Diabetes Mellitus in Pregnancy
Carbohydrate metabolism in normal pregnancy as measured by glucose changes very little. Pregnant women have a slightly lower blood glucose level then when they are not pregnant but you certainly don’t get a deterioration of glucose tolerance in normal women when they go through pregnancy. The insulin levels are way elevated in pregnancy compared to non-pregnancy and as you go from trimester to trimester they become higher and higher. Indeed when you move into that third trimester, the levels of insulin are three times higher than they were when she wasn’t pregnant, yet we just saw that her glucose doesn’t change very much at all. What this says to us is that in pregnancy there is a development of insulin resistance, and her pancreas has to put out three times as much insulin to get the same job done. It does that, and if she is normal she maintains normal blood glucose because she produces tremendous amounts of insulin in order to accomplish this with the insulin resistance of pregnancy. Insulin resistance in pregnancy. The placenta produces growth hormones that are identical in structure and sequence to the pituitary growth hormone. The difference is we don’t know of any regulators for the placental growth hormone. We know that glucose and free fatty acids regulate the pituitary growth hormone, but the placental growth hormone just keeps coming out. We don’t know of any feedback mechanisms that allow more or less coming out. The pregnant woman is producing tremendous amounts of growth hormone from her placenta and that growth hormone then is creating insulin resistance and for her to remain normal, she has to have a pancreas that puts out two to three times as much insulin.
Gestational diabetes. We now can understand the pathophysiology of this condition. We are talking about women who have an abnormal pancreas, but it is subclinical. They look all right when you test them. Now when they become pregnant they look abnormal. Why is that? They have a limited capacity to produce insulin. When they are going through the pregnancy they can make more insulin in the first trimester, and they can make more insulin in the second trimester but now they have reached their peak. The demands of the pregnancy because of that placenta require much more insulin, but they can’t make as much that is required. They are deficient in insulin in those last weeks of pregnancy. What happens then is their glucose tolerance becomes abnormal. As soon as you take the placenta out, there demand for insulin drops, they can produce enough to look normal, and they are just fine for a number of years afterwards. We have here the understanding of what gestational diabetes is. It is a limited capacity to produce insulin in a condition of pregnancy that requires lots of insulin production, and so that last portion of pregnancy they get an abnormal glucose tolerance test. When should we look for gestational diabetes? When should we test for it? Obviously the best day to test is the day before you take out the placenta because the stress on her pancreas keeps going up as she moves towards the end of gestation. We want to find all of these women, so we ought to test them the day before they deliver.
If we find them the day before they deliver, we can’t do much about their condition. What we therefore do is we come back and test them back here at the end of the second trimester, but you have to remember from this is if a woman looks normal here, it doesn’t mean she can’t become abnormal in the last weeks of pregnancy because the stress on her production of insulin is going to be much greater there then it was back when you originally tested her. Some women who look normal in our 26-week testing program will be abnormal when they get out to the term. In gestational diabetes we do test with a blood test. They gave 50 gm of glucose and drew blood one hour later and what they found was that the sensitivity and specificity of that test was much better than anything that had been used in obstetrics prior to that time. All of the major organizations, ACOG and AMA, said this is what we should use for testing pregnancy, a one-hour 50 gm glucose challenge at 26 weeks of gestation in the average mom. We test everybody at 26 weeks of gestation. How should we do the test? You do much better if you do this in a fasting state because in terms of endocrinology, you have the law of initial value. That means whenever you do a challenge test whether it is a glucose challenge or GNRH, how high you go depends on where you start. If you start here and give a challenge you go here. If just had Big Mac and a malted milk and your glucose is up here and now you take 50 gm, you make go into the abnormal zone. If you test everybody in a fasting state they will all go to the same level and that means if you do it fasting you will have many fewer false positives challenge tests, and you will have to do a lot less in the way of glucose tolerance tests.
In terms of sensitivity, a fasting challenge test is much better then is one where the women has eaten something prior to coming into the office. You have to decide what you are going to do. It may be from a compliance standpoint and difficult to get everyone in fasting, but if that is possible you have a much more sensitive and specific test then if you do it just randomly as they come into the office. We have to put a cut point into that system now to decide who gets further testing and who doesn’t, and also what kind of testing you do. Many people looked it at very carefully, and they showed that when you get down here under 140 the glucose tolerance test is very low and not cost effective. Our cut point is 140 mg per dL in plasma. They also showed when you got a very high screen over 200 they are all diabetics. If your screen is over 200 you ought to check the fasting levels before you do a glucose tolerance test because it may be high, and you may put this woman into ketoacidosis. If you are between 200 and 140 you need a glucose tolerance test. If you are under 140 you pass the screen without any further testing being necessary.
The cut point is 140, and if she is between 140 and 200 we go to a three-hour oral glucose tolerance test. That test is different then what you use in adult medicine. We use a 100 gm load where in medicine you use a 75 gm load. We take 4 points over three hours, and these other cut points, 105, 190, 165 and 145. This is plasma. If you are doing this in your office on blood you are going to have 15% lower value. You have to decide what you are going to do either blood or plasma. Obviously the blood value will depend on the hematocrit because red cell don’t have much glucose in them and they will lower the value. We do the glucose tolerance test and now we get three populations out of it. The first population has all of their values below these four points. They are normal. The second population has at least two of these values above the cut point. They are gestational diabetics. The third group has only one value that is abnormal. They are not normal. They are borderline abnormal but remember that the stress on their system is going to get worse as they move towards term. They may well then turn into diabetics in the last few weeks of pregnancy. If the one of the values is elevated repeat the glucose tolerance test in one month and that in many cases will become abnormal.
We have our gestational diabetics and now we have to look at what does this disease do, what are the risks and how do we manage it. The risk is for two people. First we just identified mom as having an abnormality and that means sometime in her life she is very likely to show clinical diabetes. We have to tell she is not normal, she has to watch her glucose as she goes through life, and we should attempt to put some prevention in there. The prevention basically is don’t become obese. If you are, lose weight. The higher her levels were during the glucose tolerance test the more abnormal she is, and the quicker she will be at risk for having diabetes. On the basis of glucose tolerance curves. The one that was the highest here had an 85% diagnosis of diabetes within five years of delivery. It is the ones that were just over the cut point had only 12 % being diabetic in five years. Again this is a continuum of disease, and the more abnormal you are during the pregnancy the sooner you will show diabetes after pregnancy. It is the most frequent of the problems that you will identify and fortunately it is a low risk problem and requires very little in the way of pregnancy management. For mom we just said her problem is later in life, and she has to screen for and watch for onset of diabetes. The only risk for the baby is macrosomia. It is not al the other things we are going to talk about in the insulin dependent diabetic. Our only problem for the infant then is getting out through the vagina at the time of labor. Babies don’t die in utero from gestational diabetes. Babies don’t get anomalies from gestational diabetes. All the things that we screen for and test for in insulin dependent diabetics doesn’t have to be done here because that problem doesn’t exist. We put them on a diet and that is important an average size lady 2300 calories per day. We see them at regular prenatal visits; we don’t have to see them more frequently than anybody else in our obstetrical prenatal practice does. When they come in we test their glucose. They come in the morning so we see that they are fasting and one hour after breakfast glucose is. As long as that is normal with their diet we continue, and we go to term. We don’t deliver them early, and we don’t do any other testing. Basically what we have is the most common problem here gestational diabetes is really not much of a problem. Identify it, watch out for macrosomia and tell mom to stay thin and check her blood once a year as she goes through life.
Now we are talking about the woman who comes into your practice, and she may have been taking insulin for 10 years as a diabetic. What do we know about that? We know three things. During the pregnancy the problem is going to be for baby and not mom. Mom is going to be just like she always was. I will show you a tremendous amount of data that says that glucose that causes all of the problems for the baby. Too much glucose creates problems for the infant. Remember normal women have a lower glucose value in pregnancy than when they are not pregnant. We end up with an outcome of the pregnancy that is going to be normal. She may get infections, particularly in the urinary tract. She can have changes in her blood vessels with diabetes and that will show up. She may have excess accumulations of amniotic fluid. When we talk about hyperglycemia we have seen already now why that is. Her placenta is making growth hormones, and the growth hormone is creating insulin resistance and that means what she is injecting every morning is having less and less activity as she goes to term. Therefore, if she doesn’t inject more insulin she is going to get hyperglycemic. That is what causes the problems. We are going to have to watch for that in the second half of pregnancy. I think this is a good example in medicine how data is created and very secure, and it tells us answer, but it gets forgotten as we go through different generations. It is in the second half of pregnancy that you need more insulin because you have insulin resistance and you get hyperglycemic.
What about infections? We know diabetics have infection at an increased rate, but the one that is of particular importance in the antepartum of the time period for us is the problem of urinary tract infections. It is doubled in frequency in the woman with diabetes because she has glucose in urine and that is a substrate for the bacteria. That is a problem because asymptomatic bacteria have a 25% chance of developing pyonephritis. We are going to do several cultures on this woman. Every pregnant woman ought to have a culture of her urine at the first prenatal visit. I never do urinalysis because that doesn’t tell you anything, but you need a culture. You need another one on the diabetic at 32 weeks. Obviously if she becomes symptomatic for a UTI she needs another one. What about her blood vessels? This looks at changes in the eye grounds of diabetics according to how long they have had their clinical problem. The longer you have had diagnosed diabetes, the more likely you are to have eye ground changes from this disease. One of my fellows just published a report of ophthalmologic studies of the retina in gestational diabetes. 350 gestational diabetics having a careful exam of their eyes and not one had any abnormality. That is a low risk problem. If she had been on insulin for some time, she runs a risk of having vessel disease in the eye. The real threat here is the production of new vessels, proliferative retinopathy because they can expand rapidly and create blindness. What makes new vessels grow? It is small growth factors, small polypeptides. They are regulated by growth hormone. Now we have a woman who has the potential for developing new vessels in her eye, and she has tremendous amounts of growth hormones coming out of her placenta. She is at very great risk for progression of this vessel disease and developing permanent blindness during the pregnancy.
If you leave these proliferative lesions alone 85% will progress significantly during the pregnancy. That means she needs a good ophthalmologic exam at each trimester because we can control this disease today. It is no longer an indication for termination. If those new vessels are coagulated with lasers we can control that disease. It is a big potential problem for mom, and if it is neglected we can end up with blindness and that means we need careful study of those eye grounds as we go through the gestation. The longer you have had diabetes the more likely you are to have vessel disease, and then you get subsequent problems in pregnancy like hypertension. Priscilla White’s classification of diabetics into A, B, C, D was really on the basis of how long you had the disease; therefore, how probable is it that you have arterial disease. You can see here as you advance in her classification you have more and more hypertension complicating the pregnancy. It is not unexpected because you have arterial disease, and she gets pregnant and as a result gets hypertension. Those are mom’s problems. We can handle them and manage them. We can prevent morbidity long-term from this. This is our real problem. This is the infant of the diabetic mother. This infant on the screen weighs 6700 gm. That is called macrosomia by everybody’s definition. This is the kind of infant that you see described where it’s fat, it has trouble with vaginal delivery, and it has anomaly and profound hypoglycemia. It gets into low calcium and high bilirubin. This is our patient of concern as obstetricians. What do we know about the creation of these problems? What is the path of physiology in this patient of ours that is at risk? This is the transport of glucose across the placenta. If we measure glucose in mom and into fetus we get this kind of a relationship. Glucose crosses the placenta by facilitated diffusion. That means that the placenta membrane has a coupling and a release on the other side. In a steady state the concentration of glucose in the fetus is almost the same as it is in the mom. When mom eats, and her glucose changes a gradient develops between the two concentrations that mom usually isn’t eating. Most of the time she is in a steady state. We always have this nice relationship. Glucose is freely going into the fetal compartment. In perinatal medicine we like to sample the fetal blood to see what is going on. Here the problem for the fetus is glucose levels. We can do chordocentesis today. We can isolate the umbilical cord with ultrasound and out a needle in and draw fetal blood. We do that all the time. We can’t do that five times a day for seven months in this pregnancy, or we would knock off the fetus. There is a risk of doing that about 1% death. We don’t do that here. What we do here is rely on this relationship which is present in every mom.
If we measure blood glucose over here in mom’s blood we know what it is in the baby. It is almost the same. Our key to management is going to be looking at what is the concentration of glucose in the maternal compartment. Patterson in 1954 set forth a theory as to what is going on. We now know with subsequent experimentation that he was absolutely correct. Mom has very tight control over blood glucose during pregnancy, and she does that by releasing tremendous amounts of insulin. We have seen that data already this morning. The glucose coming to the fetus is all controlled. The fetus doesn’t have to release insulin to control its glucose. Mom is regulating it, and it comes in all controlled. The normal fetus in utero has not learned to release insulin. When we take this baby off the cord and put it in the nursery it may get glucose tolerance and tomorrow morning it would be a diabetic. Every baby you deliver is a diabetic. We have all been there. We have a normal beta cell mass. After those beta cells see hyperglycemia for about one week they learn to release to insulin. All newborns are diabetics and by about a week of age they convert back to normal. They stay there in most cases. If mom’s glucose isn’t held in this normal range, and it comes up here that also comes into the fetal compartment. The out of control diabetic is having hyperglycemia go into the fetus. Her fetus has a normal pancreas. Her fetus begins to release insulin in utero. It releases tremendous amounts. It tries to get that glucose down. It grows excessively large, and it gets fat. Now when we cut the cord it is still releasing insulin, and it gets profound hyperglycemia within a few hours of life. What we have are the problems of the infant and the diabetic mother. It is all related to one point and that is moms glucose wasn’t kept in the normal range. If we had done that the baby that we pulled off the cord would look like every other baby.
Now let’s go through the some of the problems for the infant of the diabetic mother. We will talk about first trimester problems, and we will zero in on spontaneous abortion and congenital anomalies. Then we will talk about some second half of pregnancy problems like macrosomia, RDS, hyperglycemia and we will look at some of those. For the first half of pregnancy this is a study by the NIH looking at the effects of high glucose in early pregnancy on spontaneous abortion. They are looking with a memory, and the memory that is using is hemoglobin A1C, which looks at a previous month of glucose control. We have normal women, and they have diabetic women. The diabetics are solid lines, and the normal is dotted. When A1C’s are normal in the first trimester the spontaneous abortion rate between normal women and diabetic women is no different. If diabetics have high glucose, high hemoglobin A1C’s up goes their spontaneous abortion rate. Spontaneous abortion can be caused by hyperglycemia in the first trimester of pregnancy. That is complete disruption of embryogenesis. What about anomalies? This is the unique congenital anomaly of the infant who comes form a diabetic mom. This is sacral agenesis. There is no nerve intervention of the lower extremity. This baby will be paralyzed from the waist down for life. This is unique. When the baby has this, the only cause is the baby’s mom has diabetes. It is a simple diagnosis to make. Do a lateral x-ray. There is no sacrum. It is very infrequent.
Most of the anomalies in these IDM’s are cardiac or neural tube. If we look at all of the anomalies that occur in these babies we will try and get to a time period when the insult occurred. We will do that and here Mills did that and what he found in a variety of different anomalies is that the insult had to occur between the 3rd and 6th week of gestation. It is a very narrow window of time. Here in that very narrow window something happened, and we ended up with a congenital anomaly. What happened? The first thing to look at is the high glucose. Many people have looked at that.
If any one hemoglobin A1C level going through that 3rd to 6th week of gestation were normal, then the anomaly rate is no different then what you would expect, 3%. As you increase the glucose level in that 3rd to 6th week your A1C level is going up. You can see anomoly rates get up to 20-25%. Glucose that is elevated in that 3rd to 6th week can create disruption in terms of embryogenesis and end up with either congenital anomalies or if they are very severe spontaneous abortion. How does it do it? It does it by interfering with metabolism and creating free oxygen radicals. We now know that the mechanism is the production of free oxygen radicals that disrupt membranes and as a result of that embryogenesis doesn’t occur normally. There are many studies on this in the last couple of years to zero in on what is the mechanism. We now know that. Let me show you a couple of these studies. This is a nice study of transgenic mice. What they have done is put in a scavenger for free oxygen radicals. It is a new enzyme that eliminates free oxygen radicals that happens to be superoxide dismutase. They created these fetuses with this enzyme that gets rid of the free oxygen radical. Now they make the mom diabetic with streptozocin, and you can see anomoly rates here now. If you talk about control animals the anomoly rate was 8%. If you talk about the hyperglycemic moms you can see the anomaly rate doubled at 16%. If the moms are treated with insulin so they are diabetic but they are normal glucose, the anomoly rate is not increased. If mom is carrying a fetus that has this enzyme now to get rid of free oxygen radicals it doesn’t increase the anomoly rate. We see that it is the free oxygen radical that is the result of the hyperglycemia that is causing the anomoly.
Here is another study that they are giving something that is an anti-oxidant, a scavenger for free oxygen radical and what that is arachidonic acid. If you give those moms excess aractodonic acid or vitamin E or any number of free oxygen scavengers you bring anomalie rates down to zero. We now know a lot about that. Can we do anything about this in pregnancies we are managing? Yes. The answer is getting moms glucose normal before she becomes pregnant. This is a nice study again by Pitzller and now he has moved to San Francisco, and he does preconceptual counseling with his diabetics. He gets them in good control before they attempt to become pregnant. In his group that come for preconceptual counseling there is only one anomalie in this whole group. All the other diabetics that register in the first trimester, but they didn’t come into the preconceptual counseling and get into control before they conceived, many anomalies occurred. It changed the rate of anomalies from 11 to 1%. That is an important concept in managing your patients. We can summarize the first half of pregnancy. We can say this; hyperglycemia in mom will produce an increase in spontaneous abortion and congenital anomalies. The mechanism is the production of free oxygen radicals. The time that is critical is the 3rd to the 6th week of gestation. Sacral agenesis is unique, but it is rare. Most of the anomalies are in the cardiovascular or neural tubes. That means for the fetus that survives in the second half of pregnancy we need to study that fetus carefully to see whether it has an anomalie. We do echocardiography on these fetuses to look for cardiac problems that may need special care as soon as that baby is delivered. That says for our women who we have in our practice who are thinking about getting pregnant, we need to do two things which are get in control before they ovulate and put a ovulation indicator in place so that when they do ovulate you know it and now you have timed the pregnancy. You know from all of the presentations that have been going on here and what you read that there is no other way to know how far a pregnancy has gone if you don’t have an ovulation indicator. Sure you can have last menstrual period. You can have physical exam, and you can have ultrasound. They are all very inexact; therefore, if you have an ovulation indicator you don’t need those other things. You know how far that pregnancy is. A simple one is either use basal body temperature that tells you when she is pregnant or some women like to use a urinary gonadotropin test.
Let’s move into the second half of pregnancy. Now we have a number of problems and the first one is over growth or macrosomia. The fetus only eats glucose, so you will get macrosomia if there is too much glucose for the baby, or if it has too long of a period to eat. We get three kinds of women that will have macrosomic babies; diabetics, fat women and babies that stay in their eating post states. The three kinds of pregnancy that you worry about macrosomia are these. We will come back to looking of that and managing that as we go along. You can see here very naturally that the level of glucose in mom relates to how fat babies are as measured by skin fold thickness. Babies that are from diabetics can be fat but more importantly they grow differently. They grow more in their truck then they do anywhere else. What that does is create for you a potential problem because their shoulders are bigger which can damage them at delivery. Weight for weight babies coming from diabetic moms versus non-diabetic had two times the frequency of shoulder dystocia. That means that if they are 4500 gms ore more there is a 50% chance of shoulder dystocia at the time of delivery. That is a reasonable risk. If I was going to get on the airplane to go to Tampa this afternoon, and they said the pilot crashes 50% of the time, I would take the train. You have to remember now that when your diabetic patient has macrosomia you are two times as likely to have a sever shoulder dystocia and the problems resulting from that. Also you create a health problem for this baby for life.
Fat newborns end up fat people. As you stimulate fat cells to develop in the fetus you create the environment that will stay for life. Obesity in adulthood is really an obstetrical problem. We have control of that. If you let the fetus become fat you have a created a health problem for that child and adult forever. What other problems do we have? This is a mircrograph of the lungs from a baby that expired with respiratory distress, and it is classic in that the alveoli are collapsed. In some of the alveoli you see this pink membrane. This is hyaline membrane disease. We know a lot about lung development and function in the fetus and neonate. For any gestational age the infant coming from a diabetic had many more times the problem of breathing than did the same aged baby coming from a normal woman. Diabetes leads to respiratory distress in the neonate. There are 4 hormones that regulate the function of the lung of the fetus. One of these is cortisol, and we know that cortisol can accelerate lung maturation in the fetus by turning on an enzyme in the type II pneumocyte of the alveoli. When we study that enzyme we see that if you give cortisol you produce more surfactin. For every enzyme that is turned on by cortisol whether it is in the liver, lung or muscle it is blocked with insulin. If we do the same experiment with a lot of insulin around nothing happens. If that fetus is hyperglycemic, and it is releasing a lot of insulin then when it releases its cortisol nothing will happen in its lung. It comes out with a lung that doesn’t produce surfactin and surface tension, and it has difficulty in terms of respiration. This looks at the level of glucose in baby as it goes through early hours of life. When you clamp the cord you see the glucose falls in the neonate, but in a normal situation it hangs above 40 mgs per dl. That is important because the central nervous system only uses glucose as a substrate. If the fetus has been making a lot of insulin then it may just drop its glucose right down to zero. Now there is no food for the brain and what you end up with is destruction of cells. You can have cerebral pulsy and mental retardation as a consequence. Neonatal hyperglycemia is a very serious problem because a baby laying in the nursery with a glucose level of 3 looks normal and like every other baby. You need to prevent this by controlling glucose in mom’s blood. You need to come into a delivery and tell your neonatologist this baby is high risk for hyperglycemia, so they can check the glucose frequently in those early hours of life. If it does develop hyperglycemia you need to give it IV glucose until it stops making so much insulin, which is at about 48 hours of life. This is a preventable problem in terms of central nervous system damage.
We have talked about a lot of problems here, and we are now going to turn to management. Management becomes very easy once we understand the whole problem that we are dealing with, and its path of physiology. Management of the insulin dependent diabetic is only two things. What we need to do is keep moms glucose perfectly normal, and we have to deliver her early. We will time it by biochemical and biophysical tests. Let’s just elaborate very briefly on these two things. Let’s talk first about controlling glucose. We do a team approach to the management, and they are all working with an understanding of what are goal is. The most important person on this team is the one who probably knows least about this problem and probably gets less communication about then anybody else and that is the patient. The patient is the most important person on the team. What does mom need to do in her role as a team player? She has to come frequently for care. We don’t put these people in the hospital anymore. Hospitals cost a lot of money. They are dirty. The food doesn’t taste very well, and the bed hard. They do much better at home, and you save tremendous amounts of money. We see all on an ambulatory basis, but we see them frequently. We may see then every day or twice a week. She has to come as often as we decide we want to see her. Secondly she has to stay on a very rigid diet. We develop a diet for her, and she has to be extremely compulsive about that in terms of total calories and timing the calories every single day until she delivers. If she doesn’t do that there is no way you can control glucose. If she takes in 2300 one day and 1800 one day and 3800, you can’t control glucose.
We have her do the blood glucose tests. She does the glucose levels on her blood, and we get those at least three times a day. Fasting is the most important and one hour after a meal is the second most important. You want to know the peak flow to the fetus and then we get one when she goes to bed. She learns to use a glucometer. We determine what levels her glucose will fluctuate at in her blood. We set those limits, and we know that as she eats her glucose will go up. If she is extremely active it will come down a little bit. We can really bring it down if we increase the insulin. That is the way we manage her glucose during pregnancy. We monitor this box. We fix the diet, and we adjust the insulin. For most diabetics they are in broader levels of glucose then for non-diabetics. We let them be a little bit loose. For mom this yellow box is a little wider then it would be if she weren’t a diabetic. Our second patient, the fetus, is very sensitive to hyperglycemia and gets permanent damage from hyperglycemia. We want the fetus to be in a very tight range in glucose. The only way we can put the fetus in that tight range is to put mom in the blue box during pregnancy. Now we are going out her in a controlled situation for her glucose that she has never been in, and she won’t like it because as we stay tighter and tighter it is more work. We have to monitor the glucose. We do it with the blood that she checks, and in my practice I see these women every other day. Every time they come to my office they bring a 24-hour urine. They just learned the on day 1, and they bring it every visit. I dip it and throw it away. It adds zero cost. I don’t send it to laboratories because that costs money. This tells me about her 24-hour glucose profile, and if she is good control when I dip it is no more than a trace of glucose. If I dip it and it is 4+, she has high glucose going on. She may bring in this chart of her bloods, and it may say 70-80 every day, and she looks at one hour after meal and it is 105-109. When I dip her urine it is 4+, we ahead a problem here. She is either not reading her data right off the machine, or she is not checking it at the right times. She is giving me data she wants me to smile at and make me happy rather than what is real. I know something is wrong, and I can check and figure out what that is. I get bloods at least three times a day and a 24-hour urine at every single visit. I also get hemoglobin A1C once a month. If all of those are okay, now I am in the box. You can see here that excellent relationship between 24-hour urine glucose and hemoglobin A1C. It is an expensive test that will tell you a very great amount about her glucose control. Hemoglobin A1C is extremely important in monitoring because it tells you about previous four weeks.
Plasma glucose and A1C in pregnant women. Glucose goes down in pregnancy. In the middle of pregnancy it is lower than it was in the beginning or end. Actually the low point is at 20 weeks. Hemoglobin A1C follows that and A1C goes down and its four weeks later. This shows you what happens to glucose. It also shows you that A1C is tracking the previous four weeks of blood glucose control. What we call good control is fastings down around 70 to 80, after a meal under 120, 24-hour urine dipping no more than 1+ and hemoglobin A1C drops to around 4 or 5. Remember when she does her bloods at home she is measuring blood glucose. That is 15% lower than plasma glucose. If you have her plasma at 105 when she measures her blood it is going to be 90. Just by moving to her machine don’t be fooled by it looking a whole lot better. You want it 15% lower than what you will tolerate in plasma. What we have then is the patient in good control. Do you need machines of constant infusion of insulin or multiple injections? It doesn’t make any difference. What you need is enough insulin. There is no limit on how much insulin you get. If we give 20 units or 2000 what we want is an end point, and the end point is normal blood glucose. Finally, timing delivery. This is critical. There are only two places that the infant can die. This makes perinatal medicine very easy. It is either going to die in the uterus, or it is going to die in the nursery. This all we have to worry about. We see in the B curves over here the chance of dying in the uterus. If mom is a perfectly normal woman the risk for that fetus does not go up until 41 weeks, and then it goes up at each week after up. If mom has a problem like hypertension, insulin dependent diabetes, then the risk for dying in the uterus can go up way back in here. We are going to have to put in place some sort of test in this pregnancy to see the risk of dying inutero. The curves over here represent death in the nursery. In the nursery if you don’t have anomalies, the basic death is due to prematurity. There are two reasons why you die from prematurity. You can bleed into your ventricles, intra-ventricular hemorrhage, or you can have problems carrying on adequate respiration or respiratory distress. Those are the two big causes of death in premature. We don’t know how in the fetus to test for the strength of the blood vessels in the germinal plate that break open and cause intra-ventricular hemorrhage. We don’t have a test for that, but we know at 32 weeks of gestation those vessels are thick, and you no longer get a major bleed in the central nervous system. Once you are past 32 weeks you don’t worry about intra-ventricular hemorrhage in any fetus. Now all we have to worry about is breathing, and we can test for that. How do we test for death in the uterus and breathing in the nursery?
What about contractions and looking for late deceleration. It works extremely well in the insulin dependent diabetic. Here are almost 500 pregnancies and not a death in the whole group with once a week NST. How do we test for respiratory function in the nursery? When we developed the LS ratio we thought it work on everybody. When we looked at our population after implementing it we found that the insulin dependent diabetic baby still had RDS even when they had a mature LS ratio. If you waited a little bit longer and measured phosphatidylglycerol you would have a test that would work. This is the only kind of pregnancy where you need to do phosphatidylglycerol. There are many studies like this in the literature that show babies coming from moms with diabetes having RDS and mature LS ratios, but they don’t have PG. What you need is this. You need glucose control. You need contraction stress test once a week from 32 weeks. We deliver all of these pregnancies at 38, so if I have an ovulation indicator in place I don’t worry about amniotic fluid studies, I just deliver at 38 weeks if I know their dates. If I don’t know their dates, I start testing the amniotic fluid at 37 weeks and when PG is present out the baby comes.
Now we will talk about delivery. In this population we know that if you look at section rates in published literature versus perinatal mortality there is no relationship. It doesn’t make any difference whether you section them or deliver them vaginally with one exception, that is a macrosomic baby, and that obviously will have an effect. How do we pick out those macrosomic babies? They should not vaginally in terms of damage from shoulder dystocia. Measures by parietal diameter of macrosomic babies are normal. You need to do ultrasound assessment for macrosomia before you attempt vaginal delivery. It is extremely precise. You can get about 80% accuracy of finding these babies, and I believe that because shoulder dystocia is too times more frequent in the infant of the diabetic mother compared to other babies that if you have a baby that is over 4500 grams by your best ultrasound estimate, I tell those women I want to section them. The membrane for transport is 11 square meters. That is a huge membrane in there for transport into the fetal compartment. That is a bigger membrane then a king-size bed spread. This is the placental surface area for transport. On the curve here we are looking at changes in weight of the fetus per unit of time. If we were to look at the depositive of calories on that carcus rather than weight change there would be straight line all the way up here because in those last four weeks the fetus in laying down fat. It is putting more calories down for every gram of deposit as opposed to four. We have a tremendous growth rate here. If that infant continued to grow at that rate, at the age of five it would weight two tons. As a result of that enormous metabolism that is going on that fetus is much hotter than mom. It is a half a degree centigrade hotter than mom is. The heat that is generated by this rapid metabolism is carried by blood across the placenta, and mom is loosing it by convection off her skin. We all know that we deliver an LDR today the first thing that happens after mom has the baby the mom start shiver. She just lost her little heat pump. Then we need three critical substrates that the fetus uses for growth. The first substrate that goes across is oxygen. Oxygen goes across this membrane by simple diffusion. That means physiologically there is absolutely no impairment to transport across the membrane. Oxygen goes right straight across. There is no barrier to transport. The regulation of oxygen transport is really dependent on two things. How much oxygen is there in mom’s blood and how much of mom’s blood is going to the membrane. The second critical substrate we have already looked at and that is glucose. It goes by facilitated effusion. That is all the fetus eats is glucose. The third substrate is amino acids, and they are actively transported into the fetus. Every amino acid is in higher concentration in fetal blood compared to mom’s blood. We have three critical substrates that are going into that compartment across that big membrane. What is the fetus doing with it? It is burning glucose with oxygen to create energy, and the energy is in the form of ATP. That energy then is being used on those amino acids to make protein. In the last three to four weeks of gestation the fetus is getting ready for its neonatal adductation. What it needs is something to live on until mom’s breasts begin to have milk. It needs some food for three days. It does that by laying down fat, so in those last few weeks it makes free fatty acids and deposits triglycerides, and it makes all of its fat from two carbon acetates pieces off that glucose. All of the fat in a newborn is C16 pelmatase. It is all made denova from glucose. Our fat has a variety of links of free fatty acids because we are absorbing fat from our diet. This is what is going on inutero for growth and development.
I. Summary
A. Pregnancy is characterized as a diabetogenic state in which insulin resistance occurs. In order to maintain glucose hemostasis, the pancreatic beta cells need to secrete more insulin. The causes of this insulin resistance are multiple, are related to the placenta, and include high levels of placental growth hormone, progesterone, cortisol, estrogens, human placental lactogen, and prolactin, all of which accompany pregnancy
B. Routine blood glucose screening of all pregnant women is critical for the detection of abnormalities and should be done at 24--28 weeks. The screening test draws a plasma glucose level 1 hour after a 50 g oral glucose load; normally the value should be <140 mg/dL. If it is above this, a 3-hour test is necessary, using a 100 g glucose load; the upper limits of normal for the plasma are fasting--105, 1 hour--190, 2 hours---165, and 3 hours--145 mg%. If two or more values are elevated, the woman has diabetes. If one value is elevated, the test is abnormal and needs to be repeated in 1 month
C. Gestational diabetes (GD) is common, and it poses a low risk for mother and fetus. It can usually be treated by diet alone. It carries a risk for macrosomia and, therefore, needs little monitoring until term, when ultrasound (US) studies of fetal weight are needed before vaginal delivery. Nonstress tests and home glucose monitoring of the diet-controlled GD are not necessary. The gestational diabetic may benefit from insulin treatment if the fasting blood glucose is not controlled by diet alone. The risk for the mother is the development of diabetes later in life
D. Insulin-dependent diabetes ODD) is a high risk for mother and infant during pregnancy. The maternal mortality in diabetic patients who become pregnant is <1%
1. There are six frequently complications
a. Hypoglycemia
b. Hyperglycemia
c. Urinary tract infections (UTIs)
d. Retinopathy
e. Hydramnios
f. Hypertension
2. In general, hypoglycemia occurs during the first half of pregnancy, and hyperglycemia occurs during the last half. Hyperglycemia can have an adverse effect on the fetus. Most of the problems for the infant of the diabetic mother (IDM) seem to be caused by hyperglycemia. Because the pregnant diabetic has varying amounts of glucosuria, blood glucose control can only be determined by frequent blood glucose studies and not urine studies. Good control is the most important pan of pregnancy management. Insulin requirements usually increase 2-3 times between weeks 20 and 30 of gestation. Following delivery, they decrease precipitously
3. Persistent glucose in the urine plus the stagnation of urine with hydronephrosis, which normally accompany pregnancy, combine to increase the frequency (20%) of UTIs. Urine cultures should be taken several times in pregnancy. Retinopathy can also advance in pregnancy and may need laser treatment. An ophthalmologic exam is needed each trimester
4. Diabetic pregnancies are often complicated by hydramnios and hypertension
II. Problems of the Infant of a Diabetic Mother
A. Six most common
1. Spontaneous abortion
2. Congenital anomalies
3. Macrosomia
4. Hypoglycemia
5. Respiratory distress
6. Fetal and neonatal deaths
B. The spontaneous abortion rate is elevated when poor glucose control occurs in early pregnancy. The incidence of congenital anomalies is increased. Sacral agenesis is the most common defect is intraVentricular septal defect, and a unique anomaly. The anomalies occur between the third and sixth week of gestation and are related to hyperglycemia. The occurrence of excessive oxygen-free radicals are responsible for the anomalies. There may be a high frequency of both fetal and neonatal deaths, and the cause of the former is not always known. The IDM often has macrosomia, and because its trunk is disproportionately large, the risk of shoulder dystocia is increased two times. Neonatal hypoglycemia and respiratory distress are common. They may also develop hyperbilirubinemia and hypocalcemia in the neonatal period. As the child grows, it suffers an increased risk of developing diabetes mellitus (10%), nervous dysfunction, and pancreatic fibrosis. As a group, these children tend to be shorter and heavier than their peers
III. Management of the Pregnant Diabetic Patient
A. Maternal blood glucose levels must be kept as near normal as possible to achieve optimal fetal salvage. The glucose level is best controlled using frequent blood glucose determinations done by the patient at home, a proper diet, and an adequate amount of insulin. The diet should be 300 calories above the mother’s prepregnancy diet. Ideally, the fasting blood glucose should be less than 90 mg% and the 1-hour pc blood glucose <140 mg%. In addition, measurements of the 24-hour urine glucose excretion, hemoglobin A1C level, and amniotic fluid glucose concentrations may aid in determining the adequacy of control
B. The infant should be delivered when it is mature, which is usually at about 38 weeks of pregnancy. The timing of delivery is accomplished by utilization of both serial fetoplacental function testing (FPT) and fetal maturity testing (FMT). The most practical FPT results are with weekly oxytocin contraction tests (OCT), which are started at 32 weeks gestation. The most reliable FMT results are measurements of the amniotic fluid phosphatidylglycerol content. The method of delivery does not seem to influence the results significantly, except that macrosomic infants should be delivered by cesarean. US assessment of fetal weight is important. Despite mature test results, the infants may have RDS and other problems requiring careful neonatal monitoring and, therefore, these infants should be delivered in a tertiary center
IV. Postpartum Contraceptive Advice
--In view of the women’s metabolic defect, barrier or intrauterine devices are the best methods