Exposure to the Chinese Great Famine in Early Life and Thyroid Function and Disorders in Adulthood: A Cross-Sectional Study

Abstract

Background:

Malnutrition in early life may permanently change the structure and function of the body, which lead to a number of diseases in adulthood. The effect of famine exposure during the early life on thyroid function and disorders remains unclear. This study investigated the association between exposure to the Great Chinese Famine (1959–1961) in early life and thyroid function and disorders in adulthood.

Methods:

Nine thousand eight hundred eighty-one subjects with appropriate birth dates derived from the Thyroid disorders, Iodine status, and Diabetes Epidemiological survey were included. Thyroid function and disorders were defined by the test results of blood sample and ultrasonography of all participants. Associations between famine exposure in early life and thyroid function and disorders in adulthood were assessed with binary logistic regression and linear regression.

Results:

Participants exposed to the Great Chinese Famine during the fetal stage was associated with a higher thyrotropin (TSH) level in adulthood (β = 0.024; p = 0.038), compared with the nonexposed participants. The association was significant among rural participants (β = 0.039; p = 0.02) but not in urban participants (β = 0.005; p = 0.77). Fetal-exposed group did not show a higher risk of thyroid disorders than the age-matched balanced control group, including overt hyperthyroidism, subclinical hyperthyroidism, overt hypothyroidism, subclinical hypothyroidism, autoimmune thyroiditis, and thyroid nodules (p > 0.05).

Conclusions:

Famine exposure during the fetal stage was associated with a higher TSH level in adulthood. The fetal stage could be the critical period for programming the pituitary–thyroid axis.

Introduction

The fetal origins hypothesis proposes that disorders originate through developmental plasticity, whereby malnutrition during the fetal stage, infancy, and early childhood permanently change the structure and function of the body (1). Famine research is a common method of evaluating this hypothesis in humans. The Great Chinese Famine, which lasted three years, from 1959 to 1961, affected almost all people living in the Chinese mainland and resulted in ∼30 million excess deaths (2).

Previous studies have found that famine exposure during the fetal stage significantly increased the risks of cardiovascular and metabolic diseases in adulthood (3,4), which suggested that famine exposure during the fetal stage might have effect on fetal programming. Previous studies also have reported that the hypothalamic–pituitary–adrenal (HPA) axis and pituitary–thyroid axis can be affected by prenatal malnutrition (5 –8), which indicated that the fetal stage might be a crucial time for programming the hormone axis. However, famine exposure during the fetal stage have not shown an association with the HPA axis activity in adulthood in previous famine studies (9,10), and limited famine study has investigated the relationship between famine exposure and thyroid function in adulthood (11).

The Thyroid disorders, Iodine status, and Diabetes Epidemiological survey (TIDE study) is a national cross-sectional study, covering all 31 provinces of Chinese mainland. The study was conducted from 2015 to 2017. In this study, 9881 subjects with appropriate birth dates were selected from the TIDE study to examine the association between fetal famine exposure and thyroid function and disorders in adulthood.

Methods

Study design and population

The TIDE study included all 31 provinces of Chinese mainland with a sample of 75,880 individuals according to the age and sex composition and urban–rural ratio of each community in 2010 China's national census data (12). The study was conducted from 2015 to 2017 and was designed to evaluate the current situation of iodine nutrition and the prevalence of thyroid disorders in Chinese mainland, especially in different geographical locations and subpopulations. The study were approved by the Medical Ethics Committee of China Medical University.

The Great Chinese Famine lasted three years, from 1959 to 1961, but the exact starting and ending dates of the famine in each of the provinces are not clear. To minimize misclassification bias, 9881 subjects born on October 1, 1956 to September 30, 1964 with analyzable data were selected from the TIDE study. Participants were categorized into five groups according to their birth dates. We defined participants born between October 1, 1956 and September 30, 1958 as the early childhood-exposed group; participants born between October 1, 1959 and September 30, 1961 as the fetal-exposed group; participants born between October 1, 1962 and September 30, 1964 as the nonexposed group; the other participants born between October 1, 1958 and September 30, 1959 and participants born between October 1, 1961 and September 30, 1962 were defined as the potentially exposed group A and potentially exposed group B separately, because it was not possible to determine their exposure to famine.

Using the excess death rate (EDR) of 100.0% as a threshold, all provinces were categorized into severely affected areas (EDR ≥100.0%) and less severely affected areas (EDR <100.0%), except for Tibet, which had no EDR records for the famine period (13). The research protocols were approved by the Medical Ethics Committee of China Medical University. All subjects provided written informed consent after a thorough explanation of the research procedures.

Diagnosis of thyroid disorders

Blood samples were collected from participants after an overnight fasting to measure the concentrations of thyroid hormones and autoimmune antibodies. Serum thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb) were measured, using electrochemiluminescence immunoassay on a Cobas 601 analyzer (Roche Diagnostic, Switzerland), in a central laboratory in Shenyang. Free thyroxin (fT4) and free triiodothyronine (fT3) levels were measured only if the TSH level was outside the reference range. One or more nodules (>5 mm) without goiter on B-mode ultrasonography was defined as thyroid nodules.

Test kit manufacturers provided the diagnostic criteria for thyroid dysfunction or thyroiditis. The definition of overt hyperthyroidism was TSH <0.27 mIU/L, and fT4 > 22.0 pmol/L or fT3 > 6.8 pmol/L; subclinical hyperthyroidism was TSH <0.27 mIU/L, and fT4 and fT3 within the normal range (fT4 within 12.0–22.0 pmol/L; fT3 within 3.1–6.8 pmol/L); overt hypothyroidism was TSH >4.2mIU/L, and fT4 < 12.0 pmol/L; subclinical hypothyroidism was TSH >4.2 mIU/L, and fT4 within 12.0–22.0 pmol/L, TPOAb positive was TPOAb >34 IU/mL; TgAb positive was TgAb >115 IU/mL; and autoimmune thyroiditis (AIT) was TPOAb >34 IU/mL or TgAb >115 IU/mL.

Covariates

Demographic characteristics, including birth date, sex, current smoking status, education level, living region, and family income level, were measured by self-reports. Race/ethnicity was categorized as Han or not. Education levels was categorized as junior school and below and high school or above. Family income was categorized into less than or equal to 30,000 Chinese Yuan per year and more than 30,000 Chinese Yuan per year. Participants who smoked at least one cigarette per day were defined as current smoker. Body weight and height were measured by trained health workers according to standard protocols. Body mass index (BMI) was calculated according to the measured body weight and height. Systemic obesity were defined according to the World Health Organization (WHO) criteria (systemic obesity: BMI ≥30.0 kg/m²; overweight: BMI ≥25.0 and <30.0 kg/m²) (14).

Statistical analysis

In descriptive analysis, continuous variables are expressed as means ± standard deviations and categorical variables are expressed as frequencies and percentages. The Kruskal–Wallis test and Mann–Whitney U test were used for continuous variables with a skewed distribution and chi-square test was used for categorical variables.

As there were no overlaps in the birth dates among the five groups of participants, the age adjustments may have no impact on the risk estimates (15). To control the effect of age differences, which was a potential source of bias because age is a known risk factor for multiple chronic diseases, we generated an age-balanced control group by combining the nonexposed group and early childhood-exposed group. The mean age of age-balanced group was 55.6 years, which was close to the mean age of fetal-exposed group, which was 56.0 years.

We used binary logistic regression models to estimate the adjusted odds ratios (OR) with confidence interval (CI) of the risks for thyroid disorders in the fetal-exposed group using the other groups as the control. Multiple linear regression analyses were used to estimate the levels of TSH, TgAb, and TPOAb between the exposed and nonexposed groups. Analyses were adjusted for sex, living region, race/ethnicity, famine severity, education level, household income, current smoking status, and BMI.

The Statistical Package for Social Science (SPSS) version 22.0 (IBM Corporation, Armonk, NY, USA) was used to perform the statistical analyses. p-Value with two sides of less than 0.05 was considered as statistically significant.

Results

Table 1 presents the general characteristics of the participants selected from the TIDE study by birth dates. Among these 9881 participants, 19.0% participants were exposed to the Great Chinese Famine in fetal stage, and 25.3% participants were exposed in early childhood. The overall prevalence of thyroid disorders in the participants were 0.8% (79 cases) of overt hyperthyroidism, 0.6% (57 cases) of subclinical hyperthyroidism, 1.5% (144 cases) of overt hypothyroidism, 16.3% (1612 cases) of subclinical hypothyroidism, 10.5% (1036 cases) of TgAb positive, 11.0% (1087 cases) of TPOAb positive, 15.8% (1560 cases) of AIT, and 29.9% (2932 cases) of thyroid nodules.

Table 1.

Basic Characteristics of Study Population According to the Chinese Famine Exposure

	Early childhood-exposed	Potentially exposed A	Fetal-exposed	Potentially exposed B	Nonexposed	p
Birth date	January 10, 1956 to September 30, 1958	January 10, 1958 to September 30, 1959	January 10, 1959 to September 30, 1961	January 10, 1961 to September 30, 1962	January 10, 1962 to September 30, 1964
N	2496	928	1875	1220	3362
Age (years)/mean (SD)	58.94 (1.04)	57.48 (0.96)	56.00 (1.02)	54.45 (0.88)	53.05 (1.02)	<0.001
Sex, n (%)						0.04
Men	1262 (50.6)	443 (47.7)	888 (47.4)	570 (46.7)	1572 (46.8)
Women	1234 (49.4)	485 (52.3)	987 (52.6)	650 (53.3)	1790 (53.2)
Region, n (%)						<0.001
Urban	1337 (53.6)	506 (54.5)	991 (52.9)	555 (45.5)	1682 (50.0)
Rural	1159 (46.4)	422 (45.5)	884 (47.1)	665 (54.5)	1680 (50.0)
Race/ethnicity, n (%)						0.28
Han	2249 (90.1)	828 (89.2)	1657 (88.4)	1085 (88.9)	3027 (90.0)
Other	247 (9.9)	100 (10.8)	218 (11.6)	135 (11.1)	335 (10.0)
Famine severity, n (%)						<0.001
Severely affected area	824 (33.8)	268 (30.1)	519 (28.8)	394 (33.5)	1231 (37.7)
Less severely affected area	1611 (66.2)	623 (69.9)	1281 (71.2)	781 (66.5)	2033 (62.3)
Education, n (%)						<0.001
Junior school and below	1509 (60.7)	514 (55.7)	974 (52.3)	690 (56.8)	1891 (56.5)
High school and above	976 (39.3)	408 (44.3)	890 (47.7)	524 (43.2)	1456 (43.5)
Self-reported family income per year, n (%)						0.06
≤30,000 Chinese Yuan	1263 (51.1)	480 (52.4)	939 (50.6)	622 (51.5)	1604 (48.2)
>30,000 Chinese Yuan	1207 (48.9)	436 (47.6)	918 (49.4)	585 (48.5)	1725 (51.8)
Current smoker, n (%)	759 (30.4)	265 (28.6)	582 (31.0)	350 (28.7)	968 (28.8)	0.32
Height (cm)/mean (SD)	161.74 (8.36)^{^*}	161.90 (8.14)	162.22 (8.18)	162.03 (8.23)	162.59 (8.05)	0.01
Weight (kg)/mean (SD)	65.02 (11.21)^{^*}	65.35 (11.06)	65.52 (11.70)^{^*}	65.97 (11.87)	66.29 (11.54)	0.001
BMI (kg/m²)/mean (SD)	24.79 (3.39)^{^*}	24.88 (3.41)	24.83 (3.61)^{^*}	25.04 (3.63)	24.99 (3.42)	0.05
Overweight/obesity, n (%)	1090 (43.8)^{^*}	426 (46.1)	838 (44.8)	585 (48.1)	1568 (46.8)	0.06
Overt hyperthyroidism, n (%)	17 (0.7)	3 (0.3)	15 (0.8)	14 (1.1)	30 (0.9)	0.26
Subclinical hyperthyroidism, n (%)	12 (0.5)	7 (0.8)	12 (0.6)	12 (1.0)^{^*}	14 (0.4)	0.19
Overt hypothyroidism, n (%)	32 (1.3)	13 (1.4)	30 (1.6)	28 (2.3)^{^*}	41 (1.2)	0.09
Subclinical hypothyroidism, n (%)	422 (16.9)	139 (15.0)	282 (15.0)	209 (17.1)	560 (16.7)	0.29
TgAb positive, n (%)	257 (10.3)	95 (10.2)	181 (9.7)	150 (12.3)	353 (10.5)	0.21
TPOAb positive, n (%)	257 (10.3)	92 (9.9)	212 (11.3)	158 (13)	368 (10.9)	0.12
AIT, n (%)	386 (15.5)	143 (15.4)	299 (15.9)	213 (17.5)	519 (15.4)	0.52
Thyroid nodules, n (%)	803 (32.4)^{^*}	290 (31.5)^{^*}	576 (30.9)^{^*}	351 (28.9)	912 (27.4)	0.001
TSH (mIU/L)/mean (SD)	3.01 (3.11)	3.10 (4.30)	3.16 (5.38)	3.36 (4.95)	2.98 (3.05)	0.14
TgAb (IU/mL)/mean (SD)	79.74 (329.68)	77.35 (306.28)	85.06 (375.93)^{^*}	92.37 (370.72)^{^*}	70.44 (279.35)	0.11
TPOAb (IU/mL)/mean (SD)	33.4 (87.28)^{^*}	31.73 (86.97)^{^*}	36.2 (96.45)	39.96 (98.11)	35.51 (90.73)	0.003

There were 49 missing values of education; 102 missing values of income; 21 and 29 missing values of height and weight; 70 missing values of thyroid ultrasonography.

^{^*}Compared with the nonexposed cohort, p < 0.05.

AIT, autoimmune thyroiditis; BMI, body mass index; SD, standard deviation; TgAb, thyroglobulin antibodies; TPOAb, thyroid peroxidase antibodies; TSH, thyrotropin.

The fetal-exposed group had a higher mean level of TSH than the nonexposed group, but this was not statistically significant. Compared with the nonexposed group, the fetal-exposed group had a higher mean level of TgAb and the early childhood-exposed group had a lower level of TPOAb, but the prevalence of TgAb positive and TPOAb positive were not significantly different between the exposed and nonexposed groups. As age was a known risk factor for thyroid nodules, the prevalence of thyroid nodules was higher in older groups. In addition, younger participants had higher education level, weight, BMI, and prevalence of overweight/obesity. No significant difference in proportions of current smoking status was found between the exposed and nonexposed groups.

Table 2 shows the association between fetal famine exposure and the risks of thyroid disorders using different control groups. Compared with the age-balanced control group, the fetal-exposed group did not show a significantly different risk of thyroid disorders (p > 0.05), including overt hyperthyroidism (OR = 0.91 [CI 0.49–1.69]), subclinical hyperthyroidism (OR = 1.32 [CI 0.62–2.78]), overt hypothyroidism (OR = 1.14 [CI 0.72–1.82]), subclinical hypothyroidism (OR = 0.93 [CI 0.80–1.08]), TgAb positive (OR = 0.92 [CI 0.76–1.10]), TPOAb positive (OR = 1.04 [CI 0.87–1.23]), AIT (OR = 1.03 [CI 0.89–1.19]), or thyroid nodules (OR = 0.98 [CI 0.87–1.11]). All ORs were adjusted for sex, living region, race/ethnicity, famine severity, education level, household income, current smoking status, and BMI.

Table 2.

Associations Between Fetal Famine Exposure and Thyroid Disorders with Different Control Groups

Fetal-exposed group	Control groups		OR [CI]	p
No. of cases/simple size (%)	Control groups	No. of cases/simple size (%)	OR [CI]	p
Overt hyperthyroidism
15/1875 (0.8)	Nonexposed	30/3362 (0.9)	0.79 [0.41–1.53]	0.48
	Potentially exposed B	14/1220 (1.1)	0.60 [0.28–1.30]	0.20
	Potentially exposed A	3/928 (0.3)	2.13 [0.60–7.56]	0.24
	Early childhood-exposed	17/2496 (0.7)	1.17 [0.55–2.49]	0.68
	Age-balanced	47/5858 (0.8)	0.91 [0.49–1.70]	0.77
Subclinical hyperthyroidism
12/1875 (0.6)	Nonexposed	14/3362 (0.4)	1.30 [0.57–3.00]	0.53
	Potentially exposed B	12/1220 (1.0)	0.78 [0.30–2.01]	0.61
	Potentially exposed A	7/928 (0.8)	0.65 [0.25–1.73]	0.39
	Early childhood-exposed	12/2496 (0.5)	1.21 [0.50–2.93]	0.68
	Age-balanced	26/5858 (0.4)	1.28 [0.61–2.71]	0.52
Overt hypothyroidism
30/1875 (1.6)	Nonexposed	41/3362 (1.2)	1.15 [0.69–1.92]	0.59
	Potentially exposed B	28/1220 (2.3)	0.67 [0.38–1.19]	0.17
	Potentially exposed A	13/928 (1.4)	1.22 [0.58–2.56]	0.60
	Early childhood-exposed	32/2496 (1.3)	1.12 [0.65–1.93]	0.68
	Age-balanced	73/5858 (1.2)	1.15 [0.72–1.83]	0.56
Subclinical hypothyroidism
282/1875 (15.0)	Nonexposed	560/3362 (16.7)	0.95 [0.81–1.12]	0.57
	Potentially exposed B	209/1220 (17.1)	0.92 [0.74–1.13]	0.41
	Potentially exposed A	139/928 (15.0)	1.08 [0.85–1.36]	0.53
	Early childhood-exposed	422/2496 (16.9)	0.90 [0.76–1.07]	0.24
	Age-balanced	982/5858 (16.8)	0.93 [0.80–1.08]	0.35
TgAb positive
181/1875 (9.7)	Nonexposed	353/3362 (10.5)	0.91 [0.75–1.11]	0.37
	Potentially exposed B	150/1220 (12.3)	0.73 [0.57–0.93]^*	0.01
	Potentially exposed A	95/928 (10.2)	0.94 [0.71–1.23]	0.64
	Early childhood-exposed	257/2496 (10.3)	0.88 [0.71–1.08]	0.23
	Age-balanced	610/5858 (10.4)	0.91 [0.76–1.09]	0.30
TPOAb positive
212/1875 (11.3)	Nonexposed	368/3362 (10.9)	1.01 [0.84–1.22]	0.91
	Potentially exposed B	158/1220 (13.0)	0.82 [0.65–1.03]	0.08
	Potentially exposed A	92/928 (9.9)	1.22 [0.93–1.60]	0.15
	Early childhood-exposed	257/2496 (10.3)	1.04 [0.85–1.27]	0.68
	Age-balanced	625/5858 (10.7)	1.03 [0.86–1.22]	0.78
AIT
299/1875 (15.9)	Nonexposed	519/3362 (15.4)	1.04 [0.88–1.22]	0.68
	Potentially exposed B	213/1220 (17.5)	0.87 [0.71–1.06]	0.16
	Potentially exposed A	143/928 (15.4)	1.08 [0.86–1.36]	0.51
	Early childhood-exposed	386/2496 (15.5)	0.99 [0.84–1.18]	0.93
	Age-balanced	905/5858 (15.4)	1.02 [0.88–1.18]	0.79
Thyroid nodules
576/1863 (30.9)	Nonexposed	912/3330 (27.4)	1.10 [0.96–1.26]	0.15
	Potentially exposed B	351/1215 (28.9)	1.09 [0.92–1.28]	0.34
	Potentially exposed A	290/921 (31.5)	0.91 [0.76–1.09]	0.33
	Early childhood-exposed	803/2482 (32.4)	0.85 [0.74–0.98]^*	0.02
	Age-balanced	1715/5812 (29.5)	0.98 [0.87–1.11]	0.79

All the analysis adjusted for sex, residential areas, race/ethnicity, famine severity, education level, household income, current smoking status, and BMI.

Compared with control group, p < 0.05.

CI, confidence interval; no., numbers; OR, odds ratio.

Table 3 shows the association between famine exposure and TSH, TgAb, and TPOAb levels by multiple linear regression. After adjusting for sex, living region, race/ethnicity, famine severity, education level, household income, current smoking status, and BMI, the serum TSH concentrations were positively associated with fetal famine exposure (β = 0.024 [CI 0.013–0.461]). No significant difference was found in TgAb (β = 0.018 [CI −3.731 to 34.697]) or TPOAb (β = −0.001 [CI −5.601 to 5.051]) levels between the fetal-exposed and nonexposed groups. There was also no significant difference in TSH, TgAb, and TPOAb levels between the early childhood-exposed and nonexposed groups.

Table 3.

Associations Between Famine-Exposed Groups and Thyrotropin, Thyroglobulin Antibodies, Thyroid Peroxidase Antibodies Levels

Groups	TSH (mIU/L)				TgAb (IU/mL)				TPOAb (IU/mL)
	Model 1		Model 2		Model 1		Model 2		Model 1		Model 2
	β [CI]	p	β [CI]	p	β [CI]	p	β [CI]	p	β [CI]	p	β [CI]	p
Total
Early childhood-exposed	0.004 [−0.174 to 0.239]	0.76	0.009 [−0.123 to 0.286]	0.43	0.012 [−7.602 to 26.217]	0.28	0.013 [−7.541 to 27.517]	0.26	−0.010 [−6.855 to 2.633]	0.38	−0.006 [−6.132 to 3.586]	0.61
Potentially exposed A	0.009 [−0.172 to 0.407]	0.43	0.003 [−0.248 to 0.329]	0.79	0.006 [−16.816 to 30.649]	0.57	0.005 [−18.967 to 30.507]	0.65	−0.012 [−10.433 to 2.883]	0.27	−0.016 [−11.936 to 1.778]	0.15
Fetal-exposed	0.017 [−0.047 to 0.403]	0.12	0.024^* [0.013 to 0.461]	0.04	0.018 [−3.819 to 33.075]	0.12	0.018 [−3.731 to 34.697]	0.11	0.003 [−4.477 to 5.873]	0.79	−0.001 [−5.601 to 5.051]	0.92
Potentially exposed B	0.031^* [0.114 to 0.636]	<0.01	0.033^* [0.127 to 0.645]	<0.01	0.022^* [0.546 to 43.328]	0.04	0.023^* [1.083 to 45.499]	0.04	0.016 [−1.55 to 10.452]	0.15	0.018 [−1.214 to 11.098]	0.12
Nonexposed	[Reference]		[Reference]		[Reference]		[Reference]		[Reference]		[Reference]
Urban
Early childhood-exposed	0.007 [−0.201 to 0.324]	0.65	0.014 [−0.138 to 0.363]	0.38	0.024 [−5.39 to 41.502]	0.13	0.025 [−5.780 to 43.166]	0.13	−0.007 [−8.157 to 5.148]	0.66	0.001 [−6.645 to 7.113]	0.95
Potentially exposed A	0.011 [−0.228 to 0.499]	0.47	−0.002 [−0.367 to 0.328]	0.91	−0.006 [−38.777 to 26.113]	0.70	−0.008 [−43.044 to 24.829]	0.60	−0.011 [−12.67 to 5.742]	0.46	−0.013 [−13.736 to 5.341]	0.39
Fetal-exposed	−0.001 [−0.297 to 0.277]	0.94	0.005 [−0.233 to 0.314]	0.77	0.020 [−9.121 to 42.129]	0.21	0.019 [−10.517 to 42.930]	0.23	−0.001 [−7.441 to 7.101]	0.96	−0.008 [−9.295 to 5.727]	0.64
Potentially exposed B	0.019 [−0.126 to 0.575]	0.21	0.021 [−0.105 to 0.567]	0.18	0.025 [−5.687 to 56.962]	0.11	0.026 [−4.860 to 60.719]	0.10	0.013 [−4.905 to 12.871]	0.38	0.015 [−4.836 to 13.597]	0.35
Nonexposed	[Reference]		[Reference]		[Reference]		[Reference]		[Reference]		[Reference]
Rural
Early childhood-exposed	0 [−0.325 to 0.319]	0.99	0.003 [−0.301 to 0.352]	0.88	−0.001 [−24.960 to 23.943]	0.97	0 [−25.058 to 25.313]	0.99	−0.014 [−9.699 to 3.857]	0.40	−0.014 [−9.855 to 3.905]	0.40
Potentially exposed A	0.006 [−0.366 to 0.552]	0.69	0.007 [−0.367 to 0.572]	0.67	0.02 [−11.708 to 58.027]	0.19	0.021 [−11.526 to 60.900]	0.18	−0.013 [−13.957 to 5.374]	0.38	−0.018 [−15.739 to 4.046]	0.25
Fetal-exposed	0.035^* [0.037 to 0.737]	0.03	0.039^* [0.084 to 0.803]	0.02	0.015 [−13.865 to 39.349]	0.35	0.017 [−12.755 to 42.666]	0.29	0.007 [−5.791 to 8.961]	0.67	0.005 [−6.283 to 8.856]	0.74
Potentially exposed B	0.040^* [0.116 to 0.888]	0.01	0.041^* [0.119 to 0.903]	0.01	0.020 [−10.790 to 47.885]	0.22	0.019 [−11.476 to 49.006]	0.22	0.019 [−3.171 to 13.095]	0.23	0.020 [−3.001 to 13.521]	0.21
Nonexposed	[Reference]		[Reference]		[Reference]		[Reference]		[Reference]		[Reference]

Model 1 unadjusted for any covariate. Model 2 adjusted for sex, residential areas, race/ethnicity, famine severity, education level, household income, current smoking status, and BMI.

Compared with nonexposed group, p < 0.05.

The association between the famine exposure and TSH, TgAb, and TPOAb levels was further stratified by living region. The association between the fetal famine exposure and TSH level was stronger in the rural residents (β = 0.039 [CI 0.084–0.803]), but not significant in urban residents (β = 0.005 [CI −0.233 to 0.314]). Moreover, no significant association was found between famine exposure and TgAb or TPOAb levels in either the urban or rural participants.

Discussion

To the best of our knowledge, this is the first cross-sectional study with a large sample size to explore the association between famine exposure in early life and thyroid function and disorders in adulthood. Our study found that famine exposure during fetal stage was associated with a significantly higher TSH level in adulthood. After stratifying by living region, the association between fetal famine exposure and TSH level in adulthood was stronger among rural participants but not in urban participants, which might be related to rural residents' greater suffering, compared with citizens, during the Great Chinese Famine (16). We also observed that famine exposure during the fetal stage does not affect the levels of thyroid autoimmune antibodies in adulthood. Moreover, fetal famine exposed group had no significant difference in the risk for thyroid disorders, including overt hyperthyroidism, subclinical hyperthyroidism, overt hypothyroidism, subclinical hypothyroidism, TgAb positivity, TPOAb positivity, AIT, and thyroid nodules with age-balanced control after adjustments.

Previous studies have suggested the existence of a crucial period in which regulation of pituitary–thyroid axis function is programmed (17). However, the effects of malnutrition during the fetal stage on thyroid function were inconsistent in previous studies. An epidemiological analysis revealed women who developed hypothyroidism in adulthood were characterized by low weight and short length at birth (18). The only famine study on thyroid function with 616 participants showed that postnatal-exposed group had higher TSH and lower fT4 levels in adulthood than the nonexposed group (11). However, another study quantified the thyroid hormones in the cord blood of neonates, and found that neonates of calorie-restricted mothers had higher levels of thyroxine (T4), lower levels of reverse triiodothyronine (rT3), and similar levels of triiodothyronine (T3) with the control group (6).

Study in animals also showed inconsistent results of the association between perinatal malnutrition and thyroid function. A study in rats reported that undernutrition during the perinatal period produced permanent changes in the hypothalamic–pituitary–thyroid axis, and decreased fT4 and increased TSH levels, resulting in decreased relative metabolic rate and facultative thermogenesis (8). However, another study in sheep reported that late gestation undernutrition caused hyperthyroidism in adulthood, which was associated with increased expression of genes regulating the synthesis of thyroid hormones and deiodination (19). Moreover, malnutrition has also been reported to affect the levels of thyroid hormone binding globulins, which might also affect the thyroid function (20).

Previous studies have also reported that thyroid dysfunction in adulthood may depend on maternal nutrition during lactation. Protein-restricted lactating rats were found to cause alterations in milk by increasing the composition of iodine and T3 (21,22). Moreover, protein- and energy-restricted diets in rats during lactation had different effects on the thyroid function of offsprings (23). The offsprings of protein-restricted diet group had higher thyroid function than the controls, whereas the energy-restricted diet group only showed an increase in the deiodination of T4.

Iodine is an important component of the thyroid hormones, which play a crucial role in growth and brain development. Moderate and mild iodine deficiencies existed in China until the Universal Salt Iodization legislation was implemented nationally in 1996, covering all regions of the mainland. Therefore, the changes in iodine nutrition might have also affected the thyroid function and disorders of contemporary adults. Other nutrients such as selenium, zinc, vitamin B12, and vitamin D deficiencies might have also played a role in the association between famine exposure during early life and the affected thyroid function in adulthood (24 –27).

There are some limitations to our study. First, as the Great Chinese Famine affected all areas in mainland China, the major limitation of our study was the inability to select participants who were not affected by the famine as controls. The age differences between fetal-exposed and control groups might bias the results of our study. The participants in our study were survivors of the famine and might have been relatively healthier than individuals who died in the famine from severe metabolic and structural disorders, which might bias our results as well.

Second, as the exact starting and ending dates of famine in different provinces were unclear, we could not accurately define the fetal-exposed group by birth date. Thus, there might have been some misclassifications of the participants.

Third, the interprovincial migration history of participants might affect the analysis of the association between thyroid function and famine exposure. However, despite the increasing mobility in China, the immigrants are mainly young laborers in their 20s. In this study, we only included participants more than 50 years old, which is close to retirement age, so they were unlikely to be mobile. In addition, the inclusion criterion of our study was participants who lived in the selected community for at least five years (28). According to the latest population census, only 1.6% of population moved to provinces for at least five years other than their birthplaces (12). Therefore, we do not expect that migration would lead to measurement errors in participants.

Moreover, we lacked detailed information about the studied subjects, including birth weight, and personal experience with famine exposure, which might influence the association between thyroid function and famine exposure. Further studies with large sample size and more detailed personal information are warranted to verify the association of famine exposure during early life with thyroid function and disorders in adulthood.

Several strengthens of our study should be noted. First, we analyzed data from the TIDE study, which was conducted ∼60 years after the Great Chinese Famine and included a large number of representative individuals from all provinces in Chinese mainland, enhancing the generalizability of our findings to the entire country. Second, we used an age-balanced control group to minimize the effect of age differences on the analysis, which increases the reliability of our results. Last, the same trained staff conducted all examinations of blood samples from participants nationwide to ensure quality control of our test results.

TSH receptor has been identified in various tissues, including the brain, testes, kidney, heart, bone, lymphocytes, and adipose tissue, suggesting that TSH might have a larger functional role in multiple diseases (29). Persistent increases in serum TSH levels have been described in subclinical hypothyroidism, which is related to metabolic syndrome and heart failure (30). As malnutrition during the fetal stage might have an influence on the TSH level in adulthood, more attention should be paid to the mothers' nutritional condition during pregnancy.

In conclusion, we found that famine exposure in the fetal stage was associated with increased TSH level in adulthood, especially among rural residents. The fetal stage could be the crucial period for programming the pituitary–thyroid axis.

Footnotes

Acknowledgments

We thank the participants of this study. For continuous support, assistance, and cooperation, we thank Jiang He and Chung-Shiuan Chen (Tulane University); Wei Gong, Chenling Fan, Hong Wang, Hongmei Zhang, Shuangning Ding, Xiaochen Xie and Tingting Liu (The First Hospital of China Medical University); Caiping Li and Jian Huangfu (The Affiliated Hospital of Inner Mongolia University); Nan Jin (Chinese PLA General Hospital); Wuquan Deng, Fang Deng (Third Military Medical University); Haicheng Zhou (The First Affiliated Hospital of Dalian Medical University); Qingling Lu (Cardiovascular and Cerebrovascular Disease Hospital of Ningxia Medical University); Yunfeng Shen (The Second Affiliated Hospital of Nanchang University); Guodong Liu (The First Affiliated Hospital of Harbin Medical University); Junxiu Hou and Zhiqiang Zhang (The Affiliated Hospital of Inner Mongolia Medical University); Hong Zhang (The Second Xiangya Hospital); Xiaodong Mao, Qifeng Wang and Kun Wang (Nanjing University of Chinese Medicine); Yanping Wang (Fujian Medical University Union Hospital); Xiaojun Ma (The First Affiliated Hospital of Zhengzhou University); Liheng Meng (First Affiliated Hospital of Guangxi Medical University); Weihua Linle and Tuanyu Fang (Hainan General Hospital); Xingjun Liu and Yanru Zhao (The First Affiliated Hospital of Xi'an Jiaotong University); Lulu Chen, Jiaoyue Zhang and Hanyu Wang (Huazhong University of Science and Technology); Jingfang Liu and Songbo Fu (The First Hospital of Lanzhou University); Qingguo Lv (West China Hospital); Chenglin Sun (The First Hospital of Jilin University); Qiuming Yao and Ronghua Song (Shanghai University of Medicine & Health Science Affiliated Zhoupu Hosipital); Tingting Chen (The First Hospital of Anhui Medical University); Ben Niu (The First People's Hospital of Yunnan Province); Mingtong Xu and Feng Li (Sun Yat-sen Memorial Hospital); Lizhen Lan (The First Hospital of Shanxi Medical University); Jun Yue and Jia Song (People's Hospital of Tibet Autonomous Region); Yanan Li and Wei Luo (Qinghai Provincial People's Hospital); Xiaoming Lou and Zhe Mo (Zhejiang Provincial Center for Disease Control and Prevention); Nianchun Peng and Lixin Shi (Affiliated Hospital of Guiyang Medical University); Mian Wang, Qiuxiao Zhu and Lingling Yuan (Second Hospital of Hebei Medical University); Haiqing Zhang (Shandong Provincial Hospital affiliated with Shandong University); Yong Fan (The First Affiliated Hospital of Xinjiang Medical University); Hongyan Wei (Tianjin Medical University General Hospital).

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study is supported by the Research Fund for Public Welfare from National Health and Family Planning Commission of China (Grant No. 201402005).

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