9UNP0149SD_Pamela Kling_WordPress

- Thank you very much Dr. Wald. I'll go a little more into why I think iron is the bad boy of nutrition, but I have one more title. This is a T-shirt given to me by my lab manager, so "Irony." 
(laughter)
 So okay. So the outline of the talk will cover a little bit of the background of iron accretion as a fetus, iron deficiency in infancy, talk a little bit about iron overload. The iron overload was put in because Dr. Greer, being the chair of the Committee on Nutrition has been traveling all over the country and the world. 

And he hears these talks on a regular basis. And he thought that this would be good for us to cover in Grand Rounds, as well. 

So, we'll talk about a lot of the non-hematologic manifestations of overload, including immune development, cardiovascular development, neurologic development. And then deficiency, we'll also talk about the hematologic, just because we have to, but we'll focus more on the other non-hematologic manifestations. Immune development, cardiovascular and cardio-renal development, neurologic development, and then a little bit about screening for and treating iron deficiency in the early life. 

So I'm going to ask you to think outside of the box and think about iron deficiency as a total body iron deficiency, not just hematologic. 

So this slide shows, you can see the arrows going back and forth. Let me see if I can get this arrow to go. So you've got iron going in and out of various and sundry places, 75% of the iron is in the circulating red blood cells, as well as the erythroid marrow. So that's why these circles contribute to a larger percentage. 

There's some in storage, in the blue, here. There's a itty bit in transport, transferrin, that's in the green. So going in and out of all of these storage compartments. And then the GI tract is over here. We've done a lot of work on that. I won't be showing as much of that work today, but I will be showing some of our work, so it will be a hybrid between clinical knowledge and research. 

So iron is the fourth most abundant element on the earth, and is very abundant in dirt. So why should such an abundant element be associated with a clinical deficiency syndrome? I think the key point is that the body knows that excess iron is toxic. And the window between iron deficiency and excess is small. 

Hence, iron the bad boy, he can do well, but he has to be right in the right concentrations, 75mg/kg of iron in total body iron as you're born. And your circulating red cells take up 75% of it; Storage 10%, and myoglobin and cytochromes, 10%. 

I think this is why iron is deficient. This is a picture shot by a friend of mine who trekked Nepal. So you can see, she's dirty. She's very filthy dirty. She lives in a dirty hut. She breast feeds on dirty breasts. The baby is dirty. But here in the U.S., and this is a picture that I just got out of a magazine, how pristine, white, clean our nurseries are. 

Babies are bathed just about every day. Moms are bathed every day. We don't see dirt like we used to. And we've evolved to see dirt. 

Let's talk about the background then, of iron excess. Why does it happen, and why is the newborn and the early infant at highest risk? When you're born, your transferrin saturation is greater than 50%. So, you're hanging on to lots of iron stores. Greater than 90% of the preventive antioxidant activity is associated with caruloplasmin and transferrin. And almost all of that is transferrin. 

So it is part of the antioxidant system of the body. And if you're saturated with iron, it's unable to scavenge up any iron. 

The disease has been coined oxygen radical disease of the newborn. The reason why the newborn is also iron deficient in that all the other antioxidants are lower in concentrations. So, you have lower vitamin E, lower glutathione peroxidase, lower superoxide dismutase, lower catalase. All of these are lower. And your transferrin is partially saturated. 

One example of that is G6PD deficiency induced hemolysis. It's a very serious oxidative disorder that causes a lot of problems in the newborn and infant period. Quoting Dr. 

Barness, here, back in the '60s and early '70s, premature formulas were very deficient in vitamin E and had high polyunsaturated fatty acids, PUFA content. And there was a lot of hemolysis going on in the NICU, because these premature formulas were inadequate. But Frank could tell you that all the current premature formulas and human milk are extremely high in vitamin E and low in PUFA. And this just doesn't happen much any more. So it's usually not a problem, unless something else is a major factor. 

Recent evidence, and I wrote on editorial for this article, is that there was really actually no evidence of free radical disease in premature infants from Norway, that get as much as 18mg/kg of ferrous sulfate. So if the human milk, which was the predominant source of nutrition for these children is adequate in its antioxidant capacity, even for three times the iron that we give here in the U.S. So a slightly different form, which might be a little less free radical generating, but still it's the same amount of iron. In Japan and other countries there's an addition of lactoferrin in the premature formulas that may also decrease the free radical generation. 

When you look at it in the test tube, putting human milk in all of these various and sundry formulas, it's clear that human milk is the most protective of all of the formulas. So again, as long as you give human milk, which you didn't do so much in the '60s and '70s, as long as you give the formulas with the high E to PUFA ratios, you tend to not get into trouble. 

Even giving erythropoietin back five ten years ago, we would have shuddered at the thought that IV iron would be safe in premature newborns, and it appears to be so, as long as you're giving erythropoietin. 

However, transfusions are another matter. And I like to point this out. These are data from our lab. We looked at multiples of baseline of both mal- and dialdehyde, which is a by-product of oxidation. We looked at hemoglobin rise, and we saw sort of a parallel rise, 1-1/2 to almost two times baseline of mal- and dialdehyde in hemoglobin. So hemoglobin is in the blue, and virtually superimposable above the mal- and dialdehyde. 

The reason is that premature infants receive one milligram her ml of iron when they get of a transfusion. So if you're following up a newborn who's been multiply transfused, their irons test is going to be very different than a child who never received a transfusion in the NICU. 

Of note, one red cell transfusion of 10ml/k that we give in the NICU contains more iron than the whole total iron binding capacity of the transport system of iron. 

So it can be problematic if it's hemolyzed. We tend to give our transfusions through a 24 gauge catheter, so there can be some hemolysis. Older data has shown that there's a lot of hemolysis. I think nowadays, we do it a little bit safer. 

Okay, so moving on, away from hematologic to immune function. I think this is kind of an interesting concept. Chronic or acute iron overload increases susceptibility to infection. Microbial pathogens love iron, just like everything else, and transferrin and lactoferrin do have very high affinity for iron, and may remove it from the microorganisms. If transferrin is not saturated, your circulating free iron is ten to the minus 18th mol/l. so that's pretty darn low. 

However, if you get IM iron or IV iron, you have excessive and measurable free iron, or detectable iron, that will last for two to three days, if you're giving it IV, and up to two to three weeks if you're giving it IM. So if there is loose free iron, then it would be more available for microbial pathogens. 

And many of you may know of the study back in the '70s where they gave IM iron to Polynesian infants, because there was a massive epidemic of iron deficiency. They all had an extremely high incidence of neonatal sepsis, especially E. coli, which is obviously, a very bad pathogen. Once they stopped the practice, that should be decreased, incidence decreased after the practice was discontinued. 

Again, also in a third world situation, a developing country, Bangladesh, oral iron given to them increased their incidence of dysentery. They're in a high pathogen area and received some side effects of iron. 

But the biggest news that you may all remember back from your textbooks is that malaria really is a problematic disease when there's excess iron. Malaria and other infectious organisms that spend part of their life cycle intracellularly are the ones that seem to love the iron, and seem to cause the most problem when there's iron excess. 

So IM iron Dextran was given to two-month-old infants in New Guinea, and found an increased incidence of malaria. Other studies show that even oral iron, or parenteral in some studies, increased the transmission rate by about 50%, and increased the malarial load by a number of organisms. Clearly chelators will protect from malaria, suggesting that this is a cause effect. It's probably the iron. If treating for iron deficiency in the malaria belt, generally clinicians do it in the off-season, and do aggressive anti-malarial therapy at the same time, in order to bring up the status before the season comes on. 

There's a lot of animal data also supporting the pro-infectious role of parenteral iron, probably related to transferrin saturation. And neisseria meningitis, again, a very iron-loving organism. The direct mechanisms have been somewhat worked out. The cell number of neutrophils have gone down, and lymphocytes, as well. T-helper cell response is very decreased. 

There's deficient iron enzyme activity. Phosphorylation of cytokine membrane receptors are also decreased, interfering with the immune function. 

In the U.S. and in a developed country, oral iron does indeed change the gastrointestinal flora, where there's more E. coli and less bifidobacteria. That sounds bad and it probably is. Although, study after study has interrogated it in a sophisticated way and found that contrary to their thought, that there's probably no evidence for increased infectious diarrhea in the U.S. But a lot of the studies that were done early were very difficult to separate out formula versus human milk, because human milk is productive and formula is not. So formula is clearly less protective against infections than human milk. But if you add additional iron, and it generally does not change the mix. 

Along with that and the different colonizations, clearly well done studies show that iron fortified formulas in the U.S. do not increase fussiness. They do not cause loose stools, or infectious diarrhea, do not cause constipation on both sides of the stool issue. 

They do make the stools darker and they do stain the teeth. 

Moving off of immunologic, we'll talk about cardiovascular. Because the preemie has been predisposed to cardiovascular diseases, such as NEC and cardio pulmonary, such as BPD, iron has been examined and is probably a factor in that. At least in animal models, hypoxia re-perfusion does cause free radical damage, and is a risk factor for development of NEC. In the clinical practice, it's a little harder to tease out but we do know that preemies do have decreased perfusion of their GI tract. 

There is a direct association between elective red cell transfusions, and a negative association between recombinant and erythropoietin. It also increases enterocyte growth, and clearly decreases the NEC. So there's clearly something to do, because we know that erythropoietin is a free radical scavenger. And so NEC, at least, plays a partial role in the development of that disease, or in some children with that disease. 

Prematurity. 

Some older data from the early '90s shows that if your transferrin saturations were high with multiple transfusions, you tend to have the worst BPD. And they also looked at plasma ferritin and total T-bars or mal- and dialdehyde type assay, and showed that free radicals were generated and correlated to transfusion volume that the premature infant had. Some work that was done in our lab. In vitro, on lung cells, rhEpo does improve lung function and we're still unclear of all of the mechanisms. We know it changes some of the ion channels. And Peter DeYoung, who is our fellow, did the work. We're going to also continue and look at the free radical implications of that as we move on research-wise. The rhEpo does work as an antioxidant, decreasing BPD in some small studies, but not in a Cochran review. So it may not be important enough clinically to make a difference in the BPD rate. 

Vascular and neurologic diseases that are seen in the newborn period, hypoxic-ischemic encephalopathy. 

In animal models, it's clearly been shown that oxygen-induced free radicals are part of the reason why the brain is damaged so much. Epo has been given in animals, and actually in humans, showing that it improves the neurologic outcome, and the histologic outcome when it's looked at in animals. So iron may be part of that disease process. Retinopathy of prematurity and other neurodisease. We know that human milk fed premature infants that have more lactoferrin have less ROP. ROP is also higher with higher transfusion volumes when you calculate it and standardize it per kilogram. ROP is higher with higher plasma ferritin levels and in children with multiple transfusions. It's independently associated in correlation in multiple regression analysis. 

But when the one study that's been out there that's prospective that said let's give these babies a lot of transfusions and keep their hematocrit high, and let's give these babies very few transfusions and keep their hematocrit low, it has not shown that it protected from ROP. Although, when you look at the incidence, 83% versus 73% in children less than 1250g, that's a really high ROP rate. 

We don't see that rate in our nursery. 

So I want to conclude on the iron excess, and we'll move on to deficiency. The key to preventing iron excess in early development is to keep the transferrin saturated. Iron excess can cause hemolysis and free radicals, especially with children with deficient antioxidant levels, such as premature infants. Iron excess can interfere with immune function, especially in the malaria belt. Iron excess contributed to the pathogenesis of several diseases of premature and ill infants. Okay. 

Let's talk about iron deficiency and have children of all colors up there, but it's kind of important to note that iron deficiency is very different in white populations versus minority populations in the United States. Prevalence of iron deficiency in Caucasian is somewhere between 5-6%. And as you go down the list, Hispanics are three times that. 

African American children are double. Southeast Asian are five times that. Immigrant children four times as well. If you're overweight your incidence is quite high, again, four times the Caucasian population. And if you're not in day care, you're double the Caucasian population. So it's kind of a big problem when you're dealing with 30% of the population, such as the Southeast Asian Hmong children. 

I think Frank wanted me to put this in. And I'm sorry that the boxes and circles didn't come out, but on this axis is Body Calcium in Grams. This axis is Body Iron in Milligrams. Iron is acquired from the placenta, 16 weeks all the way up to 40 weeks in sort of a linear pattern with weight, and so very similar to other minimals such as calcium. 

And if you have a normal functioning placenta, and that's a big if, if you have a normal functioning placenta. You get most of your iron, then, in the last half of pregnancy and definitely the last third. 

If you're pregnancy is normal, your iron stores correlate with your birth weight, and you are protected from iron deficiency when you live in a developed world. That's the notion that I learned when I was a resident, and I learned when I was a fellow. And I was taught, you know, as I keep going on. But I'm not sure that's going to be a real notion at this point in time, based on a lot of data that have come out recently. 

But we did know at that time, that if were premature infant, you did have decreased stores at birth. You had blood loss, or fetal hemorrhage, or if you were a donor twin in a twin-to-twin, you lost a lot of blood and you were very iron deficient. 

About 10-12 years ago, a lot more information is known about what happens in abnormal placental states, such as intra-uterine growth retardation, placental insufficiency preeclampsia, infants of diabetic mothers, twin pregnancy, and when moms have severe maternal iron deficiency, and clearly, the placenta is unable to keep pace in those situations. 

There's a couple other caveats on the iron deficiency concept which is that there is an iron maldistribution. 

So if you're going to, because of fetal hypoxemia, shunt all your iron into your red cells, then you have decreased tissue stores, even though you may calculate your red cell iron to be okay. So hypoxia, IDM, hemolysis do have iron in the wrong place. But the conventional teaching back when I was a resident, and ongoing, is when you're birth weight is doubled, your stores are depleted. So it's important to note that the birth weight is doubled very rapidly in a premature infant. This is a little different framework put forth in a review article by an expert in iron deficiency. And if you look at it, she puts a huge emphasis on iron at birth. Including the mother's iron status, including what happened to her. What was her diet? Was she smoking? And gestational age, and delayed cord clamping, which I could come back and talk about at some point in time. 

But in premature infants, delayed cord clamping may improve iron status in a very remarkable way, and is practiced in a lot of places in Europe. 

So it looks at iron needs, available iron sources, enhancers, that you've learned about, including ascorbic acid inhibitors, such as tea and the phytates that are there. And then you have iron losses and other confounders. I wanted to just mention the confounders down here. Infection, inflammation, chronic illness, sex, ethnicity, in here as well, and socioeconomic status climb right in there. So I think that the review pointed out, and I agree that we need to just look at what happened to the baby before they were born, as well as what they're feeding afterwards. 

So some nontraditional thoughts about risk of iron deficiency. Red cells trump all tissues whene iron supplies are short. It's a survival response, in response to hypoxia or anemia, erythropoietin. And animal data. 

Lots of human data show that red cells have the iron and very key tissues do not. 

Another interesting thought is that healthy infants born large for gestation, who have large BMIs, have a higher prevalence of iron deficiency. I think they grow, and they grow and they grow, and they outgrow the ability of their body to assume the iron. This is data from Scandinavia. 

The Hispanic data and monkey data both show that growth contributes to iron deficiency anemia. So in Rhesus monkeys over at the primate center, one of my collaborators, Dr. Coe, has looked at this. and has been really interested in how growth outstrips the ability for iron to maintain. 

He also has looked at Rhesus monkeys showing that stress during pregnancy also increases the prevalence and severity of anemia in the offspring. This is probably because during stress situations, you scavenge away your iron as part of the stress response. 

And apparently it is interfering with the placental delivery. And he's examining that in a lot more detail, and we're working with him. 

Also some new data that we've just published by Baumann-Blackmore, et al., Black and Hispanic children may have higher cord blood iron. It looks like if they're not in day care, they're very high risk for higher weight gain, higher BMIs and poorer iron status, as well. So I'll talk about Nicole's data in a little more detail later. 

So this is back to the trafficking of iron, just to bring us sort of back into, yes, iron goes into all of these different compartments, but we need to look at the iron indices, because we need to sort out how do we measure iron deficiency. And most of my research over the years has focused on how to you measure iron in early life, including preemies. And so with a critical eye looking at all of the things that we use clinically, and hemoglobin and hematocrit are extremely late indicators of iron status, especially tissue iron. And it's probably not sensitive. 

I know Frank is working with the Committee on Nutrition to look at what is a better measure. They're struggling with concepts of what a could be a better measure. Mean cell volume is a good one. I was taught that here when I was a resident. But it also, again, falls very late in process of body iron deficiency. Red cell iron, our red cell distribution width increases relativity late. But it was also pretty good along with the three of those that you get in a simple CBC. So they work pretty well, but they are late sort of measures. 

We've also spent a lot of time in transferrin receptors. So transferrin receptor is the truncated form of the receptor that sits on the cell's surface. 

It is a very early measure of poor marrow iron, but is not clinically available in Madison right now. The World Health Organization thinks it should be and they're pushing for that. They're having some problems, because they don't have a standard. At least, it's not ready for prime time just yet, and it might be available soon, and it might be good for us. 

We're also looking a lot at Zinc Protoporphyrin/Heme ZnPP/H. It measures the decreased iron incorporation into the red cell. When zinc substitutes for iron, they're both divalent cations. It goes into the red cell and it auto fluoresces, and is extremely easy to measure. It measures on a drop of blood. It's a little black box type thing, you put it in and it comes right out and gives you the as a result. 

It can be used in third world studies. It's a simple test, and is more sensitive than storage iron in one-year-olds and more mature individuals. But it's just not really caught on as a test used in the United States at this point. 

So talking about the children at risk and what we need to think about and do about. Start with prematurity, since that's where my love is. Take a 28-week gestation child, about 1,000 grams, has 75mg of iron at birth, three-fourths of that in his blood. His iron status hinges on his blood loss and his packed cell transfusions. He's discharged at 37 weeks post conceptional age, week nine, and lost about 18% of his iron. That's exactly the amount that can be given by a delayed cord clamping maneuver, and the math is there. So sorry about the math this early in the morning. 

This one also shows some math. This is adapted from a study. We included some of our data in it. And over on here on your left, is a 3.5kg child. If you go through all the machinations of the math, you figure out that he needs to, over the course of his first year of life, absorb .55mg per day of iron. So that would be normal. If you're a little bit smaller, at 2.5 kilos in the middle column, you have to absorb .75mg per day. And if you look way over to the right column, the same one-kilo child that I just showed you, has to absorb over a milligram, double what a term child does. The maximum iron absorption you and I, or even growing infants can do is two. It's over half of his maximal ability, so he's got a tough task ahead of him that we as clinicians need to keep ahead of. 

So this is the truncated transferrin receptor that I showed you, because we'll show you some transferrin receptor data here in a second. If you take a nucleated red blood cell, there's lots of transferrin receptors on its surface. And as it sheds it in the reticulocyte stage, it's present in the plasma and it's truncated so it's easier to measure. The number goes up when either the number of red cells increases, or the density of transferrin receptors on the same number of red cells increase. 

And this didn't come out, our boxes didn't show. Preemies are in the blue one, and they have a peak in their transferrin receptor much earlier, as they're doubling their birth weight much earlier. These term children are healthy, and term formula fed children. They also have a peak, as well. So you do have to know what the normal values are. But clearly, the preemie is way above the normal term child the whole time. 

So this is a massive task. There's always a little bit of iron deficient erythropoiesis going on as they grow and are healthy. 

These are some more data from our ZnPP/H, So, ZnPP/H is this insufficient iron incorporation into the red cells. The blue, I should take a little time to explain that. The blue is that they don't receive the treatment. The two treatments are either transfusion or recombinant human erythropoietin. So if you transfuse a child, the ZnPP numbers do fall, supporting that you improve the iron delivery to the red cell population that's being made. These are our data. And then recombinant human erythropoietin. If you treat, you're pushing the iron status much more severely and you have iron deficient erythropoiesis that's going on. 

Right now, the meta analyses of Epo are that it probably doesn't effectively improve the erythropoiesis and hemoglobins and decreased transfusion. So most of us are not using rhEpo clinically any more. Although some people are still studying it for the effects on brain and other tissue, such as the GI tract. 

So preemies are in trouble. This is a composite of term, small for gestation children, large for gestation children, and large for gestation diabetic infants and diabetic mothers. This is the data from our work. And this is the data from Juul work. We had it at cord blood. She had it at a week of life, showing that term is here, large for gestation children are consistent with term. Small for gestation children probably are higher. 

Large for gestation diabetics are massively higher. Their undergoing a tremendous deficiency of iron, probably related to their size and their placental dysfunction. 

So this is replotting some of the data that you just saw on the previous slide. The blue circles are these large for gestation diabetics that I received at the University of Arizona and studied. These are some large for gestation healthy babies that did not have diabetes, were screened and did not have them. They are about the same size, and they do have a ratio of weight to length, so a surrogate of BMI. If you want to call it a cheap BMI. And the lines are parallel, the Y-intercepts are different, but clearly showing that if babies keep getting bigger and bigger and bigger with time, they may push themselves into an iron deficiency state, as they get bigger and bigger, and the placenta is unable to keep pace. 

And again in the diabetics. the placenta is very dysfunctional and transferrin receptors are very sick. 

It interferes with its ability to transport iron. And in theory, the large for gestation babies that we have here do not have that problem. 

But as we were looking at the Arizona data, we noticed that the Hispanic-surnamed children had a higher ZnPP than the people that did not have Hispanic surnames. So we went ahead and studied this at Meriter. So we obtained ZnPP and plasma ferritin as a measure of iron stores on cord blood from women born at Meriter. We matched women of minority status with Caucasian, and this is Nicole's work. We found that the women at Meriter that were reporting their minority status were very much lower socioeconomic status. They took slightly fewer multivitamins with iron, but it was in the 85% range. African Americans took a lot more iron than the other groups, even though everyone was taking the multivitamins with iron. They must have been prescribed additional iron supplements because they were anemic. 

We found the same rates of depression between all the groups, the minority, the Hispanics, but we found that the minorities received less antidepressants. So consistent with the stress hypothesis that I described that Dr. Coe is interested in, so maybe they were untreated depression, maybe they didn't receive the medical care that they needed to diagnose the depression. But anyway, these were the reports. 

We couldn't find any other additional information, since we didn't have access to all of their charts, but this is what we found. In the Caucasian are the black areas. The white are the African American and Hispanics. We found that the ZnPP was statistically higher in both the minority groups compared to their gestation matched Caucasian controls that we carefully matched. The ferritins were clearly lower. The hemoglobin levels were similar. 

But there clearly was a difference in iron stores. That's currently in press, I just got the notice yesterday. 

So an interesting concept that hasn't been thought before. This is what I kind of do for the resident's clinical talks. You know, who's at risk for iron deficiency. A preemie; blood loss; cow's milk or low iron formula; If your mom had diabetes; if you're eligible for WIC; if you do exclusive human milk for six months; if your mom has severe iron deficiency; if your growth retarded; or you're multiple gestations; and if you're Hmong or an immigrant. So going through the alphabet, thinking about who's at risk. 

So taking off the hematologic sort of concept of iron deficiency and moving on to what does iron deficiency do for immunity. We know that iron deficiency interferes with immune function, decreases a whole lot of white cell functions. Go down the list there. 

But in a developed world, very little clinical impact has been shown. There are slightly more post-op infections if you have iron deficiency. And if you treat children with iron fortified formulas, or other iron treatment, the number of infections do decrease slightly, keeping in mind that acute phase response of inflammation is to scavenge away iron, so you decrease your transferrin and you increase your ferritin. So the inflammation infection sort of area is complicated by the fact that the body's protecting its iron and storing it away. 

This one is kind of an interesting concept, and we have a lot of animal data on this right now. But all the rage of fetal programming of adult disease, you see higher blood pressure and increased cardiovascular morbidity in children who are born small for dates, or after diabetes. Note that the babies who are born after diabetes and are small for dates have extremely low tissue iron stores. And I'll show you those data in a minute. And they exhibit disturbed renal development. If you look histologically at their kidney development, it's very abnormal, very markedly decreased number of nephrons. 

And our animal data support that iron may be an independent factor that's causing this higher blood pressure later on in life, and we're continuing to do studies on that. I won't show you any of those data, but keep that in mind. 

This is a flow diagram from Dr. Low's office as well. Summarizing a Cochran review of iron deficiency in early development. There's clearly nonreversible-- I repeat that, non-reversible cognitive deficits that occur in iron deficiency in early development. There are 27 studies addressing that of varying quality, but some of them are very good. 

And how does that work? If you look over at the left side of the diagram, you've got your iron deficiency, and some environmental input on the right. And you've got disturbed gene and protein profiling, you've got disturbed neurochemistry, neuroanatomy, and neurometabolism, which translates then into neurophysiologic disturbances, cognitive, sensor motor and then also social and effective disorders. 

So this is kind of a new concept that people have not been thinking about for years. But the evidence is pretty clear that there is a major problem. This is a slide from a friend of mine, a doctor from the University of Minnesota, who does a lot of this work. He's just showing that there's iron transporters here on every cell in the CNS, and showing where they're at. He's done a lot of immuno-histochemistry, doing that. There's iron in the spinal fluid dealing with the blood-brain barrier. You have to have iron crossing as well. And so, if you don't have enough iron, it interferes with ongoing neurologic growth, development, oligodendrocytes, making myelination, all sorts of problems in an early developing child. 

So this is sort of a brief summary of those 27 studies, moderately severe iron deficiency in term infants diagnosed at 12-23 months. You have lower mental and motor functioning at school entry. 

You have lower behavioral and developmental scores that persisted at 11-14 years and then persisted at 19 years, and actually the gap widened at 19 years, when you can do more sophisticated cognitive testing. 

If you're a term infant with iron deficiency anemia diagnosed earlier than we diagnose it in this community, at six months, you have delayed auditory evoked potentials in the first year. You have persistent delayed auditory and visual potentials at four years. And early interventions, such as treating iron deficiency between that six month and 12 month window, actually can improve some auditory, visual and mental outcomes. 

And one of the treatments and one of the studies was meat, believe it or not. And Frank is really intrigued by that. They're talking about that all over the world, about how good of a source meat is for iron, and how we don't give it very early on in the U.S., and is that an okay or a not okay practice. 

And then if you look at hemoglobin values, it doesn't have iron status per se, but hemoglobin values from the WIC database, it is definitely inversely correlated to children being in special education. 

So again, a lot of inferential and some more sophisticated data showing that iron deficiency causes long-term cognitive delays. This is to introduce the fetal dysfunctional, fetal hypoxemia sort of process. 

You can go down the columns and can see there's increased red cell mass, iron redistribution, and markedly decreased tissue iron for the stores. And that's adapted from Dr. Georgieff's work in Minnesota. 

They found at autopsy, a 40% decrease in brain iron in IDM's versus controls. And the placenta is unable to do it. Even though the brain should be of high priority, the red cells do trump it, and the iron is located in the red cells. 

Also in IUGR infants at autopsy, a 33% decrease brain iron. The lower the amniotic fluid volume, the less transplacental iron, so it's clearly related to placental dysfunction. When you have low cord plasma levels, you do have low plasmaferritin levels at nine months, when you're mom is diabetic or you're small for dates. 

These are some rat data. 

I'm not a neuro-histologist but this is the normal rat data, this is -- neurons, and you can just see there's markedly different hippocampal sort of function. These are low power and these are high power. So clearly visually, there's something really wrong anatomically going on there. 

Now the developmental studies of the small for dates, IUGR and IDMs, even with heed-sparing in the small for dates, there's altered auditory evoked potentials that persist. The IDMs have poorer neonatal recognition memory and lower PDI's at one year. The diabetics have poorer iron stores have birth, have poorer neonatal recognition memory, doing sophisticated recognition tests, lower MDI's at one year compared to those with better stores, and that were diabetic as well. So control of diabetes may improve the iron transport in this situation. 

Those in the lowest quartile of cord blood ferritins, also had impaired psychomotor development, worse language and worse fine motor skills as well. 

So in the group of diabetics and IDM's, and those are in our practice every day, that diabetes risk for gestational diabetes is really high in this population. 

And this is here to remind me that it's not just a physical anatomical impairment of neurologic function, but it's actually neurotransmitter impairment. 

Dopamine and other mono-immune transmitters are disturbed in iron deficiency. Iron is a huge part of the function of those. So iron deficiency is also associated with some more common problems. And as a neonatologist, I treat breath holding with caffeine, since apnea in our unit-- but some of you do treat breath holding spells in patients in their first year or two of life. Breath holding spells caused by increased vagal tone interplay between hyperventilation followed by apnea, or if it's prolonged, it could be an arrhythmia, and arrhythmias needs to be ruled out. 

But iron deficiency in the mother or child may be also associated with breath holding spells. And I know the residents have been talking about this in morning report or been around. They have been discussing this. But in a randomized controlled trial of 6 mg/k of iron in children, showed an 87% response, i.e., improvement in the breath holding spells. 

Complete resolution in 50% of them, partial resolution in about 36% versus a little bit of resolution as a partial and controls. 

And it's clear that the catecholamines that antagonize the vagal tone the mono-immune transmitters are deficient in iron deficiency. So there is not just a structural problem, but it is a chemical, biochemical problem. 

There's also some association between sleep and poor sleep. If you're iron deficient as an infant, you spend less time sleeping on sleep studies generally, multiple night waking, tossing and turning and moving your legs more. Dopamine regulates the sleep wake cycles. It decreases the D1 and D2 receptors, the dopamine receptors and decreases dopamine levels in rats. So a lot of animal data to report this. In Chilean children that were studied, they were iron deficient as infants and toddlers. There was less REM sleep during the last third of sleep compared to controls. 

And a pattern with less REM sleep does impair learning, as well. So better sleep clearly correlates to better learning. 

This one's on TV. I see the ads for restless leg syndrome, RLS, I guess it's now called. I don't obviously treat anybody with that, but it occurs in 5-10% of adults and 2% of children. There are obviously some Parkinson drugs that help this disease. But iron deficiency itself, or anemia itself, may predispose. So iron deficiency should be part assessed as part of the work-up of restless legs, because it's easily treatable. an empiric iron trial may be necessary if your evidence does not support you're anemic, because sometimes the blood indices lag behind the CFS levels. And specifically in the substantia nigra, which controls a lot of this activity, there's a focal area of real susceptibility to low iron. 

With correlation, with iron deficiency or iron deficiency anemia or anemia itself, sometimes the symptoms do resolve and they do actually work. Sometimes though don't. 

With chronic diseases such as kidney disease, you can get RLS, but some patients also respond to iron therapy, and clearly iron deficiency anemia is very common in kidney diseases. RLS is also seen in pregnancy. From talking to my OB colleagues, especially in the last trimester. The symptoms usually disappear within four weeks of delivery. Again, four weeks after delivery, you have less of an iron load, because you're not delivering iron to your fetus at that point. 

There's also some softer data. I'm not going to defend all of this, because of the study designs are not what I would call optimal as a scientist, but it could be that iron deficiency also predisposes to depression. Iron deficiency in pregnant women. 

They were more apathetic, more cognitive function, so physical, hand-eye function tests were poor. But they've not shown any developmental outcome of the children whose mothers have iron deficiency, and whether or not treatment improved that. So it's unclear what's happening to the fetus at that point. 

Iron deficiency in postpartum women is associated with poor memory when they're testing, more stress, more depression. There's a 25% improvement if you treat. Their response to their babies was very abnormal, they were apathetic and more controlling of their infants. They want their infants to be well-behaved. Iron deficient newborns and infants do respond less positively to their mothers, so if you have iron deficiency in both the mother and child, there's a major impairment in social interactions and the environment. They were more irritable. 

The study designs, like I say, were of softer science, but still a suggestion that it might be that there's either the apathy or the lethargy that's interfering with the bonding. 

Or it could be the monoimmune transmitters again, since they're working there. 

So in conclusion for the iron deficiency, there's hematologic manifestation. There's probably mild impairment of immune function in the U.S. There's cardiovascular implications. And there's major neurologic implications as well. This says, "I may be iron deficient, but I have nerves of steel," coming out of the phlebotomy office. 

So how do you screen for iron deficiency? The AP clearly recommends universal screening or selective screening. But as you look down, their selective screening criteria based on my opinion, it's not complete. They need to put low socioeconomic status. They need to put a few other things on there. 

They do recommend screening at four months premature infants, and I'm not sure that that happens in our community. That they should be screened, especially because in our community, we don't transfuse a lot. We're very stingy about our blood draws and they don't get a lot of transfusions. 

All of the screening by the AP recommended is hemoglobin, but sensitivity as I explained to you before, is pretty poor. They're looking at other measures, but I think clinically available measures are difficult to come by. And they're revising their statement, Frank says. 

The CDC was a little more complete. It listed the children at risk, and it recommended selective screening at 9-12 months, repeat at 15-18 months, and yearly, until five years. They include a little more complete list of who I think might be at risk. Again, they recommend hemoglobin screening. 

So treatment, "I'm suffering from iron deficiency." "Take six of these." "Clink, clank clang." And they're iron. All right. 

So what do you do? GI tract absorbs more iron when you're iron deficient. The maximal is 2mg per day. Human milk contains nowhere near that, and less than 50% of iron in human milk is absorbed. So you get only .13mg a day, if you're normally feeding human milk. 

If you're feeding formula, because a lower amount is being absorbed, it's less bioavailable, you get .2mg a day. And then 50% of FeS04/MVI is absorbed, so you get 1.3mg a day. Meat is extremely well-absorbed and studies show that it even works at six months of age. 

This is for preemies. We kind of do a sliding scale of preemies. The more premature you are, the higher you get iron, up so 6mg/kg per day in their unit. You should escalate that dose up to 15mg, or until the baby gets about 4 kilos. Then you can stop escalating it. But continue it probably for the first year and a half. If you're a human milk fed term infant, keep in mind the higher viability of iron than formulas. 

You probably need some form of iron supplementation by four months, because that's when they're doubling their birth weight. But if you're giving the multivitamins with iron, which meet the vitamin D requirements, then you're covering it when you start the vitamin D, as well. And if you're a term child with excessive phlebotomy loss, other risk factors, you may want to start even earlier than four months. And then formula fed, probably okay with 2mg/kg per day of the formula. If you identify risk factors, you may need a slightly more. 

Keep in mind that day care, and ear infections, those kinds of things do interfere. And keep in mind that oatmeal and meat are both excellent iron sources, because they're iron fortified oatmeal. And I think that's it! Questions?