NEONATAL THYROTOXICOSIS

(1)

(Accepted Fel)rimary 1 1,1959; SumI)miiitte(1 1)ecemmiber 1, 1958.)

ADDRESS: (S.N.J.) 904 Medical Cemitre, 209 Jeppe Street, Johannesl)urg, South Africa.

65

PEDIATBmCS, Jumly 1959

NEONATAL

THYROTOXICOSIS

By S. N. Javett, M.D., B. Senior, M.D., J. 1. Braudo, M.D., and

Seymour Heymann, M.D.

W

HILE it is 1)0s5i1)le that minor (legrees

of hvperthroidism may be present in

infants born of mothers with thyroid

dis-ease, frank thvrotoxicosis in the newborn is

extremely rare. \Ve have seen reports of

only seven unequivocal cases’6 (Table I).

In each instance the mother ‘as suffering

or had suffered from thvrotoxicosis. This

paper describes two further cases of

neona-tal thvrotoxic exophthalmic goiter in infants

l)orn of mothers with exophtiialmos and

imia(ld(IuIat(’IVcolitrolled thvrotoxicosis. The

infants were gravely ill but responded

satis-factorily to treatrnemit.

Case

1 CASE

REPORTS

HIsToR : The mother was well until July’,

1952, at liich timne she complained of

tired-ness 111(1 palpitations. Physical exaniination

re-ealed tacliVcar(hia ,miioderate exophthalmos and

enlargenient of the throid. A diagnosis of

thvrotoxicosis as niade, and Lugol’s solution

Clhidl sedatiyes were pr(’scril)ed. Omi Decembem

:30, 1952, a therapeutic dose of radioactive

iodimie ‘as a(lmimiistered. However, 7 months

later she was still thvrotoxic, the uptake of

radioactive iodine in 24 hours 1)eimig 84%. A

further therapeutic dose of radioactive iocliiie ias gi’en. There as defimiite iml)rovememit ill

the clinical condition, but exophthalmiios

P-sisted. Shortl thereafter, she becanie pregnamit.

No further tests of basal miietabolic rate or

radioactive iodine iml)take vere performed

dur-ing the pregmiancv, bimt clinicall’ she remnained

thvrotoxic. After :36 weeks of pregnamicv, on

May’ 1, 1954, she was (lehivered of a male

in-fant weighing 2,180) gui. At birth the infant

cried vigoroumslv, and extrenie restlessmiess and

iivl)eractivitV were mioted. The doctor stated

that the imifamit aj)1)edme(l as excitable as its

iiiother had l)eemi (luring the active I)liase of

hem h\1)emth\roi(hismfl. 1)mmrimig the first 24 lioimrs

Fic. 1. Photograph showing edenia of eyelids on second day of life in infant vith neonatal

thyrotoxicosis (Case 1).

the child’s comiditiomi deteriorate(1 and he was first seen b one of us on the second (la\ of life.

PHYSICAL FINDINGS: The immfant was

cx-tremely cyamiosed, restless, jittery, undul alert. vith a coarse tremor of the hands, and was criticall ill. The respirator rate was 100 ‘miii, the ti1se rate regular amid umicoumntal)le at miiore

than 200,”miii. The temperature was :36.4#{176}C,

amid the ssstolic 1)lood presstmre in the right armii

90 mm Hg (flush method). \Iarked i)ilateral

exophthalmos vitli puffy eelids was 1)resent

(Fig. I

).

The head was slightl retracted. The

thyroid gland was ummiiformlv enlarged ,smiiooth, soft, non-tender, without I)rumit on auscultatiomi

(

Fig. 2). The cervical veins were not distended. There ‘as moderate suprastermial and subeostal

recession, but the entry of air imito both hugs

‘as norm’nal. The superficial veimis of the chest

vere l)romimiemit Chimiical examimiation of the

heart failed to reyeal enlargernemit. The heart

soummahs veme miornial. The inferior edges of liver

(2)

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ARTICLES

FIG. 2. Photograph showing goiter at age of 36 hours

(Case 1).

SpectRe costal margimis. The femoral pulses

were boundimig amid the skin moist, but the

feet and hands were cold and blue. Acute

thvrotoxicosis of the newborn was diagnosed.

LABORATORY FINDINGS : The concentration

of hemoglobimi was 21.6 gm/100 ml, the

ervthrocvte count 7,370,000/mm3 and the

leukocvte count 14,400/mm3 with 63.5%

neu-tropliils, 0.5% eosinophils, 1.5% monocytes and

31 .5% lymphocytes. The sedimentation rate

(

Wintrobe) was 0 mm in 1 hour. The

concen-tration of protein-bound iodine in the serum

was 17.5 pg/lOO ml (normal range from birth

to 3 days of age, 12 2.4 ug/100 ml7). The

concentration of cholesterol in the serum was

95 mg/100 ml and the alkaline pliosphatase

16.8 King-Armstrong units. Blood cultures were

sterile.

ELECTROCARDIOGRAPHIC AND

ROENTGENO-GRAPHIC FINDINGS: The electrocardiogram

showed a tachycardia of 240/mm, peaked P

waves in leads 2 and V-i and flat T wave in

lead 1 (Fig. 3). The tracing on the next day

showed a rate of 220/mm, upright T waves

and a suggestion of left ventricular strain.

Cardiomegaly was seen (Fig. 4) on the portable

roentgenogram made at a distance of 1.83 m

(6 ft.).

COURSE: The therapy comprised oxygen,

sedation with chioral hydrate, prophylactic

ad-ministratiomi of oxytetracycline, ami(1 an

intra-vi

i±±

I

7

wks.J

Fmc. 3. Electrocardiographic findings in Case 1. (a) 36 houmrs of age showimig tachycardia (240/nun),

(4)

Fic. 4. Roentgenograms of thorax in anteroposterior projection made with portable apparatus from 1.8.3 iii (6 ft), showimig (upper) gross cardiomegaly at 60 hours of age and (lower) normal

cardiac size at 5 weeks of age. venous infusion of 5% glucose in half isotonic

saline. Initially 2 minims of Lugol’s solution

was given intravenously and this was repeated

an hour later. Four hours later the pulse rate

had fallen to 180/mimi. Peripheral cyanosis and

tachypnea decreased, and the infant appeared

more restful. Tube feeding was commenced

48 hours after birth and 1 minim of Lugol’s

solution was given orally three times daily. Slow improvement was maintained with this therapy during the next few days and at the age of 6 days, the pulse rate stabilized at 140/

mm and the respiratory rate at 40/mm.

The baby was not unduly active at this stage

but had insatiable hunger. Administration of

(5)

ARTICLES

delivery’, amid improvememit continued with

de-crease in exophthalmos and disappearance of cyanosis.

However, despite taking his feeds well,

weight remained stationary. Six days after the

cessation of therapy, when 15 days old, the

protein-bound iodine had risen to 19.3 tg/100

ml, possibly because of the earlier administra-tion of iodine; however, this value is not out of

keeping with the clinical status since 1 week

later, at 22 days of age, there was deterioration

in his condition; exophthalmos became more

prominent and the goiter increased in size. He

was very tremulous and peripheral cyanosis

re-turned. The blood pressure was 120/60 mm Hg.

Oral administration of Lugol’s solution was

re-commenced, 1 minim every six hours. At the age

of 30 days he had improved slightly with some

gaimu in weight, but the pulse rate was still 160/ muuimu.Accordingly, 3 days later, propylthiouracil,

25 nig three times daily, was started and the

pulse rate decreased to 110/mm within 24

hours. He became lethargic and took 35

mm-utes instead of his usual 5 to 7 minutes to take

his feed. The medication was discontinued after

3 days, at which time the thyroid gland was

distinctly smaller and the exophthalmos less.

At 5 weeks of age, the size of the heart was

normal roentgenographically (Fig. 4). At 8

weeks of age, the weight was 3,830 gm, pulse

rate 130/mm, and the exophthalmos slight

(Fig. 5). Thyroid enlargement was minimal.

The concentration of protein-bound iodine had

now falleiu to 10.6 p.g/100 ml and the

electro-FIG. 5. Photograph at 8 weeks of age

demon-strating residual exophthalmos (Case 1).

cardiogram was nornual. At the age of 3 months

the weight was 5 kg, exophthalmos was no

longer present and the thyroid gland was not

palpable. The infant appeared perfectly normal.

The concentration of protein-bound iodine was

3.7 p.g/100 ml. The patient was last seen in

May, 1957, at the age of S years, and was

normal in all respects. Case 2

HISTORY: In 1946, when 23 years of age,

Mrs. W. developed exophthalmic

thyrotoxico-sis. Partial thyroidectomy was done in 1947.

She remained exophthalmic and mildly

thyro-toxic until 1950 when she became pregnant.

During the pregnancy the thyrotoxicosis in-creased and the exophthalmos became so

marked that diplopia and ophthalmoplegia

de-veloped. No antithyroid treatment was

pre-scribed. Fetal tachycardia was noted during

pregnancy. Labor was normal and she was

de-livered at term of a male infant weighing

2,840 gm, on November 17, 1950. Immediately

after birth rapid respirations and restlessness were noted. The infant was febrile and had a shrill cry.

PHYSICAL FINDINGS: He was first seen by

one of us when 40 hours of age on November 18,

1950. Physical examination revealed an acutely

ill baby with a temperature of 38.0#{176}C, pulse

rate 200/mm, and respiratory rate of 120/mm.

He was wide-eyed, anxious, over-alert and

tremulous. The face was cyanosed and the

eye-lids were edematous. Exophthalmos was

evi-dent. The heart sounds were booming and

there were no murmurs. The entry of air into

both lung fields was normal. The spleen was

enlarged to a point 2.5 cm below the left

costal margin. The liver was not palpable.

A goiter was not detected at this time. A

diagnosis of congenital thyrotoxicosis was

made.

COURSE: The therapy comprised antibiotics,

oxygen and Lugol’s solution orally, 1 minim

three times daily. He remained critically ill,

cyanosed and tachypneic. The temperature was

38.3#{176}C, pulse rate 180 to 200/mm, and

respira-tory rate 120/mm. The dosage of Lugol’s

solu-tion was increased to 1 minim every 3 hours.

On the fourth day of life the pulse rate had

decreased to between 160 and 180/mm.

How-ever, the exophthalmos and chemosis of the

eyelids increased and a goiter became obvious

(6)

palpable-amid a slight )itting edema of the legs was 1O)ted. Imitrayenoums imifimsioui of 5% glucose vas ulimiinistemec1 111(1 .1 miiimuiniof Luigol’s solution

‘as giveum intra’u’emmommslv evemv 3 hours. After

48 hours, the condition ‘as som’mievhiat

imil-1)rOved. The i)mmlse rate had decreased to 150/ mm and the respiratory’ rate to 90/mimi.

Cyano-sis was no longer present. The goiter was

smaller. The spleen was just palpable, but the

size of the liver was unchanged. The edema

of the legs had disappeared. Nevertheless,

be-cause of continued thvrotoxicosis,the dosage of

Lugol’s solution was imicreased to 1 minim

intravemiously every 2 hours. At the age of 8

days further improvement was evident. The

pulse rate was 120/mm and the respiratory

rate was 40, ‘mm. The weight was 2,930 gm,

90 gm more than the birth weight. Intravenous

therapy was discontinued and Lugol’s solution

1 minim three timnes dail was given orally.

At 12 days of age lie was gaining weight

steadil, though mild exophthalmos and goiter

were still noticeable. Therapy with Lugol’s

solution was discontinued On the twenty-sixth day of life. It took a further month, however,

before the exophthalmos and goiter subsided

completel’. When seemi at the age of 5 months

he was normal, amid has since remained so.

DISCUSSION

Both patients suffered from congenital

goiter with tliyrotoxicosis and

exophthal-mos. In Case 1, the mother developed

thy-rotoxicosis 21 months before the birth of

the infant. She was treated with two

cour-ses of radioactive iodine and there was

some clinical improvement. She then

be-came pregnant. Mild thyrotoxicosis and

se-vere exophtlualmos persisted throughout

pregnancy. The premature newborn infant

showed extreme restlessness and when seen

on the second clay of life was critically ill.

Tachypnea, marked tachycardia (more than

200/mm

),

bilateral exophthalmos and

goi-ter were present. Lugol’s solution was

administered intravenously initially, and

orally thereafter. The infant responded

dramatically. After cessation of

administra-tion of Lugol’s solution on the ninth day,

thyrotoxic symptoms recurred,

exophthal-mos increased, as did the size of the goiter.

Oral administration of Lugol’s solution was

reintroduced and at 5 weeks of age

propyl-tliiouracil was added. The infant became

very lethargic and all medication was

dis-continued after 3 days. He remained vell

thereafter. In all, the goiter persisted for 2

months and exophthalrnos for 3 months. In Case 2 the mother developed acute

thyrotoxic goiter and exophthalmos in 1946.

Despite subtotal thyroidectomy in 1947 she

remained exophthalmic and thyrotoxic

un-til 1950 when she became pregnant. The

thyrotoxic state was aggravated by

preg-nancy and the exophthalrnos increased

markedly. No antithyroid treatment was

given. Fetal tachycardia in utero was noted.

The infant, first seen by us when 40 hours of age, was acutely ill with a pulse rate of

200/mm. Exophthalmos was present but

only on the fourth day of life did the goiter

become visible and palpable. Oral and in-travenous administration of Lugol’s solution was begun and the response was most

satis-factory. Therapy with Lugol’s solution was

stopped on the twenty-sixth day of life and

the patient remained well. The

exophthal-mos and goiter took 2 months to subside.

These infants were desperately ill at

birth with a state resembling thyroid storm.

Intravenous and oral administration of

Lu-gol’s solution proved life-saving.

Medica-tion was required for 4 to 5 weeks, the pa-tients remaining well thereafter. It thus

ap-pears that this illness runs a self-limited

course. However, the patient may be

gravely ill or die during the acute phase

and, accordingly, prompt measures are

es-sential to preserve life.

In view of the uncertainty of the

patho-genesis of adult thyrotoxicosis, it is inter-esting to note how the current theories

ac-cord when applied to neonatal

thyrotoxico-sis. The two main concepts ascribe the

dis-ease either to a primary excess of thyroid

horrnone,8 or a secondary thyroidal

re-sponse to a pituitary thyrotropic hormone.

In each reported case of neonatal

thyrotoxi-cosisl-6 the mother had had thyrotoxicosis

during or before pregnancy. It is highly

probable that the disease in the infant is

(7)

Further-I

uuore, comi genital thyrotoxicosis . in turn, (0111(1 ariS(#{176}freon the I)lacental trauismiiission of one or other of these agents.

Maternal thyroid hormone is kmuown to

cross the placenta.9 It is possible that an

excessive amount is transmitted by the

thy-rotoxic mother and is responsible for the

symptoms in the infant. However, neither

exophthalmos nor goiter, which were

prom-inent features in all the reported cases of congenital thyrotoxicosis, can be produced in this fashion. Further evidence against

the sole causative role of maternal thyroid

hormone is provided by the therapeutic

effi-cacy of the Lugol’s iodine. Whatever the

exact mode of action of iodide, the

effec-tive result is decrease in the release of

hormone by the thyroid gland.1#{176}

Thus, the clinical response to Lugol’s

so-lotion in the patients described here dem-onstrates control of over-production of thy-roid hormone by the fetal thyroid. This

would suggest that the picture of

thyrotoxi-cosis in the infants resulted primarily from

overactivity of the infant’s thyroid gland.

The case described by Koerner3 is

illumi-nating. The mother, previously thyrotoxic,

became myxedematous after thyroidectomy and had marked residual exophthalmos. The newborn infant exhibited acute

thy-rotoxicosis with goiter and exophthalmos.

Here the quantities of thyroid hormone transmitted to the fetus would have been

less than normal. Thus, the evidence does

not favor the hypothesis that maternal thy-roid hormone is the main or sole agent

re-sponsible for neonatal thyrotoxicosis,

al-though it may play an as yet undetermined

role. The probability is that a

thyroid-stimulating agent derived from the mother’s

pituitary is the main responsible factor.

The literature reveals a variety of clinical

states in infants born of mothers with

thyroid disorders. During pregnancy the

mother may be untreated and have frank

thyrotoxicosis, may be thyrotoxic despite

treatment, or be euthyroidic or even

myx-edematous. The infant may be unaffected,

euthyroidic with goiter, thyrotoxic with

goi-ter and exophthalmos, or myxedematous.

The association of these fiuudings in the

iii-fant with those of the niother lwars further comusideratiomi. It \\‘Ohil(l &Lpl)(tI that SOfli(

relationship exists between the severity of

the disease in the mother and the outcome in the child. Furthermore, this outcome is

influenced by antithyroid medication em-ployed either before conception or during

pregnancy.

The

untreated

thyrotoxic

female

rarely conceives and if she does so, usually aborts. However, if she proceeds to term, a

thyro-toxic infant may be expected, as in the

clas-sic case reported by White,1 the infant

fail-ing to survive. This rule is not absolute, euthyroidic children having been born of thyrotoxic mothers. Presumably, the

thy-roid of the infant is less sensitive to the action of the thyroid-stimulating agent than is the thyroid of the mother.

Partial treatment of the mother before

conception with residual thyrotoxicosis may result in a thyrotoxic infant, as occurred in

the two cases reported here and in others in the literature.26 The maternal thyroid is

but partially suppressed and the circulat-ing thyroid-stimulating agent is present in excess. This is then transmitted to the in-fant and produces neonatal thyrotoxicosis.

In the case reported by Koerner3 the mother had been “over-treated” by thy-roidectomy before conception and was

myxedematous, though remaining markedly exophthalmic. The transpiacental passage of thyroid-stimulating agent unaccompa-nied by any antithyroid agent produced

severe hyperthyroidism in the infant.

If adequate antithyroid medication is given during pregnancy the infant is

usu-ally euthyroidic though on occasion a

goi-ter lasting 1 to 2 months has been present.1’ The antithyroid medication evidently suf-flees to prevent overactivity of both mater-nal and fetal thyroids. In other instances, the use of antithyroid medication in preg-nancy has been associated with the birth of infants who were either

hyperthy-24 (1 or hI13 It would

seem that the outcome in the infant is

(8)

transpla-cental stimulating agent acting on the fetal

thyroid, and time inhibitory agent given to

the mother concurremitly crossing the

phacen-tal harrier. Excessive muiaternah antithyroid medication could render the infant myx-edematous despite the action of the thy-rotropic ‘3 An interesting variant of congenital thyrotoxicosis is the delayed

appearance of symptoms when the mother

has been treated in pregnancy. Frisk and

J osefsson’

described such a case. A

se-verely thyrotoxic woman was given

meth-ylthiouracil during pregnancy. The

new-born infant was sluggish and lost an exces-sive amount of weight in the first month of life. In the second month thyrotoxicosis and exophthalmos developed, both later im-proving spontaneously. They suggested that the methylthiouracil inhibited the fetal

pi-tuitary gland. After birth the unhampered

pituitary produced thyrotoxicosis. An

al-ternative explanation is that both maternal thyrotropin and methylthiouracil were transmitted to the infant, the action of the former outlasting that of the latter.

Finally, some mention should be made of the part played by exophthalmos in this

unusual disease. In adults exophthalmos and thyrotoxicosis may be present singly or together. Similarly in the congenital

dis-ease, exophthalmos may be present alone.15

This would conform with experimental evi-dence that the pituitary elaborates both a thyroid-stimulating, and an exophthalmic agent, either of which may pass through the placenta.’6

SUMMARY

Two cases of congenital goiter with se-vere thyrotoxicosis are described. In one instance, unusual tachycardia was noted

in utero. The mothers, treated before con-ception with radioactive iodine and

thyroi-dectomy, respectively, were, at the time of

delivery, not only thyrotoxic, but markedly

exophthalmic.

Treatment of the infants with Lugol’s solution intravenously and orally, with the addition of propylthiouracil in one case,

re-suIted in a return to normal after a fev

weeks.

Appraisal of the pathogenesis of

mieona-tal thyrotoxicosis favors the transplacental passage of a thyroid-stimulating agent,

probably derived from the mother’s

pitui-tary.

The thyroid status of neonates born of mothers taking medication for

thyrotoxico-sis reflects the interaction between the

transmitted thyroid-stimulating agent and the particular drug being employed.

REFERENCES

1. White, C. : A foetus with congenital heredi-tary Crave’s disease.

J.

Obst. & Cynaec. Brit. Emp., 21:231, 1912.

2. Fischer, P. M. S. : Hyperthyroidism in the

first year of life; report of a case

oc-curring in the neonatal period. South

African M.

J.,

25:217, 1951.

3. Koerner, K. A. : Congenital goiter with

exophthalmos and hyperthyroidism.

J.

Pediat., 45:464, 1954.

4.

Bongiovanni, A. M., Eberlein, W. Thomas, P.

Z.,

and Anderson, W. B.: Sporadic goiter of the newborn.

J.

Clin. Endocrinol., 16:146, 1956.

5. Lewis, I. C., and MacCregor, A. C. :

Con-genital hyperthyroidism. Lancet, 1:14,

1957.

6. Riley, I. D., and Sclare, C. : Thyroid dis-orders in the newborn. Brit. M.

J.,

1:

979, 1957.

7. Danowski, T. S., et al.: Protein-bound iodine in infants. PEDIATRICS, 7:240,

1951.

8. Werner, S. C., Spooner, M., and Hamilton,

H. : Further evidence that

hyperthyroid-ism (Crave’s disease) is not

hyper-pituitarism : effects of tri-iodothyronine and sodium iodide.

J.

Chin. Endocrinol., 15:715, 1955.

9. Crumbach, M. M., amid Werner, S. C.: Transfer of thyroid hormone across the human placenta at term.

J.

Chin. En-docrinol., 16:1392, 1956.

10. Goldsmith, R. E., and Eisele, M. L. : The effect of iodide on the release of thyroid hormone in hyperthyroidism.

J.

Clin. Endocrinol., 16: 130, 1956.

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12. Elphinstone, N. : Thiouracil imi pregmiancv.

Its effect upomu the foetus. Lancet, 1:

1281, 1953.

13. Morris, D. : Tramusient hypothyroidism in a

newborn infant. Lancet, 1:1284, 1953.

14. Frisk, A. R., amid Josefsson, E.:

Thyro-toxicosis in a newborn, one month

post-partum. Acta med. scandinav., Suppl.,

196:85, 1947.

15. Keynes, C. : Obstetrics and gynaecolog imu relation to thyrotoxicosis and myasthenia gravis.

J.

Obst. & Cynaec. Brit. Emp.,

59:173, 1952.

16. Dobyns, B. M., and Steelman, S. L. : The

thyroid-stimulating hormone of the

an-tenor pituitary as distinct from the

exophthalmos-producing substance.

En-docrinology, 52:704, 1953.

KEmlNIcTRuius IN RATS WITH AN INHERITED DEFICIENCY OF CLUCURONYAL

TRANSFERASE, Lois Johnson et a!. (A.M.A.

J.

Dis. Child., 97:591, May, 1959.)

Aside from the great theoretic interest, the experiments described in this

paper have considerable practical importamuce in providing a means of study-ing the efficacy of treatments designed to prevent kernicterus. A comprehensive

stud of a strain of rats (the Gunn strain) which have a hereditary deficiency

of the emizme required to conjugate bilirubin, and thus develope jaundice due

to increased concentratiomi of unconjugated bihirubin in the blood and tissues.

The rats developed kernicterus which was apparently identical with that seen

hi human beings and is the only example of kernictertms in animals that fulfills rigid criteria outlined by the authors. Extensive data on the natural history of

the bihirubinemia and development of kernicterus in the rats, as determined by’

chemical and pathologic techniques, are provided. Bilimubin itself is

incrimi-miated as the toxic agent producing the characteristic changes in the brain in

kemnicterus. Sulfonamides were found to augment the toxic effects of bihirubimi,

apparently because of competition between bihirubin and sulfonamides for

binding sites on serum albumin. Neither infection nor hypoxia appeared to

aggravate the effects of bihimubin.

Admimuistration of sodium glucuronate to jaundiced rats was followed by a

decrease iii bilirubin in the serum which at times exceeded 50%. This was not

accompanied b’ amuv postponement of the onset of signs of damage to the

cen-tral nervous system and did not prevent development of kernicterus. It

ap-peared that the decrease in bilirubin in the serum may have resulted from an

increased transferral to tissues rather than elimination through renal excretion.

On the basis of the kmuowledge of this strain of rats, it should be possible to

explore the usefulmiess of proposed therapeutic regimens in the experimental

animal without jeopardizimug the course of human infants who might be

sue-cessfully treated with exchange transfusion pending the discovery of a more

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1959;24;65

Pediatrics

S. N. Javett, B. Senior, J. L. Braudo and Seymour Heymann