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Thyroid function in human pregnancy
Thyroid function in human pregnancy I. The significance
of serum butanol-
extractable
iodines
EVELYN
B.
WILLIAM WALTER Providence,
in the last trimester
MAN, A.
PH.D.
REID,
M.D.
S. JONES,
M.D.
Rhode
Island
T H E butanol-extractable iodine (BEI), as was previously reported for the proteinbound iodine (PBI), of normal euthyroid women rises early in pregnancy to concentrations almost double those of the nonwoman.leg Simultaneously with pregnant the rise in PBI or BE1 the serum thyroxinebinding globulin (TBG) also doubles. lo, I1 After these increases occur early in pregnancy, elevated plateau concentrations of PBI or BE1 and TBG of euthyroid women persist until delivery. These serum concentration changes during pregnancy affect not only the PBI, BEI, and TBG, but also alter red-cell or resin uptake tests.7-9 These phenomena may not occur in women with proved or suspected thyroid dysfunction, nor in patients with past or present reproductive failures. Data being collected now suggest that test values may vary in different age groups. The course of pregnancy and development
of infants are being observed, in association with the National Collaborative Study, in alternate clinic registrants at the Providence Lying-In Hospital. The number of patients is large enough to select thyroid metabolism study groups of statistical significance. Previous articlesle5 and publications of wellknown investigators’+I1 supply basic information on which the present investigation was planned. Pertinent articles not quoted here have been included in the bibliographies of summary articles by Freedberg and Hamolsky, Herbst and Selenkow, Benson, Nicoloff, and Dowling.6-‘1 Subjects
and
methods
Women in control group. As a norm
for thyroid function during pregnancy, the sample comprises euthyroid women in the childbearing age 18 through 34 years, with successful outcome of the current pregnancy (a living full-term infant weighing 2,500 grams or more). At least 2 blood serum samples during the first trimester or before the twenty-fourth week and also 2 BEI’s subsequent to the twenty-fourth week after the last menstrual period were required to test the significance of BE1 determinations of the control women. Thirty of the 155 euthyroid women observed, aged 18 through 34, met the requirements of early registration, serum BE1 de-
From the Thyroid Laboratory and Department of Obstetrics, Providence Lying-Zn Hospital; Instttute for Health Sciences, Brown University. This investigation was supported by Public Health Service Research Grant AM 04890-02 from the National Institute of Arthritis and Metabolic Diseases but is now supported by transfer to Grant HD 00415-03 from the National Institute of Child Health and Human Develofwent.
474
Volume Number
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Thyroid
terminations at frequent and regular intervals (Table I), and pregnancies without clinical signs or histories of pre-eclampsia, organic cardiac dysfunction, or unusual medication such as antibiotics, tranquilizers or anticonvulsive therapy which might affect the concentration of the BEI. One hundred and sixty-four BEI’s of these 30 pregnant women are tabulated in Table I; and 98 per cent were representative of values without random chemical errors or clinical complications. Three BEI’s (9.4 for j in first column, 4.8 for cc in second column, and 10.7 for z in sixth column) appeared inconsistent when mean and standard deviations (SD.) were calculated for all 164 BEI’s. These 3 exceptional BEI’s were excluded and means and SD. for the remaining 161 BEI’s, 98 per cent, were re-examined statistically and are at the bottom of Table I. Exclusion of 3 BEI’s is compatible with unrecognizable errors in procuring the blood sample and in a determination as sensitive as the BEI. The values 10.7 for z in the fourth column and 4.8 for cc in the first column were omitted on clinical grounds. z had been vomiting, had a cold and had had an accident prior to her BE1 of 10.7 pg per 100 ml. Also she had been given gamma globulin 3 weeks previously after exposure to a virus infection. cc had had an acute upper respiratory infection with vomiting and intake of 18 Anacin* before the BE1 of 4.8 pg per 100 ml. Women
with
nonplateau
BEI’S
These women had BE1 patterns which diverged from those of control women. The 14 women, whose nonplateau serum BEI’s are tabulated in Table II, were 18 through 32 years of age except for 3 older women (A, C, and L) . Seven (C, D, E, I, J, L, and M) had had reproductive difficulties; 3 (G, H, and K) had equivocal signs of thyroid dysfunction such as tremor, heat intolerance, slight muscular reflex abnormali-
“Whitehall Products Corp.,
Laboratories, New York
Division 17, New
of York.
Arm&an
Home
function
in pregnancy
475
ties, pulse rate over 100, enlargement (2 times) of the thyroid gland; one (A) was in the over 34-year-old group; three (B, F, and N) were sample alternates who exhibited abnormal BEI’s. Parity and Rh factor were examined; no correlation was apparent with these reproductive data. Other women were clinically excluded from the control group; they had sporadic BEI’s outside the normal pregnancy range for this clinic but failed to have 2 blood samples within and 2 outside this range. Methods Thyroid activity may be measured chemically by: serum precipitable iodine (SPI) ,* now generally included under the nonspecific term of protein-bound iodine (PBI) ; thyroxine-like or butanol-extractable iodine (BEI) ?-% 12; thyroxine-binding globulin pre-albumin thyroxine-binding (TBG); (TBPA) I31 14; and by in vitro red cell and resin triiodothyronine uptake tests.?+ This resport deals specifically with serum BEI’s; TBG and TBPA values will be discussed separately. No outstanding familial aberrations of TBG or TBPA have been observed in the control women or in the women with atypical serum BEI’s. Not all women had TBG and TBPA measurements, but an attempt was made to determine these when BEI’s were abnormal. Results The minimum was 5.6 and the maximum 10.2 pg per 100 ml. of 98 per cent of the 164 serum BEI’s of the 30 control patients from the twelfth to the fortieth weeks after the last menstrual period (Table I) . This characteristic plateau is shown in Fig. 1 and can be compared with BEI’s 6 weeks or longer after delivery.* Only 17 of these 30 women returned for *The minimum and maximum agree closely with the ranges af Benson~ and a similar New Haven population.‘-’ From 144 sera of 33 New Haven patients, the normal BE1 range extended (in duplicate analyses on single samples of serum) from 5.5 to 10.5 fig per 100 ml. although 5.5 and 9.5 pg per 100 ml. were the minimum and maximum mean BEI’s for any one euthyroid pregnant w~man.~-’ The means of BEI’s calculated at approximately 4 week intervals were constant in a range 3f 7.1 through 7.9 pg per 100 ml.
476
Man,
Reid,
and
Jones
Table 1. One hundred women between a living. full-term
and sixty-four serum plateau BEI’s of 30 euthyroid pregnant the tenth week after the last menstrual period and delivery of infant, more than 2,500 grams in weight ’ Post
i Abortions
Length gestation (wk.)
2835 3714 2892
38% 40% 40
1 1 yJ 12 12
3600 4338 4479 3317 3147 2807 3430 3005 2637 2637 3430 3714 3147 3714 3827 2863 3997 3118 2920 3062 3515 3374 3232 2693 2920 3317 3685
40% 40%
17 13:/, 14% 11 20 13 13 10 % 8 16 17 20
;: c
d e f R h i ; 1 m n 0 P g P s t 11 v w x Y z aa bb :
9:s 43 40 39% 37 36 43 40 40 42 40 41 41 40 41 39 39% 40 40 39 40% 40 42 42
Mean Standard deviation No. of determinations Minimum Maximum BEI’s included in 100 per cent sample excluded below 98 per cent Mean
or 161
of 164
+Labor $Chemical $ClinicaI
weeks. Room
or
within
hours
after
delivery.
difficulties. complications
First BEI (wk.)*
:;s 16 21% 20 15% 19 12% 19 20 19 20 15% 14 16
determinations
after Serum
10 through 6.2 5.6 7.0
6.4 7.0 8.9 5.9 8.9 8.5 7.0
8.4 6.5 7.9 (9.4) 6.0 8.0
6.1 7.9 7.6 6.7 8.5 9.2
8.0
8.5 6.8 6.5
9.0 7.3 8.1 7.5
7.1
7.3 1.11 12 5.6 (9.4)
7.7 (4.8) 6.7 7.4 1.20 22 (4.8) 9.2
la,t BEI
menstrual pg/lOO
24 weeks 6.4 7.2
8.0
8.4
7.3 6.8 8.5 8.8 8.0
6.7 8.1 7.8
7.9 9.2 7.0
8.2 8.0 6.9
7.6 7.2 5.7 8.3 9.0 7.5 7.8 8.4 7.6 9.2 7.8 7.7
7.8 7.7 6.7 7.7 9.0 7.5 7.0 6.8
6.9 7.1 7.1
6.6 8.4 7.0 7.2
24
6.6 7.6
6.7 6.3 8.3
7.0 7.4 9.1
6.3 6.3 7.2 6.5 5.6 8.9 7.2 7.7 6.9 8.5 7.9
6.2 10.1 6.3 7.6 7.7 8.6 8.0 6.1 8.7 8.9
7.4
8.1 6.7
7.8 7.4
7.5 8.0 8.1 7.3 8.9 8.0 7.5
6.5 7.8 7.4 8.5 8.2 8.6 7.8 7.8 8.1 7.2 8.6 9.5 7.5
7.8 (10.7) 7.2 8.0
7.0 7.7 0.91 23 5.7 9.2
7.6 0.95 22 6.0 10.2
7.4 7.6 0.61 1.07 17 25 6.6 5.6 8.4 (10.7)
or more
weeks
7.8
6.7 10.2 8.4 6.7
Wt?ehS
ml. After
8.2 6.0 7.5 8.8
period
7.1f 8.6 8.Ot 5.7+ 8.7t 8.9t 6.1 7.4
9.1 7.1$
(10.7)
described
in
text.
7.1
7.6
0.92 11 5.6 8.4
1.07 21 5.9 9.2
Same as above
7.4
0.87 24 5.6 8.9
4.8 5.8 5.5 5.7 5.0
6.4 3.4
8.5
4.9
8.5
6.2 4.2
7.4t 7.7t
7.0
6.9 6.7+
7.9 1.00 27 6.1 10.1
7.6 1.05 16 5.7 9.1
but (9.4)$(4.8)$
5.8
4.2 5.3
I
BEI’s
Standard deviation No. of determinations Minimum Maximum *Menstrual
BEI
Birth weight (grams)
parturn 6
.4s above
3.4 5.7
5.0 4.1
Volulne Number
90 4
Thyroid
6 weeks or longer postpartum ob servation after delivery. Postpartum BEI’s had rcturned to nonpregnant euthyroid range for all these 17 women.
function
in pregnancy
34) serum BEI’s were within the euthyroid range. Conversely, during the last 16 weeks 68 per cent of BEI’s (36 of 53) were within normal pregnant ranges. Because these women registered late, abnormal BEI’s early in pregnancy may have been missed. Analysis of these data indicates that all 14 of these women who failed to follow the standard plateau exhibited at least 1 different patterns. Eight (A, B, C, D, E, F, G, and I j with registration between the tenth and twenty-eighth weeks had low initial BEI’s, but concentrations rose to essentially normal values near term. Two women (H and J) had normal BE1 concentrations initially, with later decreases below the plateau. These women had a history of thyroid dysfunction and reproductive difficulties, ‘2 previous abortions and delivery of a premature, respectively.
Women with BEI’s deviating from plateau BEI patterns of control group. Although 14 of the presumably euthyroid women had F&t’s in the normal range in the last 16 wecsks or at delivery, their BEI’s (Fig. 2) did not conform to the plateau pattern throughout pregnancy. Their 87 serum BEI’s, aftrr the tenth week, tabulated at approximately 4 week intervals, are presented in Table II. Values below and above normal range are underlined. Each patient had at least 2 BET’s on different blood serum samples, below the normal minimum of 5.5 OI above the maximum of 10.4 pg per 100 ml. of the New Haven and this series. During thrb first 24 weeks only 38 per cent (13 of
Table II.
Eighty-seven serum BEI’s of 14 women with normal pregnancy near term but with two or more BEI’s below or above the pregnancy range earlier in gestation* BEI
Age A B c D
Gravida
Para
Abortions
Birth weight (crams)
Length gestation (weeks)
determinations
10 through weeks
E
5 8 3 7 4
4 6 2 6 3
0 1 0 0 0
3,459 2,892 3:742 3,629 2.917
40 40 44 408 44
10 13 11 73 15
F G I-K
25 ‘2 31
4 2 4
3 1 3
0 0 0
4,167 2,750 3.147
41% 40 40
27%
I
3 7
2 4
0 2
2,268 3,487
381/s 40s
30§
J
28 30
K L hf
23 38 24
5 7 4
4 3 3
0 2 0
3,941 2,722 2,466
41 40 38
27 17 19
Ii
18
1
0
0
2,155
36
tMenstrua1 $Labor SLMP menstrual
values
are
below
or above
nnrmal
4.6 5.2 ----4.3 4.1 --3.9
20 lOf/z
6.2
pg/lOO
period Post partum 6 weeks or more
ml.
24 After
24 weeks 6.4 7.2$ 5 7
_5.4 --5.4
6.5 5.8 6.8 5.8 -5.2
4.8 -5.7
4.8 -5.3
4.8 --5.0
4.1 5.8 5.2
6.7 5.4 z
::i: 6.1 5.6::
7.4
5.1 52
5.4 r7
6.4 5.4
11.6 8.9 9.5
10.5 9.9 9.2
H-l$
5.9
11.7 11.0 11.7 ~-9.8 11.1 9.4 9.4 -
5.5 5.3 _1 9.1 9.1 12.7
4.9
6.2
10.4
9.5
--12.2
11.3
20
4.8 4.9 5.6 _5.1 6.6
menstrual
5.7 6.8 6.8 6.7 5.8
6.1
5.8 4.5 4.8 5.1 3.5
BEI
last
BEI’s
6.6 6.3 6.4 6.1 5.0
18s
pregnancy
after Serum
First BEI (wk.lt
37 32 37 27 27
*Underlined
477
5.5
4.3 4.0
6.6
11.2$
7.4 (6 weeks) 7.5 (12 weeks)
range.
weeks. Room
or within
hours
after
delivery.
indeterminate. By neonate’s clinical cvcle, sometimes ct. 2 months.
symptoms
of
prematurity
or postmatul-itv.
Patient
I has always
had
an
irregular
478
Man,
Reid,
and
Jones
IZ-
is‘I0 ’ a? 2 5 2 w In
xx --=I-------
__-_
MEAN:‘---
-*.=-A-
-4--__ * . ; .* : . .
6-
. * .
4-
KEY: -
2
MEAN
t 2SD
1
Fig. 1. Serum BEI’s of 30 euthyroid pregnant women aged 18 to 35 years at Providence Lying-In HospitaI Clinic. Outer solid lines represent mean BEI’s ?. 2 S.D. for all 164 BEI’s of these women. Inner solid lines represent mean BEI’s k 2 S.D. for 98 per cent (161 of 164) of these BEI’s. See methods for clinical or chemical exclusion of 3 BEI’s represented by crosses (X) in
this figure. Middle intermittent lines give means 98 per cent of BEI’s with insignificant differences. The three isolated dots ( ) represent minimum BEI’s at any period of gestation when such values mean -I 2 S.D. See bottom of Table I for mean, SD., number tions, and minimum and maximum BEI’s. l
Two women (K and L) between 25 and 32 weeks had above normal BEI’s, but a decrease of BEI’s to normal ranges before and at delivery. A decrease from high BEI’s during the last trimester to normal pregnancy concentrations occurred for 2 other women who failed to meet the criterion of enough early sera. M and N had BEI’s rising above normal during the last trimester. Each of these women delivered neonates under 2,500 grams in weight at 38 and 36 weeks of gestation. Six and 12 weeks post partum, M had BEI’s of 7.4 and 7.5 pg per 100 ml., values above the nonpregnant euthyroid range. A 17-year-old girl was delivered at 38 weeks with a butanol-extractable iodine level which had risen to 10.3 at the time of delivery. Comment
in
The previously behavior of
described wide the BE1 during
variation the last
for 100 and or maximum exceeded the of determina-
trimester points up the fallacy of depending on one or two test samples to assess thyroid function throughout pregnancy. A PBI or BE1 late in gestation may have no diagnostic significance in evaluation of thyroid activity in the early months, when fetal growth and development are critical. Furthermore, a single test at only one stage of pregnancy may have contributed to the confusing reports concerning thyroid function in relation to premature and postmature deliveries.l”-I’ Evaluation of the thyroid environment in relation to the fetus must be based on multiple testing during the entire intrauterine period. Zondek’sls observation that a myxedematous woman improved clinically during the latter part of pregnancy, only to relapse to a hypothyroid state after delivery, is frequently cited as evidence that thyroxinelike compounds cross the placenta. SmithI discussed altered development, function and size of the fetal thyroid relative to maternal
Volumc~
90
h-umber
4
Thyroid
function
in pregnancy
479
2-
APPRCP~MATE WEEKS AFTER LAST MENSTW’L
f’ERC0
kz=
Fig. 2. Atypical BE1 patterns of 14 women with nonplateau BEI’s (Table II). (For clarity BEI’s of only 9 women are plotted.) Heavy lines represent mean 2 2 S.D. of 100 per cent of BEI’s of control group (Table I) in normal reproductive age of 18 through 34 years. A, B, C, D, had low BEI’s soon after registration, with normal BEI’s for pregnancy from the twenty-eighth week to delivery. J had normal BEI’s which fell below normal just before delivery. K and L with high BEI’s soon after registration had BEI’s similar to those of the control group following the twenty-eighth week after the last menstrual period. M and N had high BEI’s near term and were delivered of premature infants by weight, at 38 and 36 weeks, respectively.
dietary iodine intake. Kelly and Snedden” confirm enlargement of the fetal thyroid in endemic goiter areas but include 2 definite references in the concept of unusual fetal thyroid overactivity as compensatory for underfunction of the maternal gland. In Christchurch, New Zealand, where 60 per cent of mothers had goiters, the neonate’s thyroid had enlarged “sometimes to a degree sufficient to interfere with normal flexion of the head at delivery.” In endemic goiter areas animals have similar disturbances. In Nepal, India, Bramley “saw a goat bring forth a kid with a goitre as large as its head.” These observations from 3 diRerent geographical areas outside the United States are of interest in relation to experiences in this laboratory. From widely scattered areas of the United States serum BEI’s have been requested because of enlargement of the thyroid of pregnant women, infants, and adolescent girls and boys. The greatest ma-
jority had low BEI’s and regression of thyroid size with appropriate replacement therapy. Reports of other investigators add to the concept that the high incidence of normal maternal BEI’s during the last trimester indicate that fetal thyroid function may complement maternal thyroid function. Maternal serum TBG doubles approximately during pregnancy.lO Thus sufficient TBG is in the maternal circulation to accept and bind any thyroxine available from the fetus. Since serum fetal TBP fractions are lower in concentration than materna1 serum TBP fractions, the gradient of transport of thyroxine could vary from fetus to fetus, or woman to woman. Fisher and Oddie” summarized data that infants have significantly higher thyroxine secretion rates than adults. On a micrograms per kilogram per day basis the infant’s secretion rate was seven times that of an adult. These calculations are com-
480
Man,
patiblc with Cottino’s”” calculated, high degradation rates of thyroxine-like compounds during infancy. Studies of Pickering and associates”“. ” on fetal and maternal thyroid secretion rates in the macaque monkey and on mono-, diiodotyrosine, and thyroxine content of thyroid glands suggest an increasing fetal thyroxine secretion rate during the last weeks in utero. Studies of Andreoli and Kobbins” on young fetuses, only 8 to 20 weeks in gestational age, dovetail earlier into this framework. In such early fetuses PBI’s were as low as 1.4 to 1.6 pg per 100 ml. In contrast to the complementary effects of maternal and fetal thyroid function on third trimester maternal serum BEI’s, are many reports that maternal thyroid dysfunction is significant in delivery of prematurely underweight or of heavy, possibl) postmature neonates. Dokumov17 is one of numerous investigators who have discussed course of pregnancy, labor and the puerperium in relation to hypothyroidism, endemic goiter, and hyperthyroidism. Such data tend to incriminate maternal thyroid dysfunction as one cause of abnormal length of gestation. It is important in observations of liose. Kussell and Starr’” that their normal maternal PBI’s at delivery of premature infants should not quickly be misinterpreted as diagnostic of the woman’s thyroid function throughout pregnancy. Data presented in this article include delivery of 3 premature infants born to women with nonplateau BEI’s during gestation (Table II, I, M, and N‘I. Four neonates or stillbirths under 2,500 grams in weight were born to 4 of the 7 women with nonplateau BET’s in the series of Greenman
REFERENCES
1. 3. 3.
4. 5.
Ortoher 15, 1964 Am. J. Ohst. & Cynec.
Reid, and Jones
Peters, J. P., Man, E. B.. and Heinemann. M.: Obst. & Cvnec. Surv. 3: 647. 1948. Lum, J., and Man. E. B.: Yale .J. Biol. Med. 28: 10-5; 1955. Man. E. B.. Shaver. B. ,4.. Tr.. and Cooke. R. E.: AM. J. ORST. & C~NEC. 75: 738. 1958. Man, E. B.. and Bondy, P. K.: J. CIin Endocrinol. 17: 1373. 1957. Man, E. B.: J. Lab.’ & Clin. Med. 59: 528. 1962.
and associates” (Table II). As yet, it is too early to compare 8 month psychological and 1 year neurological development of infants born to the control women and to the women with atypical patterns of serum thyroxine-like iodine during pregnancy. However, seven of the children, born to the 14 women with nonplateau BEI’s have aroused suspicions of retarded neurological or psychological development. Summary
Thirty euthyroid women between the inclusive ages of 18 through 34 years exhibited d urmg ’ the first trimester serum BEI’s increased above nonpregnant concentrations and maintained at plateau elevations until delivery. Elevations were similar to those for a different population in New Haven, Connecticut. For both euthyroid series serum BEI’s, except for sporadic determinations with a few BEI’s as high as 10.4. were hetween 5.5 and 9.5 pg per 100 ml. Fourteen women, with 11 in the same age range as the 30 controls, failed to follow a plateau elevated pattern of serum BEI’s during pregnancy. Eleven of these 14 women with serum BEI’s below or above the normal range before the third trimester had normal BEI’s for pregnancy near delivery. These data demonstrate that thyroid function during pregnancy can not be evaluated by a single thyroid function test during the last trimester. In spite of the usual plateau elevation of serum PBI or BE1 several thyroid function tests, at different stages of pregnancy, are requisite for diagnosis of maternal thyroid function throughout gestation.
6.
7.
8. 9. 10.
Benson, R. C.. Pickering, D. E., Kontaxis, N. E., and Fisher. D. ‘4.: Obst. & Gynec. 14: 11, 1959. Freedberg, I. M.. Hamolskv. M. W.. and Freedberg, A. S.: New Englazd J. Med: 256: 505. 551. 1957. Hamolsky, M. W.. and Freedberg. .4. S : New England J. Med. 262: 23, 70, 129, 1960. Herbst, A. L.: and Selenkow, H. A.: Obst. & Gynec. 21: 543, 1963. Dowling, J. T.. Freinkel, N.. and Ingbar, S. H.: J. Clin. Invest. 35: 1263, 1956.
Thyroid
11. 12.
13. 14. 15.
16. 17. 18. 19.
Nicoloff, J. T., Nicoloff, R., and Dowling, J. T.: J. Clin. Invest. 41: 1998, 1962. Man, E. B.: In Sunderman, F. W., and Sun&man, F. W., Jr., editors: Evaluation of Thyroid and Parathyroid Functions, Philadelphia, 1963, J. B. Lippincott Co., p. 77. Ingbar, S. H.: JI Clin. Invest. 40: 2053;1961. Drever. D. T.. and Man. E. B.: T. Clin. Endbchnol. c ‘Metab. 22: il, 1962. ” Greenman, G. W., Gabrielson, M. 0.. Howard-Flanders, J., and Wessel, M. A.: New Enaland T. Med. 267: 426. 1962. Rose, H.,” Russell, K. P., and Starr, P.: AM. J. OBST. & GYNEC. 86: 767, 1963. Dokumov, S. I.: Acta Endocrinol. 38: 161, 1961. Zondek, H.: Acta med. scandinav. 103: 251, 1940. Smith, C. A.: In The Physiology of the Newborn Infant, ed. 3, Springfield, Illinois,
20.
21. 22.
23. 24. 25.
function
in
pregnancy
Charles C Thomas, Publisher, p. 1951, 307. Kelly, F. C., and Snedden, W. W.: In Endemic Goitre, World Health Organization. Switzerland, 1960, pp. 27-233, Prevalence and Geographical Distribution of Endemic Goitre. Fisher, D. A., and Oddie, T. H.: J. Clin. Endocrinol. 23: 811, 1963. Cottino, F., Colombo, G., Ferrara, G. C.> and Costa, A.: Panminerva Med. 3: 471. 1961. Pickering, D. E., Settergren, K. F., and Kontaxis. N. E.: 1. Endocrinol. 23: 261. 1961. Pickering. D: E., and Kontaxis, ‘N. E.: J. Endocrinol. 23: 267, 1961. Andreoli, M., and Robbins, J.: J. Clin. Invest. 41: 1070, 1962. 50 Maude ProGdence,
Street Rhode
Island
02908
Erratum In the article, “The Milk-ejecting Effect Induced by Oxytocin and Vasopressin Human Pregnancy,” by Nestor L. Sala, M.D., in the July 1 issue of this JOURNAL, sentence on page 628 should read, “During this period, which extends until the Table I of this same article, page 630, the last column should read: Differences > < < <
between (P) 0.1 0.01 0.02 0.05
481
.
During the last . . . ” In
of serum butanol-
extractable
iodines
EVELYN
B.
WILLIAM WALTER Providence,
in the last trimester
MAN, A.
PH.D.
REID,
M.D.
S. JONES,
M.D.
Rhode
Island
T H E butanol-extractable iodine (BEI), as was previously reported for the proteinbound iodine (PBI), of normal euthyroid women rises early in pregnancy to concentrations almost double those of the nonwoman.leg Simultaneously with pregnant the rise in PBI or BE1 the serum thyroxinebinding globulin (TBG) also doubles. lo, I1 After these increases occur early in pregnancy, elevated plateau concentrations of PBI or BE1 and TBG of euthyroid women persist until delivery. These serum concentration changes during pregnancy affect not only the PBI, BEI, and TBG, but also alter red-cell or resin uptake tests.7-9 These phenomena may not occur in women with proved or suspected thyroid dysfunction, nor in patients with past or present reproductive failures. Data being collected now suggest that test values may vary in different age groups. The course of pregnancy and development
of infants are being observed, in association with the National Collaborative Study, in alternate clinic registrants at the Providence Lying-In Hospital. The number of patients is large enough to select thyroid metabolism study groups of statistical significance. Previous articlesle5 and publications of wellknown investigators’+I1 supply basic information on which the present investigation was planned. Pertinent articles not quoted here have been included in the bibliographies of summary articles by Freedberg and Hamolsky, Herbst and Selenkow, Benson, Nicoloff, and Dowling.6-‘1 Subjects
and
methods
Women in control group. As a norm
for thyroid function during pregnancy, the sample comprises euthyroid women in the childbearing age 18 through 34 years, with successful outcome of the current pregnancy (a living full-term infant weighing 2,500 grams or more). At least 2 blood serum samples during the first trimester or before the twenty-fourth week and also 2 BEI’s subsequent to the twenty-fourth week after the last menstrual period were required to test the significance of BE1 determinations of the control women. Thirty of the 155 euthyroid women observed, aged 18 through 34, met the requirements of early registration, serum BE1 de-
From the Thyroid Laboratory and Department of Obstetrics, Providence Lying-Zn Hospital; Instttute for Health Sciences, Brown University. This investigation was supported by Public Health Service Research Grant AM 04890-02 from the National Institute of Arthritis and Metabolic Diseases but is now supported by transfer to Grant HD 00415-03 from the National Institute of Child Health and Human Develofwent.
474
Volume Number
90 4
Thyroid
terminations at frequent and regular intervals (Table I), and pregnancies without clinical signs or histories of pre-eclampsia, organic cardiac dysfunction, or unusual medication such as antibiotics, tranquilizers or anticonvulsive therapy which might affect the concentration of the BEI. One hundred and sixty-four BEI’s of these 30 pregnant women are tabulated in Table I; and 98 per cent were representative of values without random chemical errors or clinical complications. Three BEI’s (9.4 for j in first column, 4.8 for cc in second column, and 10.7 for z in sixth column) appeared inconsistent when mean and standard deviations (SD.) were calculated for all 164 BEI’s. These 3 exceptional BEI’s were excluded and means and SD. for the remaining 161 BEI’s, 98 per cent, were re-examined statistically and are at the bottom of Table I. Exclusion of 3 BEI’s is compatible with unrecognizable errors in procuring the blood sample and in a determination as sensitive as the BEI. The values 10.7 for z in the fourth column and 4.8 for cc in the first column were omitted on clinical grounds. z had been vomiting, had a cold and had had an accident prior to her BE1 of 10.7 pg per 100 ml. Also she had been given gamma globulin 3 weeks previously after exposure to a virus infection. cc had had an acute upper respiratory infection with vomiting and intake of 18 Anacin* before the BE1 of 4.8 pg per 100 ml. Women
with
nonplateau
BEI’S
These women had BE1 patterns which diverged from those of control women. The 14 women, whose nonplateau serum BEI’s are tabulated in Table II, were 18 through 32 years of age except for 3 older women (A, C, and L) . Seven (C, D, E, I, J, L, and M) had had reproductive difficulties; 3 (G, H, and K) had equivocal signs of thyroid dysfunction such as tremor, heat intolerance, slight muscular reflex abnormali-
“Whitehall Products Corp.,
Laboratories, New York
Division 17, New
of York.
Arm&an
Home
function
in pregnancy
475
ties, pulse rate over 100, enlargement (2 times) of the thyroid gland; one (A) was in the over 34-year-old group; three (B, F, and N) were sample alternates who exhibited abnormal BEI’s. Parity and Rh factor were examined; no correlation was apparent with these reproductive data. Other women were clinically excluded from the control group; they had sporadic BEI’s outside the normal pregnancy range for this clinic but failed to have 2 blood samples within and 2 outside this range. Methods Thyroid activity may be measured chemically by: serum precipitable iodine (SPI) ,* now generally included under the nonspecific term of protein-bound iodine (PBI) ; thyroxine-like or butanol-extractable iodine (BEI) ?-% 12; thyroxine-binding globulin pre-albumin thyroxine-binding (TBG); (TBPA) I31 14; and by in vitro red cell and resin triiodothyronine uptake tests.?+ This resport deals specifically with serum BEI’s; TBG and TBPA values will be discussed separately. No outstanding familial aberrations of TBG or TBPA have been observed in the control women or in the women with atypical serum BEI’s. Not all women had TBG and TBPA measurements, but an attempt was made to determine these when BEI’s were abnormal. Results The minimum was 5.6 and the maximum 10.2 pg per 100 ml. of 98 per cent of the 164 serum BEI’s of the 30 control patients from the twelfth to the fortieth weeks after the last menstrual period (Table I) . This characteristic plateau is shown in Fig. 1 and can be compared with BEI’s 6 weeks or longer after delivery.* Only 17 of these 30 women returned for *The minimum and maximum agree closely with the ranges af Benson~ and a similar New Haven population.‘-’ From 144 sera of 33 New Haven patients, the normal BE1 range extended (in duplicate analyses on single samples of serum) from 5.5 to 10.5 fig per 100 ml. although 5.5 and 9.5 pg per 100 ml. were the minimum and maximum mean BEI’s for any one euthyroid pregnant w~man.~-’ The means of BEI’s calculated at approximately 4 week intervals were constant in a range 3f 7.1 through 7.9 pg per 100 ml.
476
Man,
Reid,
and
Jones
Table 1. One hundred women between a living. full-term
and sixty-four serum plateau BEI’s of 30 euthyroid pregnant the tenth week after the last menstrual period and delivery of infant, more than 2,500 grams in weight ’ Post
i Abortions
Length gestation (wk.)
2835 3714 2892
38% 40% 40
1 1 yJ 12 12
3600 4338 4479 3317 3147 2807 3430 3005 2637 2637 3430 3714 3147 3714 3827 2863 3997 3118 2920 3062 3515 3374 3232 2693 2920 3317 3685
40% 40%
17 13:/, 14% 11 20 13 13 10 % 8 16 17 20
;: c
d e f R h i ; 1 m n 0 P g P s t 11 v w x Y z aa bb :
9:s 43 40 39% 37 36 43 40 40 42 40 41 41 40 41 39 39% 40 40 39 40% 40 42 42
Mean Standard deviation No. of determinations Minimum Maximum BEI’s included in 100 per cent sample excluded below 98 per cent Mean
or 161
of 164
+Labor $Chemical $ClinicaI
weeks. Room
or
within
hours
after
delivery.
difficulties. complications
First BEI (wk.)*
:;s 16 21% 20 15% 19 12% 19 20 19 20 15% 14 16
determinations
after Serum
10 through 6.2 5.6 7.0
6.4 7.0 8.9 5.9 8.9 8.5 7.0
8.4 6.5 7.9 (9.4) 6.0 8.0
6.1 7.9 7.6 6.7 8.5 9.2
8.0
8.5 6.8 6.5
9.0 7.3 8.1 7.5
7.1
7.3 1.11 12 5.6 (9.4)
7.7 (4.8) 6.7 7.4 1.20 22 (4.8) 9.2
la,t BEI
menstrual pg/lOO
24 weeks 6.4 7.2
8.0
8.4
7.3 6.8 8.5 8.8 8.0
6.7 8.1 7.8
7.9 9.2 7.0
8.2 8.0 6.9
7.6 7.2 5.7 8.3 9.0 7.5 7.8 8.4 7.6 9.2 7.8 7.7
7.8 7.7 6.7 7.7 9.0 7.5 7.0 6.8
6.9 7.1 7.1
6.6 8.4 7.0 7.2
24
6.6 7.6
6.7 6.3 8.3
7.0 7.4 9.1
6.3 6.3 7.2 6.5 5.6 8.9 7.2 7.7 6.9 8.5 7.9
6.2 10.1 6.3 7.6 7.7 8.6 8.0 6.1 8.7 8.9
7.4
8.1 6.7
7.8 7.4
7.5 8.0 8.1 7.3 8.9 8.0 7.5
6.5 7.8 7.4 8.5 8.2 8.6 7.8 7.8 8.1 7.2 8.6 9.5 7.5
7.8 (10.7) 7.2 8.0
7.0 7.7 0.91 23 5.7 9.2
7.6 0.95 22 6.0 10.2
7.4 7.6 0.61 1.07 17 25 6.6 5.6 8.4 (10.7)
or more
weeks
7.8
6.7 10.2 8.4 6.7
Wt?ehS
ml. After
8.2 6.0 7.5 8.8
period
7.1f 8.6 8.Ot 5.7+ 8.7t 8.9t 6.1 7.4
9.1 7.1$
(10.7)
described
in
text.
7.1
7.6
0.92 11 5.6 8.4
1.07 21 5.9 9.2
Same as above
7.4
0.87 24 5.6 8.9
4.8 5.8 5.5 5.7 5.0
6.4 3.4
8.5
4.9
8.5
6.2 4.2
7.4t 7.7t
7.0
6.9 6.7+
7.9 1.00 27 6.1 10.1
7.6 1.05 16 5.7 9.1
but (9.4)$(4.8)$
5.8
4.2 5.3
I
BEI’s
Standard deviation No. of determinations Minimum Maximum *Menstrual
BEI
Birth weight (grams)
parturn 6
.4s above
3.4 5.7
5.0 4.1
Volulne Number
90 4
Thyroid
6 weeks or longer postpartum ob servation after delivery. Postpartum BEI’s had rcturned to nonpregnant euthyroid range for all these 17 women.
function
in pregnancy
34) serum BEI’s were within the euthyroid range. Conversely, during the last 16 weeks 68 per cent of BEI’s (36 of 53) were within normal pregnant ranges. Because these women registered late, abnormal BEI’s early in pregnancy may have been missed. Analysis of these data indicates that all 14 of these women who failed to follow the standard plateau exhibited at least 1 different patterns. Eight (A, B, C, D, E, F, G, and I j with registration between the tenth and twenty-eighth weeks had low initial BEI’s, but concentrations rose to essentially normal values near term. Two women (H and J) had normal BE1 concentrations initially, with later decreases below the plateau. These women had a history of thyroid dysfunction and reproductive difficulties, ‘2 previous abortions and delivery of a premature, respectively.
Women with BEI’s deviating from plateau BEI patterns of control group. Although 14 of the presumably euthyroid women had F&t’s in the normal range in the last 16 wecsks or at delivery, their BEI’s (Fig. 2) did not conform to the plateau pattern throughout pregnancy. Their 87 serum BEI’s, aftrr the tenth week, tabulated at approximately 4 week intervals, are presented in Table II. Values below and above normal range are underlined. Each patient had at least 2 BET’s on different blood serum samples, below the normal minimum of 5.5 OI above the maximum of 10.4 pg per 100 ml. of the New Haven and this series. During thrb first 24 weeks only 38 per cent (13 of
Table II.
Eighty-seven serum BEI’s of 14 women with normal pregnancy near term but with two or more BEI’s below or above the pregnancy range earlier in gestation* BEI
Age A B c D
Gravida
Para
Abortions
Birth weight (crams)
Length gestation (weeks)
determinations
10 through weeks
E
5 8 3 7 4
4 6 2 6 3
0 1 0 0 0
3,459 2,892 3:742 3,629 2.917
40 40 44 408 44
10 13 11 73 15
F G I-K
25 ‘2 31
4 2 4
3 1 3
0 0 0
4,167 2,750 3.147
41% 40 40
27%
I
3 7
2 4
0 2
2,268 3,487
381/s 40s
30§
J
28 30
K L hf
23 38 24
5 7 4
4 3 3
0 2 0
3,941 2,722 2,466
41 40 38
27 17 19
Ii
18
1
0
0
2,155
36
tMenstrua1 $Labor SLMP menstrual
values
are
below
or above
nnrmal
4.6 5.2 ----4.3 4.1 --3.9
20 lOf/z
6.2
pg/lOO
period Post partum 6 weeks or more
ml.
24 After
24 weeks 6.4 7.2$ 5 7
_5.4 --5.4
6.5 5.8 6.8 5.8 -5.2
4.8 -5.7
4.8 -5.3
4.8 --5.0
4.1 5.8 5.2
6.7 5.4 z
::i: 6.1 5.6::
7.4
5.1 52
5.4 r7
6.4 5.4
11.6 8.9 9.5
10.5 9.9 9.2
H-l$
5.9
11.7 11.0 11.7 ~-9.8 11.1 9.4 9.4 -
5.5 5.3 _1 9.1 9.1 12.7
4.9
6.2
10.4
9.5
--12.2
11.3
20
4.8 4.9 5.6 _5.1 6.6
menstrual
5.7 6.8 6.8 6.7 5.8
6.1
5.8 4.5 4.8 5.1 3.5
BEI
last
BEI’s
6.6 6.3 6.4 6.1 5.0
18s
pregnancy
after Serum
First BEI (wk.lt
37 32 37 27 27
*Underlined
477
5.5
4.3 4.0
6.6
11.2$
7.4 (6 weeks) 7.5 (12 weeks)
range.
weeks. Room
or within
hours
after
delivery.
indeterminate. By neonate’s clinical cvcle, sometimes ct. 2 months.
symptoms
of
prematurity
or postmatul-itv.
Patient
I has always
had
an
irregular
478
Man,
Reid,
and
Jones
IZ-
is‘I0 ’ a? 2 5 2 w In
xx --=I-------
__-_
MEAN:‘---
-*.=-A-
-4--__ * . ; .* : . .
6-
. * .
4-
KEY: -
2
MEAN
t 2SD
1
Fig. 1. Serum BEI’s of 30 euthyroid pregnant women aged 18 to 35 years at Providence Lying-In HospitaI Clinic. Outer solid lines represent mean BEI’s ?. 2 S.D. for all 164 BEI’s of these women. Inner solid lines represent mean BEI’s k 2 S.D. for 98 per cent (161 of 164) of these BEI’s. See methods for clinical or chemical exclusion of 3 BEI’s represented by crosses (X) in
this figure. Middle intermittent lines give means 98 per cent of BEI’s with insignificant differences. The three isolated dots ( ) represent minimum BEI’s at any period of gestation when such values mean -I 2 S.D. See bottom of Table I for mean, SD., number tions, and minimum and maximum BEI’s. l
Two women (K and L) between 25 and 32 weeks had above normal BEI’s, but a decrease of BEI’s to normal ranges before and at delivery. A decrease from high BEI’s during the last trimester to normal pregnancy concentrations occurred for 2 other women who failed to meet the criterion of enough early sera. M and N had BEI’s rising above normal during the last trimester. Each of these women delivered neonates under 2,500 grams in weight at 38 and 36 weeks of gestation. Six and 12 weeks post partum, M had BEI’s of 7.4 and 7.5 pg per 100 ml., values above the nonpregnant euthyroid range. A 17-year-old girl was delivered at 38 weeks with a butanol-extractable iodine level which had risen to 10.3 at the time of delivery. Comment
in
The previously behavior of
described wide the BE1 during
variation the last
for 100 and or maximum exceeded the of determina-
trimester points up the fallacy of depending on one or two test samples to assess thyroid function throughout pregnancy. A PBI or BE1 late in gestation may have no diagnostic significance in evaluation of thyroid activity in the early months, when fetal growth and development are critical. Furthermore, a single test at only one stage of pregnancy may have contributed to the confusing reports concerning thyroid function in relation to premature and postmature deliveries.l”-I’ Evaluation of the thyroid environment in relation to the fetus must be based on multiple testing during the entire intrauterine period. Zondek’sls observation that a myxedematous woman improved clinically during the latter part of pregnancy, only to relapse to a hypothyroid state after delivery, is frequently cited as evidence that thyroxinelike compounds cross the placenta. SmithI discussed altered development, function and size of the fetal thyroid relative to maternal
Volumc~
90
h-umber
4
Thyroid
function
in pregnancy
479
2-
APPRCP~MATE WEEKS AFTER LAST MENSTW’L
f’ERC0
kz=
Fig. 2. Atypical BE1 patterns of 14 women with nonplateau BEI’s (Table II). (For clarity BEI’s of only 9 women are plotted.) Heavy lines represent mean 2 2 S.D. of 100 per cent of BEI’s of control group (Table I) in normal reproductive age of 18 through 34 years. A, B, C, D, had low BEI’s soon after registration, with normal BEI’s for pregnancy from the twenty-eighth week to delivery. J had normal BEI’s which fell below normal just before delivery. K and L with high BEI’s soon after registration had BEI’s similar to those of the control group following the twenty-eighth week after the last menstrual period. M and N had high BEI’s near term and were delivered of premature infants by weight, at 38 and 36 weeks, respectively.
dietary iodine intake. Kelly and Snedden” confirm enlargement of the fetal thyroid in endemic goiter areas but include 2 definite references in the concept of unusual fetal thyroid overactivity as compensatory for underfunction of the maternal gland. In Christchurch, New Zealand, where 60 per cent of mothers had goiters, the neonate’s thyroid had enlarged “sometimes to a degree sufficient to interfere with normal flexion of the head at delivery.” In endemic goiter areas animals have similar disturbances. In Nepal, India, Bramley “saw a goat bring forth a kid with a goitre as large as its head.” These observations from 3 diRerent geographical areas outside the United States are of interest in relation to experiences in this laboratory. From widely scattered areas of the United States serum BEI’s have been requested because of enlargement of the thyroid of pregnant women, infants, and adolescent girls and boys. The greatest ma-
jority had low BEI’s and regression of thyroid size with appropriate replacement therapy. Reports of other investigators add to the concept that the high incidence of normal maternal BEI’s during the last trimester indicate that fetal thyroid function may complement maternal thyroid function. Maternal serum TBG doubles approximately during pregnancy.lO Thus sufficient TBG is in the maternal circulation to accept and bind any thyroxine available from the fetus. Since serum fetal TBP fractions are lower in concentration than materna1 serum TBP fractions, the gradient of transport of thyroxine could vary from fetus to fetus, or woman to woman. Fisher and Oddie” summarized data that infants have significantly higher thyroxine secretion rates than adults. On a micrograms per kilogram per day basis the infant’s secretion rate was seven times that of an adult. These calculations are com-
480
Man,
patiblc with Cottino’s”” calculated, high degradation rates of thyroxine-like compounds during infancy. Studies of Pickering and associates”“. ” on fetal and maternal thyroid secretion rates in the macaque monkey and on mono-, diiodotyrosine, and thyroxine content of thyroid glands suggest an increasing fetal thyroxine secretion rate during the last weeks in utero. Studies of Andreoli and Kobbins” on young fetuses, only 8 to 20 weeks in gestational age, dovetail earlier into this framework. In such early fetuses PBI’s were as low as 1.4 to 1.6 pg per 100 ml. In contrast to the complementary effects of maternal and fetal thyroid function on third trimester maternal serum BEI’s, are many reports that maternal thyroid dysfunction is significant in delivery of prematurely underweight or of heavy, possibl) postmature neonates. Dokumov17 is one of numerous investigators who have discussed course of pregnancy, labor and the puerperium in relation to hypothyroidism, endemic goiter, and hyperthyroidism. Such data tend to incriminate maternal thyroid dysfunction as one cause of abnormal length of gestation. It is important in observations of liose. Kussell and Starr’” that their normal maternal PBI’s at delivery of premature infants should not quickly be misinterpreted as diagnostic of the woman’s thyroid function throughout pregnancy. Data presented in this article include delivery of 3 premature infants born to women with nonplateau BEI’s during gestation (Table II, I, M, and N‘I. Four neonates or stillbirths under 2,500 grams in weight were born to 4 of the 7 women with nonplateau BET’s in the series of Greenman
REFERENCES
1. 3. 3.
4. 5.
Ortoher 15, 1964 Am. J. Ohst. & Cynec.
Reid, and Jones
Peters, J. P., Man, E. B.. and Heinemann. M.: Obst. & Cvnec. Surv. 3: 647. 1948. Lum, J., and Man. E. B.: Yale .J. Biol. Med. 28: 10-5; 1955. Man. E. B.. Shaver. B. ,4.. Tr.. and Cooke. R. E.: AM. J. ORST. & C~NEC. 75: 738. 1958. Man, E. B.. and Bondy, P. K.: J. CIin Endocrinol. 17: 1373. 1957. Man, E. B.: J. Lab.’ & Clin. Med. 59: 528. 1962.
and associates” (Table II). As yet, it is too early to compare 8 month psychological and 1 year neurological development of infants born to the control women and to the women with atypical patterns of serum thyroxine-like iodine during pregnancy. However, seven of the children, born to the 14 women with nonplateau BEI’s have aroused suspicions of retarded neurological or psychological development. Summary
Thirty euthyroid women between the inclusive ages of 18 through 34 years exhibited d urmg ’ the first trimester serum BEI’s increased above nonpregnant concentrations and maintained at plateau elevations until delivery. Elevations were similar to those for a different population in New Haven, Connecticut. For both euthyroid series serum BEI’s, except for sporadic determinations with a few BEI’s as high as 10.4. were hetween 5.5 and 9.5 pg per 100 ml. Fourteen women, with 11 in the same age range as the 30 controls, failed to follow a plateau elevated pattern of serum BEI’s during pregnancy. Eleven of these 14 women with serum BEI’s below or above the normal range before the third trimester had normal BEI’s for pregnancy near delivery. These data demonstrate that thyroid function during pregnancy can not be evaluated by a single thyroid function test during the last trimester. In spite of the usual plateau elevation of serum PBI or BE1 several thyroid function tests, at different stages of pregnancy, are requisite for diagnosis of maternal thyroid function throughout gestation.
6.
7.
8. 9. 10.
Benson, R. C.. Pickering, D. E., Kontaxis, N. E., and Fisher. D. ‘4.: Obst. & Gynec. 14: 11, 1959. Freedberg, I. M.. Hamolskv. M. W.. and Freedberg, A. S.: New Englazd J. Med: 256: 505. 551. 1957. Hamolsky, M. W.. and Freedberg. .4. S : New England J. Med. 262: 23, 70, 129, 1960. Herbst, A. L.: and Selenkow, H. A.: Obst. & Gynec. 21: 543, 1963. Dowling, J. T.. Freinkel, N.. and Ingbar, S. H.: J. Clin. Invest. 35: 1263, 1956.
Thyroid
11. 12.
13. 14. 15.
16. 17. 18. 19.
Nicoloff, J. T., Nicoloff, R., and Dowling, J. T.: J. Clin. Invest. 41: 1998, 1962. Man, E. B.: In Sunderman, F. W., and Sun&man, F. W., Jr., editors: Evaluation of Thyroid and Parathyroid Functions, Philadelphia, 1963, J. B. Lippincott Co., p. 77. Ingbar, S. H.: JI Clin. Invest. 40: 2053;1961. Drever. D. T.. and Man. E. B.: T. Clin. Endbchnol. c ‘Metab. 22: il, 1962. ” Greenman, G. W., Gabrielson, M. 0.. Howard-Flanders, J., and Wessel, M. A.: New Enaland T. Med. 267: 426. 1962. Rose, H.,” Russell, K. P., and Starr, P.: AM. J. OBST. & GYNEC. 86: 767, 1963. Dokumov, S. I.: Acta Endocrinol. 38: 161, 1961. Zondek, H.: Acta med. scandinav. 103: 251, 1940. Smith, C. A.: In The Physiology of the Newborn Infant, ed. 3, Springfield, Illinois,
20.
21. 22.
23. 24. 25.
function
in
pregnancy
Charles C Thomas, Publisher, p. 1951, 307. Kelly, F. C., and Snedden, W. W.: In Endemic Goitre, World Health Organization. Switzerland, 1960, pp. 27-233, Prevalence and Geographical Distribution of Endemic Goitre. Fisher, D. A., and Oddie, T. H.: J. Clin. Endocrinol. 23: 811, 1963. Cottino, F., Colombo, G., Ferrara, G. C.> and Costa, A.: Panminerva Med. 3: 471. 1961. Pickering, D. E., Settergren, K. F., and Kontaxis. N. E.: 1. Endocrinol. 23: 261. 1961. Pickering. D: E., and Kontaxis, ‘N. E.: J. Endocrinol. 23: 267, 1961. Andreoli, M., and Robbins, J.: J. Clin. Invest. 41: 1070, 1962. 50 Maude ProGdence,
Street Rhode
Island
02908
Erratum In the article, “The Milk-ejecting Effect Induced by Oxytocin and Vasopressin Human Pregnancy,” by Nestor L. Sala, M.D., in the July 1 issue of this JOURNAL, sentence on page 628 should read, “During this period, which extends until the Table I of this same article, page 630, the last column should read: Differences > < < <
between (P) 0.1 0.01 0.02 0.05
481
.
During the last . . . ” In