Page 625 - Hematology_ Basic Principles and Practice ( PDFDrive )

534 Part V Red Blood Cells

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developing fetus. Preferential delivery of folate to the fetus can cause cochlear cells leading to severe hearing loss and learning and
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or aggravate folate deficiency in the mother. This is observed clini- memory deficits. 197
cally when a mother with severe folate deficiency gives birth to a baby There is additional clinical support for a relationship between
who has normal folate stores. 63 suboptimal folate delivery to the developing fetal brain and abnormal
The rapidly proliferating tissues in children also have an absolute behavior. For example, 18-month-old children of mothers who took
requirement for exogenously supplied folate. Although human milk folate supplements had less “internalizing” patterns of behavior
can maintain folate balance in breastfed infants, the breast milk (emotionally reactive, anxious/depressed, somatic complaints, with-
content of folate is low when the mother’s folate status is poor. drawn) and less “externalizing” syndromes involving attention
Before the advent of routine folate supplementation during problems and aggressive behavior compared to offspring of women
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pregnancy, the incidence of megaloblastic marrows in the United who did not take folate supplements. There is a link between
States, Canada, and the United Kingdom during late pregnancy was periconceptional folic acid supplements for women and a lower risk
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about 25%, but in South India, it was about 55%. Folate deficiency of autistic disorder (the most severe of the autism spectrum disorders)
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is eight times as high in twin pregnancies. Multiparity (multiple in their young children. These findings are consistent with other
frequent pregnancies with a prolonged state of negative folate balance) recent studies from Asia, Europe, and North America, suggesting that
and hyperemesis gravidarum commonly lead to folate deficiency. children of mothers with higher blood folate concentrations or
Because the anemia of pregnancy is most frequently caused by iron mothers receiving folic acid supplements had improved neurodevel-
deficiency, combined iron and folate deficiency (dimorphic anemia) opmental outcomes. 200–203 Conversely, low maternal folate status
is the more frequent clinical presentation. Increased use of folates by during early pregnancy is associated with a higher risk of emotional
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the newborn leads to a drop in serum folate levels by about 6 weeks problems in the offspring. Thus it appears that we are likely peering
of age. This drop is exaggerated in premature infants (who have through the mist into a new field whereby nutritional folate insuffi-
feeding difficulties, infection, or hemolytic disease leading to pure ciency during fetal neurodevelopment predisposes to neuropsychiatric
folate deficiency); hence supplementation is routine for them. 15 illness!
The long-lasting benefit to the offspring of women who take iron
and folic acid during the early stages of pregnancy appears to be a
Folates and Neurodevelopment consistent theme; in Nepalese women, such supplementation pro-
vided significant benefits to the proper neurodevelopment of their
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All inborn errors of folate metabolism, which result in reduced folate babies in utero. Children of these women exhibited improved brain
availability to the developing brain, give rise to mental retardation function, manifest by improvement in both general intellectual
and related mental health problems. The fetal brain is dependent on ability and some aspects of executive functions as well as fine motor
sufficient provision of maternal folate during embryogenesis. Thus it skills when tested at ages 7 to 9 years. Although this clinical study
can been predicted that, under conditions where maternal folate was unable to assign whether iron or folic acid was the more impor-
deficiency can compromise the delivery of folate to the developing tant, there is sufficient supporting experimental evidence in the lit-
fetal brain, and depending on the degree of deficiency, there could erature for both being critically important. Indeed, these human
be a spectrum of neurologic abnormalities; this could range from parallels to murine studies are consistent with the Barker hypothesis
full-blown NTDs to more subtle changes that manifest in childhood on the developmental origins of disease. Finally, there is also evidence
as behavioral abnormalities. 57,69,193 Because routine folate supplemen- to suggest that suboptimal folate intake that leads to low-folate status
tation is now the norm for women, we must rely on experimental during adolescence can affect cognition and academic achievement,
205
studies in animals to clarify the pathologic effects of folate deficiency independent of socioeconomic status. And another recent large
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in pregnancy. Such studies indicate that folate deficiency will sig- observational study has also identified that maternal use of folic acid
nificantly compromise early pregnancy outcomes (including the rates supplements in early pregnancy was associated with a reduced risk
201
of pregnancy, rate of implantation, and effects on the number of live for severe language delay in children at age 3 years. Collectively
births). Even lesser degrees of folate deficiency to only one-third of these clinical and experimental studies strongly support the impor-
optimum dietary folate for 2 months before and throughout gestation tance of folate during neurodevelopment.
in dams, which coincidentally mimics the extent of insufficient The new finding that homocysteinylated-hnRNP-E1 orchestrates
dietary folate availability among women in vast areas of Northern a nutrition-sensitive posttranscriptional RNA operon that includes
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India, also resulted in subtle histologic aberrations and defects mRNAs that are important for the integrity of myelin and neu-
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during murine fetal development. These included increased apop- ronal intermediate neurofilament-middle molecular mass proteins,
totic cell loss involving nearly every organ and fine architectural as well as tyrosine hydroxylase, which generates dopamine and
anomalies, as well as adverse influences on fetal brain development norepinephrine, provides insight into how folate and cobalamin
and unexpectedly profound abnormalities in the white matter, reflect- deficiency during pregnancy can influence neurodevelopment. 57,59,194
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ing perturbed neuronal development. Surprisingly, despite postnatal Indeed, the activation of multiple members of the hnRNP family by
folate replenishment, these mice exhibited an anxiety phenotype in high intracellular homocysteine, via folate or cobalamin deficiency
194
adulthood. The latter studies indicate a new paradigm for the in pregnancy, may in fact activate several such nutrition-sensitive
developmental origin of neuropsychiatric disease that points to poor posttranscriptional RNA operons, which, acting together in concert
maternal folate nutrition during pregnancy. These data also suggest as a higher-order nutrition-sensitive (homocysteine-responsive)
the existence of a sensitive window during fetal neurodevelopment posttranscriptional RNA regulon, would lead to the modulation
when folate deficiency dysregulates the expression of certain genes of several diverse mRNAs that exert a profound effect on fetal
and/or proteins, which leads to the imprinting of abnormal neural neurodevelopment. 59
circuits in utero that predispose to anxiety in adulthood. In concor-
dance with these studies in mice, a prospective cohort human study
has reported that lower maternal folate status in early pregnancy was Folate-Responsive Neural Tube Defects
associated with childhood hyperactivity/inattention and peer prob- and Neurocristopathies
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lems in early childhood. The associations between low maternal
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folate and head circumference at birth are similar to murine studies NTDs are the most common major congenital malformation of the
in which a net reduction in the number of cells (by approximately central nervous system. They arise from disturbances in neurulation
20%) in the brains of murine fetuses that experienced gestational that involve incomplete closure of neural tissues, leading to major
folate deficiency 57,193 was observed; this increased brain cell loss was midline defects. The neural tube, which begins as a tiny ribbon of
because of apoptosis arising from megaloblastosis of folate-deficient tissue, normally folds inward to form a tube by the 28th day after
cells during development. Folate is also critical during the early conception. Thus NTDs originate in the first month of pregnancy
postnatal period and deficiency (in rodents) results in apoptosis of (before many women know they are pregnant). The expression of