cc >> 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?