Endocrine Journal 2013, 60 (9), 1095-1106

Original

Gestational changes of thyroid function and urinary iodine inthyroid antibody-negative Japanese women
Yozen Fuse1), Yoshimasa Shishiba2) and Minoru Irie2)
1)
2)

Department of Health Policy, National Research Institute for Child Health and Development, Tokyo 157-8535, JapanFoundation for Growth Science, Tokyo 113-0033, Japan

Abstract. Iodine is an essential nutrient for thyroid hormone synthesis, and iodine deficiency especially in pregnant andlactating women results in serious damage to their infants. To characterize iodine nutrition throughout gestation by using
a food frequency questionnaire (FFQ) and urinary iodine concentration (UIC) measurement, and to establish appropriate
gestational age-specific reference ranges for serum TSH and FT4 in thyroid autoantibody (ThAb) negative euthyroid
Japanese women, a total number of 563 pregnant women including 422 subjects with negative ThAbs, 105 postpartum
women and their 297 newborn infants were included in the study. Dietary iodine intake (DII) was evaluated by FFQ.
Serum TSH, FT4 and UIC were sequentially determined in the three trimesters of pregnancy and at the 31st postpartum day.
The overall median UICs throughout pregnancy and in the postpartum period were 224.0 and 135.0μg/L, respectively,
suggesting sufficient iodine nutrition. The median DII was 842.4μg/day in pregnant women. In the longitudinal study, themedian UIC in the first trimester (215.9μg/L) significantly decreased in the second trimester (136.0μg/L). The prevalenceof pregnant women with a UIC below 150μg/L was 31.6% and that in lactating women with a UIC below 100μg/L was
33.3%. The pattern of gestational change in serum TSH and FT4 was comparable to that in iodine-sufficient areas. A
substantial percentage of women might be at risk for iodine deficiency if there is a restriction of iodine-rich foods. However,iodine supplementation for pregnant women must be carefully balanced against the risk of iodine excess particularly inJapan. Further research in larger samples is needed.
Key words: Iodine, TSH, FT4, Food frequency questionnaire, Pregnancy

IODINE is an essential nutrient for thyroid hormone
synthesis, and iodine deficiency remains a major global
threat to health and development especially in fetuses,
newborns and young infants [1]. In 2013, as definedby a national or subnational median urinary iodine(UI)
concentration of 100–299μg/L in school-aged children, 111 countries have sufficient iodine intake and 30
countries remain iodine-deficient [2].
The major source of iodine intake is daily foods andmore than 90 percent of all ingested iodine is excreted inurine [3]. Therefore, the median urinary iodine concentration (UIC) is a reliable biomarker for recent iodine
intake and used to classify a population’s iodine status[4]. An alternative method that is considered to be the‘gold standard’ to directly assess nutrient intake is the
Submitted May 5, 2013; Accepted Jun. 4, 2013 as EJ13-0184
Released online in J-STAGE as advance publication Jun. 28, 2013

Correspondence to: Yozen Fuse, M.D., Ph.D., Savai Clinic, 1225-1
Kawashimacho, Hodogaya-ku, Yokohama 240-0045, Japan.
E-mail: fuseyz@savaiclinic.jp©The Japan Endocrine Society

diet study including 24-hour dietary recall, food record
method, duplicate meal, dietary history and food frequency questionnaire (FFQ) [5]. There are limited data
regarding dietary iodine intake using FFQ [6-9], and in
pregnant women several studies have been carried out
in the UK [7], Italy [8] and Norway [9]. The approximate daily iodine intake estimated by FFQ was well correlated with either the 24-hour urinary iodine excretion(UIE) [9] or the iodine intake by 24-hour recall [7].
During and after pregnancy, daily iodine requirements are higher than those in non-pregnant adults
because of increased thyroid hormone production,
increased renal iodine excretion, iodine requirement
for a fetus and iodine secretion into breast milk. In
iodine-deficient areas, total body iodine stores decline
gradually during pregnancy and results in impaired
maternal and fetal thyroid hormone synthesis [10-12].
Recently iodine intake during gestation is reported to
be insufficient, even in the areas that have been iodine
sufficient for several decades [13-14] or where thereFuse et al.

1096

are iodine prophylaxis programs to promote the consumption of iodized salt [15-18]. The World HealthOrganization (WHO) [19], United Nations Children’s
Fund (UNICEF) [20] and the International Council
for Control of Iodine Deficiency Disorders (ICCIDD)
Global Network [21] have endorsed the policy ofiodine supplementation in pregnant and breast-feeding women. According to new guidelines of both theAmerican Thyroid Association (ATA) [22] and the
Endocrine Society [23] daily intake of 250μg iodine
has been advised for all pregnant and breast-feeding
women, not only in iodine-deficient areas but also
iodine-sufficient countries. However it is not clear if
this policy is appropriate and applicable in Japan, along-term iodine-sufficient country.
From the early 1990s to the present, there havebeen a number of reports on the iodine status during
pregnancy and lactation in the countries or regionswith various iodine statuses. However, few longitudinal studies on gestational changes of UIC and thyroid parameters have been carried out in iodine-replete regions. We have recently reported the reference
range and changing pattern of trimester-specific UIC
during and after pregnancy in Japanese women [24].
Our results suggested that the iodine status in Japanesepregnant and lactating women assessed by median UIC
was regarded as adequate according to WHO/UNICEF/ICCIDD-recommended criteria.
The purpose of the present study is to assess thenutritional status of iodine and gestational change of
UIC as well as iodine intake by using FFQ and UI measurement, and to determine a trimester-specific reference range of serum thyrotropin (TSH) and the freethyroxine (FT4) value in serum thyroid autoantibody(ThAb) negative Japanese pregnant women.

Materials and Methods
Subjects
As part of a larger study assessing iodine status in
Japanese, healthy pregnant and lactating women without known thyroid disease were consecutively recruitedfrom Yamaguchi Hospital in Funabashi City, Chiba
Prefecture between 2005 and 2006. The total population of this city was 570,000-590,000 in this period.
This hospital is a private women’s hospital and theaverage number of deliveries was 2,024 annually during the study period.

Study design
All the participants completed an iodine-specific
FFQ and provided one spot urine sample at the first
visit. In pregnant women blood and spot urine samples
were collected in the first, second and third trimesters.
Urinary iodine, serum TSH and FT4 concentrations
as well as two ThAbs, i.e. thyroperoxidase antibody(TPOAb) and thyroglobulin antibody (TgAb) were
measured and the subjects with thyroid autoantibodies
detected during the study were excluded from the reference interval analysis for serum TSH and FT4.
Serum and casual urine samples were kept frozen
at -30˚C before analysis. A heel-prick blood sample
was taken at 4.0±0.1 postnatal days from all infants.
Gestational dates were confirmed by ultrasound in thefirst trimester of pregnancy.
Ethical approval
The study was approved by the local ethics committee, and written informed consent was obtained fromeach of the participants at the initial study visit.
Daily dietary iodine intake assessed by FFQ
We have developed a semi-quantitative FFQ to estimate daily dietary iodine intake (DII) for Japanese. The
reproducibility and validity of iodine intake measurement by the FFQ used in this study were described indetail elsewhere [25]. It contained 50 different iodinerich food items classified in 10 categories with a specified serving size (Table 1). For each food item, participants indicated their average frequency of consumption
in the previous months by checking 1 of 10 frequency
categories ranging from “almost never” to “3 times/day.” The selected frequency category for each food
item was converted to a daily intake. Daily iodine intake
from each food was calculated on the basis of frequency
of consumption and iodine content of the specific foodand given in μg iodine per day. The iodine content infood stated in the Japanese Food Composition Table
2010 [26] was used, except for processed food where
new figures were used [27]. In our preliminary study,
daily DII and UIC were determined in 28 non-pregnant
healthy women without known thyroid disease using
the same method. Their mean (SD) age was 32.6 (4.6)
years (range, 22 to 39 years), and the median with interquartile range (IQR) values of daily DII and UIC were764.3 (545.4 to 1421.0) μg/day and 196.0 (115.3 to334.8) μg/L, respectively (unpublished data).

Thyroid function and iodine in pregnancy

1097

Table 1 Foods and iodine content in FFQ to estimate the iodine intake
Foods of food groups

Food items

Reference portion size

Iodine content (μg) /Portion size
1100.03240.06848.6252.0
1143.4
778.8
156.0
121.9
31.5
18.1
6.3
120.0
9400.0
56.0
13.7
16.5
61.6
20.0
4.0
16.8
16.1
16.7
6.4
260.0
39.0
24.0
9.6
9.8
0 (53.2)*
94.5 (103.9)*
157.5 (258.3)*
63.0 (143.5)*
126 (109.3)*
157.5 (268.8)*
216.1
51.4
51.4
43.7
7.8
23.2
23.2
22.5
100.0
270.6
24.0
14.0
650.0
78.0
16.5
576.3

10g
1. Tsukudani 1
30g
2.
Kobumaki 2
Kombu(Laminariaceae)
3. Tororo Kombu (tangle flakes)
3g
4. Soup with Kombu extract
200mL
5. Wakame Salad or Vinegarded Wakame
20g
Wakame
6.
Miso
or
clear
soup
10g
(Undaria pinnatifida)
7. Fruit-bearing leaves (Mekabu)
40g
Algae
8. Purple laver, Seasoned and toasted
2g
Nori
9.
Purplelaver,
Toasted
1.5g(Seaweed)
10g
10. Hitoegusa Tsukudani 3
30g
11. Mitsumame 4Agar jelly
50g
12. Tokoroten5
13. Hijiki
20g
Other brown algae
14. Mozuku
40g
15. Horse mackerrels
65g
16. Sardines
50g
17. Eel80g
18. Skipjack
80g
19. Salmons
80g
20. Mackerels
80g
21. Pacific saury
75g
Fishes & Shell fishes
22. Shishamo (spirinchus lanceolatus)
30g
23. Sea breams
80g
24. Cod fishes
100g
25. Walleye pollack (Tarako)
30g
26. Yellowtail
100g
27. Tunas
80g
28. Oysters
15g
29. Miso-soup
150mL
Soup
30. Clear soup
150mL
250mL
31. Noodles in hot broth (Kakeudon6, Kakesoba7)
Noodle
100mL
32. Dipping noodles (Tsukemen8)
200mL
33. Oden9One-pot dish (Nabemono)
250mL
34. One-pot dish (Yosenabe10, Sukiyaki, etc.)
35. Instant one-pot dish36. Instant clear soup
37. Instant soupPrepared foods
one meal
38. Instant miso-soup
39. Instant noodle
40. Chazuke11
41. Furikake12
42. Vinegar with Kombu extract
5mL
Seasonings & Spices
43. Soy sauce with Kombu extract
5mL
44. Salt with Kombu powder or extract
6g
45. Hen’s egg
50g
Eggs
46. Japanese quail’s egg
10g
50g
47. Iodine-riched egg13
48. Potato chips
30g
Confectioneries
49. Rice cracker (Shio-senbei)
15g
Tea
50. Kobu-cha (Kombu powder for drink)2g* one portion using homemade soup stock (ready-made soup stock)1, Kombu boiled in soy sauce; 2, a roll of tang containing dried fish in it cooked with sugar and soy sauce; 3, Nori simmered in soy
sauce and sugar; 4, a mixture of gelatin cubes, boiled beans and fruit topped with molasses; 5, a jelly-like food made from red seaweed(tengusa); 6, Udon noodles in broth; 7, Buckwheat noodles in soup; 8, Cold noodles accompanied by soup for dipping; 9, a dish containing
all kinds of ingredients cooked in a special broth of soy sauce, sugar, sake, etc.; 10, a mixed stew of chicken, seafood and vegetables
cooked at the table; 11, a quick dish of boiled rice with tea poured on it; 12, a tastily seasoned dried food for sprinkling on rice; 13, Eggs
produced by hens raised on feed containing seaweed1098

Fuse et al.

Analytical methods
Serum TSH and FT4 were measured by electrochemiluminescence immunoassay (ECLIA) using ECLusys
TSH and FT4 (Roche Diagnostics K.K., Tokyo, Japan).
Detection limit and reference ranges for Japanesegiven by the manufacturers were: TSH, 0.0022mU/L,
0.50 to 5.00mU/L; FT4, 0.01ng/dL, 0.90 to 1.7ng/dL.
Neonatal blood TSH was measured in the dried heel
blood spot samples by ELIZA using Enzaplate N-TSH(detection range; 0.5-80mU/L, Bayer Medical Ltd.
Tokyo, Japan). TPOAb and TgAb were measured inmaternal serum by RIA using TPOAb Cosmic II (detection limit and range; 0.04U/mL, 0.3 to 60U/mL) andTgAb Cosmic II (0.15U/mL, 0.3 to 100U/mL) (RSR
Limited, Cardiff, UK), respectively. The TPOAb andTgAb values above the manufacturer’s reference limit(0.3U/mL) were considered positive. Iodine in urine
was measured by the ammonium persulfate digestion
on microplate (APDM) method based on the Sandell
Kolthoff reaction [28]. The analytical sensitivity foriodine was 1.39μg/dL and the intra-assay and inter-assay coefficients of variation were 4.4 and 3.9%, respectively. The creatinine (Cr) concentration in urine wasestimated by colorimetric enzymatic assay. All urine
samples were assayed in duplicate. Urinary iodine concentration was expressed relative to creatinine excretion (μg/gCr) or as a concentration (μg/L) and SI units(μmol/L) in parentheses. (For conversion to SI units:
1μg/L=0.0079μmol/L).
Statistics
The results were presented as median, geometricmean, mean with SD, range or percentile. The urinary
iodine and serum TSH concentrations were distributed
asymmetrically and their logarithmically transformed
values were therefore used to normalize the distribution. The normality of the transformed data was tested
using the Kolmogorov-Smirnov test. For the reference
interval analysis means and standard deviations of logarithm of the concentration was then used as parameters to fit a normal distribution, and the 25th and 75th
percentiles (IQR, Interquartile range) were calculated
based on the standard normal distribution by transforming back to the linear scale. Differences between
paired data or groups were examined using one-way
analysis of variance (ANOVA) with Tukey’s multiple
comparison test, the Kruskal-Wallis test and Dunn’sMultiple Comparison Test. Differences between two
unmatched groups for normally and non-normally dis-tributed data were tested using the unpaired t test andMann-Whitney test, respectively. Simple linear regression analysis was used to test for correlations between
urinary iodine and serum TSH or FT4 concentrations.
A p-value less than 0.05 was considered significant.
All data were processed and statistically analyzed using
GraphPad Prism version 6.00 for Windows (GraphPad
Software, San Diego, CA, U.S.A.).
Epidemiological criteria of IDD in pregnant and lactating women
The median UIC expressed as micrograms of iodine
per liter (μg/L) is used for better comparison of the
population’s iodine status with the WHO-defined deficiency grades, and the iodine intake in pregnant andlactating women is regarded as follows: insufficient,below 150μg/L; adequate, 150 to 249μg/L; more thanadequate, 250 to 499μg/L; excessive, 500μg/L or higher
for pregnant women and insufficient, below 100μg/L;
adequate, 100μg/L or higher for lactating women [19].

Results
A total number of 563 pregnant and 105 lactating
women agreed to complete the study. All the lactating women were not identical with individuals fromthe study group of pregnant women. The mean±SDage of pregnant women was 30.9±4.2 (range, 19 to 43)
years and that of lactating women at 31.7±1.3 postpartum days was 30.7±4.4 (range, 20 to 40) years.
Venous blood samples were obtained from 484 of
the 563 pregnant women and after excluding 62 pregnant women with positive ThAb, 422 pregnant womenand their 297 newborn infants comprised the study
sub-group and their mean±SD age was 30.1±4.2 years(range, 19 to 43 years). In a cross-sectional study atotal of 695 blood samples from 422 subjects included
multiple measurements from the same subjects (221women provided single samples, 129 women provided
two samples, and 72 women provided three samples).
The mean±SD gestational age and birth weight of
the infants were 39.8±1.2 weeks (range, 36.7 to 43.7
weeks) and 3101.0±344.5g (range, 2260 to 4140g),
respectively, and the male/female ratio was 1.02.
There was no infant classified as a small-for-age neonate that was defined as a birth weight below the mean
minus 2.5SD on the growth curves of Japanese children reported in 2010 by the Japan Pediatric Society.
A total of 65 ThAb negative pregnant women serially1099

Thyroid function and iodine in pregnancy

Table 2 Dietary iodine intake, urinary iodine and creatinine concentrations during pregnancy and in postpartum
Category of Gestational Period
Number of subjects
Gestational weeks (mean±SD)
Dietary Iodine Intake (μg/day)Median (IQR)
Geometric mean (95%CI)
UIC (μg/L)
Median (IQR)
Geometric mean (95%CI)
UIC below 150μg/L,%
UIC exceeding 1000μg/L,%
Urine Creatinine (g/L)
Mean (SD)UIC (μg/gCr)
Median (IQR)
Geometric mean (95%CI)

First Trimester
166
8.9 (1.6)

Second Trimester
221
21.9 (4.6)

743.1* (434.4-1482) 945.9 (572.8-1556)
740.2* (646.3, 847.8) 916.2 (820.9, 1023)

Third Trimester
176
34.2 (3.3)

Postpartum
105
31.7 (1.3) a

876.2 (516.6-1420)
859.9 (766.2, 965)

1071 (690.5-1708)
1052 (919.1, 1204)

226.5* (144.8-434.5) 259.0* (120.5-660.0) 204.5* (116.0-459.0)
135.0 (82-258)
285.5* (239.8, 340.0) 277.8* (239.1, 322.9) 257.3* (218.6, 302.9) 161.3 (133.7, 194.7)
25.9
32.1
36.4
(33.3)b
13.9
14.5
13.1
4.8
†

1.38 (0.73)

0.99 (0.62)

0.92 (0.53)

0.92 (0.53)

186.6‡ (116.8-349.7) 272.6* (161.6-658.3) 259.0* (163.4-548.3) 159.2 (105.3-406.0)
247.9‡ (208.8, 294.4) 344.2* (298.4, 397.0) 339.4* (289.7, 397.6) 209.6 (173.1, 253.7)

The total number of subjects is 668. a, Postpartum days; b, Percentage less than 100μg/L; IQR, Interquartile range (25-75th
percentiles); SD, Standard Deviation; CI, Confidence Interval; Cr, Creatinine*, Different from postpartum (p<0.05); †, Different from the second and third trimester and postpartum (p<0.05); ‡, Different
from the second and third trimester (p<0.05)

provided three samples for TSH, FT4 and UI measurements in each trimester and comprised the longitudinal
study group. Their mean±SD age was 31.8±4.2 years.
Iodine status and gestational change of UIC in pregnant and lactating women
The UIC values in pregnant women were highlyvariable (18 to 16300μg/L) and the median (IQR)
value for the overall UI samples throughout pregnancy(mean±SD gestational week, 21.9±10.5) was 224.0(131.0 to 466.0) μg/L or 243.1 (149.0 to 531.7) μg/
gCr. In lactating women the median (IQR) UIC was
135.0 (82.0 to 258.0) μg/L or 159.2 (105.3 to 406.0)
μg/gCr. The percentage of subjects with a UIC below
150μg/L or above 1000μg/L was 31.6% and 13.9%,
respectively, while in postpartum samples the rates of
UIC below 100μg/L or above 1000μg/L were 33.3%
and 4.8%, respectively.
The median UIC values during pregnancy were significantly higher than that in postpartum women (204.5
to 259.0μg/L vs. 135.0μg/L). There were no significant
differences in the median and mean UIC values among
the three trimesters. The rate of the subjects with a
UIC below 150μg/L increased from 25.9 to 36.4% in
the third trimester (Table 2).
The median value of creatinine-adjusted UIC was
lowest in the first trimester (186.6μg/gCr) reflecting thehighest creatinine excretion (1.38g/L); it increased to272.6μg/gCr in the second trimester and subsequently
decreased slightly to 259.0μg/gCr in the third trimester
but remained above those in the first trimester and postpartum (159.2μg/gCr). A similar pattern was observed
for the mean UIC values (Table 2).
Dietary iodine intake during pregnancy and postpartum
The overall DII calculated by FFQ in pregnant andlactating women ranged from 35.7μg to 8.7mg/day.
The distribution of daily DII of pregnant women isshown in Fig. 1. The median (IQR) values were 842.4(495.7 to 1469.0) μg/day during pregnancy and 1071.0(690.5 to 1708.0) μg/day in the postpartum period. The
percentage of subjects with a daily DII below 250μg/
day or above 1100μg/day was 7.9% and 36.4%, respectively, in the pregnant women, while those of the lactating women were 2.8% and 49.5%, respectively. There
was no significant difference in the median DII value
among the four groups; however, the median value inthe first trimester group was significantly lower thanthat in the postpartum group (743.1 vs. 1071.0μg/day)(Table 2).
Daily DII was positively correlated with UIC, both
expressed as μg/L (Pearson’s r=0.09, p<0.0214) or μg/
gCr (Pearson’s r=0.11, p<0.0089) during pregnancy.
In each trimester there was no significant correlation

Fuse et al.

1100
60

Number of subjects

median value : 842.4μg/day

40

20

0

Fig. 1

100 500 1000

2000

3000
4000
5000
Dietary iodine intake (μg/day)

7000

8000

Frequency distribution of daily DII during pregnancy
The number of subjects is 563. The median dietary iodine intake determined by FFQ was 842.4μg/day.

2.0

3.0

*

*

2.0

FT4 (ng/dL)

4.0

TSH (mIU/L)

6000

1.5

*

*

2nd
Gestational Trimester

3rd

1.0

1.0
0.0

1st

2nd
Gestational Trimester

3rd

0.5

1st

Fig. 2 Changes in serum TSH and FT4 concentrations during pregnancy
The boxes represent median TSH and FT4 concentrations with IQR. Whiskers denote 10 to 90 percentile. The number of blood
samples is 181 in the first trimester, 181 in the second trimester and 333 in the third trimester. The mean (SD) gestational ages are 8.7 (1.2) weeks in the first trimester, 26.9 (4.1) weeks in the second trimester and 34.3 (2.3) weeks in the third trimester.
*, p<0.05 vs. first trimester.

of daily DII with maternal TSH, FT4 or neonatal TSH(data not shown).
Gestational change of serum TSH and FT4 in ThAb
negative pregnant women
The gestational change of serum TSH and FT4 concentrations is depicted in Fig. 2. Serum TSH concentration ranged from less than 0.005 to 7.34mU/L andthe median value increased from 0.92mU/L (IQR,
0.04 to 3.93) in the first trimester to 1.35mU/L (IQR,
0.43 to 3.01) in the second trimester and subsequently
decreased slightly to 1.17mU/L (IQR, 0.40 to 2.92) inthe third trimester. Serum FT4 concentration ranged
from 0.62 to 5.8ng/dL and the median FT4 concentration in the first trimester was 1.34ng/dL and decreased
to 0.98ng/dL in the second trimester and remained stable. A similar pattern was observed for the mean TSH
and FT4 values (data not shown).
Gestational trimester-specific reference range ofserum TSH, FT4 and UIC (Repeated measurement)
In 65 pregnant women the pattern of gestationalchange in serum TSH, FT4 and UIC was essentiallycomparable to that in our present cross-sectional study in1101

Thyroid function and iodine in pregnancy

Table 3 Gestational trimester-specific reference range of serum TSH, FT4 and UI concentrations in ThAb
negative pregnant women (Repeated measurement)
Category of Gestational Period
First Trimester
Second Trimester
Third Trimester
Gestational weeks, Mean (SD)
9.1 (1.7)
25.5 (5.2)
36.0 (0.6)
TSH (mU/L)Median (IQR)
0.95 (0.7-1.35)
1.11 (0.96-1.33)
1.12 (0.99-1.33)
Mean (95%CI)
0.90 (0.78, 1.03)
1.10* (1.03, 1.17)
1.12* (1.05, 1.2)
FT4 (ng/dL)
Median (IQR)
1.34 (1.12-1.76)
0.94 (0.78-1.11)
0.91 (0.82-1.12)
Mean (SD)1.43 (0.58)
0.94* (0.10)
0.94* (0.10)
UIC (μg/L)
Median (IQR)
215.9 (149.0-314.5)
136.0* (73.0-271.5)
147.9 (80.9-221.4)
Mean (95%CI)
243.2 (184.0, 321.8)
143.3* (107.4, 191.1)
155.9 (116.2, 208.9)
UIC (μg/gCr)
Median (IQR)
187.5 (110.7-327.0)
204.6 (117.4-372.0)
196.2 (124.8-468.7)
Mean (95%CI)
240.8 (177.5, 327.0)
238.2 (184.2, 308.0)
237.7 (182.4, 310.1)
The number of subjects is 65. Serum TSH and FT4 were measured by using ECLusys TSH and FT4 (Roche
Diagnostics K.K., Tokyo, Japan). IQR, Interquartile range (25-75th percentiles); SD, Standard Deviation; CI,
Confidence Interval; Cr, Creatinine *, Different from first trimester (p<0.05)

Fig. 2; however, there was a significant decrease of UIC
in the second trimester (215.9 vs. 136.0μg/L) (Table 3).
Relationship between serum TSH and FT4 concentrations
There was a significant negative correlation between
TSH and FT4 in all serum samples (Pearson r=-0.51,
p<0.0001) and in each trimester (1st trimester, Pearson
r=-0.63, p<0.0001; 2nd trimester, Pearson r=-0.21,
p=0.007; 3rd trimester, Pearson r=-0.42, p<0.0001).
Relationship between UIC and serum TSH or FT4
concentrations
The overall UIC during pregnancy was correlated
positively with serum TSH (Spearman r=0.1365,
p=0.0006) and negatively with FT4 concentrations(Spearman r=-0.1446, p=0.0003). There were significant direct correlations of UIC with serum TSH
concentrations in the third trimester (Spearman r =0.2724, p=0.0009, n=145) and with FT4 concentrations in the first trimester (Spearman r = -0.2074, p=
0.007, n=168).
Relationship between maternal TSH, FT4, UIC andneonatal TSH
Neonatal TSH concentration in 297 infants ranged
from 0.02 to 11.03mU/L and the median (IQR) and geometric mean (95%CI) of TSH values were 2.28mU/L(1.43 to 3.56) and 2.09mU/L (1.90 to 2.29), respectively. The recall rate was 0.67% (2 of 297 infants)

and no infant was diagnosed as being congenitally
hypothyroid.
There was significant correlation between neonatal
TSH and maternal UIC exclusively in the third trimester(Pearson r=0.1579, p=0.007, n=290), while neonatal
TSH was not correlated with maternal TSH nor FT4.

Discussion
The present study confirmed the previous findings byothers [29] and us [24] that iodine intake in Japanesepregnant and lactating women is regarded as adequate
according to WHO criteria. However, 31.6% of pregnant women and 33.3% of lactating women have UIC
less than 150μg/L or 100μg/L, respectively, which indicate insufficient iodine intake, although the median
UICs for all the subjects were 224.0μg/L in pregnant
and 135.0μg/L in lactating women. This observationsuggests that even in an iodine-sufficient area, an additional iodine supply might be necessary in pregnant
and lactating women who do not consume iodine-richfoods. The Endocrine Society recommends and emphasizes the need for routine supplementation of all pregnant women with adequate iodine in the form of prenatal vitamins containing 150-200μg iodine. However,in the present study more than two thirds of the pregnant women (36.4%) were ingesting iodine exceeding
1100μg daily, which is double the recommended nutrient intake for iodine in the US. Therefore, iodine supplementation for pregnant women must be carefully

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balanced against the risk of iodine excess particularly inJapan, an iodine-sufficient area. It is important to evaluate accurately the iodine status and the signs of iodine
deficiency in pregnant women and small children [30].
The primary sources of iodine in the United Statesand European countries are dairy products, iodized salt,
bread with iodate dough conditioners, eggs, and iodinecontaining supplements [6, 8-9, 31-32]. In Japan iodine
fortification of household salt is prohibited and major
food categories that contribute to dietary iodine include
marine products and processed foods that contain seaweed extracts. Our recent study of healthy adults indicated that 80.6% of total iodine resources were seaweeds
such as kelps and kombu, while 5.9 and 13.5% were fishand processed foods, respectively [25]. Japanese iodine
intake from seaweeds is highest in the world [33-34].
However, national survey data for iodine intake is not
currently available because iodine is not included as atarget nutrient in the national health and nutrition survey. According to our collaborative studies with WHO
in Tokyo and Hokkaido, the median UI value in schoolaged children is 281 to 288μg/L, suggesting a sufficient
iodine status with more than adequate iodine intake[35-37]. In addition, children with a high UI excretion
and increased thyroid gland volume were observed in acoastal area of Hokkaido [37].
In Japanese pregnant and lactating women the median
DII determined by FFQ was 842.4 and 1071.0μg/day,
respectively, and far higher than their median UIC values (224.0 and 135.0μg/L). Although the exact reason
for this discrepancy between the UIC and daily DII by
FFQ is not clear, there may be some factors other thanthe complexity of iodine physiology during pregnancy[11-12]. Firstly, in healthy non-pregnant adults approximately 90% of iodine of dietary origin is excreted inurine and 10% of iodine intake in faces. Secondly,
the UIC in a spot urine sample may vary up to threefold in an individual during a single day [30]. Thirdly,
the median UIC given as μg/L will be lower than the
median iodine excretion per 24 hours because the average urine volume passed by adults is more than one
liter in 24 hours. Therefore the UI excretion of groupsof healthy adults measured as μg/24h is often equal to
UI measured as μg/L×1.5 [30]. Fourthly, the FFQ retrospectively evaluates daily iodine intake over a periodof time, whereas the UIC reflects iodine intake over the
recent few days rather than usual intake. Lastly, it has
been reported that the level of iodine intake measured
by the FFQ tends to be overestimated and the reason is

not clear [6]. However, the FFQ can be used to classify subjects into low and high iodine intake groups[6]. Further studies are necessary to improve the accuracy of dietary intake by FFQ.
The ATA and Endocrine Society recommended that asustained iodine intake of 500 to 1100μg daily should be
avoided during pregnancy due to concerns on the potential
for fetal hypothyroidism [22-23]. In the US and Europe
the tolerable upper intake limits of iodine for pregnant
and lactating women are 1100 and 600μg/day, respectively [1], while in Japan it is determined as 2200μg/day[38]. Supporting data for this value is a case report ofneonates with thyroid dysfunction born to mothers whodaily ingested approximately 2.3-3.2mg of iodine during
pregnancy [39]. In our study the 90th percentile valueof daily DII was 2126μg/day and the ratio of pregnant
women with more than 1000μg of UIC was 13.9%, suggesting no possible risk of adverse health effect due toiodine excess in our subjects as a population.
The median UIC in our cross-sectional study was
highest as early as in the first trimester, then decreased
and remained stable until term without showing significant differences among the three trimesters. However,the longitudinal analysis of data revealed a significant decrease of UIC at mid-gestation. The gestational change of UIC has been reported from various
countries and the results are discordant irrespectiveof the iodine status of the study subjects or areas [24,40-53]. The peak UIC value is observed at the firsttrimester in Ireland [40-41], Switzerland [45], Bosnia
and Herzegovina [48], Iran [46], Sri Lanka [41],Tasmania (Australia) [47] and Japan [24], at the second trimester in Iran [44] and Mexico [50] or at thethird trimester in Sweden [42], France [53], Sudan [42]and Hong Kong [43]. With the progression of pregnancy, the median UIC either declined in Ireland [41],the United Kingdom [41], Switzerland [45], Bosnia
and Herzegovina [48], Iran [46], India [52], Tasmania(Australia) [47] and Japan [24] or increased in iodinedeficient areas from Spain [49], France [51, 53] andHong Kong [43]. However, a statistically significant
change was observed only in one study from Hong
Kong [43], and the median UICs were not different
between gestational stages in the studies from Sweden[42], northern Paris (France) [51], Sudan [42], Iran[44], Sri Lanka [41], Mexico [50] and Japan [24]. Allregions except Sudan and northern Paris are regarded
as optimal iodine status suggesting that under the situation of sufficient iodine intake the increased renal

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Thyroid function and iodine in pregnancy

UI excretion steadily decreases throughout gestation.
These variable results on UIC may reflect the difference in regional and/or individual iodine status i.e.,
initial thyroid iodine content and daily dietary iodine
intake, in alteration of renal threshold for iodine excretion, or in study design and sample size.
In normal pregnancy, as the direct consequence ofthe markedly increased serum TBG levels by estrogenstimulation, total serum thyroid hormone levels increasesignificantly from early gestation, reach plateau levels
by 20 weeks gestation and remain stable until term.
Serum FT4 substantially decreases with the progressionof gestation. The serum TSH level remains stable andcomparable to pre-gestation levels after the transient
decrease in the first trimester due to the thyrotrophic
effect of high hCG secretion and its reference range
is lower throughout pregnancy [10-11]. In our longitudinal study, TSH values in ThAb negative Japaneseare generally comparable to the reference range forserum TSH during pregnancy defined in populations
with optimal iodine intake recently reported by the
ATA [22]. Although slight but significant ethnic differences in serum TSH concentration have been reported[54], our median TSH values are not lower than in
Caucasian women. Free T4 reference intervals in pregnancy varied widely between methods and were also
influenced by the iodine status of the population. The
ATA recommended that method-specific and trimesterspecific reference ranges of serum FT4 are required ineach laboratory. Our results regarding the gestationalchange of FT4 and TSH values and negative correlation between serum TSH and FT4 during pregnancy
are consistent with the previous report in Japanese [55]using the same analytical method for TSH and FT4 as
ours. A similar correlation was reported in an area withinsufficient iodine intake from France [56], suggesting
the contribution to the maternal thyroid adaptation by
serum TSH in any iodine status.
There was a direct correlation of UI values with FT4
negatively and with TSH positively during pregnancy.
This finding is consistent with the recent report on UIC
in early gestation from Japan [29].
Data on the association of maternal UIC during pregnancy and postpartum with neonatal thyroid parameters are conflicting [24, 56-59]. In our study there wasa positive direct correlation between maternal UIC andneonatal TSH concentration exclusively in late pregnancy. However, no direct correlation of maternal UIC
with neonatal TSH concentration was observed in sev-

eral studies including our previous study [24], thosein the mildly iodine-deficient areas from Australia[57-58], and in the pregnant women with extremely
high UI excretion (1.2mg/L) in China [59], whose UIC
positively correlated with neonatal FT4 concentration.
The exact reason for the discrepancies is not clear andfurther large epidemiological studies are necessary in
different iodine statuses.
The strengths of the study include the assessment of
iodine intake by FFQ and the longitudinal measurementof urinary iodine and serum TSH and FT4 concentrationsin ThAb negative euthyroid subjects during pregnancy.
The study was limited by a local data with the relatively
small sample size of subjects, therefore iodine supplementation to all pregnant and breastfeeding womenshould be determined with caution in Japan.
In conclusion, this study is the first report regarding the iodine status throughout gestation by using dietstudy and UIC in an iodine-sufficient area and also provides the local reference range for serum TSH and FT4values during pregnancy. Although Japan has been
regarded as an iodine-sufficient or even excessive country, a substantial percentage of pregnant and lactating
women have a UIC below 100μg/L and might be at risk
for iodine deficiency if there is a restriction of iodinerich foods. Currently there are no national estimate ofiodine status among Japanese women of reproductive
age as well as in infants and children. Further researchon the iodine status of vulnerable populations in larger
samples and the development of reliable methods toselect individuals with low iodine intake are needed.

Acknowledgments
The authors gratefully acknowledge the contributionof Dr. Satoru Yamaguchi, Dr. Minoru Yamaguchi andall the staff in Yamaguchi Hospital. We are indebted to
Mr. Toshinori Ohashi, Hitachi Chemical Co., Ltd., for
his biochemical analysis of iodine. We wish to express
special thanks to Ms. Sheryn Mason for assistance inthe preparation of the manuscript.
This work was supported in part by research grants
from the Japanese Foundation of Growth Science inTokyo, Japan.

Disclosure
None of the authors have any potential conflicts on
interest associated with this research.

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Fuse et al.

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Erratum
Endocrine Journal
Vol. 60 (9): 1095-1106, 2013
Gestational changes of thyroid function and urinary iodine in thyroid antibody-negative Japanese women
Yozen Fuse, Yoshimasa Shishiba and Minoru Irie
Table 3 contains some typographical errors. Median (IQR) of FT4 should be median (5-95th percentile) andthe median (IQR) values of TSH are replaced with median (5-95th percentile) values.
The correct version of Table 3 is given below:

Table 3 Gestational trimester-specific reference range of serum TSH, FT4 and UI concentrations in ThAb
negative pregnant women (Repeated measurement)
Category of Gestational Period
First Trimester
Second Trimester
Third Trimester
Gestational weeks, Mean (SD)
9.1 (1.7)
25.5 (5.2)
36.0 (0.6)
TSH (mU/L)Median (5-95th percentile)
0.95 (0.44-1.69)
1.11 (0.81-1.48)
1.12 (0.81-1.55)
Mean (95%CI)
0.90 (0.78, 1.03)
1.10* (1.03, 1.17)
1.12* (1.05, 1.2)
FT4 (ng/dL)
Median (5-95th percentile)
1.34 (1.12-1.76)
0.94 (0.78-1.11)
0.91 (0.82-1.12)
Mean (SD)1.43 (0.58)
0.94* (0.10)
0.94* (0.10)
UIC (μg/L)
Median (IQR)
215.9 (149.0-314.5)
136.0* (73.0-271.5)
147.9 (80.9-221.4)
Mean (95%CI)
243.2 (184.0, 321.8)
143.3* (107.4, 191.1)
155.9 (116.2, 208.9)
UIC (μg/gCr)
Median (IQR)
187.5 (110.7-327.0)
204.6 (117.4-372.0)
196.2 (124.8-468.7)
Mean (95%CI)
240.8 (177.5, 327.0)
238.2 (184.2, 308.0)
237.7 (182.4, 310.1)
The number of subjects is 65. Serum TSH and FT4 were measured by using ECLusys TSH and FT4 (Roche
Diagnostics K.K., Tokyo, Japan). IQR, Interquartile range (25-75th percentile); SD, Standard Deviation; CI,
Confidence Interval; Cr, Creatinine *, Different from first trimester (p<0.05)