Hypothyroxinemia in Sick

and Well

Preterm Infants Frank B. Diamond, M.D.,* John S. Parks, M.D., Ph.D.,* Alfred Tenore, M.D.,* Jean M. Marino, M.A.,* Alfred M. Bongiovanni, M.D.†

Editorial ~’~’c~~~c’ In the

current era




there is debate as to whether hypothyroxinemia in this context signifies hypot~ayr~~d~~m, ’~~e have measured other indicators of thyroid status ~~’ sick. premature infants and the results with those obtained/in well term infants and in infants with congenital primary hypothyroidism. Assays of.thyroid stimulating hormone


infants stand out as a genital hypothyroidism, preterm a very high incidence of abnormal T~ with population results, but an incidence of true hypothyroidism, which

no different from that of term infants. The authors demonstrate that a majority of sick preterm infants have tow filter paper -1’4 levels. Ic1 contrast to the con-


T3 uptakes, genitally hypothyroid infants, they have highnormal TSH tow levels of thyroxine-binding globulin, and normal CPK levels.

(TSH), triiodoth-yronine uptake (T3 Uptake), ’

thyroxine’ binding g!obu!in~TBG)~ creatinc phosphokinase (CPK), and scrum thyroxine


RETERM INFANTS pose special problems in mass screening programs for the detection of congenital hypothyroidism. Since their thyroxine levels, measured in serum’ .2 and dried blood3 specimens, tend to be lower

indicate that the sick preterm infants are truly hypothyroxinemic but otherwise, do not resemble infants with congenital hypo-

than those of term infants, a high prop’ortion of preterm infants are recalled for further testing. We have measured ’thyroxine :: ~’T~3 ~ay a dried blood filter paper technique in serial specimens from 49 sick and well pre- ~.: term infants to determine the effects ~~ respiratory.:-distress syndrome (RDS) and ..: other illness on the incidence and duration ’~ -: /, ~f~MQEmaMy~:~~~:T~,~eve!:s~~~~ defined by standards developed for term, infants, Since ~’



~ From the University of Pennsylvania School of Medicine, Philadelphia, * and the School of Medicine, Catholic



~~a~roidi~m* Materials and Methods


Parental consent for blood sampling obtained under guidelines Iapproved by


the human expenm~~t~~ic~~a. ~~.p~i~~~~ ~~~c~~ u~~~ ~k~~aine~ by



institutions’ committees on


.hee!~puh€MTe~a~d/spotted’ dirlectly on filter paper ~~‘~~ ~‘~~ measurement of T4 and TSH.


::~ &dquo;Additi.ooai~ blood was collected in ~.4-mt ~&dquo; ; miC3’’otubes.,and serum was ’frozen at - 20 C ;~

until assayed for ’T,,,, T3 u ta c ,TBG and CPK., Filter paper T4 was measured in dupli- : cate in the Micromedic, ’Concept 4 1 System. .;:, the..mean intra-assay coefficient of variation. ’;~

University of PuertoRico.† Supported in part by National Institutes of Health Grants HD-00215; GM-20138 and RCDA 1KO 4 00005. ! (C’vt) was 10.6 per cent and the inter’-ass’ay / Correspondence to: John S. Parks, Associate Director, ~ ~as 17.9 per :c€M.:~iFHt~’ ,p4ppr I and ’&dquo; ~ Division of Endocrinology, Children’s Hospital of Phila34th Street and One Children’s Center, Civic delphia, ~ ~~~°u~a ’T~~ ~~~~~ ~~~~aa~~~ ~.s~~a~ ~’~a~irr~~~i~ ~. ~:, PA 19104. Center Boulevard, Philadelphia, and T3 u~~~ ~.~ ~~: ~ Received for publication March 31, 1979 and ac- reagents. Serpm,~ T4 Klitie ~i~r~~z~c~SmtRt . ~meSsM~€~~,[email protected]!~ cepted May 15, 1979. ~.~ ~ ~ ’J:.I~;’~;: -~: ~r’ ~.~ ./~ ]~ ~ ’~ :&dquo;’~’

(C( )ntinued, on p, aic 559)’

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Downloaded from cpj.sagepub.com at Australian National University on March 16, 2015

Downloaded from cpj.sagepub.com at Australian National University on March 16, 2015

.. ~&dquo;tc:. 1. The left panel shows individual FP T., results obtained eh’-ing the first c7str~atal week from preterm infants with illnesses other than RDS, preterm infants with F2I~~i, .~~~a~ well .preterm infants (Prein. control, l1 , The mean, -1 S.D. and -2 S.D..standards for 533 unselect(~d infants tested between 3 and 5 days of age are shown for comparison (random). The center panel shows individual and mean values obtained during the second week of life m the same prcterm infants. The right panel shows individual and mean changes between first and second’week specimens. ’-’.’.’ ’




from page


measured by the radioimmunoassay. Scrum ~PI~ was Corning measured using Chemical procedure number 45,, modified to accept 25,-ixl, ’.’ ’’. ’ ~’ s~m~l~~. Preterm infants in. this study, were classified as well (~1 25) mean gestational age ~. ,~~& weeks :t 1.4 S.D.;/m€an’.birth,:; weight .’ = 1949 g :t,342, having respiratory ~~~t~~~~ ~. ~ syndrome , (N = 22) mean gestational age = 31.6 wks ± 3.0; mean birth weight - 1612, ~; ~ : g.~~ 591, or having medical diagnoses other than RD$, (N = 17) mean gestational, age, 32.4, weeks :t 2.4; mean birth weight ~ 1646 g ±, 52 1. The study was confined to .~.,: infants wiiCi~-, birth weight a,p pro’p riate for .’ gestational, age as defined by the Dubowitz, tube method and TBG


sampled between 3 and 5 days of age was 11.6 ug/di t 3.4. A majority of sick preterm infants (!5of22 with RDS and 11 of 17 with other illnesses) had F~&dquo; T4 values during the first week that were below 4.8 gg/di and thus more than 2 standard devm’&dquo;tion.s~b’e!’ow:lh.c mean for’unseated infants. Mean FP T4, values of 4.6 :t 2.1 ~dt for newborns











RDS and 5 ’.4 :t 3.,l /.kgfdl for non-RDS infants lower than the mean of 7.9 :L-,2.5 I 4g/dl


for 25 well preterm infants


~p’< 0.001).


preterm, ~~~~~~’~1~~ ~a~~.~ ~~ ~C‘~ infants w as ~~~ni~~~~~~~ ~c~~~~ than the mean ~&dquo;~~ ~~~~~~~~~~ ~~f~~~~ ~~ ~ ~.~~~g’~~1~ ~ of 25 ~~.~~~ for well



had values, more than 2 standard deviations ~~~~~~ ~~~ ~~~~* ~~~ . ’’.~ ..~~’’~ ’; ~;.,,F.T..:~&dquo; ~./. ’

right panels of T4 values in ~.pretcrmj~infsMs.’ . ...~ B .:’&dquo;~:’&dquo;; ’ ~ ~~.’ .~ :::~B.’’.’ ’~&dquo;.~Figure 1’,, ’FP changed ,very little between the first and, !: second ~~~~k~~ ~~ life. Mean ~~aog’€’s!:’wcre;,&dquo;: /~ .’/~ ~su!ts::.~:~’~’ ~:.~’~~;’.: ~~::&dquo; .:’.,~B:;~j~&dquo;’ ~ :~.’’ ~’ .~’.~~ .~,~ ~~;~-’ ’~.’’~ -0’.7 Agldl for RDS~,’’,~~0.3 ~~~c~~ for ~non-RDS in ~’. are shown ~.~d -~~.~ ~~1~~ ~’~a- ~~~~ preterm inf*ants.~ ~~~.BMt~~~’p~€r/B:.T4~’~esuN ~’/’..As:shown:’M&dquo;th€.(cent€r.~



.Figure 1. The mean value

for 533 unsele-cted.

~.’~~j~~i~~ ~~’ ~h~ ~’ and: non-RID,S groups

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the first, T3 uptake measurements were done to estimate the degree of saturation of thyroxine binding proteins and the results were multiplied by total T4 values to give a &dquo;T7&dquo; or free thyroxine index (FTI 1 of Tabte 1). Mean T3 uptake values were similar in sick preterm and healthy term infants (49 and 47~I~). Thus the mean FTI (1) value for the sick preterm infants was, like the serum T~ value, less than half the mean value for the term infants. The mean Tg uptake was 29 per cent in hypothyroid infants. A second method of assessing free thyroxine involved radioimmunoassay of serum TBG. With new techniques, this assay can be performed on as little as 10 ikl of serum. The mean TBG level of !8 izg/mi in sick preterm infants was significantly lower than the value of 26 in term infants and this, in turn, was lower than the value of’ 39 >g/ml in hypothyroid infants. ~ second variety of FTI was calculated by muttipiying the ’1’4 value by 10 and dividing by the TBG value. This more discriminating approach --narrowed the difference in FTI between the sick preterm and healthy term groups by rais-

still had FP T4 levels below 4.8 bcgldl during the second postnatal week. In 13 infants who were retested during the third week, the FP T4 level rose a mean of 1.3 ~.g/dl.

Capillary blood specimens were obtained for additional measurements of thyroid function in 211 preterm infants with RDS or other illnesses and in 12 healthy term infants (Table 1). Filter paper T4 estimates in simultaneously obtained specimens were lower than serum T4 levels in sick preterm infants (4.5 versus 6.8 ~t-g/dl, p < ~.~1). The two methods of T4 assay gave similar mean values (13.9 and 14.7 gg/dl) in the 12 term infants. Linear regression coefficients for FP T~ on serum T,, were 0.68 for the sick preterm and 0.68 for the term infants. Thus, the FP T4 screening technique provided a reasonable approximation of total thyroxine. More than 99 per cent of total circulating thyroxine is bound to thyroid hormone binding proteins which include albumin, prealbumin and the specific thyroxine binding globulin, TBG. Two approaches were used to levels of the physiologically important free thyroxine fraction in patients’ sera. In TABLE 1. rtr~ti~i~rrcr~t

,~:: The


fVte~sur~»aeral.s’r~f ’~‘h~yr~art F~i3~ct~~r~s’

sigpific9iitly from resM~ifor.term’..~’ ~ , by Student’s t-test. ~~ ~~~.r ~ ~:~&dquo;; ~~.~ ~.-. ° t’T4 values below I >g/ml were treated as 3 ~.~~~a~ ~’c~r ~.,

/’ ,.; ~ * Results difier of . infants, p ~~ 0.01

range of results as, determined in the

~~~~~~’ ~,~~:r~~~~~~s ~rf ~~~ ~~i~d~~r~’s Hospital

~~i~~~~I~~z~. ~’~~ ~~.~~dr~~a ~ ~~ ~~ ~~~~~ c~~ age

the the name of each

Is listed

laboratory or or ~~1~~~~~i~~.

~.. ~:



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&dquo;~j,,:~&dquo;;~:~ ;~

infants also had lower serum T4 levels, similar T3 uptake values reflecting a high degree of’ saturation of thyroid hormone binding proteins, and significantly lower TBG levels. Serum CPK levels were lower in the preterm infants and TSH levels were not increased. In contrast, infants with primary hypothyroidism who were tested at a later age had extremely low serum T4 values, low Tg uptake values, elevations of TBG, high CPK levels and hundred-fold increases in’~’&dquo;5~. Detection of primary hypothyroidism in preterm as in term infants is best accomplished by assay of TSH in niter paper specimens which show a low T4 level. Sick preterm infants who have low initial T4 but normal TSM results should be retested with a repeat filter specimen for T4 and TSH at 4 to 8 weeks of age. Among those with persistently low T4 and normal TSH values, assay of serum TBG will distinguish between infants with: deficiency of TBG, who do-not require treatment, and infants, with pituitary or hypothalamic hypothyroidism who will benefit from treatment. Taking into account the possible adverse effects of hypcrthyroxi ne 111 ia the dinician is well-advised, to require additional evidence of hypothyroidism before beginning a hypothyroxinemic. preterm infant on thyroid hormone treatment.

ing the former and lowering the latter values. Mean FTI values for the six hypothyroid infants were identical by the two techniques. Primary congenital hypothyroidism proelevation of CPK and an even striking elevation of TSH. If the low free thyroxine estimates in sick preterm infants reflect a mild degree of primary hypothyroidism, then one would expect an increase in CPK and TSH levels in comparison to those of term infants. Serum CPK levels in the sick preterm infants were lower than in term infants and declined during the second postnatal week. No correlation was observed between CPK and serum T4 or birth weight in the preterm infants. Among the six hypothyroid infants, CPK levels were higher in the four who were beyond one month of age and had thyroid dysgenesis than in the two who had in the of iodme and .were before one month of age. Mean FP values were similar in the sick and healthy term infants ..and were not related to serum T~ levels. The mean serum TSH’ in the hypothyroid infants was. approximately tOO times the FP TSH levels in the other groups, duces








&dquo; .

~ .~



~ .

~p~~a~~.t~c~n ~~° filter paper :scr€ening.. tests’ for.. T~ to’ ::a group .of .sick..preterm infants showed that the majority had values which :


c,~~r~ ~more ~han, 2 ’.standard ~deviations be-&dquo; ~c~w t.h~ m~~n fcT an unsclected population ~~ infants’. tested.. in. -the,....first’:..week’; o.f 1i~’~,


: ..





1. Jacobsen BB, Andersen HJ, Peitersen B, DigePetersen H, Hummer L: Serum levels of thyrotropin, thyroxine and triiodothyronine in full-

~ ..Infants:,with’.iUn€sseso,the’r’than.’RDS:.:h~ v~I-


term, small-for-gestational age and preterm new-

born babies. Acta Paediatr Scand 66:681, 1977 2. Cuestas RA: Thyroid function in healthy premature infants. JPediatr 92:963, 1978 3. Dussault JH, Morisette J. Fiset P, Laberge E, Laberge conC:Factors influencing results for inthyroxine filter centration in blood, as measured paper spots in a screening program for neonatal hypo-

thyroidism. Clin Chem Acta 22:1392, 1976 MJ, Friedman Z. Murray F, Kulin H, Utiger R: Thyroid function studiesin preterm infants recovering from the respiratory distress syndrome.J Pediatr 92:968. 1978 5. Weischel ME, Jr: Thyroid hormone replacement 4. Uhrmann S, MarksKH,Maisels

&dquo;:.. m~~~~geMta! ~~~~tl-~y~~i~~~~~ ~~~~n ~~~a- ~( therapy in the perinatal period: neurologic considerations. J Pediatr 92:1035, 1978

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Hypothyroxinemia in sick and well preterm infants.

ENDOCRINOLOGY Hypothyroxinemia in Sick and Well Preterm Infants Frank B. Diamond, M.D.,* John S. Parks, M.D., Ph.D.,* Alfred Tenore, M.D.,* Jean M...
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