(Received April 9; revision accepted for publication May 24, 1969.)
This research was supported by U.S. Public Health Service Grant (AM 12475) from the National
In-stitute of Arthritis and Metabolic Disease.
ADDRESS FOR REPRINTS: (D.A.F.) Harbor General Hospital, 1000 West Carson Street, Torrance,
Cali-fornia 90509.
PEDIATRICS, Vol. 44, No. 4, October 1969 526
THYROID
FUNCTION
IN
THE
TERM
FETUS
D. A. Fisher, M.D., W. D. Odell, M.D., Ph.D., C. J. Hobel, M.D.,
and R. Garza, B.S.
The Departmentx of Pediatrics, Medicine, and Obstetrics and Gynecology, Harbor General Hospital, Torrance, California, and the University of California Los Angeles, School of Medicine
ABSTRACT. Measurements of serum total
thyrox-ine, free thyroxine (FT4) and/or immunoreactive thyrotropin (TSH) concentrations were conducted on 21 pairs of maternal and cord blood specimens obtained at the time of normal vaginal or cesarean
section delivery. Thyroxine concentrations were
limilar in maternal and cord blood. FT, and TSH
concentrations were significantly higher in cord blood samples obtained from infants delivered
va-ginally or by cesarean section. Serum TSH
concen-trations also were measured in 11 paired maternal and fetal scalp blood specimens obtained during
labor 9 to 177 minutes prior to deliver; fetal scalp
blood TSH concentrations exceeded maternal
values in all instances. The higher TSH
concentra-tions in cord blood were not due to cross reaction
with HCG in the radioimmunoassay procedure; the
gradient of HCG was opposite to that of TSH. It
is also unlikely that the higher TSH concentrations
were due to placental thyroid stimulating factor,
since this material cross reacts poorly with the
TSH antiserum used in the present studies. It is
concluded that the gradient of free thyroxine in
the human fetus at term is fetal-maternal and that
this gradient is probably attributable to a higher
fetal serum TSH concentration. Pediatrics, 44:526,
1969, NEWBORN INFANTS, THYROID FUNCTION,
THY-ROID HORMONE, TSH, HCG, FREE THYROXINE.
T
HYROID FUNCTION ifl the term fetus hasnot been clearly defined. Total serum
thyroxine
(
T4)
concentrations appear toincrease rapidly near term; values in cord
blood of newborn premature infants have
been shown to increase progressively witil
birth weight and gestational age.1 This
near-term increase in total T4 concentration
occurs without significant increase in
T4-binding globulin or T4-binding pre-albumin
concentrations so that a progressive
satura-tion of these binding proteins must occur.1
This increasing saturation might be due to
increased placental transfer of maternal
hormone near term23 or to a progressive
increase in fetal thyroxine secretion. Fetal
thyroid radioiodine uptake also increases
during the last half of gestation in monkeys
and man;4#{176} this observation supports the concept of increasing fetal thyroid function.
However, the direction and extent of net
placental thyroid hormone transfer near
term and the relative maternal and fetal
contributions to total fetal thyroid hormone
needs are not known. Previous investigators
have not identified a gradient of free
thy-roxine in maternal and cord blood.7’
Earlier reports of human thyrotropin
(
TSH)
concentrations in maternal and cordblood have been conflicting; both
maternal-fetal#{176} and fetalmaternalb0 concentration gradients, and identical maternal and fetal
concentrations have been reported. The
present studies were undertaken to clarify trans-placental gradients of T4, free T,, and
TSH concentrations at term using recently
developed, sensitive methods for
measure-ment of these parameters of thyroid
function.
METHODS AND PROCEDURE
Serum T4 concentrations were measured
by the method of Murphy and Pattee12 as
recently modified.13 Free T4 concentrations
were measured, using a modification of the
method of Sterling and Brenner.14 All T4
1125 was pre-dialyzed as suggested by
1:10 for assay; percent dialyzable T4 J125
was corrected for dilution, using a
correc-lion factor derived by comparing
measure-ments of replicate diluted and undiluted
aliquots of a single pooled serum. Human
chorionic gonadotropin (HCG
)
concentra-tions were measured using the double
anti-body radioimmunoassay procedure of Odell
and coworkers.161I All T4 and HCG
samples presently reported were run in
duplicate in single assays; all free thyroxine
determinations were run on a single day,
using the same reagents but separate
dialy-sis chambers. Coefficient of variation for
each of these three assays was less than 5%.
TSH was assayed by the procedure of
Odell, et al.’9 Extensive correlative studies
with the antiserum presently employed
have shown good agreement between
bioassay and immunoassay results over a
wide range of TSH potencies; details have
been previously published.19 The intra-as-say coefficient of variation of this assay was 2.5; inter-assay coefficient of variation was 22.
Blood samples were obtained at the time
of vaginal delivery from 13 pregnant
women
(
Group 1)
and their full-term,new-born infants for measurements of total T4,
free T4, and TSH concentrations. HCG
concentrations were measured in 11 of the
paired samples. All women were
multip-arous and had experienced an uneventful
pregnancy and labor. Analgesia was
mini-mal and all deliveries were conducted using
regional (pudendal) anesthesia. On
occa-sion, supplemental nitrous oxide-oxygen
inhalent anesthesia was employed during
delivery. The newborn infants weighed
2,450 to 4,800 gm; mean weight was 3,350
gm.
Maternal and cord blood specimens for
measurements of total T4, free T4, and/or
TSH also were obtained from eight
preg-nant women (Group 2) at the time of
elective cesarean section. Cord blood
speci-mens were obtained before the infant was
removed from the uterus to avoid
environ-mental exposure. These infants also were
products of uneventful term pregnancies
of multiparous mothers. Birth weights were
2,540 to 3,900 gm; the mean weight was
3,140 gm.
Finally, 11 paired maternal and fetal
scalp blood specimens were obtained 9 to
177 nlrnutes before delivery from seven
pregnant women
(
Group 3)
to assess theeffect of labor on serum TSH
concentra-tions. Fetal scalp blood was obtained in 12
in. heparinized capillary tubes with the aid
of specially designed vaginal specula;
ap-proximately 1.5 ml samples were obtained.
A summary of the studies conducted on
the paired sanlples from each group of
sub-jects is shown in Table I. All studies were
conducted with the informed, written
con-sent and the cooperation of the mother.
RESULTS
Table II summarizes T4, free T4, and
TSH concentration data in the 17 paired
maternal-cord blood sera from the Group 1
and Group 2 subjects. Serum T4
concen-trations were similar in maternal and cord
blood (mean values 11.5 and 11.2 g/100
ml, respectively, p > 0.5). Free T4 (mean
2.3 and 2.9 mg/ 100 ml in maternal and
cord blood, respectively, p < 0.01
)
andTSH concentrations (mean 4.3 and 8.9
‘tU/ml in maternal and cord blood,
re-spectively, p < 0.01
)
were higher in cordblood than in maternal blood. These data
are displayed graphically in Figure 1.
Figure 2 shows the results of TSH
measurements in the 11 paired fetal scalp
and maternal blood specimens obtained
TABLE I
SUMMARY OF STUDIES CONDUCTED ON THE PAIRED SI’ECIMENS FROM EAch Giioue OF SUBJECTS
Number of Paired .\umber of Paired
Group .5 umber of Jfalernal-Fehzl Samples Assayed for
iiomen Sam pies T, Free TSH ll(’G
Maternal Serum Cord Blood Serum
.
Subjects 1’4
(.g/1OO ,,ml)
Free T4 TSII
(MU/ml)
T4
Cug/100 nil)
Free 7’
-(%) (rnpg/ltX.l ml)
TSH (j.sU/nml)
---(%) (mn.og/1OO ml)
She 13.0 0.014 2.5 4.0 9.4 0.027 .5 8.9
Ces 8.8 0.019 1.7 3.3 10.0 0.029 2.9 3.3
4f(( 11.4 0.019 5.0 11.8 0.027 3.2 7.0
Sd 11.0 0.018 .0 4.5 9.4 0.032 3.0 liZ.Q
I)eC 10.4 0.022 2.3
-
10.4 0.024 2.5-Wel 14.l 0.018 2.5 8.7 13.2 O.04 3.2 16.0
Wrl* 8.6 0.02 1.9 4.5 10.0 0.09 2.9 7.2
Por* 15.4 0.0’’2 3.4 5.0 ! 1’2.0 0.03’Z 3.8 6.7
Pow* 1’2.0 0.0l0 L4 4.7 10.4 0.032 3.3 5.7
lies 1’2.0 0.OiZO 2.4 3.0 10.4 0.04 il.5 13.()
Mil 5.4 0.017 0.9 .7 13.2 0.022 .9 8.4
Asc 1’2.4 0.0 2.7 3.3 H.0 0.0l6 3.1 8.3
McK 1l.0 0.019 2.3 4.0 7. 0.O’21) .1 .5
Mon 11.6 0.Q27 3.1 2.5 12.0 0.022 2.6 14.3
ltat* 11.4 0.019 3.5 13.6 0.04 3.3 11.0
Con 13.8 0.014 1.9 3.0 13.8 0.0’24 3.3 9.6
Ann 11.6 0.019 2 6.9 12.0 0.022 2.6 9.iZ
Mean
SEM
11.5
0.56
0.019
0.001
.3
0.13
4.3 11.il 0.0l6
0.40 0.43 0.001
‘2.9
0.10
8.9
0.93
TABLE II
‘I’hIYuoxINE, FREE THYROXINE, AND TSH CONCENTRATIONS IN 17 PAIRS OF MATERNAL AND CORD BLOOD SERA
* (esarean section infants.
from tile seven subjects in Group 3 during
labor and in the eight paired specimens
obtained from Group 2 subjects during
elective cesarean section. Scalp blood TSH
concentrations consistently exceeded
ma-ternal blood values during the 3 hours of
labor immediately preceding delivery. Fetal
cord blood TSH obtained at the time of
cesarean section
(
before the infant wasexposed to the extra-uterine environment)
also exceeded maternal values. Mean and
SEM fetal and maternal TSH values during
normal vaginal delivery were 9.1 ± 1.0 and
3.3 ± 0.28 ,.U/ml, respectively
(
p < 0.01).During cesarean section delivery, the
values were 7.5 ± 1.2 and 3.9 ± 0.32 tU/
ml in fetal and maternal blood,
respec-lively
(
p
< 0.01)
. In four of the eight fetalblood specimens obtained at the time of
cesarean section, free T4 also was measured
(
Table II)
; all values exceeded the pairedmaternal concentrations. HCG
concentra-lions were measured in 11 of the 17 paired
maternal cord blood samples
(
Table III);mean maternal concentration was 31,000
mIU/ml (31 U/mi), and mean cord blood
concentration was 480 mIU/ml (0.48 U/ml).
DISCUSSION
In the present study, total T4
concentra-tions were similar in maternal and cord
blood
(
Table II)
. This observation is inagreement with some1’2028 and in
disagree-ment with other5,7,8,u931 studies employing
the PBI or BEI techniques. The
explana-tion for these discrepancies is not clear. All
of these publications have reported similar
serum hormonal iodine concentrations for
maternal blood. The cord blood levels,
however, have been variable, ranging from
80 to 100% of the maternal values. The PBI
concentration has been observed to vary
with birth 8 so that the mean cord
blood concentration would tend to be lower
than the maternal concentration if the
TABLE Ill
hUMAN Cisoruoxic GONADOTROPIN CONCENTRATION IN 11 PAIRS OF MATERNAL AND CORD BLOOD SERA
Subjects
MsC Se!
\VaI Por Pow
Des
Mu
Asc Rat
Con Cha
Maternal Serum
!ICG (‘ii lU/mi)
1,83()
53,770
1’,26()
14,7()
16,040
105,660
21 700
15,100
45 ,28()
26,420
17,000
Cord Blood Scm in
JICG (mimiC/mi)
380
550 .570
4i0
380
660
6iW
666
4i0 380 380
Mean SEM
31000
8,540
480
30
E
3
I
Cl)
I-nulllber of smaller infants. Variation in fetal
PBI concentration also may depend upon
nlaternal nutritional and socioeconomic fac-tors, which may vary in the study samples.
Dialyzable T4 was assessed in the present
study using the magnesium precipitation
method.14 Results using this technique are
lower32 than results using the TCA
pre-cipitation method8’ 33 or the gel filtration
technique.7 Relative values and population
sample comparisons are valid with any of
these methods. The present results, in
agreement with earlier reports,7 S showed
that the proportion of dialyzable T4 was
significantly higher in the cord blood
samples tilan in maternal blood (Table II).
This is largely explained by the lower
T4-binding globulin concentration in cord
blood as contrasted with maternal blood;
T4-binding pre-albumin concentrations may
also be losver in cord blood than in
ma-ternal blood,1’ S further contributing to the
relatively higiler proportion of dialyzable T4.
Tile mean free T4 concentration also was
higher in cord blood than in maternal blood
(Table II) in agreement with the results
of Robbins and Nelson.23 This result is in
disagreement, however, with data of Marks
and colleagues7 and DeNayer, et al.
be-cause of the relatively higher mean cord
serum T.1 concentration in the present study
sample. Free T4 concentrations in cord blood
E
0
0
Lii
Li
U-MEAN ±SEM
FIG. 1. Serum TSH and free thyroxine concentrations in paired maternal and cord blood specimens. TSH
concentrations (sU/ml) are plotted on the left; free thyroxine (T4), in mbtg/100 ml, is plotted on the right. The lines connect the paired maternal and cord blood values. Mean maternal and cord blood
serum TSH concentrations were 4.3 and 8.9 tU/ml, respectively; mean free thyroxine concentrations
15
E
10
Cl)
I-5
MATERNAL-FETAL SCALP PAIRS CAESAREAN
SECTION PAIRS
x FETAL
#{149}MATERNAL
1
x
I
X
I
I!
x
XXXI
i,--150 -120 -90 -60 -30 BIRTH
TIME IN MINUTES BEFORE DELIVERY OF INFANT
FIG. 2. Serum TSH concentrations in paired maternal and fetal blood
speci-mens obtained at the time of cesarean section delivery or during labor. The
fetal blood during labor svas obtained from fetal scalp samples 9 to 177
minutes prior to delivery. Fetal blood at the time of cesarean section svas
obtained from the umbilical vein before the infant was removed from the
uterus. Fetal blood TSH concentrations (in tU/ml) exceeded maternal
values b’ 2 tU/ml or more in 13 of the 19 paired samples and 1 to 2
ttU/ml in six instances.
of infants delivered by cesarean section
were higher than concentrations in the
paired maternal specimens
(
Table II)
,sug-gesting that the process of vaginal delivery
does not alter this parameter of thyroid
function. The present data would therefore
support the earlier suggestion by Robbins
and Nelson23 that a fetal-maternal gradient
of thyroxine exists across the placenta at
term.
Cord blood TSH concentrations also
con-sistently exceeded maternal values
(
TableII and Fig. 2
)
. This observation is inagree-ment with that of Utiger and co-svorkers,1#{176}
who employed a radioimmunoassay
tech-nique. It is not in agreement with previous
studies employing bioassay techniques.
Using the in vitro tissue culture bioassay of
Bottari, Costa, et al.#{176}observed that
mater-nal serum TSH values at term exceeded
cord blood levels about sixfold. These
re-sults may relate to circulating human
cho-rionic thyrotropin (HCT) in maternal
blood.34 However, data obtained using the
McKenzie bioassay technique reveal much
lower and similar TSH concentrations1’ in
maternal and cord blood. The lesser
preci-sion and sensitivity of the bioassay as
con-trasted with the radioimmunoassay and! or
detection of HCT in the bioassay and not
tile radioimmunoassay presunlably accOullts
for the failure of Yamazaki, et al.1’ and
Costa, et al.9 to detect the fetal-maternal
TSH gradient reported herein.
The process of labor was not observed to
alter either maternal or fetal serum TSH
concentrations; maternal levels did not
change
(
Fig. 2) during labor. Fetal TSHconcentrations exceeded maternal
concen-trations approximately twofold, whether
measured in cord blood
(
Fig. 1),
in fetal scalp blood samples during labor(
Fig. 2),or in cord blood at the time of cesarean
section
(
Fig. 2) . Thus, the TSHconcentra-tion in cord blood would appear to be a
valid estimate of the serum TSH concentra-tion of the term fetus.
The higher TSH concentration observed
in cord blood, relative to maternal blood, is
not due to cross reaction between HCG and
the TSH antiserum in the
radioimnlu-noassay for TSH. Excess HCG (30 IU) was
added to each tube in the
radioimmu-noassay and, since the dose response curve
for HCG was relatively flat,3 a doubling of
00
90
>. eo
0
40
\HCTSF
30
20
I0
0.1 I 2 I0
MILLIMICROGRAMS
000
lU/tube) produced only a 2% decrease in
percent counts bound (precipitated).
Moreover, the HCG concentrations were 60
times higher in cord blood than in maternal
blood
(
Table III).
Therefore, any crossre-action by HCG would result in
underesti-mation of the maternal-cord blood TSH
dif-ference. LH cross reacts in the absorbed
assay system employed for the present
stud-ies’’ only to the extent of its contamination with TSH as determined by bioassay.’#{176}’3’
In 1963, Odell, et al.36 identified by
bioassay a TSH-like material in some
pa-tients with trophoblastic neoplasms derived
from the placenta. This material behaved
like pituitary TSH in extraction techniques
and was found to be elevated in plasma
from patients harboring these neopiasms. It
was also extracted and concentrated from
the tumor tissue. Later, Odell, et al.’
showed that such patients did not have
ele-vated TSH concentrations by
radioimmu-noassay, suggesting that this TSH-like
material (although biologically active)
lacked immunoreactivity in the human TSH
assay. In 1965, Hennen11 identified a
TSH-like material in extracts of normal placenta.
Subsequently, Hennen, et purified this
material by the same techniques used for
pituitary TSH and reported that highly
purified human chorionic thyrotropin
(
HCT) had a potency equivalent to about0.5 IU of TSH per nlilligram. Serum from
pregnant women also was shown to contain
increased TSH activity by bioassay. The
ac-tivity was highest early in pregnancy and
fell progressively towards term, although at
term TSH activity by bioassay was higher
than in nonpregnant women.34 Presumably,
this biologically active material in serum
from pregnant women is HCT. Through the
courtesy of Drs. Hennen and Pierce, we
have found that highly purified HCT reacts
in our human TSH inlnlunoassay, and the
dose response curve is parallel to that
pro-duced by human TSH. However, 2,000
times more HCT (by weight) is required
to produce the same response as a given
weight of human pituitary TSH (Fig. 3).
Thus, if HCT were secreted in sufficiently
0
0
>
0
II
10,000
FIG. 3. Cross reaction between human chorionic thyroid stimulating factor
(HCTSF-hurnan chorionic thyrotropin) and antiserum against human
pitui-tary TSH (HTSH). The left curve was obtained using purified human
pitui-tary TSH (International Reference preparation provided by the World
Health Organization). The curve on the right shows the reaction of Hennen
and Pierce HCTSF and the same antiserum. The curves are parallel, but
about 2,000 times more HCTSH is required than HTSH to produce
large quantities, it might be detectable by
cross reaction with human TSH antiserum.
Since maternal serun appears to contain
relatively high concentrations of HCT which
reacts poorly with human TSH antisera, it
is likely tilat the gradient of HCT, like
HCG and HPL, is maternal-fetal. Cord
blood, bs’ contrast, contains more
immuno-reactive TSH, presumably of pituitary
on-gin.
SPECULATIONS
The studies Ilerein reported support the
suggestion made by Robbins and Nelson
in 195823 that free T4 concentrations in
new-born cord blood at the time of birth are
lligher tilan maternal values. They also
support the observation of Utiger and
u#{176} that TSH concentrations are
higher in nesvbonn than in maternal blood.
Neither result can I)e attributed to the
process of labor and delivery and would
suggest that blood FT, and TSH
concentra-tions in the fetus near term exceed
ma-ternal levels. This would indicate that the
fetal llvpothalamic-pituitary-thyroid unit is
functioning independently of the maternal
system to supply all or nearly all of the
fetal thyroid hormone requirements and
tilat an’ Ilet Placental T, transfer must be
fetal to maternal. One might postulate
several reasolls to explain tile fact that the
fetal pituitary-thyroid system is more active
than tile maternal:
1. Fetal thyroid Ilormone requirements
are greater tilan those of the mother. 2. TIle Ilypothalanhic-pituitary control
nlechanism is ilot flOrnlally responsive
(suppressible) to circulating T4.
3. Some inhibitor of fetal thyroid
hor-mone feedback action exists.
4. All abnornlal stimulator of
hypotha-lanlic-pituitary TSH secretion is operative during gestation.
5. Placental HCT may be secreted in
sufficiently large quantities to stimulate
fetal thyroid function and cross react in the
TSH radioimmunoassav.
The metabolic clearance of T4 and
thy-roid hormone secretion during early infancy
are known to be Iligh, relative to the
adult,3#{176}’#{176} suggesting that postulate No. 1
may be true. The hypothalamic-pituitary
system is sensitive to T4 by 3 to 5 days of
postnatal life41’ 42 and is responsive to T4
deficiency as early as 5 months of
gesta-II suggesting that postulate No. 2 may
not be true. No evidence for or against
postulate No. 3 exists. Estrogen may act as
a pituitary-thyroid stimulator in the fetus
(
postulate No. 4)
; estradiol benzoate hasbeen shown to augment TSH secretion in
newborn infants.39 This stimulus has been
said to act at a pituitary level, for estrogen
augments TSH secretion in ovariectomized
rats with median eminence lesions.44
Finally, thyroid stimulation by placental
HCT
(
postulate No. 5)
may occur duringgestation, but in this case one would expect
stimulation of maternal as well as fetal
thyroid hormone secretion, since
concen-trations of other chorionic hormones
(
HCGand HPL
)
are much higiler in maternalthan in fetal blood
(
Table II)
;45 no increasein maternal T4 secretion has been
docu-mented during pregnancy,1#{176} but thyroid
stimulating activity probably attributable
to HCT is increased in maternal serum;
levels are highest during the first trimester
and decrease toward term.34 No
informa-tion regarding HCT activity in fetal or
new-born blood is available.
In sumnlary, it would seem that fetal
hy-pothalamic-pituitary control of thyroid
function is operative early in gestation. This
control system, at least near term, functions
to maintain a hyperthyrotropinemia and
hy-perthyroxinenlia which probably reflect a
high fetal requirement for thyroid hormone
action. Estrogen may augment fetal TSH
secretion.
SUMMARY
Total thyroxine, free thyroxine, and TSH
concentrations were studied in 17 pairs of
maternal and umbilical cord blood samples
collected during 13 vaginal and 4 cesarean
section deliveries. Mean total thyroxine
levels were similar (11.5 versus 11.2 ig/
thyroxine
(
0.019 and 0.026 mtg/ 100 ml, respectively, p < 0.01)
and TSHconcen-trations
(
4.3 and 8.9 U/ml, respectively,p < 0.01
)
were higher in the cord bloodsamples. TSH also was measured in a total
of eight cord blood samples obtained at the
time of cesarean section, before the infants
were removed from the uterus, and in 11
fetal scalp blood specimens obtained from
seven women 9 to 177 minutes prior to
delivery. These were compared with paired
maternal specimens to assess whether
fac-tors related to labor and delivery might be
influencing TSH release. The mean fetal
serum TSH concentrations exceeded
ma-ternal levels in each instance.
The high serum TSH concentration,
rela-tive to maternal leves, was not due to cross
reaction between HCG and the TSH
anti-serum ill the radioimmunoassay procedure;
excess HCG was added during the assay. In
addition, the transplacental gradient of
HCG was reversed relative to that for TSH;
maternal serum HCG concentrations
ex-ceeded cord blood levels sixtyfold, whereas
cord blood TSH concentrations exceeded
maternal levels twofold. Cross reaction
with human chorionic thyrotropin
(
HCT)also was unlikely. Altilough HCT cross
reacted with the TSH antiserum, 2,000
times as much material, on a weight basis,
was required to produce an immunoassay
reaction comparable to that of purified
hu-man pituitary TSH.
These data indicate that serum TSH and
free thyroxine concentrations in the term
fetus exceed maternal levels. Neither
mea-surement is influenced by the events of
labor and delivery. These fetal-maternal
gradients of free thyroxine and TSH
sup-port the concept of a fetal
hypothalamic-pi-tuitary-thyroid control system functioning
independently of the maternal system.
Fur-thermore, all of the thyroid hormone
re-quired by the normal term fetus is probably
derived from his own thyroidal secretion.
REFERENCES
1. Perry, R. E., Hodgman, J. E., and Starr, P.:
Maternal, cord and serial venous blood
pro-tein bound iodine, thyroid binding globulin,
thyroid-binding albumin and pre-albuniin
values in preniature infants. PEDI.ATIuCs,
35:759, 1965.
2. Fisher, D. A., Lehman, II., and I.akev, C.:
Placental transport of tl3 roxine. J. Clin. En-doer., 24:393, 1964.
3. Schultz, NI. A., Forsander, J. B., Chez, R. A.,
and Hutchinson, D. L. : The bidirectional
placental transfer of :3, 5, 3’ triiodothvronine in the rhesus monkey. PEDIATRICs, 35:743,
1965.
4. Pickering, D. E., and Kontaxis, N. E. : TllvrOi(l
function in the fetus of the niacque monkey
(macaca niulatta) II. Chemical and
mor-phological characteristics of the fetal thyroid
gland. J. Endocr., 23:267, 1961.
5. Chapman, E. NI., Corner, G. W. Jr.,
Robin-son, D., and Evans, R. D. : Collection of
ra-dioactive iodine by the human fetal thyroid. J. Clin. Endocr., 8:717, 1948.
6. Hodges, R. E., Evans, T. C., Bradburv, J. T., and Keetel, \V. C. : The accumulation of ra-dioactive iodine by human fetal thvroi(ls. j. Gun. Endocr., 15:661, 1955.
7. Marks, J. F., Hamlin, M., and Zack, P.:
Neo-natal thyroid function. II. Free thyroxine in
infancy. J. Pediat., 68:559, 1966.
8. DeNayer, P. II., Malvaux, P., Van Den
Schrieck, H. G., Beckers, C.. and De
Visscher, Ni. : Free thyroxine in niaternal
and cord blood. J. Clin. Endocr., 26:233,
1966.
9. Costa, A., Cottino, F., Dellepiane, M., Ferraris, G. M., Lenart, L., Magro, G., Patrito, G.,
and Zoppetti, C. : Thyroid function and
thy-rotropin activity in mother and fetus. In
Cassano, C., and Andreoli, M., ed. : Current
Topics in Hormone Research. New York:
Academic Press, pp. 73-748, 1965.
10. Utiger, R. D., \Vilber, J. F., Cornhlath, NI., Harm, J. P., and Mack, R. E. : TSH
secre-tion in newborn infants and children.
(Abst.), J. Clin. Invest., 47:97a, 1968. 11. Yamazaki, E., Noguchi, A., and Slingerland,
D. W. : Thvrotropin in the serum of mother
and fetus. J. Clin. Endocr., 21:1013, 1961.
12. Murphy, B. E. P., and Pattee, C. J.: Determi-nation of thyroxine utilizing the property of
protein-binding. J. Clin. Endocr., 24:187,
1965.
13. Murphy, B. E. P., and Jachan, C.: The
deter-mination of thyroxine by competitive
pro-tein-binding analysis employing an
anion-ex-change resin and radiothyroxine. J. Lab. Clin. Med., 66: 161, 1965.
14. Sterling, K., and Brenner, NI. A.: Free
thyrox-ine in human serum; simplified measurement
with the aid of magnesium precipitation. J.
15. Schussler, C. C., and Plager, J. E. : Effect of preliminary purification of 1311 thyroxine on the determination of free thyroxine in
serum. J. Clin. Endocr., 27:242, 1967.
16. Paul, W., and Odell, W. D. : Radiation macti-vation of immunological and biological
ac-tivities of human chorionic gonadotropin.
Nature, 203:979, 1964.
17. Odell, W. D., Ross, C. T., and Rayford, P. L.: Radioimmunoassay of human luteinizing hormone: physiological studies. J. Clin.
In-vest., 46:248, 1967.
18. Odell, W. D., Hertz, R., Lipsett, M. B., Ross,
C. T., and Hammond, C. B. : Endocrine as-pects of trophoblastic neoplasms. Clin. Oh-stet. Gynec., 10:290, 1967.
19. Odell, W. D., Vanslager, L., and Bates, R. W.:
Radioimmunoassay of human thyrotropin. in
Radioisotopes in Medicine: In Vitro Studies,
AEC Symposium series. 13:185, 1968.
20. Danowski, T. S., Johnston, S. Y., Price, W. C.,
McKelvv, M., Stevenson, S. S., and
McClusky, E. R. : Protein bound iodine in
infants from birth to one year of age. PEDI-ATRICS, 7:240, 1951.
21. Man, E. B., Pickering, D. E., Walker, J., and
Cooke, R. E. : Butanol-extractable iodine in the serum of infants. PEDIATRICS, 9:32, 1952.
22. Dowling, J. F., Freinkel, N., and Ingbar,
S. H. : Thyroxine binding by sera of
preg-nant women, newborn infants, and women
with spontaneous abortion. J. Clin. Invest., 34:1263, 1956.
23. Robbins, J., and Nelson, J. H. : Thyroxine
binding by serum protein in pregnancy and
in the newborn. J. Clin. Invest., 37:153, 1958.
24. Pickering, D. E., Kontaxis, N. E., Benson,
R. C., and Meechan, R. J.: Thyroid func-tion in the perinatal period. Amer. J. Dis.
Child., 95:616, 1958.
25. Spafford, N. R., Carr, E. A., Jr., Lowrey,
C. H., and Beierwaltes, W. M. : 1131 labeled triiodothyronine erythrocvte uptake of
moth-ers and newborn infants. Amer. J. Dis.
Child., 100:844, 1960.
26. Michener, W. M., Tauxe, \V. N., and Hayles,
A. B.: Capacity of thyroxine binding
globu-lin to bind triiodothyronine and thyroxine in
maternal and cord blood. PEDIATRICS,
29:369, 1962.
27. Lindergren, L., and Starr, P.: Neonatal
thy-roidolog: correlations of PBI, TBG, bone
age, and growth. Acta Endocrinol.
(Koben-havn), 51:77, 1966.
28. Russell, K. P., Tanaka, S., and Starr, P.:
Thy-roxine binding capacity of serum of mothers and newborn infants after normal
pregnan-cies. Amer. J. Obstet. C’snec., 79:718, 1960.
29. Friis, J., and Secher, E. : Protein bound iodine of serum in induced abortion and at
deliv-ery. Acta Endocrinol., 18:428, 1955.
30. Marks, J., \Volfson, J., and Klein, R. : Neonatal
thyroid function : erythrocyte T3 uptake in
early infancy. J. Pediat., 58:32, 1961. 31. Rose, H., Russell, K. P., and Starr, P.: The
serum protein bound iodine of mothers and
newborns at delivery in premature and term
pregnancies. Amer. J. Obstet. Gynec.,
86:767, 1963.
32. Anderson, B. C. : Free thyroxine in serum in relation to thyroid function. J. A. M. A., 203:577, 1968.
33. Oppenheimer, J. H., Squef, R., Surks, M. I.,
and Hauer, H. : Binding of thyroxine by
serum proteins evaluated by equilibrium
di-alysis and electrophoretic techniques.
Altera-tions in non-thyroidal illness. J. Clin. Invest., 42:1769, 1963.
34. Hennen, C., Pierce, J. C., and Freychet, P.: Human chorionic thyrotropin : further char-acterization and study of its secretion during pregnancy. J. Ciin. Endocr., 29:581, 1969.
35. Odell, W. D., Reichert, L. E., and Bates,
R. W. : Pitfalls in the radioimmunoassay of
carbohydrate containing polypeptide
hor-mones. In Protein and Polypeptide Hormones. Excerpta Med. mt. Congr. Series 161:124, 1968.
36. Odell, W. D., Bates, R. W., Rivlin, R. S., Lip-sett, M. B., and Hertz, R. : Increased thyroid function without clinical hyperthyroidism in patients with choriocarcinoma. J. Clin. En-doer., 23:653, 1963.
37. Odell, W. D., Hertz, R. Lipsett, M. B., Ross,
C. T., and Hammond, C. B. : Endocrine as-pects of trophoblastic neoplasms. Clin. Obst.
Cynec., 10:290, 1967.
38. Hennen, C. : Study of thyroid stimulating
fac-tors of different organs. Detection of a human chorionic thyroid-stimulating factor. Ann. Endocr., 27:242, 1966.
39. Fisher, D. A., and Oddie, T. H. : Thyroxine
se-cretion rate during infancy: the effect of
es-trogen. J. Clin. Endocr., 23:811, 1963.
40. Oddie, T. H., Meade, J. H., Jr., and Fisher,
D. A. : An analysis of published data on
thyroxine turnover in human subjects. J.
Clin. Endocr., 26:425, 1966.
41. Fisher, D. A., and Oddie, T. H.: Neonatal
thy-roidai hyperactivity. Amer. J. Dis. Child.,
107:574, 1964.
42. Fisher, D. A.: Endocrine correlates of
tempera-ture adaptation in the newborn. In: Clinical
Pathology of Infancy. Springfield, Illinois:
Charles C Thomas, pp. 205-218, 1967.
43. Davis L., and Forbes, W.: Effect of
OF LAUGHTER IN CHILDREN AS VIEWED BY
SIR GEORGE FREDERIC STILL (1868-1941)
44. D’Angelo, S. A., and Fisher, J. S.: Influence of
estrogen on the pituitary-thyroid system of the female rat: mechanisms and loci of
ac-tion. Endocrinology, 84:117, 1969.
45. Kaplan, S. L., and Grumbach, M. M.: Serum chorionic growth hormone prolactin and serum pituitary growth hormone in mother
and fetus at term. J. Clin. Endocr., 25:1370,
1965.
46. Engstrom, W. W., and Markardt, B.: Influence
of estrogen on thyroid function. J. Clin.
En-doer., 14:215, 1954.
AcknowIedgmenc
We are grateful to Drs. Bijan Siassi and Arthur Klein for their help in obtaining blood samples, to Mrs. Claire Pierce for help with the TSH
radioim-munoassays, and to Frances Rao, Isabelle Olson,
and Beverly Fisher for manuscript preparation.
As pediatrics has become increasingly spe-cialized, especially during the past quarter of a century, it seems to me that the dominant figures of our specialty write less and less about
the commonplace problems of childhood which
still continue-as they did in the past-to bother parents and vex more practitioners.
As towering a figure as Sir George Frederic
Still considered the everyday phenomena of
the life of a child of such importance that he
wrote a delightful book entitled Common
Hap-penings in Childhood,’ which contained eight
beautifully written chapters on such common
things as crying, laughter, temper, appetite,
and sleep in childhood.
A good example of Still’s interest in the
ordinary is the following quotation from his
chapter “Of Laughter” in this book.
To have attained a high degree of this control
has been regarded by some as a mark of
superior-ity. Chesterfield, writing to his son, aged sixteen, in
1748, says:
“How low and unbecoming a thing laughter is!
Not to mention the disagreeable noise that it
makes and the shocking distortion of the face that
it occasions. . . . I am sure that since I have had
the full use of my reason nobody has ever heard
me laugh. I could heartily wish,” he says, “that
you may often be seen to smile, but never heard to
laugh while you live.”
Chatham, in his letters to his nephew, in 1754, writes only less strongly to similar effect.
One can only think that these paragons of
self-mastery must have been nearly as dull as that
Crassus whom both Pliny and Cicero mention as
remarkable for never having laughed in the whole of his life, except on one occasion, and that was when he saw a donkey eating lettuces. . .
On the other hand, smiling or laughter is one of
the normal functions of the healthy body, perhaps even a factor in keeping it healthy. I suspect that a lively sense of humour tends not only to promote health, but to favour longevity, and that the author of Tri.stram Shandy was not far from scientific truth when he wrote: “Every time as man smiles, but much more so when he laughs, it adds
some-thing to this fragment of life.” Surely it must have
been in the bitterness of his soul that the Preacher exclaimed, “I said of laughter, It is mad; and of mirth, What doeth it?’#{176}
NOTED BY T. E. C., JR., M.D.
REFERENCE
