Hello. Welcome, everyone, to today's webinar hosted by the ADA Pregnancy and Reproductive Health Interest Groups. I'm Dr. Grainne O'Malley, and I am the early career representative for our interest group. I am now an associate professor at the Icahn School of Medicine at Mount Sinai, and I split my time clinically and research focusing on diabetes technology and technology in pregnancy. I'm also with Dr. Cassandra Henderson, who will introduce herself. Hi, my name is Cassandra Henderson. I am a maternal-fetal medicine and diabetology consultant. I'm also a certified diabetes care and education specialist. I am chair of the OBGYN section of the National Medical Association, and I'm also chair of the Pregnancy and Reproductive Health Interest Group of the American Diabetes Association. Okay. So on our agenda for today, we'll provide a few announcements, and we'll introduce our experts in a few moments. And just a reminder that for this webinar, continuing education credits are available, and we'll give you information on claiming that after the presentation. The presenter today will take questions from the audience, but we would ask that you develop them as you're listening, and don't wait to the last minute. We ask that you enter the questions in the Q&A box, not in the chat. We'd like to reserve the chat box for announcements that we'd like to deliver to you, and you could also use the chat box as a way to communicate with other attendees. We also encourage you to become a professional member of the American Diabetes Association to expand your knowledge, enhance your perspective, and grow your connections through exclusive opportunities and unmatched resources that come only with membership. And if you are interested in a group professional membership, you can learn more at professional.diabetes.org. And once you join the ADA, we would very much appreciate it if you consider joining us and the Diabetes and the Pregnancy and Reproductive Health Interest Group. We have a very active interest group. We produce events like this webinar, although this is our first CE webinar, but we have done other webinars, and we do other educational content presentations. We also have an active role in the annual meeting, and we would hope that if you join the ADA that you would join us for the 85th Scientific Session, which will be held in Chicago during a nice time of the year, June 20th to 23rd. And during that session, we have an app that will allow you to attend the pregnancy-related activities during the session in addition to all of the other ones. All right. And then finally, I would like to introduce today's panelists. So Dr. Laura Dickens earned her medical degree from Emory University and completed her internal medicine residency and endocrinology fellowship at the University of Chicago. Her clinical interests include diabetes and osteoporosis, and she co-founded the University of Chicago Diabetes and Pregnancy Clinic, a program focused on specialized care for complex diabetes and pregnancy. Dr. Dickens also serves as associate program director for the endocrinology fellowship at the University of Chicago, and her research centers on monogenic diabetes and improving quality of care for diabetes and pregnancy. We also have Dr. Celeste P. Durnwall, who is a maternal fetal medicine specialist focused on advancing care for high-risk pregnancies. Her clinical and research interests include gestational diabetes, preeclampsia, and maternal cardiovascular health. She is also dedicated to educating future physicians in maternal fetal medicine. Dr. Durnwall collaborates with interdisciplinary teams to provide comprehensive patient-centered care. Her work is driven by a commitment to improving outcomes for mothers and babies. Thank you, Dr. Durnwall. Thank you, Dr. O'Malley and Dr. Henderson. I'm going to start our webinar, When It's Not Gestational Diabetes. The first portion of our webinar will be focused on latent autoimmune diabetes in adults, also known as LADA. Here are my disclosures. Our learning objectives for the first portion of our webinar are to review the standard diagnosis of gestational diabetes and perinatal risks associated with gestational diabetes diagnosis. Then we're going to focus on defining latent autoimmune diabetes in adults, or LADA. After completion of the webinar, our attendees will be able to identify risk factors and clinical factors which would prompt consideration of LADA during pregnancy and discuss treatment options for LADA and long-term implications of the diagnosis. Gestational diabetes is one of the most common pregnancy complications. It affects approximately 14% of pregnancies worldwide. There are significant maternal and fetal and neonatal complications associated with the diagnosis of gestational diabetes, as well as long-term health implications for both the birthing parent and their offspring. Gestational diabetes is traditionally screened at 24 to 28 weeks gestation using an oral glucose tolerance test. Approximately 50 to 70% of GDM individuals can achieve glycemic targets with dietary management. Insulin remains the primary pharmacologic agent when dietary management fails. The use of oral hypoglycemic drugs such as metformin are also used in select cases. In most cases, the abnormalities in glucose metabolism rapidly resolve after delivery. The recurrence rate for gestational diabetes is high at 35 to 50%. The long-term health implications after a diagnosis of gestational diabetes include an approximately 50% development of type 2 diabetes in the mother and approximately 5% development of type 1 diabetes. This table lists the various screening strategies and criteria endorsed by our professional societies for a diagnosis of gestational diabetes. As you can see, there's no consensus as to the type of screening or the diagnostic cutoffs. Now I'd like to present a case study. V.M. is a 32-year-old, gravida 1, para 0, who had an initial hemoglobin A1c at first prenatal visit of 5.4% and a BMI of 22. She underwent GDM screening at the traditional time, 26 weeks, and was ultimately diagnosed with gestational diabetes by the two-step method Carpenter and Coustan criteria with the one and three-hour values listed on this slide. She then underwent a nutrition consult and a GDM consult with maternal fetal medicine and began finger sticks for glucose review. After her first glucose review, after one week of dietary management, it was noted that she had elevations in both fasting glucose and intermittent postprandial values. And insulin was initiated, first starting with NPH insulin given in the morning and at bedtime. Now between 28 weeks and 32 weeks on our weekly glucose reviews, there was rapid escalation of insulin doses. There was increases in both the NPH doses, the basal insulin, as well as addition of rapid acting insulin for mealtime elevations. Between 32 weeks and delivery on the weekly glucose reviews, there was continued up titration of these insulin doses to achieve glycemic control. In regard to fetal surveillance, she underwent serial growth scans and began twice-weekly antenatal testing at 32 weeks due to needing pharmacologic therapy to control her glucoses. At 36 weeks, the fetal growth scan showed an LGA fetus and she ultimately developed gestational hypertension and was induced at 37 weeks. She had a successful spontaneous vaginal delivery of an 8 pound 2 ounce infant and had no maternal or neonatal complications. So as per routine, after delivery, all of her medications were discontinued. On postpartum day one, a fasting glucose was obtained and it was 121, which was elevated. And so the decision was made by OB providers to continue to monitor her glucoses through postpartum day one. And as you can see here, she had significant elevations in her postprandial glucose values. Given this, the OB providers made a decision to reinitiate insulin therapy at one half of her last pregnancy insulin regimen and continue finger stick glucoses. On postpartum day two, after initiation of insulin, her glucoses improved, but were still not at target. This led her clinicians to be concerned about type 2 diabetes and or LADA. And so they drew some additional labs. They drew a hemoglobin A1c, which was notable at 5.7%, which was elevated compared to her initial screening A1c at the beginning of pregnancy. And then they checked autoantibodies and she had GAD antibody positivity and a reduced c-peptide level. Endocrinology was consulted and follow-up was arranged for long-term management. So what is latent autoimmune diabetes of adulthood or LADA? In 2019, the World Health Organization classified LADA as a form of diabetes that shares phenotypic, genetic, and pathophysiologic characteristics of both type 1 and type 2 diabetes. And it is also sometimes referred to as type 1.5. The incidence of LADA varies among countries and ethnicities, with the highest incidence in Europe and China. And LADA accounts for between 2 and 12% of all diabetes cases. The Immunology of Diabetes Society highlight three hallmark criteria for LADA, age over 30, antibody positivity, and the absence of insulin dependence for at least six months. Yet there continues to be debate as to the need to meet all of these diagnostic criteria. Because of the overlapping characteristics with type 1 and type 2 diabetes, as well as typically a latent and slow progression of the disease, there is an increased risk of misdiagnosis. Yet early diagnosis and appropriate treatment are crucial to preventing complications associated with LADA. So as I mentioned, one of the hallmarks of the disease is antibody positivity. And here is a list of the five most common antibodies associated with LADA. GAD antibodies have the highest diagnostic sensitivity for LADA. And depending on your health system, these antibodies can be sometimes ordered as a panel, or they may need to be ordered individually. We know that individuals with higher levels of antibodies, especially GAD antibodies, typically experience an accelerated progression and a higher rate of beta cell failure quickly, and thus early insulin initiation. So in our case, you saw that a C-peptide was ordered. And a C-peptide was ordered to assess pancreatic beta cell function. Pro-insulin is secreted from the pancreas, and the C-peptide is cleaved off of the pro-insulin. And the C-peptide is more stable and has slower degradation than insulin. So it's an easier marker to measure for pancreatic beta cell function. And the majority of times that we see for individuals with LADA, the C-peptide is decreased, but it is still present. Unlike type 1 diabetes where the C-peptide would be negligible and type two diabetes where often C-peptide is preserved except in individuals with long-standing type two diabetes. Some experts and clinicians will talk about the role of C-peptide for serial measurements if a diagnosis of LADA is made to both monitor for disease progression, progressive beta cell failure, and to stratify for risk of worsening metabolic function. C-peptides can typically be ordered as either fasting or stimulated after a meal challenge or glucagon. This table illustrates clinical features of LADA compared with both type one diabetes and type two diabetes, and specifically you can see the similarity in BMI, HLA susceptibility, and autoimmune antibodies with LADA and type one diabetes, yet you can also see similarities with insulin resistance with type two diabetes. Unlike type one diabetes, individuals with LADA again will exhibit some residual beta cell function, but the decline of beta cell function occurs much quicker than with type two diabetes. So as clinicians who are treating individuals with gestational diabetes, one of the big take-home messages for us is that autoimmune diabetes occurs in 10 percent of GDM cases. So if we're taking care of individuals with gestational diabetes, we are seeing individuals who would have autoimmunity antibody positivity and may ultimately be diagnosed with LADA. Currently, there are no recommendations for universal screening of GDM individuals, yet as clinicians, we should think about certain risk factors which may prompt us to look and to evaluate an individual for LADA. Some of those risk factors are a young age, a low body mass index, an early diagnosis of gestational diabetes, an early need for insulin therapy or rapid escalation of insulin therapy, if the individual has a personal history of autoimmune thyroid disease, if the individual has no family history of type two diabetes or potentially has a family history of autoimmune disorders. All of these clinical characteristics, either in isolation but definitely in combination, may increase the likelihood that the person who is diagnosed with gestational diabetes may ultimately carry also a diagnosis of LADA. I wanted to highlight one specific study that was published in Diabetes Care in 2007 by Nielsen and colleagues. This is a study that looked at 385 individuals who were diagnosed with gestational diabetes and they evaluated whether these individuals had antibody positivity and they looked for three specific antibodies, GAD, ICA, and IA2A. What they found is that 6% of their GDM population had antibody positivity. Interestingly enough, 23 of the 24 had GAD positivity and a little over 50% had positivity for more than one antibody. They then took the 24 individuals who had antibody positivity and they matched them in a two-to-one fashion to individuals with a diagnosis of gestational diabetes but who were antibody negative in their study. Then they followed them post-delivery. As you can see here, among the 24 individuals who had antibody positivity, 50% were diagnosed with type 1 diabetes compared to no cases in the controls or the antibody negative individuals. Notably, 50% of the individuals who were diagnosed, so 6 of the 12, were diagnosed with diabetes within one year of delivery and 10 of the 12 were diagnosed within four years of delivery. The remaining two cases were diagnosed at five years post-delivery and then seven years post-delivery. Conversely, in antibody negative individuals, 12% developed type 2 diabetes, which is the typical association that we think of when we think of individuals who have a history of gestational diabetes and that increased risk of type 2 diabetes. The rates of impaired fasting glucose and impaired glucose tolerance were similar between groups. I bring this study up because the findings highlight the role of autoantibody positivity in GDM individuals and long-term health outcomes. Circling back to our clinical case, the clues for Lada in our clinical case included that our patient had a lean body mass index, she had a need for insulin therapy, but most specifically, she had rapid escalation of insulin doses and she needed multiple insulin doses throughout her pregnancy, and then probably most notable was the sustained significant hyperglycemia after delivery. There are a couple other clinical situations where one should consider the diagnosis of Lada or screening for Lada in GDM individuals. One is a person who has been diagnosed with gestational diabetes who comes in to the hospital for diabetic ketoacidosis and also individuals who have significantly elevated both fasting and postprandial hyperglycemia. The other way to kind of look at like how best to think about a person who is diagnosed with gestational diabetes and whether we should consider screening for Lada is the useful tool that is published in the Standards of Care in Diabetes, the AABBCC approach. So when we think about this, specifically for Lada, for age, we're thinking about younger individuals who are diagnosed with gestational diabetes, certainly remembering that they would have autoantibodies and antibody positivity. They tend to have a lean body habitus and BMI. In terms of background, if we saw that, if we heard that the individual has no family history of type 2 diabetes, or if they have a family history of autoimmune disorders, that might prompt us to think a little bit more about the potential for Lada. For control, in this case for gestational diabetes, I think about early insulin initiation and higher insulin doses. And then for comorbidities, I am thinking about autoimmune disorders. So if someone has autoimmune thyroid disorder or any other particular autoimmune disorders, then that would make kind of help me think about should I think more specifically about the possibility of Lada in an individual with gestational diabetes. So the treatment of individuals with Lada should focus on achieving glycemic control and then the potential for preservation of beta cell function. It is clear that beta cell function deteriorates more rapidly in individuals with Lada compared to type 2 diabetes. And thus, it is really important to identify these individuals because they need close long-term follow-up to determine when pharmacotherapy needs to be intensified. The beta cell failure is somewhat unpredictable and there may be some individuals who will not need insulin therapy for a long period of time. We know that individuals who experience more rapid progression are those individuals who have very high antibody titers, who have more than one antibody positivity, and those individuals who have low C-peptide levels. And as with all forms of diabetes, a personalized therapeutic approach between clinician and patient is key. Treatment strategies should be individualized, but when we think about achieving glycemic control and preservation of beta cell function, the DPP4, TZDs, and GLP1 receptor agonists are reasonable options. There is limited data regarding the use of metformin, specifically in cases of Lada, but it may be an option for some individuals. And then insulin therapy may be initiated when hyperglycemia is not able to be controlled with other medications or due to specific clinician recommendations. Sulfonylureas are not recommended because they have been shown to result in earlier beta cell failure, more rapid decrease in C-peptide levels, and a more rapid progression to insulin. And our SGLT2 inhibitors have not been studied in Lada individuals, and so if they are used, education around the risk of ketoacidosis is important. So one of the main goals for identification of individuals with Lada is to provide close surveillance and appropriate follow-up so that treatment can be tailored and intensified when that beta cell failure progresses. We know that worsening glycemia and a delay in initiation of insulin therapy can increase the risk for both microvascular and macrovascular complications. And similar to type 1 diabetes, the risk of microvascular complications depends on diabetes duration and glycemic control. In a sub-analysis of the UK prospective diabetes study, in the first nine years after diagnosis, individuals with Lada had lower rates of microvascular complications compared to individuals with type 2 diabetes. Yet after nine years, individuals with Lada had a greater risk of microvascular complications compared to individuals with type 2 diabetes. And this may be attributed to worse glycemic control early in their disease development. In regard to macrovascular complications, individuals with Lada have similar rates compared to type 1 individuals, and slightly better outcomes than individuals with type 2 diabetes. Part of continued surveillance in clinical management is the assessment of end-organ disease. So individuals with Lada should be screened for end-organ disease at diagnosis. And then if they are non-insulin requiring, they would follow typically the type 2 guidelines for surveillance until therapy is intensified to insulin and then would convert to the type 1 diabetes guidelines. For cardiovascular screening, they should be screened and treated similar to type 2 diabetes. And remembering that individuals with Lada have a higher rate of autoimmune disorders, they should be screened with a TSH at the time of diagnosis and then follow type 1 diabetes guidelines for screening cadence. So in conclusion, 10% of GDM individuals have autoimmune antibodies. So as we treat our patients with gestational diabetes, we need to keep this on our radar. The most common antibodies are GAD and islet cell antibody positivity. And we should be thinking about Lada when we have an individual with gestational diabetes who is at a younger age, a lower BMI, earlier diagnosis of gestational diabetes, has a personal history of autoimmune thyroid disease. All of these factors, especially if there's a combination of these factors, may identify individuals at higher risk for Lada. GDM individuals presenting in DKA should also be screened for Lada. And one of the key things that we stress is identification of Lada so that appropriate close follow-up and surveillance can be recommended so that early identification of progressive beta cell failure and initiation of insulin are key components to prevent both microvascular and macrovascular complications and improve their overall long-term health. Thank you, Dr. Dernwald. All right, thanks so much. Hopefully, everyone can see and maybe give a thumbs up if the slides are showing up now. I got a thumbs up from Cassandra. Great. Thank you so much, Dr. Dernwald, for that wonderful section on LADA. I was interested to hear a lot of the discussion, especially the case. And thank you also to our moderators and the ADA for putting on this session today. I'm excited to be talking about the second portion of this, which is about monogenic diabetes and pregnancy. And again, I'm Laura Dickens. So coming from the University of Chicago, I have no financial disclosures. OK, and the outline of my talk is here. So we're going to begin by defining MODY or monogenic diabetes. Then we'll review some common forms of monogenic diabetes, talk about recognizing and managing monogenic diabetes and pregnancy. All right. And to frame our discussion, I'm going to start with the case of Sally. So this is a 27 year old. She's a G1P0 coming at 10 weeks gestation with a history of hyperglycemia. She'd initially been found to have elevated blood glucose when she was 23 during an unrelated presentation with appendicitis. Her glucose had been monitored since that time and had fasting ranging from 107 to 112, never treated with medication. The patient had always found this diagnosis surprising because of her normal BMI, which was 20 before her pregnancy and a very active lifestyle. So I included her glycemic testing from early pregnancy below with a mildly elevated hemoglobin A1C, as well as one and three hour glucose tolerance tests. All right, so we gathered some additional history and found that her father was known to have high glucose, but did not see doctors regularly. Some additional lab tests included detectable C-peptide and negative diabetes autoantibodies, which gave us some reassurance against LADA. She then proceeded to have genetic testing and was found to have a pathogenic mutation in the glucokinase gene or GCK. So we'll discuss more about this as we go forward, but we'll find that making this diagnosis may have been the easy part in a case like this. All right, so to begin, what is MODY? The term MODY stands for maturity onset diabetes of the young. A more accurate terminology that's gaining some favor is monogenic diabetes, which more accurately describes this group of conditions. And essentially, monogenic diabetes describes a group of inherited forms of diabetes that are caused by specific gene mutations that cause beta cell dysfunction. The prevalence is about 1 in 10,000 adults, but this is notably derived from predominantly white European populations. So the prevalence is less certain in different racial and ethnic groups. Historically, the different forms of MODY were referred to as MODY-X, MODY-1 and 2, 3, 5, etc. We're moving away from that listing and prefer the nomenclature using the gene name for clarity. So HNF1-alpha MODY rather than MODY-3, for example. All right, and so to understand the pathophysiology of monogenic diabetes, we began with the pancreatic beta cell, which is illustrated here. I'll point out two key features. The first is glucokinase. So glucose is transported into the beta cell by the GLUT2 transporter protein on the cell surface. So there, the glycolytic enzyme glucokinase will catalyze the formation of glucose-6-phosphate. So in its role enabling this reaction, glucokinase functions essentially as the glucose sensor of the pancreatic beta cell. It's important to understand the normal function to understand the dysfunction when we see mutations. The other factors I'll point out here, so the other red box are the MODY-associated transcription factors. So this is a podocyte nuclear factor HNF4A1A and 1B, 1-beta. So among others, these function in the nucleus of the beta cell and regulate the transcription of the insulin gene and genes encoding other enzymes involved in transport and metabolism of glucose. Okay, so these conditions are relatively rare. You might wonder why it's important to talk about and to make a correct diagnosis of monogenic diabetes. A few of those reasons are listed here. In many cases, once we've made a diagnosis, treatment can be optimized with precision therapy that's different from type 1 or type 2 diabetes. Family members may be at risk when we've made this diagnosis, so they can be counseled and tested. And there are sometimes additional complications that an individual can be at risk for, which requires specific monitoring. For example, with HNF1-beta, there's risk for certain types of renal disease that we screen for. All right, so here we'll talk a little bit about when to suspect monogenic diabetes. So we should think about this diagnosis in any patient that has a presentation or clinical course that's atypical for both type 1 or type 2 diabetes. So I outlined on the left the features of atypical type 1 diabetes to raise our suspicion for a monogenic cause. This can include negative pancreatic autoantibodies, low insulin requirements, detectable C-peptide years after diagnosis, and lack of DKA off insulin. Some atypical features of type 2 diabetes that could suggest a monogenic cause include a young age at diagnosis. So less than 35 is often quoted. Less than 25 years old would be even more suggestive. A normal or low BMI and lack of physical findings of insulin resistance could also point us towards a monogenic cause. The last thing I'll mention for both is family history. So an autosomal dominant pattern of inheritance is a key feature of monogenic diabetes that we should look for. We'll dig a little deeper into family history here. The statistics tell us that 2 to 6 percent of people with type 1 diabetes will have an affected parent. For type 2 diabetes, because of the shared environment and risk alleles, that percentage increases up to 18 to 38 percent. With monogenic diabetes and the autosomal dominant pattern of inheritance, there will be a 50 percent chance of having an affected parent. De novo mutations are relatively rare, so with the right questioning in almost all cases, you will identify a family history. It's important to take a specific family history if you're suspecting monogenic diabetes and include at least three generations. In addition to asking about whether they have relatives with diabetes, you should gather details about any affected family members. So that can include age of onset of diabetes, body habitus, and specific therapies. That can help us understand the likelihood that a relative would share a monogenic diabetes diagnosis. Okay, so the next section here, we're going to review some common forms of monogenic diabetes. We'll start with GCK, which has sometimes been known as the unicorn of monogenic diabetes. You'll remember back to our pancreatic beta cell. With GCK, we get a mutation in that insulin-sensing receptor on the beta cell that leads to an increased glucose set point. So insulin is released, but just requires a higher glucose in order to prompt that. So clinically, you'll see mild fasting hyperglycemia that's present at birth and does not lead to typical diabetes complications over time. This is the magical part. It's that treatment's generally unnecessary because people are not at risk for complications. And interestingly, treatments like metformin are ineffective for glucose lowering. The one caveat is pregnancy, which is the reason we're here for discussion and we'll talk in more detail about. The other common forms of monogenic diabetes I'll mention are HNF1-alpha and HNF4-alpha. HNF1-alpha is actually the most common form of monogenic diabetes. It represents 30 to 65% of all cases. So these forms arise from mutations in the genes encoding those transcription factors in the pancreatic beta cell and lead to defects in insulin secretion. So insulin's produced, it's just not released appropriately. This will present with hyperglycemia in adolescence or early adulthood. There's specific clinical features that can point to HNF1-alpha, including a lowered renal threshold for glucosuria. And then in HNF4-alpha, there's a really characteristic risk for macrosomia and fetal hyperinsulinism in affected neonates. So patients with these mutations, unlike GCK, can develop diabetes complications with suboptimal glycemic control. And those risks are similar to type 2 diabetes. So you may wonder how these differ so much from type 2 diabetes, keeping all of this in mind. A critical point is that there's a precision therapy that can improve glycemic control in many cases of HNF1-alpha and 4-alpha. And that treatment, interestingly, is sulfonylureas. So they can very specifically rescue that defect in insulin secretion for patients with HNF1-alpha and 4-alpha. So even patients that have been on basal bolus insulin, in many cases, can be successfully transitioned to a low-dose sulfonylurea alone, typically low-dose glyburide. Over time, the glycemic control can deteriorate, so the sulfonylureas may become less effective over years or decades. And other options, including insulin, may be necessary. But this is a really key opportunity not to miss the precision and greatly simplified therapy for these patients. Next, we're going to talk about recognizing monogenic diabetes in pregnancy. We're going to zero in on kind of the topic of presentation, right? So when it's not gestational diabetes, and we'll talk a lot about GCK because that's what you may find is mistaken for gestational diabetes, particularly since many young people may not have had routine glycemic testing outside of pregnancy. So GCK may first come to light when screening for pre-existing or gestational diabetes is completed. There's been variable prevalence of GCK reported in gestational diabetes cohorts, ranging from zero to as high as 80%, depending on the selection criteria. And you'll see those cohorts where the prevalence is quite high. They carefully selected patients with particular body mass index and glycemic parameters that were more likely to have this diagnosis. And the rationale for that comes from this key study from 2014, where a group in the UK looked at different cutoffs for BMI and fasting glucose, where we could differentiate GCK from gestational diabetes. So here they found that using a BMI less than 25 and a fasting glucose greater than 100 was highly specific and reasonably sensitive for identifying GCK. Yet I mentioned the study was done in the UK, so this was a predominantly white population, and the applicability of these cutoffs in other racial and ethnic groups is uncertain. All right, so once the clinical history and or glycemic testing suggests a monogenic diabetes diagnosis, the next steps in evaluation should include that thorough medical history, including the diabetes history and the family history, as well as physical exam and lab testing. The C-peptide is particularly useful for those patients that have been given a type 1 diagnosis because detectable C-peptide years after a type 1 diagnosis is inconsistent with that and should prompt consideration of monogenic diabetes. Pancreatic autoantibodies can also be helpful for identifying autoimmune diabetes. So it's quite rare to actually have positive antibodies in a patient with monogenic diabetes. So if you get a positive autoantibody result, it's very unlikely to be monogenic diabetes. And one useful tool that can quantify an individual's likelihood of monogenic diabetes is the MoDI probability calculator, which was created at Exeter. You can access this free online. You input information about your patient, and it'll give you a post-test probability of MoDI. It's recommended if that probability is greater than 25% to pursue genetic testing. And again, this tool was developed in a white European population, so uncertain applicability in other racial and ethnic groups. Okay, so that leads us to how we'll confirm a diagnosis. Genetic testing is the way to do this. You can complete genetic testing looking for single-gene mutations, a multi-gene panel, or chromosomal microarray analysis, more comprehensive testing. If you have one specific diagnosis that's highly suspected, like GCK, for example, single-gene testing is appropriate. If it's less clear-cut, the MoDI multi-gene panel typically includes the 14 known MoDI-related genes. And importantly, many times insurance will cover this testing when you have appropriate justification. The MoDI probability calculator that I just showed is one good tool to provide that justification. Our group at the U of C, University of Chicago, we also have template letters for insurance justification that we're very happy to provide. I can email it to you, and we'll provide my email at the end of the talk. Okay, all right, so I think many in the audience will be interested in this next topic for discussion, so management of monogenic diabetes in pregnancy. We'll focus our discussion about GCK, and then if there's time, talk briefly about some of the other forms. Okay, so first we'll talk about the pregnancy implications of that GCK diagnosis. The literature has shown no increase in miscarriage risk with GCK, and the risk of fetal malformations is similar to the background population. So despite the mildly elevated blood glucose, there don't seem to be early risks associated with it. The critical outcomes related to birth weight and those complications are determined by fetal genotype. So this is illustrated in the graph on the right. Affected fetuses, so if a fetus inherits that GCK mutation, it will have normal birth weight. So imagine this fetus shares that same mildly increased glucose set point and therefore senses those mildly elevated blood glucoses to be normal and proceeds with normal growth even with no treatment. So this is the black bar sort of second from the left showing a mean birth weight in that circumstance of 47 percentile. Unaffected fetuses, so these are the ones who do not inherit the GCK mutation are going to be at risk for increased birth weight. The way you can understand this, so these fetuses have a normal glucose set point and they sense that mild maternal hyperglycemia in the same way a pregnancy would with type 1 or 2 or gestational diabetes. So they respond with fetal hyperinsulinism and risk for increased birth weight. On the left, you can see that circumstance where unaffected fetuses can have an average birth weight percentile of 85%. All right, so the next obvious question is how are we going to know whether the fetus has inherited the mutation since the course and pregnancy can vary dramatically, you know, based on that question. We don't recommend genetic testing of the fetus unless that's done for other reasons with invasive testing due to risks for miscarriage from, again, invasive testing for genetic testing. Instead, the recommended management strategy is to use serial ultrasound monitoring of fetal growth essentially to infer the fetal genotype. So this figure illustrates that approach. We begin with growth scans at 26 weeks and if the fetal abdominal circumference surpasses the 75th percentile, that's taken to indicate that the fetus did not inherit the mutation. Their risk for overgrowth and insulin treatment should be initiated. If fetal growth proceeds normally, that's taken as an indication the fetus did not inherit the mutation, did inherit the mutation, excuse me, and with normal growth, no treatment, no insulin is necessary. All right, so we'll see what this looks like sort of in real life. Returning back to the case of Sally, who remember was our patient in early pregnancy, had that genetically confirmed GCK diagnosis. Her blood glucoses were monitored throughout her pregnancy, remained in that typical range for GCK, and fetal growth proceeded normally. I included her abdominal circumference and estimated fetal weight percentages here. She was not treated for her mild hyperglycemia. She presented spontaneously, near term, with rupture of membranes, had a normal vaginal delivery, normal birth weight, and no complications. So this seems like a piece of cake, right? The other side of the coin. So that circumstance may be relatively straightforward, but I'll use Kara's case to illustrate the other way this can go. So Kara was a 32-year-old. She was a G2P1. She had a known diagnosis of GCK and presented at 11 weeks gestation. In a previous pregnancy, she'd been seen to have accelerated growth on that second trimester monitoring. She was treated with insulin but had difficulty meeting glycemic targets, had persistently elevated abdominal circumference on her growth scans, and then had a difficult labor course, though her infant's birth weight was not was not excessively large in the end. So in her second pregnancy, she was treated with basal bolus insulin aggressively, in this case up to 1.2 units per kilo, still found it difficult to reach pregnancy targets, and the abdominal circumference and fetal weight percentages were still high. As you can see, abdominal circumference often over 90th percent. She delivered by a repeat C-section just after 38 weeks, fortunately had no complications, and birth weight in this circumstance again was not excessively large. So her case illustrates a couple of challenges in the management of GCK, the first two in particular. So first, the typical glycemic targets are for pregnancy are difficult to achieve with GCK even with insulin. Second, the rates of large for gestational age and C-section are high in these pregnancies, especially when offspring are not affected with GCK, even when we use insulin. And a third point for discussion is about the use of insulin in GCK-affected fetuses, so in the potential for adverse consequences of that situation. Okay, so talking to the first point, this was a study of 99 pregnancies with GCK. They looked at first and third trimester finger stick blood glucose monitoring and outlined the pregnancy targets for fasting under 90 and one hour under 140. And you can see just from a glance at the graphs that many subjects didn't meet those pregnancy targets with insulin treatment in this cohort. In our experience, it takes high doses of insulin to overcome that increased glucose set point with GCK and can make it difficult to achieve targets and potentially result in hypoglycemia. The second point about high rates of large for gestational age and C-section in those unaffected fetuses is discussed in these next couple of slides. So, this is a chart from that same retrospective study and on the left sort of column goes through the pregnancy outcomes for the unaffected fetuses. Here, the birth weight percentiles ranged from 69 to 92% in the unaffected fetuses and rate of C-section was quite common, 67 to 82%. And again, in those pregnancies where the fetus did not inherit the mutation. A couple other studies have shown similar findings. On the top, this looks at the average birth weight for those GCK unaffected fetuses was just above four kilograms and didn't differ when insulin was used, which is the black filled circles, or no insulin was used, which is the open white circles. There's actually been a meta-analysis of outcomes looking at the combined incidence of macrosomia or LGA that showed a lower rate of macrosomia when fetuses inherit the mutation versus that unaffected group and was highly significant. That odds ratio was 0.13. All right, and then the next point to consider, so when you look at points one and two, it's difficult to achieve pregnancy targets and large for gestational age and C-sections are still common in those unaffected fetuses. An argument could be made that anything we can do to give us a better chance of reaching glycemic targets for more time throughout pregnancy may be optimal to give us the best shot at controlling fetal overgrowth. So perhaps we should be using insulin in all cases to really hone in on that population. So some have advocated that we should use insulin for all pregnancies with glucokinase, essentially to allow earlier initiation of therapy. And one problem with this approach is that there can be adverse events with insulin therapy, and that's a particular concern in cases where we may not need that treatment at all because the fetus has inherited the mutation. So there have been a few studies that have shown pretty significant rates of hypoglycemia and severe hypoglycemia. Our group observed a 23% incidence of severe hypoglycemia. And then a recent study that I'll go through in just a moment showed recurrent or severe hypoglycemia in up to 75% of subjects treated with insulin. So there is a very real concern about use of insulin, particularly in cases where it's not necessary, leading to hypoglycemia. In the past, we'd wondered about fetal growth, whether using insulin again in those affected fetuses might lead to small for gestational age. That hasn't really panned out in larger sample sizes. Okay, so the last study I want to make sure we go through, it's very timely for our discussion. This was just published in February, and it's essentially as close to a randomized controlled trial about management of GCK in pregnancy as we're likely to get. This study was in France. They enrolled 45 subjects with GCK and then allowed the patients and physicians to choose a management strategy. Either they started insulin when glucose exceeded pregnancy targets, which was essentially right away, or they started insulin based on the standard guidelines of ultrasound measurements waiting until the abdominal circumference was greater than the 75th percentile. Large for gestational age was common throughout the study. So 36% of the fetuses that were unaffected had large for gestational age. And interestingly, they saw no difference in that between the treatment groups. So this tends to refute the idea that using insulin earlier can more effectively slow the excess growth for those unaffected fetuses. This is the study that I had just mentioned where they had frequent hypoglycemia, and that did limit their insulin titration some, so the doses were relatively lower, but is nevertheless kind of an interesting interesting point to add to this discussion. Okay, and this is just a graphic outline of the study we were just describing. Since early insulin therapy for all isn't clearly going to be beneficial for reducing large for gestational age and may carry risk for hypoglycemia, there's interest in earlier and more accurate determination of fetal genotype to hone in on those those patients that will really benefit from early and intensive insulin. And non-invasive prenatal testing has gained a lot of favor recently. You're all likely familiar with this, diagnosing other genetic conditions, and it's recently been studied for prenatal GCK diagnosis. So the Exeter group pioneered this strategy. They published a series of 38 pregnancies comparing the diagnostic accuracy of NIPT to the standard ultrasound monitoring. So NIPT was highly sensitive and specific and clearly superior to the ultrasound monitoring. This result has been replicated by other groups, including some in the U.S., but it's still in the research phase and unfortunately is not widely available, but is a promising development. Okay, so this is just a summary slide about the discussion of managing GCK in pregnancy. There's limited data that early insulin therapy in all pregnancies doesn't reduce large for gestational age compared to that delayed insulin therapy based on fetal growth. NIPT is a promising strategy, but still, you know, requires more development to be widely available. One just final point to make, I'm optimistic that we may find some success with these newer hybrid closed-loop systems with lower targets to achieve tighter glycemic control but minimize hypoglycemia. All right, and then as a last resource for us, I mentioned to feel free to contact us specifically about template letters for genetic testing, but any interesting cases or other questions, the Monogenic Diabetes Group at the University of Chicago is here for guidance and resources for patients and clinicians. So thank you very much. I'll end there. Thank you, Dr. Dickens and Dr. Durnwall. Really wonderful discussions. I'm grateful. We have one question in the chat that I'm not really sure what it refers to, but the question is, when is it not gestational diabetes? I'm sorry. No, that's not. Where is that? It was oh, here. Would an increase A1c in pregnancy be diagnostic of GDM? I guess versus MODY or LADA. Is that the question? Laura Mulligan, you're still on. Could you clarify that? I think Laura, actually, Dr. Dickens addressed that question because it was more specific to the GDM. Got it. Okay. One more. Actually, first, we just want to let you know later today you'll receive a post-test by email. So if you complete that, you can claim your CE credit. You can also look for today's webinar recording to share with others on the ADA's Institute for Learning page in a few weeks. You can tell others that they can watch that webinar up until December 2025 to receive CE credits. We only have a couple minutes remaining, so I have some questions that were sent in ahead of time. I'm going to focus on the ones that are very MODY and LADA specific. Dr. Dickens, you went over some tips for getting coverage for testing, but some of our input was about patients where it's cost prohibitive or even if it's covered, if genetic testing, like a consultance, aren't available for over a year out, is there something that the OB or the endocrinologist can do themselves? Yeah, that's a really good question. And again, hopefully, try to get insurance coverage because in many cases, especially if you go through that process, it can be covered. Invitae offers MODY genetic testing for $250 maximum out-of-pocket, so that's an option that we'll sometimes share. Again, that's still a significant cost. And so that covers the, you know, we used to be able to offer research-based genetic testing, which obviously varies based on funding and other circumstances, so I'd say don't give up on it and reach out. We're always happy to help if there are ways we can. From the genetic counseling standpoint, this is a really good question too. There are in many places, even if you're not um largely familiar with these diagnoses, recognizing and making a diagnosis. There are centers all around that have individuals, especially in endocrinology departments, that are seeing many of these patients. So again, as another way, we'll sometimes help link people up to someone in your area where you can refer a patient. So there are people out there that know about this diagnosis. I think recognizing it and then connecting is the best first step. And then Dr. Dernwald, when should antibody testing be conducted? And if you had to start, like, would you start with one antibody for cost-effectiveness or do the entire panel? Yeah, that's a great question. I, you know, I think the most significant impact we would have in terms of LADA positivity is really focusing on those risk factors that I spoke about. And I, if you, if the panel is available, I think that's like an obvious yes, do the panel. But if you really had to pick, I would focus on the GAD antibody. But understanding that, you know, even though it's highly specific and the majority of people had GAD positivity in the studies, we could still be missing some individuals. So if I had to, if I only had a certain, if I only had two labs to draw, I would draw the GAD positivity and the C-peptide if an auto antibody panel was not available to me. Thank you all for attending and just join the ADA and please, we communicate through the forum. And you can see, we also have notable papers for the year that we've reviewed. And thank you all. And again, to fill out the, see the question, the post-test questionnaire to get your CE. And we hope to see you in Chicago in June. Yes. Thank you all. Thank you. Bye.

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