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E ffec ts o f nu tr itio n on b ra in deve lopm en t in 2

286S Am a J C /in N u tr S upp i l993 :57 :286S-90S. P rin ted in U SA . 19 93 Am erican So cie ty fo r C lin ica l N u trition

G Robe i- i DeLong

ABS IRAC I B ra in d ev elo pm en t in h um ans is rem arkab lyresis tan t to perm anen t dam age from p ro te in -energy m alnu tri-tion . H ow ever, spec ific nu trien ts hav e cruc ia l ro les. lo d ine de-fic iency is the m os t im po rtan t an d w idespread n u trien t d efi-c iency : It causes endem Ic cre tIn ism . asso cia ted w ith deaf-m utismand cerebral pa lsy . Io d ine defic ien cy d uring pregn an cy causesbo th m ate rna l and fe ta l hypo th yrox inem ia , resu lting in irre -vers ib le im p airm en t o f b ra in deve lopm en t a t a c ritica l s tag e.N eu ropa tho log ica l da ta p lace th is a fte r 14 wk, perhaps co n tin u -ing th roug h the th ird trim es te r. G ross b ra in s truc tu re , in clud in gthe gyra l pa tte rn of the cereb ra l co r tex . deve lops norm ally ; th einsu lt a fkc ts neuron and dend rite g row th . R ecen t m agne tic -res-o nance-im ag ing (M R I) im ages of neuro log ica l c re tin b ra in s showrem arkab ly norm al appearance excep t fo r g lio tic les io ns o f theg lo bus pa llid us. co r re la ting w ith the prox im al m oto r rig id ity seenc lin ica lly . M yxedem ato us cretin ism is parado x ical in show ingm ore severe hypo thyro id ism and grow th fa ilu re, ye t be tte r in -te llectua l, m oto r, and hearing fun c tion : these o bserva tions im -p lica te a secon d in dependen t 1 c to r in its pa thog cn es is. AmJ (1 1 i i N uir Su pp i 1993:57:286S -90S .

KEY W ORD S M aln u tritio n , fe ta l b rain , iod ine , cre tin ism ,neuropa tho logy

In troduct ionThe deve lop ing hum an bra in is v irtua lly inaccessib le to in ves-

tiga tion in u te ro . G rea te r know ledge offe ta l. and particu la rly fe ta lb rain . deve lopm ent m us t be an im po rtan t fu tu re fron tie r o f b io logyan d m ed ic ine . In m y ow n departm en t, p ed iatric s is inc reas in g lyco ncerned w ith the fe tus . fo r p ren ata l d iagnos is and even trea tm en t.

T he deve lop ing hum an feta l b ra in is vu ln erab le to m any ex-o genous in fluences. ev en though it is buffered by the m other tosom e ex ten t. In th is paper m y concern is no t w ith in fec tion s,tox in s, ab norm al m etabo lic p roduc ts, o r m ate rn a l illnesses o r ac-c iden ts-all o f w hich pose risks to fe ta l b ra in deve lopm ent-bu tso le ly w ith the efl#{235}ctsf m alnu trition on the deve lop in g brain .A nd because b ra in dev elopm en t con tinues beyond fe ta l life, Icon side r postn ata l nu tritio na l e ffec ts as w ell. T o survey the sub jec tin a genera l w ay is b ey ond th e scop e of th is paper: I concen tra teon iod ine d ef ic iency . It is im portan t. how ever. to m en tion o thergen eral nu tritio n issues th at pe rta in to bra in deve lo pm ent.

P ro te in -en erg y m aln utritio nPro tein -en ergy m aln u trition is m itiga ted fo r the fetus by the

m ate rna l env ironm en t: b irth w eig h ts a re decreased in th e off-

sp ring o f m alnou rished m others , b u t b y a w ell-k now n (thou ghpoorly und erstood ) adap tive m ech an ism , b ra in grow th is sparedw hile o th er o rgans and body w eigh t and he igh t a re reduced .M ate rna l p ro te in -energy m alnu tritio n appears to pro duce nope rm an en t neu ro log ica l o r in tellec tua l de fic it in the fe tus. T hebest s tudy ofth is is the N etherlan ds da ta f rom the I zongerw in terof 1944-1945 . S ubseq uen t stud ies o fa rm y recru its born duringth is p erio d show ed no d iffe rence in in tellec tu a l fun ction com -pared w ith u naffec ted con tro l sub jects ( 1 ).A sim ila r con c lu sioncom es from stud ies o fch ild ren m alno urish ed dur in g the firs t 6m o oflife b ecause o fcystic fib ro sis o r in tes tina l d isease , a g ro upin w hich issu es o fsoc ioeconom ic depriva tion w ere no t re levan t.A fte r trea tm en t and nu tr itiona l rehab ilita tio n , the m oto r andm en ta l deve lopm ent o fthese ch ild ren w as equa l to tha t o f s ib lingcon tro l su b jec ts a fter age 5 y (2 ). A recen t stud y com pared 8-yscho o l perfo rm an ce of sm all-fo r-ges ta tiona l-age ch ild ren w ithth ree com parison g roups , one m atched fo r b irth w eigh t, onem atched fo r g es ta tion a l age , an d o ne ofte rm infan ts . T he th reepre ter rn gro ups d id n o t d iffer on a ran ge o fin tellec tua l, ach iev e-m en t, an d b eh av io ra l sca les. P re term sm all-fo r-g es ta tion a l-ag ech ild ren w ithou t d isab ilitie s had acad em ic scores s im ila r to tho seof the ir fu ll-te rm peers. bu t the ir sco res ind ica ted m ore hyp er-ac tiv ity . T he au thors conc luded tha t in trau te rine grow th re ta r-da tion d id n o t appear to im pose a d isad van tag e on the prete rmch ild ren (3 ). A ll these s tud ies co nfirm a rem arkab le res ilienceof the deve lop ing bra in in the face of m aln u trition .

C h ild ren w ith severe g row th re tarda tion second ary to pro te in -energy m alnu trition in the pos tw ean ing period m anifest a s trik ingbehav io r syndrom e tha t has been w ell desc ribed : they are to rp id ,apa the tic , inac tive , fea rfu l, cheerless, nea rly m ute , and an orex icand they lack spon tane ity . T h is syn drom e, h ow ev er , is p rom ptlyreversib le by re feed ing and there is little ind ica tio n th at it en ta ilsany p erm an en t im pa irm en t o fb ra in deve lopm ent. In young ra tsand m onkeys , fe ta l and pos tna ta l m aln u trition is assoc ia ted w ithtw o - to th ree fo ld inc reases in bra in se ro ton in and h is tam ine (4 ).On the assum p tion , w h ich w as obv iously un te stab le d irec tly ,th at s im ila r changes ob ta ined in m alnou rished ch ild ren , w e on cetrea ted n in e such ch ild ren in E cuado r w ith cypro hep tad ine , anan tise ro ton in and an tih istam ine agen t w ide ly used b y ped ia tri-cians to inc rease ap pe tite in ch ild ren (G R D elong , un pub lish edobse rva tions ). W e observed a prom p t b rig h ten ing of affec t, in -crease in spon taneous activ ity , inc reased speech an d soc ia l in -

I F rom th e D iv is ion ofP ed ia tric N euro log y , D uke U nivers ity M ed ica lC en te r. D urh am , N C .

2 A ddress rep rin t req uests to G R D eLong , D iv is io n o f P ed ia tr ic N eu-ro log y . D uk e U nivers ity M edica l C en ter . D urham , N C 27710 .

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IOD IN E A N D BRA IN D EV EL OPM EN T 287Steraction, and increased appetite (G R D elong, unpublished ob-servadons). ftc eavoraI ciiange preceded refcedng and wasmuch m or e p r om pt th an that descr ibed in refeeding programs(5). I t is tempting to suggest that the torpid state of the mal-nourished child is adaptive, tending to conserve the child s lim-ited energy resources, and the anorexia reduces the pain of hun-ger, and that both are mediated by excess brain concentrationsof serotonin and/or histamine.V it am in and m iner al def i cien cy

A n important current issue concerning the role of nutritionin brain development is the role ofnutritional deficiency in cau-sation of neural-tube defects (spina bifida, meningomyelocele,and anencephaly) . Both familial (presumed genetic) and envi-ronmental factors are implicated in causation of these defects.Possible genetic effects are shown by differing incidences of thedefect among different population groups and by an increasedrate of recurrence among siblings of affected children. Environ-mental influences are shown by the secular reduction in incidenceseen both in the British Isles and the U nited States over the past50 y (6) and by briefpeaks ofincidence seen in certain locationsduring times of nutritional deficiency [eg, post-W orld W ar I IBerlin (7)].

M aternal nutritional def iciencies produce neural- tube defectsin animals. D eficiencies offolic acid, vitamin B-l2, pyridoxine,vitamin E, and pantothenic acid have all caused neural-tubedefects in rats (8). Z inc deficiency in rats produces neural-tubedefects but, more commonly, hydrocephalus (9). N eural-tubedefects also occur with hypervitaminosis A (9, 10).

In humans, the relationship between maternal nutrition andthe incidence of neural-tube defects has been actively explored.L aurence et al ( 1 1 ) demonstrated a relationship between poordiet in the mother and the recurrence rate of neural-tube defects.A supplementation study w ith folic acid seemed to demonstratethat folic acid availability to the embryo is an important etiologicfactor in neural-tube defects and that if maternal serum folateconcentrations could be raised above critical threshold values,recurrent neural- tube defects could be prevented in a high-riskgroup of women. Smithells et al (12) conducted a controlledstudy of supplementation with multivitamins, including folicacid, to test their effect on prevention of neural-tube defects.T heir results demonstrated that women who received multivi-tamin supplementation before conception and during the f irst2 mo of pregnancy had a significantly reduced recurrence ofneural-tube defects compared with unsupplemented women.M ilunsky et al (1 3) examined the relationship of multivitaminintake in general, and folic acid in particular, to the risk of neural-tube defects in a cohort of 23 49 1 women undergoing serum a-fetoprotein screening or amniocentesis. T he prevalence of neural-tube defects for women who used folic acid-containing multi-vitamins during the first 6 wk of pregnancy was substantiallylower than for nonusers, those who used multivitamins withoutfolic acid, or those who used multivitamins containing folic acidbeginning after 7 w k of pregnancy.

In addition to vitamins, zinc has been implicated as having apossible role in the etiology of human neural- tube defects (14);an association between decreased maternal zinc and increasedrisk of neural-tube defects has been found (1 5-1 7). I n fact, thereis a close association between zinc and folic acid in the diet, andzinc is thought to be involved in the absorption of folic acid

(14). T hus, folic acid and zinc ma not be independent factorsin relation to the etiology of neural- tube defects.

M ost recently, a multicenter, prospective, controlled study(1 8) of folic acid supplementation during pregnancy in a largegroup ofwomen who had previously borne an infant with neural-tube defect def initively confirmed the protective effect of folicacid, but not ofother vitamins. Recurrence ofneural-tube defectswas decreased by 72% by supplementation with 4 mg folic acid/d. In the Peoples Republic of China, a major controlled studywill soon be launched to determine the dosage requirement offolic acid supplementation for prevention of neural- tube defects.

I have not been able to find any evidence of a primary effectof selenium deficiency on brain development. Selenium excess,by contrast, is well-known to produce selenium poisoning innearly all domestic animals, which is usually fatal. Chronic Se-lenium poisoning in cattle, sheep, and horses results in ataxia,incoordination, partial blindness, paralysis, and abnormal be-havior (19). H istologic changes in brains of selenium-toxicweaner pigs included a focal symmetrical poliomyelomalacia inbrain and spinal cord characterized by endothelial proliferation,neuronal degeneration, microcavitation, and glial-cell reaction(20). T he pathogenesis of these changes is unknown. I t mightbe asked whether selenium deficiency could in some way protectthe fetal brain against the effects ofiodine deficiency (pertainingto the pathogenesis of myxedematous cretinism; see below).

I odi ne def ici encyI odine deficiency is the most widespread nutritional cause of

impairment of brain development and its effects are the mostdramatic. I t remains one ofthe worlds most common prevent-able causes of mental retardation and cerebral palsy, despitetremendous progress in eliminating it by iodization programs.Iodine deficiency, in fact, plays the role in blighting the mentaland motor development of populations in underdevelopedcountries that researchers formerly and unsuccessfully tried toattribute to protein-energy malnutrition. Beyond those childrenaffected with frank endemic cretinism, perhaps sixfold more areaffected by lesser degrees of mental and psychomotor retardationor learning disabilities due to iodine deficiency (21).

I t is particularly pertinent to focus on the dif ferences betweenneurological and myxedematous cretinism from the point ofview of neurology and neurodevelopment. N eurological cretin-ism presents a very characteristic syndrome encompassing men-tal def iciency, deaf-mutism, and a spastic-rigid motor disorder(22). In extreme cases, the cretin may show mental vacuity orautism, primitive postural and motor reflexes, and muscle wast-ing. T he defects can be attributed, from classical clinical-ana-tomic correlation, to impairment of the cerebral cortex associ-ation areas, causing mental impairment; to cochlear dysfunction,causing deafness; and to dysfunction of the basal ganglia andother cerebrospinal motor systems, causing spasticity, rigidity,and bradykinesia. T he mental dysfunction is characterized byhaving intact primary analyzers (eg, for vision and somesthesis)but very primitive higher associative functions, as shown by theprofound disabilities in language, drawing, and abstract thought.T he cochlear lesion has been confirmed by the absence of co-chlear potentials in auditory evoked-response studies. T he motordisability is characteristic and differs from the usual cerebralpalsy in being primarily proximal-involving the pelvic andshoulder girdles but tending to spare the feet and particularly

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288S D E L O N Gthe hands. I n this it resembles extrapyramidal basal-ganglia dis-ease more than corticospinal disease. N otable in most cretins isthe absence of ataxia, seizures. and hypothalamic or vegetativedysfunction. W hen deficits are severe, the vacuity of personalitysuggests involvement of medial temporal lobe structures, hip-pocampus. and amygdala. flagrant frontal lobe release signs maybe seen. T he muscle thinness seen occasionally suggests spinalanterior-horn-cell dysfunction (22) .Can these clinical inferences be corroborated anatomically?U nfortunately. there is a paucity ofpathological studies. Brainsinvestigated pathologically or by computed tomography (CT)or magnetic-resonance imaging (M RI ) have shown no defect ofprimary embryological development; that is. the primary for-mative events of the brain-encompassing about the first 12-1 4 wk of human gestation-are completed normally, as shownby the normal structure ofcorpus callosum, ventricular system,visual pathways. etc. T he absence ofmalformations ofthe neo-cortex (lissencephaly or pachygyria) probably pushes the onsetof insult beyond the 14th week.

T here are few pathological studies ofbrains ofendemic cretins.A vailable studies are those by D eQuervain and W egelin (23)from Switzerland; Lotmar (24) from Germany; Y an et al (25)from China; and, recently, Jin Fengzhu, also from China (per-sonal communication. 1990). In addition, there are a few CT -scan studies, the first by Cruz et al in Ecuador (26). T aken to-gether, they give a useful but far from complete picture of thepathology ofendemic cretinism.

T he available pathologic studies indicate that the fundamentalstructure ofthe brain ofneurological cretins is normal, includingthe gyral pattern ofthe cerebral cortex. Brain weights have beenless than normal. un in Jilin, China. studying four brains ofadult female endemic cretins, found brain weights of920-l 182g (normal range 1200-1 500 g) (personal communication, 1990).D eQuervain and W egelin (23), reporting on autopsy results of29 cretins in Switzerland, found cerebral atrophy, thin cortex,and reduction in the total number of neurons in the cortex.A bnormalities including decreased numbers ofneurons, irregulararrangement ofneurons. and degeneration ofneurons have beendescribed in many areas of the brain, including the neocortex,hippocampus, basal ganglia, red nucleus, cerebellum, and motoranterior-horn cells of spinal cord. T hese changes are consistentwith those seen in computed tomographs (CT ) published byCruz et al (26), which showed considerable atrophy, indicatedby increased sulcal spaces, enlarged lateral ventricles, and en-larged subarachnoid spaces around the brain stem. Y an et al(25) reported a quantitative histological study of six adult neu-rological cretins compared with normal controls. Golgi stainsof pyramidal and stellate cells of the cortical motor area andauditory area showed that the size ofthe cell bodies was smallerand the number of branches of the apical dendrites of the py-ramidal cells and ofthe peripheral dendrites ofstellate cells weremarkedly decreased compared with normal subjects. T he extentofthese dif ferences corresponded to the severity ofthe cretinism.Y an et al also found the dendritic branching of cerebellar Pur-kinje cells to be short and sparse. These are similar to changesfound in experimental hypothyroidism in animals (27, 28).

T he neuropathological picture in endemic cretinism-one ofthe most important experiments of nature in regard to braindevelopment-is far from complete. Still badly needed arequantitative data on neuron number in all major brain areas;an overall picture of which areas of brain are affected and to

what extent; the timing ofonset ofthe abnormalities, which willrequire the study of fetal material; a detailed study of corticalorganization and dendritic branching; and elucidation of thepossible role of late degeneration ofnerve cells, as well as possiblelate effects on brain of myxedema continuing over years. T hreehigh-quality M RI scans of adult neurological endemic cretinsobtained in T ianjin, China, kindly made available to me by M aT ai, appeared entirely normal except for a marked increased T 2signal in the globus pallidus, consistent with gliosis, in each case.T his is the first direct confirmation ofthe presumed involvementof the basal ganglia.

L ikewise important is the preliminary report of neuropatho-logical examination of fetal brains from abortuses in iodine-deficient areas of China by L iu et al (29). T he thyroid status ofthese fetuses was thoroughly described, with 1 3 of 30 showingthyroid hypertrophy. Brain weights at the eighth fetal month,in two cases, were slightly more than halfthat ofnormal controlsubjects. N euronal cell counts in cerebral cortex of iodine-de-ficient fetuses at the sixth month showed no difference fromnormal control subjects, but two specimens at the eighth monthshowed increased neuronal-cell densities in all layers of variousareas ofcerebral cortex. These observations, while done in onlysmall numbers ofspecimens, are important because they clearlysuggest that neuronal-cell proliferation, at least in cerebral cortex,may not be impaired in iodine-deficient human fetuses, but thatsubsequent cell enlargement and differentiation are decreased.T his conclusion, ifverified, would extend the critical period foreffect ofiodine deficiency on brain development to later in preg-nancy. and suggests that postnatal treatment may be effectivein mitigating the effect of iodine-def icient cretinism, as it is insporadic congenital hypothy roi di sm .

A synthesis of the available data, including the cut-off timefor the efficacy ofiodine repletion [estimated as 3 mo of gestationby Pharoah et al (30)], the timing of neurological development(neurons of cerebral cortex, basal ganglia, and cochlea are allgenerated between 10 and 1 8 wk), the appearance of thyroidhormone receptors in the human brain [after 10 wk (3 1)], theonset offetal thyroid function [after 12 wk, increasing steadilyafter 20 wk (32)], and the fragmentary neuropathological datareviewed above. all suggest that the critical effect of iodine de-ficiency on the human fetal brain occurs during the second and,probably, third trimesters. T he duration ofhypothyroidism dur-ing development may crucially affect neurological disability.L ittle is known about the extent or duration of hypothyroidismin neurological cretins after birth. Postnatal treatment in iodine-deficient areas may mitigate or prevent neurological cretinism.W e are currently conducting a project w ith Cao and M a inX injiang A utonomous Province of China to study these ques-tions.

M yxedem atou s cr et in ismD eaf-mutism, marked spastic-rigid motor disabilities, and

normal or near-normal thyroid function are characteristic ofneurological endemic cretins. M yxedematous cretins, by con-trast, differ in each of these respects. In general, they do nothave prominent motor disability and, of course, have severehypothyroidism. Generally, their mental ability is superior tothat of neurological cretins, and hearing and speech are oftensatisfactory. Comparison of cretins from Guizhou, China (33),and Ecuador (34), w here neurological cretinism predominates,

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IOD IN E A N D BRA I N D EV EL OPM EN T 289ST A B L E 1Comparative neurological findings in endemic cretinism in China, Ecuador and Z aire

M e nt al r et ar dati onHearing

impairmentSpeech

impairment StrabismusNeuromotorabnormality

Gaitabnormality

Babinskiankle

clonusHypotonia,

musclewasting

Ch i n a (n = 247) 100% 87% 95% 16% 34% cerebralp a l s y

20% coul dn o t wa l k

46% -Ecuador (n = 67) 87% ; 13% function

normally incommunity

84% ; 48% deaf 95% ; 73% mute A few 85% increasedDTRs

5% could notwalk

22% 6%

Zaire (n = l06)* 80% 28% deaf; 10%partialheari ng l oss

28% mute; 20%dysarthria

3% 20% rigid 4% could notwalk

15% 9%

* Neurological, n = 18: combined, n = 26: myxedematous, n = 62.

with those of Z aire (34), where myxedematous cretinism pre-dominates, emphasizes these differences (Table 1). I n G uizhouand Ecuador, 85% of cretins are deaf; in Z aire, only 28% are.Speech impairment is found in 95% in both Guizhou andEcuador, but in only 48% in Z aire. W hereas 73% ofcretins aremute in Ecuador, only 28% are mute in Z aire. L ikewise, neu-romotor, gait, and ref lex abnormalities are two- to fourfoldgreater in Guizhou and Ecuador. Other researchers have madesimilar observations (2 1 ). Clearly, myxedematous cretinism isdifferent in sparing hearing, speech, and motor function.

T hese observations pose a paradox, namely: if myxedematouscretins have more severe and persistent hypothyroidism, whyare their neurological manifestations less? I fit is a matter of thetiming of the insult, why should myxedematous cretins be rel-atively spared in intrauterine life, but more severely involvedlater? T he concept that myxedematous cretins are in fact sparedwith regard to hearing and motor disability has been challenged.Clearly, it is possible to find a proportion of mixed cretins withneurological signs and myxedema, raising the possibility thatthere is a continuum between neurological and myxedematouscretinism, with myxedematous cretinism being the result of moresevere or prolonged iodine deficiency. In fact, myxedematouscretinism appears to occur in areas of more severe iodine defi-ciency (35). W e attempted to test this idea by correlating deafness(an index ofneurological cretinism) with growth retardation (anindex of myxedematous cretinism) in Z aire. In fact, there is aclear inverse correlation, which cannot easily be explained by acontinuum of severity. This result strongly suggests that inmyxedematous cretinism, for whatever reason, intrauterine braindevelopment is relatively spared, though neonatal (36) and laterhypothyroidism is found to be severe.

I n summary, a convergence of clinical, anatomic, develop-mental, and pathologic data begin to provide a picture of thepathogenesis of neurological cretinism in which maternal hy-pothyroxinemia and fetal hypothyroidism, both induced by io-dine deficiency, combine during a critical period of fetal devel-opment- localizable to the second and perhaps third trimes-ters-to produce a critical degree of thyroxin deficiency severeand prolonged enough to cause irreversible damage to the on-going program of neural development. T his damage includesimpairment of the formation of the cochlea, and either impair-ment of neuronal-cell generation or differentiation of neuronalprocesses, or both. In myxedematous cretinism, severe hypo-

thyroidism may be present at birth, and certainly obtainsthroughout later life, w ith eventual loss of the capacity of thethyroid gland to respond to iodine. A s mysterious as the eventualthyroid degeneration may be, the apparent intrauterine sparingof hearing, intellect, and motor function in the face of severeiodine deficiency is equally mysterious. #{163}3

References1 . Stein Z , Susser M , Saenger G. M arolla F. N utrition and mental

performance. Prenatal exposure to the D utch famine of 1944-1945seems not related to mental performance at age 19. Science 1972; 178:708- 13.

2. L loyd-Still JD . H urwitz I , W olff PH , Schwachman H . Intellectualdevelopment after severe malnutrition in infancy. Pediatrics 1974:54:306-11.

3. Robertson C M T , E tches PC , K yl e JM . E ight- year school perf orm anceand growth of preterm. small for gestational age infants: a compar-ative study with subjects matched for birth weight or for gestationalage. J Pediatr 1990;1 16:19-26.

4. M organe PJ, M iller M . K emper T . et aI . T he effects ofprotein mal-nutrition on the developing central nervous system in the rat. N eu-rosci Biobehav Rev 1978;2: 137-230.

5. D odge PR, Prensky A L , Feigin RD . N utrition and the developingnervous system. St L ouis: M osby, 1975.

6. L eek 1. Epidemiological clues to the causation of neural tube defects.In: D obbing J, ed. Prevention ofspina bifida and other neural tubedefects. L ondon: A cademic Press, 1983:155-87.

7. Eichmann E. Gesenius H . T he increase in birth defects in Berlinand surroundings in the after-war years. A rch Gynakol 1952:181:168-84 ( in G er man) .

8. Seller M J. M aternal nutritional factors and neural tube defects inexperimental animals. In: D obbing J. ed. Prevention ofspina bifidaand other neural tube defects. London: A cademic Press, 1983:1-22.

9. H urley L S, Schrader RE. Congenital malformations ofthe nervoussystem in zinc deficient rats. In: Pfieffer CC, ed. N eurobiology ofthe trace metals zinc and copper. L ondon: A cademic Press, 1972:7-5 1.

10. Giroud A , M artinet M . T eratogenesis by high doses of vitamin Aas a function ofthe stages ofdevelopment. A rch A nat M icros M or-phol Exp 1956:45:77-98 (in French).

1 1. L aurence K M . James N , M iller M , T ennant GB, Campbell H . D ou-ble-blind randomised controlled trial offolate treatment before con-ception to prevent recurrence of neural tube defects. Br M ed J1 9 8 l ; 2 8 2 : 1 5 0 9 - 1 1 .

7/29/2019 286S.full

5/5

290S D E L O N G12. Smithells RW , Shepherd 5, Schorah Ci, et al. V itamin supplemen-

tation and neural tube defects. L ancet 198 1:2:1424-5.13. M ilunsky A , Jick H , Jick SS. et al. M ultivitamin/folie acid supple-

mentation in early pregnancy reduces the prevalence of neural tubedef ects. JA M A 1 98 9;2 62 :2 84 7- 52 .

14. T amura T, Shane B, Baer M T. K ing JC, M argen 5, Stokstad EL R.A bsorption ofmono- and poly-glutamyl folates in zinc-depleted man.A m J Clin N utr 1978:31:1984-7.

15. N evin N C. Prevention of neural tube defects in an area of highincidence. In: D obbing J. ed. Prevention of spina bifida and otherneural tube defects. L ondon: A cademic Press. 1983:127-54.

16. Cavdar A O, A rcasoy A . Baycu T . H immetoglu, 0. Z inc deficiencyand anencephaly in T urkey. T eratology 1980:22:141-9.

17. Jameson S. V ariations in maternal serum zinc during pregnancyand correlation to congenital malformations. dysmaturity, and ab-normal partiturition. A cta M ed Scand Suppl l976;593:2l-37.

18. M RC V itamin Study Research Group. Prevention of neural tubedefects: Results of the M edical Research Council V itamin Study.L an c et 1 99 1: 3 38 : 1 3 1- 1 3 7 .

19. Edwards W C, W hitenack D L . A lexander JW , Solangi M A. Seleniumtoxicosis in three California sea lions (Zalop/iu.s callf()rnianus). V etH um T ox icol 1 989;3I :56 8- 70.

20. W ilson T M . H ammerstedt RH . Palmer I S. deL ahunta A . Porcinefocal symmetrical poliomyelomalacia: experimental reproductionwith oral doses of encapsulated sodium selenite. Can J V et Res1 9 8 8: 5 2 : 8 3 - 8 .

21. M a T , W ang Y Y, W ang D , Chen Z P, Chi SP. N europsychologicalstudies in iodine deficiency areas in China. In: D eL ong GR, RobbinsJ. Condliffe PG. eds. Iodine and the brain. N ew Y ork: Plenum.I 989:259-68.

22. D eL ong GR. Stanbury JB. Fierro-Benitez R. N eurological signs incongenital iodine-deficiency disorder (endemic cretinism). D ev M edChild N eur ol 1 98 5: 27 :3 17 -2 4.

23. D eQuervain F, W egelin C. On endemic cretinism. Berlin: Springer,1 936 ( in G erm an) .

24. L otmar F. H istopathological observations in the brain in endemiccretinism, thyroid aplasia. and thyroprival cachexia. Z N eurol1933;146:l-53 ( i n Ge r ma n) .

25. Y an Y , G uan C , L eng L . L i J. Quantitative histology study on brainnervous cells ofneurological endemic cretins. I n: D eL ong GR, Rob-

b in s J. C on dl i fl # { 2 35 }PG. eds. Iodine and the brain. N ew Y ork: Plenum.1 9 8 9: 3 5 9 .

26. ( ruz M . ( ..aI lel os P . U tre ras A , M alo L. Endemic cretinism. In: (i ULM . (. anelos P. U trcias A . M alo L . eds. Guide to computerized axialtomogI4ph Quito. Ecuador: Rodriguez: 1984.

27. Ruis-M aicos A . Q uantitative studies ofthe eff ects of h)puthyloidlsnlon the development ofthe cerebral cortex. In: L)eLong GR . RobbinsJ, ( on dl i ft e P G . ed s. I od in e a n d t h e b r a in . N ew Yor k : P len u m .1989:91-102.

28. L egrand J. Effects of thyroid hormones on central nervous systemdevelopment. I n: Y anai J. ed. N eurobehavioral teratology. A mster-dam : E lsev ier , 1984:331-40.

29. L iu J, T an Y . Z huang Z . Shi Z . Chen B. Z hangi. Influence of iodinedctIcicncy on human fetal thyroid gland and brain. In: D C L O I Ig (JR.Robbins J, Condliffe PG. eds. Iodine and the brain. N cs Y ork:Pl enum . 1 98 9:2 49 58 .

3 0. Phar oah POD. Buttfield lH , H etzel BS. T he effect of iodine pro-phylaxis on the i nci dence of endei ni c cretInIsm. A dv Exp M cd Blol1 9 72 : 3 0 : 2 0 1 - 2 1 .

31. Bernal J. Pckkonen F. Ontogenesis ofthe nuclear 3,5.3 -triiodothy-rodinc receptor in the human ktal brain. Endocrinology 1984: 1 1 4:677-84.

3 2. T h or pe -B ee st on X i. N icolaides K H . Felton CV . ButlerJ, M cGregorA M . M aturation of the secretion of thyroid huimone and thyroid-stimulating hormone in the fetus. N Engl J M ed 1991:324:532-6.

33. Shi Z . Z eng G. Z hang J, et al. Endemic goiter and cretinisni in( iuiL hou: clinical analysis of247 cretins. Chin M ed J 1984:97:689-97.

34. D eLong (JR. Observations on the neurology of endemIc cretInIsni.I n: D eL ong GR . Robbins J. Condlifl#{ 235} PG . eds. Iodine and the brain.N ew Y ork: Plenum. 1989:231-8.

35. D ue D . T hI l1 C. V andeips J. C t al . E ti ol ogy of n eu r olo gica l a n dmyxedematous cretinism in V ietnam and Z alre. I n: V ichayanlat A .N itiyanant W . Eastman Ci . N agatuki S. eds. Recent progie ss II Ithyroidolog B angkok: Crystal H ouse Press. 1986:402-6.

36. T h illy C H . De la n g e F . L agasse R. e t a l. F e t a l h yp ot h y r oid ism a n dm a t e r n a l th) I oid status fl severe endemic goiter. J (lin EndocrlnolI 9 7 8: 4 7 : 3 5 4 - 6 0 .