposity in the baby and glucose control, they were very, very similar. Adiposity was actually not different as long as you use complex carbs. There was a decrease in free fatty acids in the higher complex, low fat diet. Our concern is with that 40% low carb diet, when you substitute fat, you become more insulin resistant. But basically the diets look like they work fairly well and you can liberalize carbs as long as they're complex carbs. And adiposity is similar. What we did find out, however, is in the baby livers, we did MNR spectroscopy of these baby's livers at two years of age. And triglycerides once again were correlated with the amount of fat in the baby's livers and babies born of mothers with gestational diabetes and obesity had 68% more fat in their livers at birth. And whether this could be the beginning of non-alcoholic fatty liver disease can be a first hit is of course something we're really interested in following. Thank you. And we're almost out of time, but I wanted to sneak in one last question. Can you just comment about how you practically manage patients on pumps and CGMs on automated systems, going into pregnancy? So as everyone knows, there are basically two hybrid closed-loop pumps right now out on the market. Neither is approved in pregnancy. I am not supposed to talk too much about one versus the other, but I actually can say that I think for pregnancy, the tandem control IQ pump has some features that make it very well adapted to pregnancy. There's a few things that could even be better, but you can target glucoses more at about 112, whereas the Medtronic pump, the 670G, you really can't target them less than 120, which is a high glucose overnight. Also with the tandem control IQ, if you put it in sleep mode, you can get those fasting glucoses overnight pretty close to 100, which is nice. It keeps people from going low. I think it's a little bit more responsive algorithm for pregnancy because it's looking past how quickly the glucoses are going down, how fast they're coming up, et cetera. And you can use it immediately after delivery too, as long as you put in new settings. The only feature that's a little bit frustrating is the five-hour insulin duration. We like to be a little bit more aggressive with that and being able to correct. But I've probably had a dozen women who have actually done extremely well on that pump in pregnancy. If they can do better on that hybrid closed loop than they can manually, I think that they have less variability and more time and range between 70 and 140. I think it's a very, very reasonable choice. Okay. Thank you so much, Dr. Barber, once again, and thank you all for joining this afternoon. Thank you.

diabetes management

pregnancy

preconception counseling

obesity

gestational diabetes

glucose control

A1C

insulin

metformin

continuous glucose monitors