ANNALS O F CLINICAL AND LABORATORY SCIEN CE, Vol. 21, No. 4Copyright © 1991, Institute for Clinical Science, Inc.

Maternal Hypothyroxinemia: Psychoneurological Deficits of Progeny*!

EVELYN B. MAN, Ph .D .,Î JAMES F. BROWN, M.D..§ and SALLY A. SERUNIAN, M.S."1f

tYale University School o f Medicine, New Haven, CT

Thyroid Laboratory o f Providence Lying-In Hospital, and Institute o f Health Science, Brown University (retired)

Providence, RI and

§Department o f Pediatrics, Westerly Hospital

Westerly, RI 02891 and

11Department o f Psychology, Brown UniversityProvidence, RI

and11Portland Public Schools, Portland, ME 04103

ABSTRACTM aternal thyroid function was evaluated clinically, by reproductive his­

tory, and by serial m easurem ents of serum butanol-extractable iodine (thy­roxine-like iodine), two before and two after 24 gestational weeks during 1,349 pregnancies. Three percent of the women were hypothyroxinémie. Developm ental, intellectual, and motor abilities of progeny born to (Group I) 210 euthyroxinemic, (Group II) 15 hypothyroxinémie given adequate thyroid replacem ent therapy, and (Group III) 21 inadequately treated hypothyroxinémie women were compared. The groups of mothers exhib­ited no significant differences in in telligence, years of education, or chronological age. Mean developm ental and intellectual scores at eight months, four and seven years of Group II progeny evidenced remarkably consistent similarity to scores of siblings and controls. At each age, mean developm ental and intellectual scores were lower for Group III progeny, and motor scores of the latter were lowest. Some progeny of Group II mothers, treated only after 12 or 29 weeks, failed the ball catch and line walk tests; some had strabismus and other ocular disturbances. Could these deficits have originated w ith m aternal hypothyroxinem ia during first sem ester weeks before the thyroid-pituitary axis matures? Now in 1990—1991, early findings fit into the modern concepts of significant maternal gestational transfer of thyroxine to the fetus. The authors encourage pre­natal and/or early gestational screening for maternal hypothyroxinemia and urge prescription of adequate thyroid replacem ent therapy for hypothyrox­iném ie women.

* P re se n ted a t th e Sem inar on L aboratory D iagnosis o f D isorders o f th e F e tus, N ew born , an d E arly C h ildhood , A ssociation o f C lin ical Scientists, C incinnati, O H , N ovem ber 7—11, 1990.

t Send re p rin t req u ests to E velyn B. M an, Ph.D ., 275 S teele Road, Apt. B407, W est H artford, C T 06117.

2270091-7370/91/0700-0227 $02.00 © Institute for Clinical Science, Inc.

228 MAN, BROWN, AN D SERUNIAN

Preface

Presentations of Dr. Gabriella Morre- ale de Escobar at several international symposia on congenital hypothyroidism a n d d a ta o f o th e r p e d ia t r ic en d o - crino log ists5,14’17’18,22’24’30’31’35 stim u­la ted th is review . She em phasized a “once-and-only”30(p37) period for devel­opm ent of the mammalian brain. During the most active phase of brain growth and differentiation, adequate amounts of thy­roid hormones are essential for sequences of m aturational changes. Fetal produc­tion o f thyro id horm ones is major in d irecting brain developm ent, although recent evidence points to the need for m aternal euthyroidism. The tim etable for arrival of neurons, their m ultiplication and differentiation, the formation of glial cells, and m yelinogenesis may vary in d iffe re n t reg ions o f th e b ra in .30(p29) E ither a deficiency or an excess of thy­roid horm ones at certain hours of the tim etable may change cell differentia­tion. W ithout the organizing effect of thy­roid horm ones, portions o f the brain “grow into a tangled mass of poorly insu­lated, poorly connected neurofil.”30(p45)

Stages of developm ent of the human central nervous system (CNS) before 10, 12, or 14 weeks are dependent on thyroid horm ones. In reference to iodized oil injections, M orreale wrote, “Treatm ent before p regnancy or d u rin g the first trim este r appears to be necessary to eradicate neurological cretinism .”30 The ro le o f m a te rn a l th y ro x in e for fetal CNS d e v e lo p m e n t is re in fo rc e d by quotes from Thyroid. A Special Issue Dedicated to Life and Achievem ents o f Dr. Sidney H. Ingbar, with these quotes from Schussler.39

“Although early studies indicated that the free T4 might be low in pregnancy, it is probably normal in the second and third trimesters and somewhat elevated in the first trim ester.40”39<p27)

“ T here is increasing ev idence that physio logically sign ifican t en tities of thyroid horm one are transferred from th e m a te rn a l to th e fe ta l c i r c u la ­tion.44’45”39^

“As pointed out by Ekins,9 a maternal source of thyroid hormone is likely to be of greatest importance before fetal thy­roid horm one secretion begins. Thus, the hC G -dependent increases of mater­nal T4 and T3 in the firs t trim este r may be of physiologic significance to the fetus. ”39(p28)

The importance of thyroid hormones for developm ent of the CNS during the first trim ester of hum an gestation and the role of maternal thyroxine for fetal brain developm ent become apparent.

Introduction

The actual data that three percent of w om en in 1,349 p re g n a n c ie s w ere hypothyroxinémie, and that some prog­eny of inadequately treated hypothyrox­inémie women had low IQs and neuro­psychological deficits were reported in10 papers published 1964 to 1976.27,28

Data on pregnancies of two groups of 375 wom en from 97 pregnancies were compared. Group I included 97 pregnan­c ies o f 375 co n tro l e u th y ro x in em ic women. Group II included 97 pregnan­cies of 375 hypothyroxiném ie women. The incidence of abortions, prematurity, stillbirths, major anomalies, and offspring with subsequent retardation was 26 per­cent for the control women but 36 per­c e n t for th e h y p o th y ro x in é m ie wo- m en.28(VI) N isw ander reported a high incidence of stillbirths of hypothyroid women.34 Recently, Lazarus and Walk­er began a w orldw ide survey o f the possib le relationship betw een various c o n g e n ita l an o m a lie s an d c o n g e n i­tal hypothyroidism.26

Some thyroidologists doubted our find­ings and kept repeating that thyroid hor­

M ATERNAL HYPOTHYROXINEMIA: PSYCH ONEUROLOGICAL D E FIC IT S O F PROGENY 229m ones do not cross the placenta. The NATO Advanced Research Workshop on Congenital Hypothyroidism in Brussels, Belgium, May, 1988,14 and the study by Vulsma e t al in 198944 revolutionized the old w idely published hypothesis of pla­cental im perm eability to thyroid hor­mones. Vulsma and coworkers dem on­strated that in late gestation considerable amounts of T4 are transferred from the m o th e r to h e r h y p o th y ro id fe tu s . L a r s e n 25 r e v ie w e d th e f in d in g s o f Vulsma and cohorts44 and referred to sub­stan tia l tran sp lacen ta l passage of T4 w hen T4 cannot be synthesized by the fetal thyroid. Vulsma and coworkers dealt w ith cord serum and placental transfer of T4 to hypothyroids at term.44 Most new ­borns w ith congenital hypothyroidism and inability to synthesize T4 are asymp­tomatic at birth. This phenom enon has been assum ed to result from substantial placental transfer of m aternal T4 to the fetus during an appreciable length of ges­tation. The findings of Vulsma et al44 sup­ported our data of 20 years ago. Even Fisher acknowledges that in humans thy­roxine “clearly crosses the placenta.”20

Subjects and M ethods

The subjects in this longitudinal study were all participants in the Collaborative Perinatal Project of the National Insti­tu te o f N e u ro lo g ic a l D ise a se s and Stroke.6’7,8’9,10,11 Prenatal examinations of euthyroxinemic and hypothyroxinémie gravidae w ere conducted at the Provi­dence Lying-In Hospital from 1962 to 1967. M aternal thyroid function was eval­uated clinically by reproductive history and by serial m easurem ents of serum butanol-extractable iodines (BEIs) (thy­roxine-like iodine)28 two before and two after 24 gestational weeks during 1,349 pregnancies.28(I_IX) Women in the ade­quately treated hypothyroxinémie group had two low BEIs before 24 weeks and

thyroid replacem ent therapy* at a time interval begun at 12 or 29 gestational w eeks. W om en in th e in a d e q u a te ly trea ted hypothyroxinem ic group w ere those w ith two low BEIs but not given adequate replacem ent therapy. The orig­inal (1957) definition of serum iodine com pounds m easu red in th e B E I is as follows:27,28®

“ T o cla im th a t se rum B E I d e te rm in a tio n s are m ore p rec ise than PB I de term ina tions im p lies that th e exact chem ical n a tu re o f th e organic iod ine com ­p o u n d s in c lu d e d in m ea su re m e n t o f th e B E I is m ore accurate ly d e lin e a ted than is th e n a tu re o f th e iod ine com pounds p rec ip ita ted w ith p ro te in . “ T h y ­rox ine-like” (1, 6, 9) is th e b e s t desc rip tio n o f th e organic io d in e com pounds w hich a re in c lu d ed in B E I m easu rem en ts, in sp ite o f the resu lts o f recen t investigations o f analogues o f thyrox ine an d in v es­tig a tio n s o f th y ro x in e -b in d in g to p ro te in s (16). R ecoveries o f io d in e from thy rox ine in aqu eo u s a lka line so lu tion a lone, or w h en ad d ed to serum in- v itro , w ere b e tw een 88 and 103 p e r cen t—add in g th e am ounts found in 1 ml o f serum (1). T riiodo thy­ro n in e , triio d o th y ro ace tic acid and te tra io d o th y - roacetic acid ad d ed in v itro to serum y ie ld e d recov­e ries o f io d in e w hich w ere as com ple te as those from thyroxine. H ow ever, w h en triio d o thyron ine in m ain ten an ce doses w as ad m in iste red in v ivo , no increase in th e concentra tion o f serum B E I cou ld b e d e tected . M oreover, w h en as m uch as 32 gam m a p e r 100 m l. o f d iiodotyrosine iod ine or 1,000 gam m a p e r 100 m l. o f inorganic io d in e w as a d d ed in v itro to serum (1), no n e was recovered . In g b ar e t al. (17) in th e ir study o f bu tanol-ex tractab le I 131 found sim ilar p e rcen tile recoveries o f thyroxine I 131 an d virtual exclusion o f th e I 131 lin k ed w ith potassium iod ide or d iiodotyrosine . In our original SPI s tu d ies (3), 84 p e r cen t o f th e iod ine o f d iiodotyrosine was recov­ered . T hus th e re is a quan tita tively im portan t d if­fe rence b e tw ee n th e specificity o f th e B E I as com ­p a re d w ith th e S P I d e te r m in a tio n . T h e B E I tech n iq u e does no t e lim inate con tam ination from organic iod ine com pounds2 g iven for d iagnostic or th e rap eu tic p u rposes (9).”

2 See A ppendix for essen tia l tech n iq u e in o b ta in ­ing sera for B E I d e te rm in a tio n s.t

This study was prospective with thy­roid replacem ent therapy being provided only to gravidae, not to their progeny

* P ro lo id g e n e ro u s ly d o n a te d by th e W arn e r L am b ert C om pany, M orris Plains, NJ.

t R eproduced w ith perm ission o f J. C lin . E n d o ­crinol. XVII, 1375, 1957.

230 M AN, BROWN, A ND SERUNIAN

after birth. T-tests dem onstrated no sig­nificant differences be tw een the ade­quately and inadequately treated groups of hypothyroxinémie women in maternal intelligence quotients (T = 1.28 not sig­nificant), years of education (T = 0.29 not significant), or chronological ages (T =0.90, not significant).28(VIII,1X)

P sycho log ica l exam inations of the progeny were conducted at the Brown U niversity C hild D evelopm ent Study according to protocols for eight month, four year, and seven year examinations specified by the Collaborative Perina­tal P ro jec t. P ro ced u res for a d m in is ­tration and scoring were as prescribed in th e m a n u a ls o f s p e c i f i c a s s e s s ­ments.6’7,8,9'10,11,45 At eight months, the mental and motor scales of the research v e rs io n o f th e B ay ley S cales w ere adm inistered.28(v) At four years, the Stan- ford-Binet In telligence Scale, Form L- M,40 as well as fine and gross motor tasks, were adm inistered.28(VII) The W echsler Intelligence Scale for Children (WISC)45 and the B ender Visual-M otor G estalt Test were adm inistered at seven years. All examinations were adm inistered and scored w ithout the exam iner’s know l­edge of the thyroid status of the moth­e r or th e d e v e lo p m e n ta l h is to ry of the child.28(IX)

R e s u l t s

I n c i d e n c e o f M a t e r n a l H y p o t h y r o x i n e m i a T h r e e P e r c e n t

Figures 1, 2 and 3 are reproduced by courtesy of The C. V. Mosby Company.* In figures 1 and 2 are represented 304 serial, gestational serum BEIs of euthy- roxinemic women aged 35 and over and 24 BEIs six or more weeks after delivery. Outer solid lines show means ± 2 S.D. for 164 serial serum BEIs during pregnan­cies of 30 control euthyroxinemic women

aged 18 through 34 years.28<I) Shaded areas dem onstrate these values. Graphs for 449 gestational BEIs and 47 values at lea s t six w eeks a fte r d e liv e ry o f 94 younger euthyroxinem ic women showed sim ilar d istr ib u tio n s28*11̂ and are not reproduced here. All pregnancies were uncom plicated with deliveries of living neonates, classified normal, and weigh­ing at least 2500 grams. To summarize: 917 BEIs of euthyroxinem ic pregnant women fell w ithin the gray areas of fig­ures 1 and 2. (For 164 see reference 28(1) and for 753 see reference 28 (II).) In con­trast are the BEIs in figure 3 during 39 pregnancies of hypothyroxinemic women before adequate thyro id rep lacem en t therapy .28(v) Scales for m inim um and maximum are p lotted slightly but insig­nificantly differently. Note the BEIs in figure 3 below the minima of figures 1 and 2. The incidence of hypothyroxin­emia as shown in figure 3 illustrates our m eaning of the term hypothyroxinemia and w ill b e co m p ared w ith d a ta of V olpe,4 Solom on,! T u n b rid g e ,41 and Glinoer21 in the discussion. The overall contrast betw een figure 3 and its counter­parts, figures 1 and 2, is obvious.

P s y c h o l o g i c a l T e s t s o n P r o g e n y

In table I are m ean developm ental and intelligence quotients of the progeny at eight m onths,28(v) four years,28(VI1) and seven years.28<VII1,IX) At eight months, the m ean developm ental quotients on the mental and motor scales of the Bayley Scales were essentially identical for the infants of the euthyroxinemic and ade­q u a te ly t r e a te d h y p o th y ro x in e m ic w om en. Scores of p rogeny o f in ad e ­q u a te ly t r e a te d h y p o th y ro x in e m ic w om en w ere significantly low er than th o se o f c h i ld r e n o f e u th y r o x in e ­mic women.28(V,VII’VIII,IX)

Incidence of normal vocabulary and speech at four years among progeny of

* St. Louis, MO. t Personal com m unication to EBM.

MATERNAL HYPOTHYROXINEMIA: PSYCH ONEUROLOGICAL D E FIC ITS O F PROGENY 231

1 2

10-

- 600AEa 4ESo

co

wniMP1 1 . .. . qp iIM>N iÌiS i'Ìm ^ 'ÌiìÌlI'h i!i ’ Ì'i: i iü 1 ; '

1 « , ' * * » ■ , Í

21 Women 35 Years or Over22 Pregnancies

134 BEI during pregnancy 12 BEI post-partum

Gravida 5 or Less• = 2 BEI before 24 weeks x = 1 BEI before 24 weeks

Age 18 to 35 mean ± 2 S.D.

12 1 6 20 2 4 28 32Weeks After Last Menstrual Period

36 40

F i g u r e 1. One hundred thirty-four gestational BEIs and 12 postpartum values of 21 euthyroxinem ic women aged 35 and over and gravida 5 or less relative to 22 pregnancies.281111 Each dot represents a serum BEI determ ined in duplicate. The gray area, minimum and maximum lines, represents the means ± 2 S.D. for 164 serial gestational BEIs of 30 control euthyroxinemic women aged 18 through 34 years during uncomplicated pregnancies.28® They delivered living neonates weighing at least 2500 grams and classi­fied normal by pediatricians trained in neonatology.

a d e q u a te ly t re a te d h y p o th y ro x in ém ie w om en was 71 percen t; am ong progeny of eu thyrox inem ic w om en, 63 percen t; a n d am o n g p ro g e n y o f in a d e q u a te ly trea ted hypothyroxiném ie w om en, 44.5 percent. Almost 75 p ercen t of the prog­eny of adequate ly trea ted hypothyroxin­ém ie w om en w ere co n sid ered to have norm al vocabulary and speech, yet less than h a lf o f th e progeny of inadequately trea ted hypothyroxiném ie w om en w ere rated as norm al in these areas.

At four and seven years, the h ighest m ean IQs w ere ob tained by the progeny of adequately trea ted hypothyroxiném ie w o m en w ith th e n e x t h ig h e s t m ean ob ta ined by progeny of euthyroxinem ic w om en and th e low est m ean q u o tien t o b ta in e d by p ro g e n y o f in a d e q u a te ly trea ted hypothyroxiném ie w om en. T he d iffe rence b e tw e en the m ean IQ q uo­

tien ts o f the progeny of the two hypothy­roxiném ie groups was significant. T was 1.70 and P < 0.05. A m ost rem arkable aspect of tab le I is the stability o f quo­tien ts am ong the th ree groups o f progeny over tim e and w ith th re e in s tru m en ts o f assessm en t b u t esp ec ia lly th e co n ­s is ten cy o f q u o tien ts for th e p ro g en y o f a d e q u a te ly t r e a te d h y p o th y ro x in ­ém ie w om en.

A d istribu tion of the WISC full scale quotien ts at seven years (end o f tab le I) in c lu d ed m ore quo tien ts in th e ranges below 80 and 80 to 109 w ith few er quo­tien ts in the 110 or m ore range am ong the p rogeny of eu thy rox inem ic and in a d e ­q u a te ly t r e a t e d h y p o th y r o x in é m ie w om en than expected. T he incidence of quotien ts in the 80 to 109 range for p rog­eny of adequately trea ted hypothyroxin­ém ie w om en w as less th an ex p e c te d

12i

232 MAN, BROWN, A ND SERUNIAN

29 Women 35 Years or Over Gravida 6 to 13 ̂ 30 Pregnancies • = 2 BEI before 24 weeks

170 BEI during pregnancy x = 1 BEI before 24 weeks12 BEI post-partum f. ■" Age 18 to 35 mean ± 2 S.D.

° 8 12 16 20 24 28 32 36 40Weeks After Last Menstrual Period

FIGURE 2. One hundred seventy serial gestational BEIs and 12 postpartum BEIs of 29 euthyroxinemic women aged 35 and over and gravida 6 to 13 relative to 30 pregnancies.28<II) Each dot represents a serum BEI determ ined in duplicate. The gray area, minimum and maximum lines, represents the means ± 2 S.D. (or 164 serial gestational BEIs of 30 control euthyroxinemic women aged 18 through 34 years during uncomplicated pregnancies.28*1' They delivered living neonates weighing at least 2500 grams and classi­fied normal by pediatricians trained in neonatology.

because of the very high incidence of quotients in the 110 or more range. No progeny of adequately treated hypothy­roxinémie women obtained a quotient below 80 w hile no progeny of inade­q u a te ly t r e a te d h y p o th y ro x in é m ie wom en obtained a quo tien t of 110 or more. At both four and seven years, prog­eny of the hypo thyrox iném ie in a d e ­quately treated women (Group III) were poorest in performance of motor skills.

Three hypothyroxinémie women had two children participating in the study with one born after adequate maternal thyroid treatm ent and one after inade­quate thyroid treatm ent.28<IX) Progeny of adequate ly trea ted hypothyroxiném ie pregnancies obtained a mean fullscale IQ at seven years of 103.0 whereas the sib­lings of inadequately treated pregnancies

obtained a m ean IQ of 83.0. The differ­ence in mean full scale quotients is sur­prisingly large (more than 1 S.D.) since, in general, siblings tend to have more sim ilar quotients. All progeny of ade­quately treated pregnancies were classi­fied as overall normal at seven years of age, while none of their siblings were so classified.

P l a c e n t a s

Only weights, not gross and not micro­scopic examinations, were available for placentas of 31 euthyroxinemic (Group I), of 11 adequately treated hypothyrox­inémie (Group II) and of 14 inadequately treated hypothyroxinémie pairs (Group III) as show n in tab le II. P lacen tal weights of Groups I and II ranged from

M ATERNAL HYPOTHYROXINEM IA: PSYCH ONEUROLOGICAL D E FIC IT S O F PROGENY 233

F ig u r e 3. G esta tional B E Is o f 39 hypothyroxiném ie w om en. T h e op en area b e tw een m in im um and m axim um gestational B E Is for eu thy rox inem ie w om en m irrors th e gray areas o f figures 1 and 2 o f gesta­tional B E Is o f eu thy rox inem ie w om en.2® Sym bols on th e B E I de te rm in a tio n s iden tify som e signs or sym ptom s d u rin g 24 o f th e 39 pregnancies. Sym bols are located a t value o f serum B EI. 4-T, P revious thyroidectom y. 3-H , C lin ical hypothyroidism . 10-G, Low TB G (T hese in c lu d ed consecu tive va lues on th e sam e w om en, no t th e in c id en ce o f low TBG s).28<III) 7-R, P rev ious rep ro d u c tiv e d ifficu lties.281 V)

TABLE IPsychological Tests on Progeny

Mean Developmental and Intelligence Quotients at 8 Months. 4 Years, and 7 Years

BayleyD.Q. at 8 Months

Mean MeanBinetl.Q.

at 4 YearsWISC Full

Scale I.Q. a t 7 Years

Distribution o f WISC Full Scale 7 Year I.Q.

NumbersMother Group No. Mental Motor No. Mean No. Mean <80 80-109 >110

Euthyroxinemie 1 242 101 104 227 99.5 210 96.6 21 157 32Hypothyroxinémie adequate therapy II 29 102 104 22 102.0 15 104.5 0 8 7Hypothyroxinémie inadequate therapy III 55 95 98 23 93.0 21 91.9 5 16 0

WISC - Wechsler Intelligence Scale for Children.

234 MAN, BROWN, A N D SERUNIAN

TABLE IIPlacental Weights and Birth Weights

Birth Weiaht Placental Weiaht Birth WeightMother Group No.

MeanGram

RangeGram

MeanGram

S.D. Range Gram Gram

Placental Weight Mean Range

Euthyroxinemic * 1 31 3,226 2,580-4,791 450 + 71.0 334-579 7.17 5.39-10.15Hypothyroxinémie adequate therapy II 11 3,222 2,500-3,997 450 + 72.3 339-550 7.16 5.37-9.10Hypothyroxinémie inadequate therapy III 14 3,266 2,665-4,224 447 + 131.8 273-794 6.84 4.64-10.90

* Euthyroxinemic controls matched as to race, age, and gravida of mother and sex of child, and, if possible, by birth weight.Reproduced by courtesy of C.V. Mosby Co., St. Louis, MO.

339 to 579 grams versus 273 to 794 grams for the inadequately treated hypothyrox­inémie maternal-fetal pairs. Two of the placentas in this Group III weighed 616 and 794 grams and exceeded weights of the other 42 placentas. A low Leiter I.Q. of 76 was associated w ith a p lacen ta m ark ed ly h e a v ie r (564 gram s) th an expected for a m ale infant w ith birth weight of 2,665 grams. Any significance of these heavy placentas is still unknown. U nfortunately , gross and m icroscopic exam inations w ere no t ava ilab le for hypothyroxinémie pregnancies with poor outcomes of abortions, stillbirths, prem a­turity, and major anomalies.28(VI)

T h ree com m ents ab o u t th e ac tive m etabolism of the placenta are pertinent. In Japan, chorionic villi from human pla­centas o b ta ined by 12-week induced abortions deiodinated T4 as actively as v illi from fu ll term p la c e n ta s .1 The a u th o rs c o n c lu d e d “ fe to -m a te rn a l exchange of T4 and T3 can be regulated by primary chorionic villi, even prior to com pletion of the placental organ, via d e io d in a tio n o f th ese co m pounds.” 1 Yoshida and Suzuki have written a series

of articles about thyroid hormone con­centrations in hum an placentas and have described activity of m onodeiodinase.46

Em erson18<p31) wrote, “The placenta is usually regarded as a conduit through w hich m aternal nu trien ts pass to the fetus, or as a barrier that allows for fetal developm ent in an insu lated environ­m ent . . . ” . . .“ It is less recognized that th e p la c e n ta is a m e ta b o lic a lly ac ­tive organ.”

Discussion

I n c i d e n c e o f M a t e r n a l H y p o t h y r o x i n e m i a i n P r e g n a n c y

How many women are hypothyroxin­ém ie d u r in g th e firs t tr im e s te r and unable to supply T4 to cross the p la­centa? Before the fetal thyroid assumes autonomous functions and when thyroid hormones are essential for early central nervous system developm ent, m aternal hypothyroxinemia could result in neuro­logic deficits of progeny.

Volpé in evaluation of the total popu­lation placed up to three percent in a

MATERNAL HYPOTHYROXINEM IA: PSYCHONEUROLOGICAL D E FIC IT S O F PROGENY 235category of hypothyroid ism.4(p275) “The presence of m inor degrees of hypothy­roidism (both m ild and subclinical forms) will always be more common than the overt forms of the disease. The term will also embrace patients with ‘compensat­ed ’ hypothyroidism, i.e., normal circulat­ing thyroid horm one levels w ith high thyroid stim ulating hormones (TSH) val­ues, as well as those with equivocal or slightly low thyroid hormone concentra­tions and elevated TSH levels.26 Up to th re e p e rc e n t of th e p o p u la tio n can be placed in this category; it is much m o re com m on in fe m a le s a n d has a m u ch h ig h e r in c id e n c e w ith a d ­vanced age.35’89”4(p275)

Tunbridge made “Cross-sectional com­m unity surveys of non-iodine deficient C aucasian com m unities in E ngland .41 T h ree p e rc e n t o f such a p o p u la tio n proved to have biochemical evidence of m inor degrees of thyroid failure as well as autoim m une thyro id itis.” In te rre la ­tions of m aternal and neonatal thyroid autoimm une disease to congenital hypo­thyroidism have not been clarified but are being investigated strenuously.2,16

N iswander34 published much quoted data that during pregnancy only 0.9 per­cent of 20,000 white women and 0.3 per­cent of 20,000 black patients in the Col­laborative Project were hypothyroid. For these data, clinical diagnoses of hypothy­roidism w ere req u ired from about 14 m edical centers with variant expertise in thyroidal diagnostics. N iswander him self a d m itte d th a t th o se p e rc e n ts w ere undoubtedly falsely low. As a consultant, one o f us (EBM) worked with the Col­laborative Project at National Institutes of H ealth and recognized the defects of N isw ander’s data on thyroid diseases in pregnancy. Davies and Cobin12 em pha­sized that classical clinical symptoms of thyroid disease are masked in pregnancy. “A high degree of expertise strengthened by biochem ical param eters w ith refer­

ence to the normal pregnant ranges have to be carefully evaluated before a thera­peutic decision can be m ade.” 12

G linoer and associates21 reported in September, 1990, three percent hypothy- roxinemia in Belgium in areas of margin­ally low iodine intake.26 Glinoer e t al21 and Burrow ,3 in a covering ed itoria l, a d m it th a t io d in e in ta k e w as n o t extremely low but stress the intricacies of gestational thyroid function. Larsen and M andel29 found in primary hypothyroid­ism a need for increased thryoxine ther­apy during pregnancy. Utiger, relative to therapy for hypothyroidism, wrote, “The fact that there are situations such as preg­nancy and the postpartum period that necessitate alterations in dosage serves as a rem in d er o f the m u ltip lic ity of extrathyroidal factors that can alter thy­roid function .”42(pl27) D avid Solomon wrote in a personal letter “I just do not know [the incidence of hypothyroxin- emia in pregnancy]. The confounder is to what extent pregnancy increases dem and and therefore brings out hypothyroxin- em ia in previously normothyroxinemic but hyper-TSH-emic women. This could bum p it back to three percent. I just do not know the facts on that.”*

At Providence Lying-In Hospital, Man looked for hyperthyroxinem ia and was confounded by the high incidence of low BEIs. Standards for BEI were checked daily and cross checked with quantitative controls. In 1969, 173 of 1,394 clinic pregnancies w ere associated w ith low serum th y rox ine-like io d in es and /o r clinical diagnoses of thyroid underfunc- t io n .28(v) T his excessive p e rc e n ta g e included many m ultigraviada and older women. At that point, any patient with every and/or any possible cause for a low serum thyroxine-like iodine was elim i­n a ted from the study . I f a low B E I

* Personal com m unication to EBM .

236 MAN, BROWN, A N D SERUNIAN

occurred w hen a patient had a sudden w e ig h t gain or an u p p e r resp ira to ry infection ,28<IV) that low determ ination was classified as a sporadic false value. Only women with two authentic criteria of hypothyroxinemia were included. In 1976, Man and Serunian estim ated that at least th ree p e rcen t o f uncom plica ted pregnancies in private and clinic practice at Providence Lying-In H ospital were h y p o th y ro x in é m ie .28(IX) T h e ir da ta , Volpé’s the published report and letter by V o lp e ,4 co m m u n ity su rv e y s by Tunbridge,4 the reference by Solomon* to “pregnancy’s increasing dem ands” sup­port an incidence of th ree percen t of hypothyroxinemia in otherwise uncom­plicated pregnancies.

V i s u a l S p a t i a l D i s a b i l i t i e s

The problem of m aternal transfer of thyroxine through the p lacenta to the fetus pertains not only to the health of the m other and the fetus, bu t also to the future psychoneurological developm ent of the progeny.14

Unlooked for were low scores of some four-year-old progeny of hypothyroxin­ém ie p re g n a n t m o th e rs a d e q u a te ly treated after 12 or 29 gestational weeks in gross motor tests of line walk and ball catch. O f these 17 children, three had strabismus, two wore glasses, and only 70 percent w ere classified “eyes norm al” though 84 percent and 94 percent of the children in the other two groups were classified “eyes normal.” These hypothy­roxinémie women had not registered at the prenatal clinic until 11 or 28 gesta­tional weeks. T heir hypothyroxinem ia was neither recognized nor treated until 12 or 29 weeks. Adequate Proloidt had

* Personal com m unication to EBM . t D o n a ted g en ero u sly by th e W arner L am b ert

Co., M orris P lains, NJ.

been prescribed and the serum BEIs of these mothers were in the normal range for pregnancy after 12 or 29 weeks.28(v)

Irreversible brain damage and mental retardation of hum ans after prolonged thyroid failure during fetal and/or postna­ta l life h av e b e e n e m p h a s iz e d by D elange in his discussions of fetal in utero thyroid failure.13 Many references to neurological deficits of hypothyroid ch ild ren associate d e lay ed bone age at birth with severe deficiency of thy­roid hormones during early or prolonged fetal existence.14

Both Farriaux of Lille, F rance19 and Van Vliet of Brussels43 found screening for congenital hypothyroidism effective in p reven ting m ental retardation , bu t some children exhibited “ m ild abnor­malities of perception and coordination a t la te r a g e s .” R o c h ic c io li e t al of T o u lo u se 36 re p o rte d no rm al m en ta l developm ent of hypothyro id ch ild ren d iscovered by sc reen in g and trea ted promptly, but in a m inor degree neuro­logical abnormalities were evident. The Catalan Collaborative Group in Barce­lona23 also detailed certain ocular impair­m ents, such as strabism us associated with fetal lack of thyroid hormones.

Not only in parts of Europe (France, Spain, Belgium, etc.) bu t also in North America these psychomotor and neuro­psychological deficits of children have been found .15’16’22’37’38-33 At the 1989 Annual M eeting of The American Thy­roid Association in San Francisco, a spe­cial satellite symposium was “Thyroid H orm one in the D eve lo p in g B ra in .” Joanne F. Rovet, Ph.D. (Toronto) spoke about “ N europsychological Studies of T h y r o id H o rm o n e D e f ic ie n c y in H u m an s—W indow s on E a r ly B ra in D e v e lo p m e n t.” S u b s e q u e n tly , she described hypothyroid ch ild ren o lder than infancy bu t who had b een diag­nosed and treated and seem ed to have m ild in te llec tual im pairm ents desp ite

MATERNAL HYPOTHYROXINEMIA: PSYCH ONEUROLOGICAL D E FIC IT S O F PROGENY 237n o rm a l IQ s . T h e s e im p a ir m e n t s occurred especially w hen in trau terine thyroid deficiencies were suspected.

In Toronto, thyroid therapy for hypo­thy ro id ch ild ren was p rev iously at a lower dosage than now used there and in New England. However, many at that 1988 conference in Brussels referred to p sy ch o m o to r p sy c h o lo g ic a l d e fic its in children who, at birth, had delayed b o n e age and w ere thus su sp e c te d to h av e e n d u re d in u te r o th y ro x ­ine deficiencies.14

In contrast to some doctors in Toronto, M itchell and Klein 32,33 recom m ended higher doses of thyroid for hypothyroid infants. W hen tested at age nine to 10 years, 72 of these patients showed IQs which agreed well with those of their sib­lings and peers; however, several minor scores were noted, as in the reading com­prehension subtotal of the Peabody Indi­vidual Achievement Test (PIAT) and the v o cab u la ry s u b te s t o f th e W ISC-R. Delayed bone age at birth was reported for 53 of the 72 children, indicating pre­natal hypothyroxinemia.

One of the first persons to advocate the testing of all newborns for hypothyrox­inemia, which is now standard practice, was Dr. Man. Screening of thyroid func­tion is urged in all pregnant women as w ell as testing prior to pregnancy in women who have experienced any diffi­culty in prior pregnancies. Our data indi­cate that there may be damage to the fetus when a pregnant woman has only a m ild degree of hypothyroxinemia, even though she may appear clinically well. H ence screening is urged not only on newborns but also on pregnant women for hypothyroxinem ia to preven t brain damage in newborns.

A d d en d u m

After th e p ap er was com pleted , R obert Z. Klein, M .D . w rote, “ I w ould ap p rec ia te it i f you w ould re fe r in your lis ted supports to th e transp lacen tal

passage o f thyroxine to m y paper. T h e re fe ren ce is K lein, R. Z.: In u tero p ro tec tion o f th e hypothyro id infant. In : Topics in P ediatrics. Pom erance, H. H. and R ercu, B. B., eds. N ew York, Springer Verlag, 1 9 9 0 , p p . 2 5 - 3 3 .”

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