We discuss pathophysiology and neonatal complications for infants born to diabetic mothers. We are joined by Rashmin Savani, MBChB, Professor and Chief of the Division of Neonatal-Perinatal Medicine at the University of Texas Southwestern Medical Center.
Dr. Neeta Goli:
Welcome to Newborn News, a podcast where we discuss educational topics for medical professionals who care for newborns. I'm your host, Dr. Neeta Goli, a pediatrician in the UT Southwestern newborn nursery. Welcome back to the podcast. Today we'll talk about the management of infants of diabetic mothers. We're joined by Dr. Rashmin Savani, who's the chief of the division of neonatal perinatal medicine here at UT Southwestern. Dr. Savani, thanks for joining us today.
Dr. Rashmin Savani:
My pleasure.
Dr. Neeta Goli:
In the U.S., about 1-3% of pregnant women are diagnosed with gestational diabetes, and out of all babies born, about 0.5 to 4% are born to diabetic mothers. To start off with, can you explain to us the different classifications of maternal diabetes?
Dr. Rashmin Savani:
Sure. The obstetricians and Dr. White in particular developed a classification process for mothers with diabetes. We know that mothers that are pregnant produce a hormone called human placental lactogen, which causes insulin insensitivity. So just the mere fact of being pregnant can make you a diabetic. So this is called gestational diabetes. And the first two slots in White's classification are class A1, which is a diabetes only happening during pregnancy. And that can be controlled by diet alone. Whereas class A2 is gestational diabetes, diabetes that only occurs during pregnancy but requires insulin. So these are the mildest forms of diabetes during pregnancy, if you will.
Dr. Rashmin Savani:
The following sets of classifications in White's classification is the duration of maternal diabetes. So mom already has insulin dependent diabetes, and it depends on how long that diabetes has gone on. And that is classes B, C, and D, where mothers who have onset later than 20 years of age, duration, less than 10 years will be class B. A class C is when their duration of diabetes is 10 to 19 years, and the duration has been 10 to 19 years. And class D is where the onset is less than 10 years of age and the duration is more than 20.
Dr. Rashmin Savani:
The reason that classification is made is because the longer you have diabetes, the more complications you're going to have. And that leads us to the most severe classifications, which are what I call the “fropathies,” or the F, G, H, and R. And the reason I say that is now you've got microvascular disease and it affects a multitude of organs including the placenta. So you can get renal insufficiency, you can have cardiomyopathy, and you can have retinopathy. And as we'll talk about in a little bit, I think, we'll also see that that microvascular abnormality can affect the placenta as well.
Dr. Neeta Goli:
So if we talk about the moms for a minute, the diagnosis of diabetes during pregnancy has far reaching consequences for both mom and baby. So it's very important for them to receive appropriate support in pregnancy, including dietician support. So how can maternal diabetes affect pregnancy and the fetus?
Dr. Rashmin Savani:
Well, the physiology of this is fascinating and it was first described by Pedersen a long time ago. In the normal situation, mother and baby are separated by the placenta, but there is crosstalk between the two through the placenta. Insulin is said to not cross the placenta. There is some evidence to refute that, but for the most part, let's take it that insulin doesn't cross the placenta. So then you have a glucose insulin cycle in the mother and a glucose and insulin cycle in the baby. And the thing that connects it is the glucose. So in the normal circumstances, maternal glucose gets transported to the baby via glucose transporters. And these glucose transporters are a facilitated transport system, not active, not passive, but a facilitated transport, so that the baby's glucose is slightly higher than the mom's, for the most part.
Dr. Rashmin Savani:
The problems arise when maternal glucose levels go up, maternal diabetes, and now the baby's glucose is also increased. And that increased glucose on the baby's side now stimulates the beta cells of the pancreas to hypertrophy and produce insulin to combat this large glucose load that's coming in from the mom. This high glucose and insulin on the baby's side has some downstream effects, which can be that they can produce ketone bodies. They promote the deposition of glycogen and also cause protein modifications with more glycinated products, proteins that can affect their function and as well as altered gene expression and promote excess growth in the baby.
Dr. Rashmin Savani:
All of these are downstream effects, if you will, of the glucose and insulin increase on the baby's side. Now at the time of birth, of course, the obstetrician comes along and the umbilical cord gets cut, so this massive amount of glucose infusion that the baby was getting disappears. And now what the baby is faced with is no glucose supply from the mother, but a hypertrophied beta cell population that's churning out a lot of insulin. And so what you get is immediate hypoglycemia in the baby. And so I think that that Pedersen hypothesis has remained a hypothesis because it's very difficult to prove whether it's the glucose or the insulin causing the trouble or whether it's both. So it remains a hypothesis. But I think that that fits the physiology of what we observe.
Dr. Neeta Goli:
And you mentioned some growth complications. What are some things that we see in infants of diabetic mothers?
Dr. Rashmin Savani:
Since there is increased glucose and insulin in the baby's side, insulin is said to be a growth factor for babies. There is some controversy about that. And some people say that there's a contribution from other hormones like insulin, like growth factor, but for the most part let's take for now that insulin is a growth factor. This is increased in diabetic pregnancies and this is going to promote the growth of the baby to a point that it's in excess of what you should anticipate for the gestational age.
Dr. Rashmin Savani:
Most of this growth occurs in the third trimester and what it results in is that you have bigger babies and that is going to lead to more complications because they won't fit in the birth canal, you can get increased C-sections and operative deliveries, and you can get things like shoulder dystocia. So because of the macrosomia, you would get increased amounts of birth injuries. For 25% of the situation, we talked about the microvascular abnormalities that occur in diabetes, particularly those more severe types of White's classification. Now the placenta gets affected by microvascular disease and actually fails so that you can get a placental failure and about 25% of these infants end up being small or intrauterine growth restricted. And that actually is a worse outcome for the baby because now the baby doesn't even have the glycogen stores to supply any glucose. And we'll still have hypertrophied beta cell mass so that their hypoglycemia is very profound and they have long hospitalizations.
Dr. Neeta Goli:
In addition to growth complications, what are some other medical complications we can see in these babies?
Dr. Rashmin Savani:
We talked about the hypoglycemia and how that works, but there appears to be an abnormality in the kidneys, both in the mother and the baby in diabetic pregnancies. And what that results in is a loss of calcium and magnesium in the urine of the baby, so that the baby can actually come out and become hypocalcemic. And that, of course, can lead to tetany and seizures. Now, magnesium is a very interesting molecule, because it is required for the secretion of parathyroid hormone. When you don't have magnesium, parathyroid hormone is not secreted and you cannot mobilize calcium from the bone. So once we are born and the umbilical cord is cut, the supply of calcium goes away, and we have a PTH surge. That PTH surge counteracts that initial hypocalcemia that every baby gets, and that is blunted in a diabetic pregnancy. So they can have a more profound hypocalcemia. So whenever you're faced with a baby who is an IDM and has hypocalcemia, make sure you check the magnesium as well, because if the magnesium level is not okay, you will not be able to correct that calcium.
Dr. Rashmin Savani:
Babies can also get respiratory distress syndrome. Respiratory distress syndrome is really defined as surfactant deficiency and the critical things in surfactant or phospholipids and specific proteins. And surfactant protein B, for example, is classically required for adequate lung function of surfactant. Both increased sugars, as well as increased insulin, decrease the production of phospholipids and surfactant proteins. And so that results in an increased incidence of respiratory distress syndrome. Transient tachypnea of the newborn is also elevated. Not only because you have more C-sections happening with large babies, because the normal birth canal squeeze to get rid of that water is gone. But also the reabsorption of fluid in the lung is controlled by a molecule called ENaC or epithelial sodium channel. This is greatly elevated at the time of birth. And that elevation is blunted in diabetic pregnancies so that they can have a greater incidence of transient tachypnea of the newborn.
Dr. Rashmin Savani:
And if we go down this long list of complications, there's hypertrophic cardiomyopathy. We talked about the fact that a high amount of insulin will lead to deposition of glycogen. It's one way of dealing with this excess glucose load to the baby. And so an excessive amount of glycogen gets deposited in the septum of the heart. So that causes a transient cardiomyopathy, if you will. Sometimes it can be quite severe and both left and right ventricular outflow tracts are obstructed. And that constitutes a neonatal emergency. But for the most part, these babies have murmurs and would have to be investigated with an echocardiogram.
Dr. Rashmin Savani:
The other thing that happens to infants of diabetic mothers is, is that they have polycythemia. The mechanism of polycythemia is that all blood cells come from a single progenitor or stem cell. And it's the influence of specific growth factors that provide the lineage specification of those stem cells. So if you have erythropoietin you would become a red cell, if you have thrombopoietin, you would become a platelet. And if you have granulocyte or macrophage stimulating factors, you become a white cell or macrophage. And what happens in diabetic pregnancies is that because of that microvascular disease we talked about, there is a relative hypoxia. Most fetuses are already hypoxic compared to room air, but they have a further hypoxia in utero. And that increases the production of erythropoietin so that these babies will have a higher red cell mass when they're born and they will have relatively limited white cells and platelets. So you can get a thrombocytopenia in infants of diabetic mothers in the same way, at the same time have polycythemia.
Dr. Rashmin Savani:
And of course, getting polycythemia also has consequences. One of these consequences is renal vein thrombosis because of the increased viscosity in a low flow system in the renal vein, you now get the chance for clotting to happen. So some babies that are infants of diabetic mothers have renal vein thrombosis, and you'll get an enlarged kidney, hematuria. And that alerts you to the fact that this might be a renal vein thrombosis. Having an increased red cell mass, the neonate has a shorter half-life for red blood cells. So now they have more red blood cells. So now they're producing more bilirubin. So infants of diabetic mothers have an increased incidence of hyperbilirubinemia. We have to be on the watch out for that. They usually last longer than just physiologic hyperbilirubinemia.
Dr. Rashmin Savani:
We already talked about the macrosomia and the birth trauma, and there's a nice statistic where there's an exponential increase in the incidence of birth trauma with the lack of control of diabetes. And there's been a great correlation between the level of hemoglobin A1C, for example, and the percent of pregnancies that have a birth trauma.
Dr. Neeta Goli:
What can be done to mitigate these risks?
Dr. Rashmin Savani:
Yeah, obviously good control of the diabetes during pregnancy is absolutely required. But I would submit that we actually need to start controlling the diabetes ahead of pregnancy. So a mother or a prospective mother who has a diabetes or insulin dependent diabetes, should really seek counseling before she gets pregnant so that absolutely optimal control of the diabetes can be present at the time of conception.
Dr. Rashmin Savani:
One of the things that is more common in infants of diabetic mothers are congenital anomalies. And the most common congenital anomaly if I ask residents, usually, they say "caudal regression." But it's actually VSD. And the reason it's VSD is because that is the most common congenital anomaly period. And it just happens to be even more prevalent in a diabetic pregnancies. Caudal regression is pathognomonic of diabetes in pregnancy, and that is a profound disorder where you can get a simple coccyx missing, or the whole sacrum is missing. But I've seen babies that have, like a mermaid, two legs that are fused and they have flipper fins for feet. And so there's a wide spectrum of this caudal regression syndrome that can happen. All of these can be limited if we have good sugar control before conception, but unfortunately with congenital anomalies in mothers with diabetes, it doesn't go back to the normal population. There's something inherently wrong in mothers with diabetes that then promotes a slight increase in the incidence of congenital malformations, irrespective of the glucose control.
Dr. Neeta Goli:
So once these babies are born, when we're examining them, what should we pay special attention to?
Dr. Rashmin Savani:
There's a wide variety of things that, obviously, we need to pay attention to. Insulin, of course, is going to be increased like we've talked about the Pedersen hypothesis. So the most immediate things are the metabolic changes that occur. You have to be on the watch out for glucose, calcium, magnesium, et cetera, but there are other things that these babies suffer. Research has been done, where EEGs were done on babies that were infants of diabetic mothers. And there was a discoordinated EEG pattern in babies for the first few days. And so their suck-swallow is actually affected. So now you can imagine a baby that needs to feed to keep the sugars up can't feed properly because the suck-swallow coordination is not there and has a high amount of insulin in the system, so the incidence of hypoglycemia is even further exacerbated. So we have to pay attention to whether the baby can a suck and swallow properly and make sure that we don't have hypoglycemia. That may require tube feedings as well as continuous feeds to avoid that hypoglycemia.
Dr. Rashmin Savani:
One interesting complication that occurs postnatally is intestinal obstruction. The nervous system in the hind gut, which goes from the distal third of the transverse colon to the anorectal junction, appears to be affected by diabetes in pregnancy so that that system doesn't work and you end up with a small left colon syndrome. And that presents as an intestinal obstruction. The belly is distended, there may be vomiting, there's lack of stooling, et cetera. And the good thing is that when you do a barium or contrast enema, that actually resolves the issue so that you make the diagnosis of small left colon syndrome. When that contrast material gets evacuated, then the system is back to normal and it's resolved. So the small left colon syndrome is something we have to look out for as well.
Dr. Neeta Goli:
And then what extra precautions can we provide for these infants when they're born?
Dr. Rashmin Savani:
Surprisingly, we think of, we need to address the glucose right away. But there are studies that showed that skin-to-skin time right after birth of infants of diabetic mothers actually decreases the risk of hypoglycemia, which is remarkable, I think. It's important to have regular glucose checks. And so this varies from institution to institution, of course, but glucose should be checked right away at birth. And then very frequently until we figure out what the interventions the baby might need and whether we can then start decreasing the frequency of glucose checks. Usually 12 to 24 hours, we check calcium and magnesium. And of course, because of the polycythemia risk, you have to check the hematocrit. The best time to check the hematocrit after birth is around two hours. That's going to be the highest level of hematocrit because of the fluid shifts that happen with birth.
Dr. Rashmin Savani:
And of course, if the is in the newborn nursery, daily transcutaneous bilirubin checks can be instituted because they will have a higher incidence of hyperbilirubinemia. It's important to watch how the baby feeds, especially if they're breastfeeding. Lactation consultants should be aware of the fact that this is an infant of a diabetic mother and then pay extra attention to that suck-swallow reflex. If there's no stool in the first 24 to 48 hours, think about the left colon syndrome. Do we have any evidence of obstruction? Is it worth getting them an X-ray to see what the bowel gas patterns are? And does this baby need a contrast enema?
Dr. Neeta Goli:
What should we counsel parents in terms of long-term outcomes for their babies?
Dr. Rashmin Savani:
So it is known that there is a genetic component to diabetes. If a mom has insulin-dependent diabetes, the baby's at increased risk of developing diabetes in the future. And so it's important to counsel the parents to follow regular, healthy diets and exercise routines long-term. If hypoglycemia is corrected appropriately, there don't appear to be long-term neurodevelopmental problems, but hypoglycemia itself, if not appropriately controlled, does lead to future cognitive disturbances. And school-aged kids have some deficiencies in, for example, math skills in school age, that have been associated with the incidence of hypoglycemia during the immediate newborn period. So there's a number of long-term things that can happen.
Dr. Neeta Goli:
Was that only if it was rapidly corrected?
Dr. Rashmin Savani:
Let me say that last thing again. If hypoglycemia is corrected appropriately, there is not increased risk of neurodevelopmental outcomes that are affected long-term. If hypoglycemia is not corrected and you have episodes of hypoglycemia, there is a long-term risk for decreased school activity and school ability, particularly in math, actually. And so it's important to correct the hypoglycemia. However, one study did actually show that rapid correction of hypoglycemia was also detrimental and led to longer term neurodevelopmental abnormalities. So it's important to correct the hypoglycemia, but not to over-correct it or correct it quickly.
Dr. Neeta Goli:
Thanks so much for joining us. This has been a really great, informative discussion about the infants of diabetic mothers. To end the episode today, Dr. Savani, what's your favorite part of your workday?
Dr. Rashmin Savani:
That's a really tough question, Neeta. I enjoy everything that I do. It's always good, you never feel like you're at work. So I am blessed in that way and I love the people that I work with. And it's a chance for all of us to make things so that babies and moms have better outcomes. And we're working very hard to do that, right? On a personal note, I love swimming, and reading, and playing with my golden doodles. So I have a good time with that, too.
Dr. Neeta Goli:
I love it. Thanks so much for joining us today.
Dr. Rashmin Savani:
It's been great, Neeta.
Dr. Neeta Goli:
Thanks for listening to Newborn News. We hope you join us next time. If you like what you hear, make sure to subscribe and leave us a review. If you have questions, comments, feedback, or suggestions for future episodes, please e-mail me at NewbornNews@utsouthwestern.edu. As a reminder, this content is educational and is not meant to be used as medical advice. Views or opinions expressed in this podcast are those of myself and my guests and do not necessarily reflect the views of the university.