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resistant tion. ficiency to However, is the

of nutrition
DeLong Brain
permanent specific most

on brain development



damage nutrients important

in from have and

humans crucial widespread

is remarkably malnutriroles. lodine nutrient

spring poorly while dedefiMaternal

of malnourished understood) other organs protein-energy




a well-known

(though is spared reduced. no The during


adaptive mechanism, and body weight malnutrition

brain growth and height are appears data to


ciency: It causes endemIc cretInism. associated and cerebral palsy. Iodine deficiency during both versible ing through maternal impairment data the third and fetal of hypothyroxinemia, brain place trimester. development this after cortex. growth. 14 wk, brain Gross

permanent with deaf-mutism pregnancy causes best study
in a critical perhaps irreof 1944-1945. at stage.this period continu- pared with

ofthis showed unaffected is the Subsequent no

or intellectual
Netherlands studies ofarmy

deficit thein fetus.
from Izongerwinter the recruits born function conclusion during disease, were not


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difference in intellectual control subjects ).A 1 similar (

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including normally; magnetic-res-

the gyral pattern of the cerebral insult afkcts neuron and dendrite onance-imaging remarkably globus pallidus. (MRI) images normal appearance correlating with

develops Recent

comes from studies ofchildren malnourished mo oflife because ofcystic fibrosis or intestinal the in which issues ofsocioeconomic deprivation treatment development subjects and after nutritional rehabilitation, ofthese children was equal age 5 y (2). A recent



of neurological except for the proximal

cretin brains gliotic lesions motor rigidity in

show After of the mental seen control

the motor and to that of sibling compared with weight, The 8-y one three


clinically. Myxedematous more severe hypothyroidism tellectual, plicate motor, a second Suppi

cretinism and

is paradoxical growth failure,

and hearing independent

function: these 1tctor in its pathogcnesis.

showing school performance of small-for-gestational-age children yet better inthree comparison groups, one matched for birth matched for gestational age, and one ofterm infants. observations imAm preterrn ment, children groups and without full-term The authors did not differ scales. had but concluded their peers. on a range academic scores that ofintellectual, behavioral disabilities Preterm

achievesimilar more growth the to those hyperretarpreterm resilience

J (11ii Nuir KEY WORDS

small-for-gestational-age scores indicated intrauterine










The developing human brain is virtually inaccessible to inves-

dation did not appear children (3). All these of the developing brain

to impose a disadvantage on studies confirm a remarkable in the face of malnutrition.

Children with severe growth retardation secondary to proteinenergy malnutrition in the postweaning period manifest a striking tigation in utero. Greater knowledge offetal. and particularly fetal behavior syndrome that has been well described: they are torpid, brain. development must be an important future frontier of biology apathetic, inactive, fearful, cheerless, nearly mute, and anorexic and medicine. In my own department, pediatrics is increasingly and they lack spontaneity. This syndrome, however, is promptly concerned with the fetus. for prenatal diagnosis and even treatment. reversible by refeeding and there is little indication that it entails The developing human fetal brain is vulnerable to many exany permanent impairment ofbrain development. In young rats ogenous influences. even though it is buffered by the mother to and monkeys, fetal and postnatal malnutrition is associated with some extent. In this paper my concern is not with infections, twoto threefold increases in brain serotonin and histamine (4). toxins, abnormal metabolic products, or maternal illnesses or accidents-all solely with And because of which pose risks to fetal brain development-but that similar changes obtained in malnourished children, we once the efl#{235}cts malnutrition of on the developing brain. treated nine such children in Ecuador with cyproheptadine, an brain development continues beyond fetal life, I antiserotonin and antihistamine agent widely used by pediatriconsider postnatal nutritional effects as well. To survey the subject cians to increase appetite in children (GR Delong, unpublished in a general way is beyond the scope of this paper: I concentrate on iodine deficiency. nutrition issues It is important. that pertain however. to brain to mention other









crease in



a prompt


of affect,











Protein-energy maternal

malnutrition birth is mitigated weights are for the fetus in by the decreased Nutr


I From the Division ofPediatric Neurology, Duke University Medical Center. Durham, NC. reprint requests to GR DeLong, Division of Pediatric Neuthe 2 Address rology. Duke University Medical Center. Durham, NC 27710. off-


Ama J C/in

Suppi l993:57:286S-90S.


in USA.




for Clinical


and reduction (spina the role of nutrition supplementation of neural-tube I have not been deficiency able to find on brain any evidence of a primary Selenium effect excess. and to dysfunction of the basal ganglia and substantially other cerebrospinal motor systems. vitamin defects defects defects In the diet that in nutritional deficiencies produce Deficiencies offolic acid. postural the cretin and may motor show reflexes. incidence in the folic of neural-tube et al( 1 1 ) demonstrated mother acid and the cerebral Laurence a relationship of neural-tube tremendous progress defects. rigidity. nutrition actively between explored. from classical clinical-anaserum atomic correlation.The cochlear lesion has been confirmed by the absence of coincreased chlear potentials in auditory evoked-response studies. The mental dysfunction is characterized by folic acidhaving intact primary analyzers (eg.ation areas. and as shown by the abstract thought. which is usually fatal. of multivitamin first ism presents of tal deficiency. folic acid. plays the widespread and world’s and its most nutritional effects common palsy. beginning after 7 wk of pregnancy. in by guest on November deafness. tube defects in a cohort of 23 49 1 women fetoprotein screening or amniocentesis. Chronic Seof these defects.nearly all domestic animals. pathogenesis whether selenium brain against the during Berlin times (7)]. and anencephaly). of these changes in brains of selenium-toxic in reaction It might way protect (pertaining symmetrical poliomyelomalacia by endothelial and is unknown. affected with frank endemic cretinism. andpalsy” in being primarily proximal-involving the pelvic and of folic acid shoulder girdles but tending to spare the feet and particularly .view of neurology and neurodevelopment.IODINE teraction. in Thus. to test their effect on prevention of neural-tube defects. In addition to vitamins. able causes development (9). pigs spinal Histologic included cord changes a focal characterized microcavitation. multi. tube defects for women who used vitamins during the first 6 wk of lower than for nonusers. Iodine deficiency deficiency of of brain mental It remains is the one most ofthe retardation in eliminating acid. The motor fact. Neural-tube 10). and/or anorexia of hun. and pantothenic acid have all rats (8). including folic It is particularly pertinent to focus on the differences between acid. Smithells et al (12) conducted a controlled or learning disabilities due to iodine deficiency (21). mental and vacuity muscle or wast- al (1 3) examined autism. compared unsupplemented relationship In extreme primitive cases. or those who to the risk undergoing The prevalence folic acid-containing pregnancy was multivitamins containing implicated neural-tube those who used used multivitamins been maternal found in of neural. incidences of the incoordination. (22). Vitamin An in brain sation of and important mineral current deficiency issue is the defects role concerning ofnutritional bifida.nutrition. (presumed in causation by differing groups of affected secular United seen [eg. in it by iodization role in blighting and motor development of populations in underdeveloped etiologic countries that researchers formerly and unsuccessfully tried to factor in neural-tube defects and that if maternal serum folate attribute to protein-energy malnutrition. to cochlear dysfunction. poor humans. and folic acid in particular. zinc has possible role in the etiology of human an association risk of neural-tube between decreased defects has been between be involved zinc zinc and (1 5-1 7). during borne the Recurrence of China. maternal been neural-tube Iodine impairment anddramatic. (5). acid and zinc ma’ not be independent 287S factors and increased eiavoraI than appetite (GR ciiange that Delong. preceded in unpublished refcedng refeeding and programs state of the the child’s the pain obwas ‘ftc etiology of neural-tube prospective. determine for prevention defects.(1 8) of folic acid supplementation lim-group ofwomen who had previously defect but In the soon acid not decreased People’s be launched definitively ofother by72% confirmed vitamins. intake in general. caused neural-tube pathogenesis of myxedematous cretinism. Iodine deficiency. and horses results in ataxia. deficiency could in some effects ofiodine deficiency Maternal in animals. are cause the preventdespite programs. vitamin E. perhaps sixfold more are recurrent neural-tube defects could be prevented in a high-risk affected by lesser degrees of mental and psychomotor retardation group of women. causing mental impairment. A supplementation study with folic acid seemed to demonstrate a very characteristic and syndrome a spastic-rigid encompassing motor mendisorder deaf-mutism. hydrocephalus with hypervitaminosis relationship between defects recurrence has rate neural-tube defects to the B-l2. servadons). study of supplementation with multivitamins. to impairment of the cerebral cortex associof neural. in cau-of selenium development. there disability is characteristic and differs from the usual “cerebral in the diet. neurological and myxedematous cretinism from the point of Their results demonstrated that women who received multivi. relation Most folic to the recently. in the British by briefpeaks of nutritional Isles and the ofincidence deficiency States over the past neuronal in certain locations (20). for vision and somesthesis) as having defects but very a profound primitive disabilities higher associative functions. Beyond those children concentrations could be raised above critical threshold values. without and bradykinesia. was d. pyridoxine. glial-cell different among are of recurrence influences both y (6) and children. ronmental factors Possible defect rate mental seen 50 Both familial are implicated effects are shown siblings by the population shown genetic among by contrast. will folic concentrations histamine. In is a close association zinc is thought to and folic acid the absorption (14). much more AND BRAIN DEVELOPMENT (14). Zinc deficiency in rats but. drawing. study in a large with neuraleffect of acid/ study of folic defects prompt described a multicenter. Neurological cretinavailability to the embryo is an important tamin 2 mo neural-tube Milunsky et supplementation of pregnancy defects had before conception a significantly with the and reduced during the recurrence women. sheep. The defects can be attributed. also more occur the commonly. paralysis. lenium poisoning in cattle. Downloaded from ajcn. and are the mediated that tending by the torpid to conserve reduces excess brain mal. It is tempting nourished ited ger. development neural-tube deficiency meningomyelocele. 2012 proliferation. see below). and abnormal beby an increased Environin incidence havior weaner brain and (19). is well-known to produce selenium poisoning in genetic) and envi. the mental of most produces A (9. of energy and serotonin child that both to suggest is adaptive. Republic to by supplementation resources. controlled pregnancy an infant protective ofneural-tube with a major the dosage 4 mg folic controlled requirement defects. causing spasticity. partial blindness. The post-World War II be asked the fetal degeneration.

and hearing and speech are often areas. brain stem. and and Ecuador to (34). China (33). Postnatal or prevent rological cretins compared of pyramidal and stellate auditory and ramidal markedly ofthese Yan kinje found The the area number cells and decreased differences et al also cells to found be short showed of ofthe that branches controls. course. ability motor are disabilities. anterior-horn with those in Switzerland. endemic range and 1200-1 Wegelin brain ofthe un ofneurological cerebral in 500 Jilin. signs possible role oflate hiplate effects on brain may high-quality MRI in Tianjin. ofthe similar 28). thin cortex. pachygyria) week. on neuron of which in animals (27. after and motor reviewed ficiency probably. The thyroid as shown these fetuses was thoroughly described. thyroid hypertrophy. counts sixth but month two in cerebral showed specimens cortex no at the of eighth difference (lissencephaly Downloaded from ajcn. in the including ofneurons. ganglia. ofiodine and ifverified. the gether. been in mitigating iodine-deficient of sporadic congenital hypothyroidism. Brain weights at the eighth fetal neoin two cases. ficient cretins. generated ofneurons. characteristic cretins. irregular hormone ofneurons including the cerebellum. ofnerve continuing ofthe abnormalities. China. larged (25) subarachnoid a quantitative study birth. cells of spinal seen in computed which sulcal showed spaces. nucleus.nutrition. ventricles. basal [estimated as 3 mo of gestation of neurological development ganglia. and severe. red cord.deficient et in neurological al areas may crucially about the extent cretins after may mitigate affect neurological disability. the extent Deaf-mutism. scan studies. In addition. on the third all repletion the timing cortex. ventricular ofmalformations ofthe probably pushes 12deficient areas of China by Liu et al (29). and cochlea are all cretins in and reduction Abnormalities arrangement described hippocampus. When involvement and The amygdala.satisfactory. are important because they clearly there are a few CT. cretins cortex. of cerebral between receptors offetal thyroid 20 wk (32)]. of personality structures. be extrapyramidal disease. These the atrophy. the most development-is quantitative an overall regard to needed motor disability Generally. Comparison of cretins from Guizhou. Pur-normal or marked near-normal endemic in each of spastic-rigid thyroid cretins. a detailed and cells. muscle dysfunction. that is. for the efficacy ofiodine Pharoah et al (30)]. more absence In this than it resembles corticospinal seizures.288S the ease the hands. This that Brain studying the weights four of920-l results weights communication. (23). as in pregeffective it is in pathology ofendemic cretinism. these function Myxedematous respects. studies by (24) Jin from Fengzhu. appeared signal in the entirely normal globus pallidus. cretins. above. be seen. 2012 sonal communication. events of human normal pathways. the function and the suggest fetal [after fragmentary that the brain occurs The duration 12 wk. deficiency suggests that the effect of would on brain postnatal extend development treatment the critical period for effect nancy. 182 A synthesis by of including the cut-off time g (normal DeQuervain 29 g) (personal reporting 1990). by 10 and 18 wk). the the study and timing of dendritic degeneration of myxedema scans of China. to later may be cretinism. of six ing development en-Little is known neu. normal Neuronal fetuses control at the cell subjects. increased reported considerable enlarged lateral around histological with normal cells of the the size of ofthe the apical normal dendrites with to the sparse. of the brain-encompassing completed about the normally. spinal obtained neurological endemic made available to me for a marked with gliosis.suggest that neuronal-cell proliferation. The available pathologic studies structure the less adult gyral than female ofthe pattern normal. ofthe presumed increased in each dysfunction clinical inferences there is a paucity Tai. will the of cortical of ataxia. control iodine-defrom month of callosum. Taken tomay not be impaired in iodine-deficient human fetuses. cretinism-one in badly nature Still changes neurological trast. first gestation-are structure ofcorpus etc. These tomographs atrophy. beyond are few studies Switzerland. they by do connot and of pywere Myxedematous peripheral cells The cretinism compared corresponded the and picture dendritic severity are cretinism. anterior-horn-cell Can these Unfortunately. were slightly more than halfthat ofnormal the onset subjects. the primary mative 14 wk by the visual cortex of insult There Available from from China. study elucidation as well over years. their have severe is superior to number areas of in all major brain brain are affected are that of neurological cretins. branching. and. with 1 3 of 30 system. differ of have prominent brainhypothyroidism. on autopsy fundamental including have brains conclusion. to branching of cerebellar in experimental neuropathological important far data picture hypothyroidism in endemic of experiments from complete. first by Cruz et al in a useful but far from indicate (23) showed increased neuronal-cell densities in all layers of various al (25) areas ofcerebral cortex. adult kindly except consistent ofonset fetal material. of Likewise important forlogical examination involvement of preliminary brains from report of neuropathoabortuses in iodinestatus showing month. currently Autonomous conducting Province a project of China with to Cao study and these Ma ques- in was of smaller tions. they give 1990). where neurological cretinism predominates. while done in only also from China (per-small numbers ofspecimens. and. ofbrains DeQuervain Germany. . found brain is normal. Cruz by et al (26). changes (CT) have been onset neocortex. confirmation is the fetal ofpathological investigated pathologically or by computed tomography or magnetic-resonance imaging (MRI) have shown no defect primary embryological development. but that complete picture of the subsequent cell enlargement and differentiation are decreased. spaces are consistent published indicated and Yan adult human trimesters. (neurons neurons in the cortex. ofendemic and Wegelin Yan et Brains This is the first direct (CT) of the basal ganglia. The absence or the are 14th those pathological Lotmar recently. increasing neuropathological critical effect of during the second ofhypothyroidism dursteadily data iodine deand. the appearance of thyroid in the human brain [after 10 wk (3 1)]. These observations. deficits of are medial flagrant thinness seen (22). at least in cerebral cortex. which of as possible Three cretins by Ma T2 case. Golgi stains We are Xinjiang cortical motor area and cell bodies dendrites ofstellate subjects. Ecuador (26). suggests pocampus. temporal frontal occasionally corroborated Notable hypothalamic the vacuity lobe lobe basal-ganglia in most or DELONG diswhat cretins vegetative is require organization extent. mental In of general. many areas basal found cerebral total number of decreased numbers and degeneration of the brain. release suggests anatomically? studies. of the available data. or duration of hypothyroidism treatment neurological in by guest on November 27.

13% function Ecuador (n = 84%. development is relatively spared. anatomic. performance. This damage includes 1 1. ed. hearing. In fact. there is a continuum between neurological and myxedematous 4. Hurley system in zinc deficient rats.2. Martinet M. Dodge nervous system. with those of Zaire (34). Robertson CMT. 2012 dominates. Saenger G. Feigin RD. and either impairble-blind randomised controlled trial offolate treatment before congeneration or differentiation of neuronal ception to prevent recurrence of neural tube defects. small for gestational age infants: a comparClearly. raising the possibility that age. Leek 1. 1983:1mental. Lloyd-Still development after severe malnutrition in infancy. Science 1972. reflex abnormalities and Ecuador. Epidemiological J. n = 18: combined. there is a In: Dobbing London: Academic Press. in Zaire. clear inverse correlation. Teratogenesis by high doses of vitamin A severe as a function ofthe stages by guest on November 27. The increase in birth defects in Berlin continuum of severity. experimental animals. LS. The effects ofprotein malcretinism. Maternal nutritional factors and neural tube defects in hypothyroidism is found to be severe. Likewise. but in only 48% in Zaire. emphasizes differences (Table In Guizhou 1). myxedematous rosci Biobehav Rev 1978. it is possible to find a proportion of mixed cretins with ative study with subjects matched for birth weight or for gestational neurological signs and myxedema. Neusevere or prolonged iodine deficiency. Br Med J In myxedematous cretinism. Schwachman H. In fact. St Louis: Mosby. Morgane PJ. of thyroxin irreversible deficiency damage to to the second and perhaps third trimes7-5 1. In: Dobbing J. Miller M. Prensky AL. . Eight-year school performance with regard to hearing and motor disability has been challenged.2: 137-230. Congenital malformations ofthe nervous pathogenesis of neurological cretinism in which maternal hy. for whatever reason. 1975. is a matter Susser M. Eichmann E. of intellect. London: Academic Press. Wolff PH. Marolla F. 85% of cretins are deaf. pose severe and speech. a paradox. going program of impairment of the ment of neuronal-cell processes. muscle wasting - Mental China retardation Hearing impairment 87% Speech impairment 95% Strabismus 16% Neuromotor abnormality 34% cerebral Gait abnormality 20% could not walk increased could not 5% walk (n = 247) 67) 100% 87%. though neonatal (36) and later 8. Intellectual cretins be rel. Ecuador and Zaire Babinski ankle clonus 46% 22% Hypotonia. 1972: dine deficiency. Arch Anat Micros Morthe onphol Exp 1956:45:77-98 (in French). Gesenius H. a convergence of clinical. greater similar different These cretins are timing atively their in Ecuador. and in Guizhou observations in sparing observations have of the spared more neurological only 28% are mute in Zaire. intrauterine brain 168-84 (in German). 1Clearly. In: Pfieffer CC.282:1509-1 1. et aI. 7. and motor function in the face of severe neu-iodine deficiency is equally mysterious. Pediatrics 1974:54: severely involved 306-11. if myxedematous References 1 . combine during a critical period of fetal develinsult.9. Hurwitz I.5. gait. Whereas 73% ofcretins mute romotor.nutrition. and certainly obtains Downloaded from ajcn. Miller M. persistent less? and are tworesearchers motor throughout later life. Nutrition and mental Prenatal exposure to the Dutch famine of 1944-1945 not related to mental performance at age 19.IODINE TABLE 1 Comparative AND BRAIN DEVELOPMENT 289S neurological findings in endemic cretinism in China. with myxedematous cretinism being the result of more nutrition on the developing central nervous system in the rat. Laurence KM. 48% deaf 95%. 1983:155-87. the apparent intrauterine sparing are hearing. As mysterious as the eventual and thyroid degeneration maybe. 178: manifestations JD. Schrader RE. Arch Gynakol 1952:181: myxedematous cretinism. Other (2). where these myxedematous cretinism prethyroidism may be present at birth. Giroud A. Prevention ofspina bifida and other neural tube index of myxedematous cretinism) in Zaire. Neurobiology of pothyroxinemia and fetal hypothyroidism. partial hearing 10% loss 28% mute. #{163}3 to fourfold have made is myxedematous namely: Ifit cretinism function. Stein Z. n = 26: myxedematous. Nutrition and the developing cretinism appears to occur in areas of more severe iodine defi. James N. Etches PC. ciency (35). ed. or both. only 28% Speech impairment is found in 95% in both Guizhou Ecuador. why should myxedematous in intrauterine life. and growth of preterm. Tennant GB. Kemper T. with eventual loss of the capacity of the are. 73% mute “A few” normally community Zaire (n = in palsy 85% DTRs 6% l06)* 80% 28% deaf. Kyle JM. which cannot easily be explained by a defects. Douformation of the cochlea. London: Academic Press. why of the seems 70813. We attempted to test this idea by correlating deafness clues to the causation of neural tube defects. severe hypo198l. hypothyroidism.1 16:19-26. both induced by iothe trace metals zinc and copper. Campbell H. Prevention ofspina bifida In summary. and Ecuador. thyroid gland to respond to iodine. but more opment-localizable ters-to produce and prolonged a critical degree enough to cause 10. developand other neural tube defects. and pathologic data begin to provide a picture of the 22. Seller MJ. This result strongly suggests that in and surroundings in the after-war years. PR. dysarthria 20% 3% 20% rigid 4% could walk not 15% 9% * Neurological. (an index ofneurological cretinism) with growth retardation (an 6. neural development. J Pediatr 1990. ed. later? The concept that myxedematous cretins are in fact spared 3. n = 62.

Thorpe-Beeston Xi. Hammerstedt RH. 24. Fetal 1986:402-6. Vitamin supplementation and neural tube defects. DCLOIIg (JR. Ruis-Maicos A. Hetzel BS. Selenium toxicosis in three California sea lions (Zalop/iu. 20. Shi Z.146:l-53 34. Utrcias A. Effects of thyroid hormones on central nervous system development. Solangi MA. King JC. Condlifl#{235} PG. New York: Plenum.s callf()rnianus). Neuropsychological 33. Eastman Ci.593:2l-37. New York: Plenum. fl R. Alexander JW. 23. et al. Shi Z. Pharoah POD. Chen ZP. rodinc receptor in the human ktal brain. et al. 30. mentation in early pregnancy reduces the prevalence of neural tube defects. Iodine and the brain. 1989:231-8. Robbins (iuiLhou: clinical analysis of247 cretins. Shepherd 5. Zhangi. N Engl J 21. Cavdar AO. Buttfield lH. Quantitative histology study cells ofneurological endemic cretins. thyroid aplasia. Nevin NC. J (lin Endocrlnol I978:47:354-60. Legrand by guest on November 27. On endemic cretinism. goiter and cretinisni Med J 1984:97:689- 13. Iodine and the brain. 14. Histopathological observations in the brain in endemic cretinism.26. Prevention of neural tube defects in an area of high incidence. Milunsky A. Quantitative studies ofthe effects of h)puthyloidlsnl on the development ofthe cerebral cortex. Baer MT. Chi SP. Margen 5. Lagasse F. Felton with oral doses of encapsulated sodium selenite. al. Absorption ofmonoand poly-glutamyl folates in zinc-depleted man. Himmetoglu. Smithells RW. L)eLong GR. ThIl1 C. Maturation of the secretion of thyroid 1988:52:83-8. Vet 31. Due D. Pckkonen F. Ecuador: Rodriguez: 1984. Condliffe PG. Iodine and the brain. Can J Vet Res AM. eds. Etiology of neurological Ct and myxedematous cretinism in Vietnam and Zalre. eds.. Ontogenesis ofthe Hum Toxicol 1989. In: DeLong GR. and abnormal partiturition. 35. Stanbury JB. The effect of iodine prophylaxis on the incidence ofendeinic cretInIsm. eds. Iodine and the brain. Porcine 677-84. Jick H. Wang D. Teratology 1980:22:141-9. Lancet 1991:338:131-137. Robbins In: J. Tan Y. Ncs York: Plenum. 36. Amsterdam: Elsevier. hypothyroidism and (in German). Edwards WC. 15. Dev Med Child Neurol 1985:27:317-24. et al. Downloaded from ajcn. DELONG bins J. In: Dobbing J. focal symmetrical poliomyelomalacia: experimental reproduction 32. 1989:24958. 18. Recent progiess III thyroidolog Thilly maternal Bangkok: CH.aIlelos P. Chen B. (‘ondlifte PG. Yan Y. Arcasoy A. 1983:127-54.3’-triiodothyEndocrinology 1984: 1 14: CV. Wang YY. In: UL (‘i M. eds. ed. Fierro-Benitez R. 1972:30:201-21. and thyroprival cachexia. (. Wegelin C.262:2847-52.290S 12. In: Vichayanlat A. .nutrition. In: DeLong GR. Quito. neural tube defects. Influence of iodine dctIcicncy on human fetal thyroid gland and brain. Delange Crystal House Press. Variations in maternal serum zinc during pregnancy 29. Baycu T. Endemic studies in iodine deficiency areas in China. 1984:331-40. Bernal J. deLahunta A. Neurobehavioral teratology. eds. Prevention of spina bifida and other 28. Malo L. Rob- th)Ioid status severe endemic goiter. Tamura T. Guan C. Zhang J. Guide to computerized axial tomogI4ph. In: Robbins J. In: DeLong on brain GR. JAMA 1989. 27. Nitiyanant W.5. (‘ruz M. 17. DeQuervain F. 1936 (in German). Zhuang Z. 25. Multivitamin/folie acid supple. Jick SS.Chin J. Wilson TM. Liu J. New York: Plenum. MRC Vitamin Study Research Group. Stokstad ELR. 1989:359. stimulating hormone in the fetus. dysmaturity. McGregor huimone and thyroidMed 1991:324:532-6. Shane B. eds. Nicolaides KH. Ma T. Berlin: Springer. Whitenack DL. London: Academic Press. Nagatuki S. ButlerJ. Condlifl#{235} PG. Z Neurol 1933. Zeng G. Vandeips J. Malo L. DeLong (JR. Leng nervous L. eds.3I:568-70. 19. Observations on the neurology of endemIc cretInIsni. Adv Exp Mcd Blol nuclear 3. Iodine and the brain. Schorah Ci. Acta Med Scand Suppl l976.‘anelos P. 1989:91-102. Zinc deficiency and anencephaly in Turkey. Neurological signs in congenital iodine-deficiency disorder (endemic cretinism). Robbins J. 2012 in 22. 97. Utreras A. Endemic cretinism. New York: Plenum. ed. DeLong GR. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. 0. Lancet 198 1:2:1424-5. Palmer IS. Jameson S. Lotmar F. and correlation to congenital malformations. (. In: Yanai J. et al. Am J Clin Nutr 1978:31:1984-7. Condliffe PG. Li J. I 989:259-68. 16.