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OBGYN.net Conference CoverageFrom First Congress on Controversies in Obstetrics, Gynecology & Infertility Prague CZECH REPUBLIC - October, 1999
Dr. Mark Perloe: "I'm here with Professor Moshe Hod from Israel, who will speak to us a bit about gestational diabetes. Can you tell us about your work? First of all, where are you in practice and what sort of practice is it?"
Professor Moshe Hod: "I'm working at the Rabin Medical Center in Israel. We are considered to be the biggest medical center in Israel, with around 8,000 deliveries per year. I run the Perinatal Division, and I'm head of the department, which is for high-risk pregnancy. The main interest of the department is diabetes in pregnancy, with a lot of problems there that can be solved at this stage."
Dr. Mark Perloe: "In the population that you see, do you find that it is a problem with one ethnic group more so than another, or is your population fairly homogenous?"
Professor Moshe Hod: "Our population is fairly homogenous. We see the incidence of gestational diabetes around 3% of the whole obstetrical population, and it's constant in the various ethnical groups in Israel."
Dr. Mark Perloe: "What risk factors and screening programs are you using to pick up patients with the condition?"
Professor Moshe Hod: "Let's see... We don't pick up patients by high risk, we screen all our pregnant patients for gestational diabetes. We fill out the suggestions made by the American Diabetic Association and the American College of Obstetricians and Gynecologists that recommend screening every pregnant patient between 24 and 28 weeks of pregnancy with a 50-g glucose tolerance test. Then, if it's positive - and it's considered positive if it's over 140-mg per DL - we give a full oral glucose tolerance test, which can be either 75-gm load or 100-gm load, and it takes three or four hours. We had either three or four results, and having two results over a certain threshold identifies gestational diabetes."
Dr. Mark Perloe: "Tell us about your work, then, in terms of minimizing complications from gestational diabetes during the pregnancy."
Professor Moshe Hod: "We can divide diabetes in pregnancy into two main groups. One is pre-gestational diabetes, which is diabetes that existed before pregnancy. This is the most severe form because these are women that had diabetes before pregnancy, and they're treated either by insulin or oral hypoglycemic agents. They have to be treated appropriately in order to start pregnancy, at the time of conception, to be completely in glycemic control. Otherwise, if they don't follow this, they are not treated well during the conception and the chance of major congenital anomalies can be higher, almost six times higher than in all the population. If we have 3% in our own population, we can have as high as 16%-18% incidence of congenital anomalies in non-treated patients."
Dr. Mark Perloe: "What factors that are associated with diabetes do you believe are associated with or the cause of the congenital anomalies? Is it high sugar, insulin, or a vascular effect? Why are these people at risk for congenital anomalies?"
Professor Moshe Hod: "We actually don't know, but we are beginning to understand the basics under the causes of congenital anomalies. High glucose is only a marker. We are sure that high glucose imposes changes at the molecular level at the intracellulary. There is now more and more evidence that high glucose can induce changes in second messengers at the cellular level, like myoinositol, arachidonic acid, and the generation of free oxygen radicals. So we have two possibilities: we can either fight, reduce glycemia, and control our patients metabolically, or there are more and more thoughts now that maybe we can supplement a cocktail-like folic acid and other anti-metabolites like scavengers for the radicals and for vitamin E in order to work at the intracellular level."
Dr. Mark Perloe: "There are trials ongoing now with chiro-inositol in polycystic ovaries, and they have been promising. It may be that an agent such as this may also be helpful, and the myoinositol work is very exciting as it may shed some light on the risk of congenital anomalies."
Professor Moshe Hod: "I agree, most of our studies were done in the laboratory on rats, but there is more and more evidence. I was looking for some on myoinositol preventing congenital anomalies indirectly in the whole embryo white culture, and it works beautifully but it has to be proven in clinical - in human - pregnancy. We're now planning a study that will identify a high-risk group of diabetic patients that maybe can be supplemented with all or part of these agents. Dr. Erickson, who is considered one of the leading basic scientists in the field of congenital anomalies, is now planning the study on this. So we are now trying to combine forces between the basic scientists and clinicians like myself, combine a protocol for human pregnancy, and start doing it in the near future."
Dr. Mark Perloe: "That's exciting, and we all look forward to that. How do you get the patients under control, and what is your measure? Is it blood sugars, hemoglobin A1c's, or a combination of both?"
Professor Moshe Hod: "The combination of both of them. All of our patients have agreed to it with blood glucose monitors. They're holding self-monitoring blood glucose, they're performing pre-pregnancy and during the whole pregnancy five to seven blood tests per day, which give us a very accurate estimate of our goals of metabolic control. We want them to be fasting at below 90-mg per DL, and we hope to achieve less than 120-mg per DL at two hours post prandial, which is a very, very strict regime. We accomplish it by multiple injections of insulin, and we combine mainly two modes of treatment. One is with intermediate-acting insulin like NPH, and the other one is regular insulin which we advise pre-meals, every meal. So with some it's been four or five injections per day, and by using this strict protocol, we can maintain almost all of our patients in almost all glycemic control. This is reflected then by a lower A1c, which is almost in the near normal range."
Dr. Mark Perloe: "Do you think the women with polycystic ovaries present a unique risk factor, either for developing this following conception or for issues related to fetal anomalies when they ultimately conceive? We know there are greater risks for miscarriage."
Professor Moshe Hod: "I can't answer you. We tried to look into this matter, and we know the variance of insulin resistance, but we actually don't correlate it very nicely and with the incidence of gestational diabetes during pregnancy, that's a problem."
Dr. Mark Perloe: "That's been our finding also."
Professor Moshe Hod: "That's our finding. We have a huge clinic for polycystic ovary syndrome. We had the database, but we couldn't find any correlation between the insulin resistance and the gestational diabetes during the second half of pregnancy. It's not related to the incidence of congenital anomalies because gestational diabetes and insulin resistance are more pronounced in the second part of pregnancy - twenty weeks and beyond. By that time, congenital anomalies or organogenesis are complete. So you don't have an increased risk for congenital anomalies but you do have an increased risk for excessive fetal growth, like macrosomia and all the rest of the problems that macrosomia imposes on the mother and the fetus. We have a lot of data now regarding immediate, post-term, and no term effects."
Dr. Mark Perloe: "Now this is in the absence of elevated sugars. You were saying that insulin resistance in later pregnancy may be a risk factor?"
Professor Moshe Hod: "Yes, because GDM gestational diabetes sometimes is symptomless. That means sometimes it's even without elevated non-tolerant glucose levels, so in order to diagnose GDM gestational diabetes, you have to provoke it. You have to do a stress test. That's why we have to give an oral glucose tolerance test and look for the thresholds."
Dr. Mark Perloe: "It's interesting that we diagnose this in a postprandial or after a glucose load because that's the most sensitive test. Yet many physicians still monitor these patients only by looking at fasting or preprandial levels of the glucose rather than measuring sugars after a meal."
Professor Moshe Hod: "It's not good enough. There is a lot of controversy and some people even ask if the gestational diabetes is a diagnosis or a disease. But on the other hand, there is a lot of evidence that if you don't treat gestational diabetes, you end up with a very adverse outcome. In order to end this controversy once and for all, this year we started a multi-national, multi-center study. It's going to be funded by the NIH, the National Institute of Health. The funding is in the sum of nine million dollars, and the study's going to last for the next five years. It will be conducted in sixteen perinatal centers all over the world, I'd say in the leading centers in the world, over five continents - there will be five American centers, four European centers, four Asian and Middle East centers, and four Australian centers. We aim at collecting 25,000 deliveries that will have to go by a very strict protocol. The study's going to be blinded, and the caregivers and the patients won't have their results of the OGTT - oral glucose tolerance test - unless a certain pressure is revealed. As soon as we have this data, we'll be able to correlate it to some endpoints that are very important in gestational diabetes, like the incidence of caesarian section, macrosomia rate, hyperinsulinemia, hypoglycemia, and some other neonatal adverse cell counts. They'll be a lot of ancillary studies that are going to look at these 25,000 deliveries - mothers and offspring - for a very, very long time."
Dr. Mark Perloe: "That will be exciting to see and, ultimately, we'll get some follow-up information on those who were not diabetic prior to the pregnancy regarding what their outcome was afterwards. Too often a woman gets through the pregnancy and the obstetrician does no further evaluation or monitoring for diabetes. In your practice, what are you doing for that patient after they deliver? What kind of testing or monitoring is appropriate?"
Professor Moshe Hod: "We do follow them because we know that GDM patients are prone to the development of Type II diabetes later in life. This is the highest risk for patients that are identified during pregnancy, and they are in danger - if you can call it a danger - of a disease that will develop about ten, fifteen, or twenty years later. And maybe there is something that we can do for these patients during this ten- to twenty-year span of time in order to prevent Type II diabetes. So we follow these patients very closely. We do recommend they have oral glucose tolerance tests six weeks after the delivery."
Dr. Mark Perloe: "Would that be including insulin levels with it?"
Professor Moshe Hod: "Not yet. It would be very good to do it, but there are not enough resources to do it."
Dr. Mark Perloe: "I think that would be great. You'll need some extra blood."
Professor Moshe Hod: "I agree. If you do the test, I'll draw a lot of blood."
Dr. Mark Perloe: "Hopefully 25,000 samples, 100,000... I'm not sure I'd be able to manage it."
Professor Moshe Hod: "I know. The central laboratory for this study is going to be in Belfast. They are going to charge the study a lot of money, so millions of dollars will be shifted towards the central laboratory. There will be a DNA bank of 25,000 deliveries, some insulins, and some C peptides... but that's on the offspring, not on the mothers."
Dr. Mark Perloe: "Do you feel that C peptide is a useful tool? How are you using it, and when are you using it?"
Professor Moshe Hod: "We don't do a urine test. We won't use it in clinical monitoring of pregnancy. But we do want to collect the C peptide during this study. We know that we overestimated the insulin production of the fetus, so this is an estimate that we are going to do. But just regarding the mothers, we do recommend following up on these mothers every year with an oral glucose tolerance test in order to detect glucose intolerance as early as we can and maybe employ some regime, some treatments, in order to prevent them from becoming Type II. There is an ongoing study in the United States now - again, the NIH funded it. It's in twenty-one centers all over the States, and it's looking into this project on how to prevent Type II diabetes. Is it by exercise, prophylactic or hypoglycemics, diet, or some other variables that aren't tested?"
Dr. Mark Perloe: "Unfortunately the use of the PTR gamma Rezulin was in there, and that was pulled off the market so at least that branch of the study was closed down. So we won't have…"
Professor Moshe Hod: "You are familiar with this study?"
Dr. Mark Perloe: "I'm very familiar with it. So we won't have the data to at least say whether there's a role for PPAR gamma, whether it Rezulin, Avandia, or Actos, which are now solid PI."
"But I still think there are enough parameters ongoing in that study, so there's some help there. At least in clinical practice, we've found that diet and exercise alone may be helpful. They usually work best in association with some medicine in controlling insulin resistance in that population and inducing people to lose weight. Our patients have needed to see some results before they continue. In terms of the weight, are many of these patients, or a large percentage of them, overweight? The ones who become diabetic during the pregnancy? Is there some sort of screening for this and would education about weight management and diet be appropriate before conception? Can we prevent gestational diabetes with counseling prior to the pregnancy? We already know about the diabetics who need better control, but as physicians, is there something we can do to prevent gestational diabetes?"
Professor Moshe Hod: "It would be very helpful, but it won't prevent it completely. We know that there is a strong correlation between being overweight, high BMI's, and the development of gestational diabetes. But on the other hand, we do have GDM even in lean women, so there's some genetics involved in it. Maybe there are some other factors that we're not aware of, but being overweight is not the only factor and it is not the only cofounder there that has to do with appearance of GDM. So yes, it's important - we have to educate them. We have to bring them toward pregnancy with a better BMI, but it won't completely prevent the appearance of GDM."
Dr. Mark Perloe: "Is there any new development project that you're working on with the WHF?"
Professor Moshe Hod: "We have more than five million deliveries per year in Europe, and in order to run a quality development program, you need to compare variables to compare outcomes between centers - good centers and bad centers. If you want to improve the bad centers, you have to compare their data to the best or the highest quality centers. So we formed a database in Copenhagen, the original center for Europe, it's going to be the server for this database. We are collecting data on basic information sheets, which means every pregnancy and every visit is entered throughout the pregnancy in the book, from conception through the whole pregnancy, delivery, the neonatal, etc. There are a lot of variables. There is software that exists that we can use to collect the data and send it over to Copenhagen. On the other hand, it's still very difficult to do, and that's why if we have electronic patient files in the near future, it will make our lives much easier to collect this data. On the other hand, what we have been much more successful with is collecting the data on specific projects - diabetes in pregnancy, multi-pregnancy, high blood pressure in pregnancy - and we just finished the formation of the database regarding diabetes in pregnancy. We decided to collect twenty variables regarding the outcomes of a diabetic pregnancy, maternal and fetal, maternal outcomes like preeclampsia, caesarian section rate - just as examples - fetal outcomes as intrauterine demise, macrosomia, polyhydramnios, congenital anomalies, and some others. With these twenty variables, we can compare local, regional, and national outcomes in almost every place in Europe. It's not only limited to Europe. There are some people from the states now that have expressed an interest in joining the project, and they'll be joining it like the California Diabetic Pregnancy Study Group."
Dr. Mark Perloe: "You mentioned in the beginning centers with good results and centers with bad results. What will be easy with this database is to show that some centers are having better outcomes. Are you looking at or collecting data that will help you determine which factors may cause those different results, or is that a follow-up step?"
Professor Moshe Hod: "No. We do collect this data from the aggregated if we go back to the personal database, or personal basic information sheet, and there is a specific one already for the diabetic pregnancy. We have the software ready, which is very easy to fill in. If we look at the basic information sheet, we'll be able to identify the sources of problems, and that way we can collect these places, regions, or local places on a point. Just to give you an example, until 1996, women patients in Georgia - not the U.S. state - weren't allowed to conceive by a rule from Moscow. That's not a joke, it's real. In 1996, they weren't allowed to conceive by GDM patients. That was for a good reason, because they didn't have purified insulin, they didn't know how to treat these patients, and these patients took about a 50% chance of dying during such a pregnancy. Then we added other literature, and we formed a center in Georgia. We instructed from my department a few physicians - obstetricians and gynecologists - in Georgia on how to deal with diabetes in pregnancy. We supplied, and again the NIH and the industry, insulin and monitors for blood glucose, etc. From October of 1996 until now, there are over forty deliveries of insulin dependent diabetic patients in Georgia. We just published the results a month ago in Diabetic Medicine, which is the journal of the British Diabetic Association. This is just an example of what can be done. You identify good centers, you identify bad centers - 'bad' centers might not be the right word to use, but centers that need help, instruction, and correction - and you bring these centers that are in need to the same level."
Dr. Mark Perloe: "So it's really looking at where outcomes may be less, and then putting the muscle on it - both financial and manpower expertise - to solve the problem."
Professor Moshe Hod: "That's one way, although on the other hand, even the good centers can be improved if you compare a good center with another good center and you identify sources of mistakes. You can improve your whole center which you think is very good and doing an excellent job, but it still needs improvement, so you can identify these centers and local points too."
Dr. Mark Perloe: "Thank you."
Professor Moshe Hod: "Thanks."