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I'll go a little more into why >> Thank you very much Dr. Wald.
of nutrition, Ibut I have one more title.
This is a T-shirt given to me by my lab manager, so "Irony."
( laughter )
So the outline of the talk will cover a little bit of
the background of iron accretion
iron deficiency in infancy, talk a little bit about
iron overload.
because Dr. Greer, being The iron overload was put in
the Committee on Nutrition the chair of
all over the country has been traveling
And he hears these talks and the world.
And he thought that this would on a regular basis.
in Grand Rounds, as well. *So, we'll talk about a lot
of the non-hematologic
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
*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
Let me see if I can get this arrow to go.
So you've got iron
sundry places, 75% of the iron going in and out of various and
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.
transferrin, There's a itty bit in transport,
So going in and out of all that's in the green.
And then the GI tract of theseis over here.artments.
We've done a lot of work
I won't be showing as much on that.
be showing some of our work, of that work today, but I will
clinical knowledge and research. so it will be a hybrid between
abundant element on the earth, *So iron is the fourth most
So why should such an abundant and is very abundant in dirt.
with a clinical deficiency element be associated
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,
body iron as you're born. And your circulating red cells
take up 75% of it;
and cytochromes, 10%. St*I think this is whyobin
iron is deficient.
by a friend of mine Thwho trekked Nepal.ot
So you can see, she's dirty.
She lives in a dirty hut. She'She breast feedsrty.
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.
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.
then, of iron excess. Let's Why does it happen,ground*
and why is the newborn
at highest risk? and the early infant
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 almost all of that and transferrin.
So it is part of the antioxidant is transferrin.
And if you're saturated with iron, it's unable
to scavenge up any iron.
oxygen radical disease *The disease has been coined
The reason why the newborn of the newborn.
all the other antioxidants is also iron deficient in that
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
newborn and infant period. a lot of problems in the
back in the '60s and early '70s, Quoting Dr. Barness, here,
very deficient in vitamin E and had high polyunsaturated
fatty acids, PUFA content.
going on in the NICU, because And these premature formulasysis
were inadequate.
that all the current But Frank could tell you
human milk are extremely high in vitamin E and low in PUFA.
And this just doesn't happen
So it's usually not a problem, much any more.
is a major factor. unless something else
and I wrote on editorial *Recent evidence,
there was really actually no evidence of free radical
disease in premature infants
as 18mg/kg of ferrous sulfate. from Norway, that get as much
the predominant source So if the human milk, which was
is adequate in its antioxidant of nutrition for these children
the iron that we give here capacity, even for three times
So a slightly different form, which might be a little less
free radical generating,
of iron. but still it's the same amount
there's an addition In Japaof lactoferrinuntries
in the premature formulas that may also decrease
the free radical generation.
in the test tube, putting human milk in all of these
various and sundry formulas,
is the most protective it's clear that human milk
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,
the thought that IV iron would we would have shuddered at
and it appears to be so, be safe in premature newborns,
erythropoietin. *However, transfusionsng
are another matter. And I like to point this out.
These are data from our lab.
of baseline of both mal- and dialdehyde, which is
a by-product of oxidation.
and we saw sort of We looked at hemoglobin rise,
to almost two times baseline a parallel rise, 1-1/2
in hemoglobin. of mal- and dialdehyde
and virtually superimposable So hemoglobin is in the blue,
*The reason is that premature above the mal- and dialdehyde.
one milligram her ml of iron infants receive
So if you're following up wa newborn who's been multiply.
transfused, their irons test
than a child who never received isa transfusion in the NICU.t
*Of note, one red cell transfusion of 10ml/k that
we give in the NICU contains
total iron binding capacity of the transport system of iron.
So it can be problematic
We tend to give our transfusions if it's hemolyzed.
so there can be some hemolysis. throOlder data has shownter,
that there's a lot of hemolysis.
we do it a little bit safer. I think nowadays,
away from hematologic *to immune function.
I think this is kind of an interesting concept.
Chronic or acute iron overload
to infection. Microbial pathogens love iron,
just like everything else,
do have very high affinity and transferrin and lactoferrin
from the microorganisms. for iron, and may remove it
your circulating free iron If transferrin is not saturated,
so that's pretty darn low. is ten to the minus 18th mol/l.
or IV iron, you have excessive However, if you get IM 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
where they gave IM iron to Polynesian infants, because
there was a massive epidemic
They all had an extremely high of iron deficiency.
especially E. coli, which is incidence of neonatal sepsis,
Once they stopped the practice, obvthat should be decreased,en.
incidence decreased after the practice was discontinued.
*Again, also in a third world
Bangladesh, oral iron situgiven to them increasedntry,
their incidence of dysentery. They're in a high pathogen area
and received some side effects
*But the biggest news that you may all remember
back from your textbooks
a problematic disease when there's excess iron.
Malaria and other infectious
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
increased incidence of malaria. in NeOther studies showd an
that even oral iron,
increased the transmission rate oby about 50%, and increaseds,
the malarial load by a number of organisms.
Clearly chelators will protect
this is a cause effect. froIt's probably the iron.hat
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
the pro-infectious role of parenteral iron, probably
related to transferrin
And neisseria meningitis, again, saturation.
The direct mechanisms have been somewhat worked out.
The cell number of neutrophils
and lymphocytes, as well. T-helper cell response
is very decreased.
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,
the gastrointestinal flora, owhere there's more E. colie
and less bifidobacteria.
and it probably is. Although, study after study
has interrogated it in a
that contrary to their thought, sopthat there's probablyund
no evidence for increased infectious diarrhea in the U.S.
But a lot of the studies
very difficult to separate that were done early were
because human milk is productive out formula versus human milk,
So formula is clearly less and formula is not.
than human milk. protective against infections
and it generally does not change But if you add additional iron,
*Along with that and the different colonizations,
clearly well done studies show
in the U.S. do not increase that ironfussiness. formulas
They do not cause loose stools, or infectious diarrhea,
do not cause constipation on
They do make the stools darker both sides of the stool issue.
*Moving off of immunologic, and they do stain the teeth.
Because the preemie we'll has been predisposedcular.
to cardiovascular diseases, such as NEC and
cardio pulmonary, such as BPD,
is probably a factor in that. At least in animal models,
hypoxia re-perfusion
and is a risk factor does cause free radical damage,
In the clinical practice, foit'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,
between recombinant andand erythropoietin.tion
It also increases enterocyte
the NEC. growth, and clearly decreases
to do, because we know So there's clearly something
is a free radical scavenger. that erythropoietin
plays a partial role in the development of that disease,
or in some children with that disease.
*Prematurity.
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
that the premature infant had. to transfusion volume
in our lab. In vitro, on lung cells,
rhEpo does improve lung function
of all of the mechanisms. We know it changes some
of the ion channels.
our fellow, did the work. We're going to also continue
and look at the free radical
as we move on research-wise. implications of that
antioxidant, decreasing BPD Thin some small studies,n
but not in a Cochran review.
enough clinically to make a difference in the BPD rate.
*Vascular and neurologic diseases that are seen
in the newborn period,
In animal models, it's clearly hypoxic-ischemic encephalopathy.
free radicals are part of beethe reason why the brainced
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.
and other neurodisease. We know that human milk fed
premature infants that have more lactoferrin have less ROP.
ROP is also higher
when you calculate it and standardize it per kilogram.
ROP is higher with
and in children hwith multiple transfusions.s
It's independently associated in correlation
in multiple regression analysis.
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
in children less than 1250g, the incidence, 83% versus 73%
We don't see that rate that's a really high ROP rate.
*So I want to conclude on the in our nursery.
to deficiency. iron excess, and we'll move on
iron excess in early development The key to preventing
saturated. is to keep the transferrin
and free radicals, especially Irwith children with deficients
antioxidant levels, such as premature infants.
Iron excess can interfere with immune function, especially
in the malaria belt.
pathogenesis of several diseases Iron excess contributed to the
Okay. of *Let's talk about ironnts.
deficiency and have children
but it's kind of important of all colors up there,
is very different to nin white populationsency
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.
as well. Immigrant children four times
incidence is quite high, If you're overweight your
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
children. *I think Frank wanted meg
to put this in. And I'm sorry that the boxes
and circles didn't come out,
is Body Calcium in Grams. This axis is Body Iron
in Milligrams.
the placenta, 16 weeks Iron is acquired from
in sort of a linear pattern all thewith weight,0 weeks
and so very similar to
And if you have a normal other minimals such as calcium.
and that's a big if, functioning placenta,
a normal functioning placenta. if you have
then, in the last half You get most of your iron,
definitely the last third. of pregnancy and
your iron stores correlate with Iyour birth weight, and you are*
protected from iron deficiency
in a developed world. That's the notion that I learned
when I was a resident, and
And I was taught, you know, I leaas I keep going on.ellow.
But I'm not sure that's going to be a real notion
at this point in time,
that have come out recently. based on a lot of data
that if were premature infant, *But we did know at that time,
stores at birth. you did have decreased
or fetal hemorrhage, You had blood loss,
in a twin-to-twin, or if you were a donor twin
you were very iron deficient. y*About 10-12 years ago,and
a lot more information is known about what happens in
abnormal placental states,
growth retardation, placental insufficiency preeclampsia,
infants of diabetic mothers,
moms have severe twin pregnancy, and when
and clearly, the placenta mais unable to keep pace,
in those situations.
on the iron deficiency concept There's a couple other caveats*
an iron maldistribution. which is that there is
because of fetal hypoxemia, Sshunt all your irono,
into your red cells,
tissue stores, even though then you have decreased
your red cell iron to be okay. you may calculate
do have iron in the wrong place. So hypoxia, IDM, hemolysis
back when I was a resident, But tand ongoing, is whenhing
you're birth weight is doubled, your stores are depleted.
So it's important to note that the birth weight is doubled
very rapidly
This is a little different in a premature infant.
a review article by an expert fin iron deficiency.in
And if you look at it,
on iron at birth. sIncluding the mother'ss
iron status,
What was her diet? including what happened to her.
And gestational age, Was she smoking?
I could come back and talk about and delayed cord clamping, which
But in premature infants, delayed cord clamping.
may improve iron status in a very remarkable way,
and is practiced
*So it looks at iron needs, in a lot of places in Europe.
enhancers, that you've available iron sources,
ascorbic acid inhibitors, such as tea and the phytates
that are there. And then you have iron losses
and other confounders.
the confounders down here. I wanted to just mention
chronic illness, sex, ethnicity, Infection, inflammation,
and socioeconomic status in here as well,
So I think that the review climb right in there.
that we need to just look at pointed out, and I agree
they were born, as well as what happened to the baby before
So some nontraditional thoughts* wabout 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.
Lots of human data show that red cells have the iron
and very key tissues do not.
is that healthy infants *Aborn large for gestation,t
who have large BMIs,
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.
*The Hispanic data Thand monkey data both showia.
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
ability for iron to maintain. in*He also has looked atthe
Rhesus monkeys showing
also increases the prevalence thaand severity of anemiancy
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.
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
higher BMIs and poorer iron status, as well.
So I'll talk about Nicole's data
*So this is back ito the trafficking of iron,r.
just to bring us sort of back into, yes, iron goes into all
of these different compartments,
the iron indices, because we need to sort out how
do we measure iron deficiency.
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
and hemoglobin and hematocrit are extremely late indicators
of iron status, especially tissue iron.
And it's probably not sensitive.
with the Committee on Nutrition I know to look atorking
what is a better measure. They're struggling with concepts
of what a could be
Mean cell volume is a good one. I was taught that here
when I was a resident.
very late in process But it also, again, falls
Red cell iron, of body iron deficiency.
increases relativity late. our red cell distribution width
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.
of poor marrow iron, It is a very early measure
in Madison right now. bThe World Health Organizatione
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 good for us. and it might be available soon,
at Zinc Protoporphyrin/Heme *We're alsZnPP/H.ng a lot
It measures the decreased iron incorporation
into the red cell.
they're both divalent cations. When zinc substitutes for iron,
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.
in third world studies. It's a simple test, and is
more sensitive than storage iron
and more mature individuals. in one-year-olds
caught on as a test used in the United States
at this point.
the children at risk *So talking about
and do about. and Start with prematurity,bout
since that's where my love is.
about 1,000 grams, Take a 28-week gestation child,
three-fourths of that has 75in his blood. birth,
His iron status hinges
his packed cell transfusions. He's discharged at 37 weeks
post conceptional age,
about 18% of his iron. week nine, and lost
can be given by a delayed Thacord clamping maneuver,that
and the math is there.
this early in the morning. So sorry about the math
This is adapted from a study. TWe included some of our data.
in it.
is a 3.5kg child. AnIf you go through all theft,
machinations of the math, you figure out that he needs to,
over the course of his first year of life,
absorb .55mg per day
So that would be normal. of iron.
at 2.5 kilos If you're a little bit smaller,
have to absorb .75mg per day. iAnd if you look way over
to the right column,
that I just showed you, has to absorb over a milligram,
double what a term child does.
you and I, or even growing The maximum iron absorption
is two. It's over half of his
maximal ability, so he's got
that we as clinicians a need to keep ahead of.m
*So this is the truncated
that I showed you, transferrin receptor
transferrin receptor data becauhere in a second. some
If you take a nucleated red blood cell,
there's lots of transferrin receptors on its surface.
And as it sheds it
it's present in the plasma in the reticulocyte stage,
so it's easier to measure. and it's truncated
either the number of red cells The number goes up when
of transferrin receptors increases, or the density
of red cells increase. on the same number
our boxes didn't show. *And this didn't come out,
and they have a peak Preemies are in the blue one,
much earlier, as they're in their transferrin receptor
much earlier. These term children are healthy,
and term formula fed children.
So you do have to know They also have a peak, as well.
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
So, ZnPP/H is this insufficient iron incorporation
into the red cells. The blue, I should take
a little time to explain that.
don't receive the treatment. The blue is that they
are either transfusion The two treatments
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
erythropoiesis that's going on. *Right now, the meta analyses
of Epo are that it probably doesn't effectively improve
the erythropoiesis
and decreased transfusion. and hemoglobins
rhEpo clinically any more. So most of us are not using
studying it for the effects Alon brain and other tissue,ll
such as the GI tract. *So preemies are in trouble.
This is a composite of term,
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
We had it at cord blood. from Juul work.
at a week of life, She had it
large for gestation children showing that term is here,
Small for gestation children are consistent with term.
Large for gestation diabetics are massively higher.
Their undergoing a tremendous deficiency of iron,
probably related to their size
*So this is replotting some and their placental dysfunction.
on the previous slide. of the data that you just saw
large for gestation diabetics The bthat I received these
at the University of Arizona
These are some large and studied.
that did not have diabetes, for geswere screenedy babies
and did not have them.
and they do have a ratio They are about the same size,
so a surrogate of BMI. of weight to length,
a cheap BMI. If you want to call it
the Y-intercepts are different, but clearly showing that if
babies keep getting bigger
they may push themselves and bigger and bigger with time,
as they get bigger and bigger, into an iron deficiency state,
to keep pace. And again in the diabetics. the*
placenta is very dysfunctional
are very sick. and transferrin receptors
to transport iron. It interferes with its ability
for gestation babies And in theory, the large
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
did not have Hispanic surnames. thSo we went aheadat
and studied this at Meriter.
plasma ferritin as a measure So we obtained ZnPP and
from women born at Meriter. We matched women of minority
status with Caucasian,
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,
African Americans took a lot but it was in the 85% range.
even though everyone was taking mothe multivitamins with iron.s,
They must have been prescribed
because they were anemic. a*We found the same ratests
of depression between all the groups, the minority,
the Hispanics, but we found that the minorities
received less antidepressants.
hypothesis that I described that Dr. Coe is interested in,
so maybe they were untreated
receive the medical care depression, maybe they didn't
to diagnose the depression. thBut anyway,ded
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
The white are the African American and Hispanics.
We found that the ZnPP was
in both the minority groups compared to their gestation
matched Caucasian controls
The ferritins thawere clearly lower.hed.
The hemoglobin levels were similar.
But there clearly was a difference in iron stores.
That's currently in press,
*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.
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;
iron deficiency; if your mom has severe
or you're multiple gestations; if your growth retarded;
or an immigrant. and if you're Hmong
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
We know that iron deficiency do for immunity.
decreases a whole lot inteof white cell functions.ion,
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
keeping in mind that acute phase do decrease slightly,
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
we have a lot of animal data interesting concept, and
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.
born after diabetes and are small for dates have extremely
low tissue iron stores. And I'll show you those data
in a minute.
renal development. And they exhibit disturbed
at their kidney development, If you look histologically
very markedly decreased number it's very abnormal,
*And our animal data support that iron may be an independent
factor that's causing this
later on in life, and we're continuing to do
studies on that.
data, but keep that in mind. I won't show you any of those
from Dr. Low's office as well. *This is a flow diagram
of iron deficiency Summarizing a Cochran review
There's clearly nonreversible-- I repeat that, non-reversible
cognitive deficits
in early development. There are 27 studies addressing
that of varying quality,
*And how does that work? but soIf you look over at good.
the left side of the diagram, you've got your iron deficiency,
and some environmental input
And you've got disturbed gene and protein profiling,
you've got disturbed
and neurometabolism, neurochemistry, neuroanatomy,
neurophysiologic disturbances, which translates then into
and then also social cognitive, sensor motor
So this is kind of a new concept and effective disorders.
thinking about for years. But the evidence is pretty clear
that there is a major problem.
of mine, a doctor from This is a slide from a friend
who does a lot of this work. the University of Minnesota,
iron transporters here He's just showing that there's
and showing where they're at. on eHe's done a lot ofNS,
immuno-histochemistry,
There's iron in the spinal fluid doing that.
barrier. dealing with the blood-brain
crossing as well. And so, if you don't have
enough iron, it interferes
development, oligodendrocytes, with ongoing neurologic growth,
all sorts of problems in an early developing child.
*So this is sort of a brief
moderately severe iron deficiency in term infants
diagnosed at 12-23 months.
functioning at school entry. You have lower mental and motor
and developmental scores You have lower behavioral
and then persisted at 19 years, tand actually the gap widened
at 19 years, when you can do more sophisticated
cognitive testing.
with iron deficiency anemia diagnosed earlier than we
diagnose it in this community,
you have delayed auditory evoked at six months,
You have persistent delayed auditory and visual potentials
at four years.
treating iron deficiency And early interventions, such as
and 12 month window, actually can improve some auditory,
visual and mental outcomes. *And one of the treatments
and one of the studies
And Frank is really intrigued was meat, by that.it or not.
They're talking about that
how good of a source meat is all over the world, about
give it very early on for iroin the U.S.,e don't
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,
correlated to children it is definitely inversely
So again, a lot of inferential* being in special education.
data showing that andiron deficiency causesed
long-term cognitive delays. This is to introduce the fetal
dysfunctional, fetal hypoxemia
You can go down the columns and can see there's increased
red cell mass,
and markedly decreased iron redistribution,
And that's adapted tissue iron for the stores.
in Minnesota. *They found at autopsy,rk
a 40% decrease in brain iron
And the placenta in IDM's versus controls.
Even though the brain should be of high priority,
the red cells do trump it,
in the red cells. *Also in IUGR infantsed
at autopsy, a 33% decrease
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.
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
These are low power hiand these are high power.n.
So clearly visually,
anatomically going on there. there's something really wrong
of the small for dates, *Now the IUGR and IDMs,studies
even with heed-sparing
there's altered auditory evoked potentials that persist.
The IDMs have poorer
and lower PDI's at one year. neonatal recognition memory
iron stores have birth, Thehave poorer neonataler
recognition memory, doing sophisticated recognition tests,
lower MDI's at one year compared
and that were diabetic as well. to So control of diabeteses,
may improve the iron transport
*Those in the lowest quartile in this situation.
also had impaired psychomotor development, worse language
and worse fine motor skills as well.
*So in the group of diabetics
our practice every day, that and IDM's, and those are in
diabetes is really high diabein this population.ional
*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
in iron deficiency. traIron is a huge partrbed
of the function of those. So iron deficiency is also
associated with some more common
And as a neonatologist, I treat breath holding
with caffeine,
but some of you do treat since apnea in our unit--
in patients in their first year breor two of life.lls
Breath holding spells caused by increased vagal tone
interplay between hyperventilation followed by
apnea, or if it's prolonged,
and arrhythmias itneeds to be ruled out.a,
*But iron deficiency in the mother or child
may be also associated
And I know the residents have wbeen talking about this in
morning report or been around.
But in a randomized controlled They have been discussing this.
in children, trial of 6 mg/k of iron
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 it's clear that the catecholamines
that antagonize the vagal tone
are deficient the in iron deficiency.tters
So there is not just
but it is a chemical, abiochemical problem.
*There's also some association between sleep and poor sleep.
If you're iron deficient
you spend less time sleeping as an infant,
multiple night waking, on sleep studies generally,
and moving your legs more. tossing and turning
the sleep wake cycles. Dopamine regulates
D2 receptors, the dopamine It decreases the D1 and
dopamine levels in rats. receptors and decreases
to report this. SoIn Chilean childrenta
that were studied,
as infants and toddlers. they were iron deficient
during the last third of sleep There was less REM sleep
And a pattern with less REM sleep does impair learning,
as well.
correlates to better learning. So better sleep clearly
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
and 2% of children. There are obviously
some Parkinson drugs
But iron deficiency itself, thaor anemia itself,se.
may predispose. So iron deficiency should
be part assessed as part of the work-up of restless legs,
because it's easily treatable.
necessary if your evidence an empiric iron trial may be
because sometimes dothe blood indices lag behind,
the CFS levels. And specifically
in the substantia nigra,
activity, there's a focal area which controls a lot of this
to low iron. of real susceptibility
iron deficiency or iron deficiency anemia
or anemia itself, sometimes the symptoms do resolve
and they do actually work.
*With chronic diseases such as kidney disease, you can get RLS,
but some patients also respond
iron deficiency anemia is very common in kidney diseases.
RLS is also seen in pregnancy.
my OB colleagues, especially From talking to
The symptoms usually disappear in the last trimester.
Again, four weeks after widelivery, you have less ofy.
an iron load, because you're not
at that point. delivering iron to your fetus
I'm not going to defend all Tof this, because of the study*
designs are not what I would
but it could be that call optimal as a scientist,
to depression. iron deficiency also predisposes
in pregnant women. Iron deficiency
more cognitive function, They were more apathetic,
tests were poor. so physical, hand-eye function
any developmental outcome of the children whose mothers
have iron deficiency, and whether or not treatment
improved that.
to the fetus at that point. So it*Iron deficiency inappening
postpartum women is associated
testing, more stress, with pomore depression.hey're
There's a 25% improvement if you treat.
Their response to their babies
they were apathetic and more was very abnormal,
They want their infants to be controllwell-behaved.infants.
Iron deficient newborns and infants do respond
less positively to their
iron deficiency in both the mother and child,
there's a major impairment
and the environment. in social interactions
The study designs, like I say,* They were more irritable.
but still a suggestion that it might be that there's either
the apathy or the lethargy
with the bonding. Or it could be the monoimmune
transmitters again, since they're working there.
*So in conclusion
hematologic manifestation. for the iron deficiency, there's
of immune function in the U.S. There's probably mild impairment
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
*So how do you screen office.
The AP clearly recommends universal screening?
or selective screening. But as you look down, their
selective screening criteria
it's not complete. based on my opinion,
low socioeconomic status. They need to put
a few other things on there.
four months premature infants, They do recommend screening at
that happens in our community. and I'm not sure that
especially because That they should be screened,
we don't transfuse a lot. We're very stingy about our
blood draws and they don't get
All of the screening by the AP* a lot of transfusions.
but sensitivity as I explained recommended is hemoglobin,
They're looking at other to you before, is pretty poor.
clinically available measures are difficult to come by.
And they're revising
*The CDC was a little more their stacomplete.rank says.
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
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.
GI tract absorbs more iron *So what do you do?
The maximal is 2mg per day. whenHuman milk containsent.
nowhere near that,
in human milk is absorbed. and less than 50% of iron
if you're normally So you get only .13mg a day,
If you're feeding formula, feeding human milk.
is being absorbed, because a lower amount
you get .2mg a day. And then 50% of FeS04/MVI
is absorbed,
Meat is extremely well-absorbed and studies show that it
even works at six months of age.
We kind of do a sliding scale *This of preemies.ies.
The more premature you are, the higher you get iron,
up so 6mg/kg per day
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
If you're a human milk fed for the first year and a half.
the higher viability of iron term infant, keep in mind
You probably need some form of iron supplementation
by four months, because that's
their birth weight. wBut if you're giving
the multivitamins with iron,
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
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?