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*Pregnancy
The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 3 1010-1014
Copyright © 2002 by The Endocrine Society

Endocrine Care

The Effect of Pregnancy on Thyroid Nodule Formation

A. W. C. Kung, M. T. Chau, T. T. Lao, S. C. F. Tam and L. C. K. Low

Departments of Medicine (A.W.C.K.), Obstetrics and Gynaecology (T.T.L.), and Paediatrics (L.C.K.L.), University of Hong Kong; and Departments of Radiology (M.T.C.) and Clinical Biochemistry (S.C.F.T.), Queen Mary Hospital, Hong Kong, China

Address all correspondence and requests for reprints to: Annie Kung, M.D., Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. E-mail: .

Abstract

Epidemiology data have revealed a higher prevalence of nodular goiters in women than men in both iodine-sufficient and iodine-deficient areas. Increased prevalence of thyroid nodules has also been reported in women with higher gravidity. However, the association between pregnancy and thyroid nodule formation has never been studied. The aim of our study was to evaluate the incidence of thyroid nodules during pregnancy and determine whether pregnancy will induce thyroid nodule formation. Two hundred twenty-one healthy southern Chinese women in the first trimester of their pregnancy were studied prospectively. Thyroid ultrasonography, thyroid function tests, and urinary iodine excretion were measured at first, second, and third trimesters of pregnancy as well as 6 wk and 3 months postpartum. Thyroid nodules (>2 mm in any dimension on ultrasonography) were detected in 34 (15.3%) subjects at first trimester, with 12 (5.4%) subjects having more than one nodule. Eight subjects had clinically palpable nodules. Women with thyroid nodules were older (P < 0.01) and had higher gravidity (P < 0.02) than those women without thyroid nodules. The volume of the single/dominant nodules increased from 60 (14–344) mm3, median (interquartile range) at first trimester to 65 (26–472) mm3 at third trimester (P < 0.02). These nodules remained enlarged at 103 (25–461) mm3 6 wk postpartum (P < 0.005) and 73 (22–344) mm3 at 3 months postpartum (P < 0.05). Patients with thyroid nodules had lower serum TSH values (P < 0.03) and higher Tg levels (P < 0.05) throughout pregnancy. Appearance of new nodules was detected in 25 (11.3%) women as pregnancy advanced so that by 3 months postpartum, the incidence of thyroid nodular disease was 24.4% (P < 0.02 vs. first trimester). Compared with those with no detectable nodules throughout pregnancy, subjects with new nodule formation had higher urinary iodine excretion from second trimester onward (P all < 0.05). However, no difference could be detected in their TSH and Tg levels throughout pregnancy. Fine-needle aspiration on nodules greater than 5 mm in any dimension after delivery (n = 21) confirmed the majority having histological features consistent with nodular hyperplasia. No thyroid malignancy was detected. In conclusion, pregnancy is associated with an increase in the size of preexisting thyroid nodules as well as new thyroid nodule formation. This may predispose to multinodular goiter in later life.

THYROID NODULAR DISEASE (TND) is a common condition in the adult population. Clinically apparent nodules have been estimated to occur in 4–7% of the adult population, predominantly in women (1, 2). Using ultrasound studies the prevalence of incidentally discovered TND in healthy adults has been reported to vary between 10% and 60%, depending on the sensitivity of the machine used (3). The incidence of TND in healthy nonpregnant populations diagnosed by ultrasonography had previously been reported to be 17–23% in areas of borderline to low iodine intake (3, 4, 5). Furthermore, as many as 40% of patients with a clinically apparent solitary nodules were found to have multiple nodules by ultrasound examination (4, 5, 6, 7). The vast majority of the nodules found are nonfunctioning and benign. The incidence of malignancy in solitary thyroid nodule is approximately 5% (8, 9, 10). Iodine deficiency is known to be an important cause for goitrogenesis (11), but the pathogenesis of TND remains less well understood.

Epidemiological data revealed a higher prevalence of nodular goiters in women than in men from both iodine-deficient as well as -sufficient areas (12, 13). The incidence of TND increases with increasing age in women (20–46%) and men (7–23%) (9, 14, 15). A higher prevalence of nodular goiters was noted in women with higher gravidity (16). Thyroid nodules had been detected by ultrasonography in 9.4% of women between the age of 36 and 50 yr who had not been pregnant. In contrast, 25% of those who had been pregnant had ultrasonographic evidence of thyroid nodules (16). These data indirectly suggest that pregnancy may induce thyroid nodule formation. However, the behavior of the thyroid nodules during pregnancy has never been well documented. Whether pregnancy is associated with a higher incidence of malignancy is controversial (17, 18). This study reported the findings of the first prospective ultrasonographic study on the incidence and nature of TND in healthy women during pregnancy.

Materials and Methods

Subjects

Healthy southern Chinese women attending the maternity hospital of the University of Hong Kong between the period 1997 to 1998 were invited to participate in the study. Subjects with a history of thyroid dysfunction were excluded. A total of 719 women in their first trimester of pregnancy was consecutively screened and underwent ultrasound assessment. Because of limitation of resources, only those subjects recruited between March and July 1997 were continued to be followed up in the prospective study (n = 221). These women were prospectively studied at approximately 12–14, 20–24, and 36 wk of gestation as well as 6 wk and 3 months postpartum for thyroid function, thyroid volume by ultrasound examination, and urine iodine concentration. None of them received iodine supplementation during pregnancy. To study the natural behavior of thyroid nodules during pregnancy, fine-needle biopsy was done only at 3 months postpartum for lesions 5 mm or greater in diameter. Written informed consent was obtained from all subjects. The study was approved by the Ethics Committee, Faculty of Medicine, University of Hong Kong. Previous population studies revealed that the median urinary iodine excretion from healthy adults was 0.77 µmol/liter (19), which was close to the World Health Organization cut-off value of 0.79 µmol/liter (or 100 µg/liter) for iodine sufficiency (11).

Urine iodine estimation

Early-morning urine samples were collected and urinary iodine was determined by the modified Sandell-Kolthoff reaction as previously described (19, 20). The urine was first digested with chloric acid and iodine was determined from its catalytic reaction of ceric ammonium sulfate in the presence of arsenious acid (20).

Thyroid function tests

Serum-free T4 (fT4) was determined by a competitive chemiluminescent immunoassay and TSH by a two-site immunochemiluminometric assay using an automated chemilumminescence system (ACS 180, Ciba Corning, Inc. Diagnostic Corp., Medfield, MA). Serum-free T3 (fT3) was measured by microparticle enzyme immunoassay (Abbott Laboratories, Abbott Park, IL). Tg was measured by sequential competitive RIA with separation by polyethylene glycol-accelerated double-antibody method (Diagnostic Products, Los Angeles, CA).

Thyroid ultrasound

Thyroid ultrasound examination was performed by a real-time ultrasound machine, Acuson 128 x 10 (Acuson, Mountain View, CA) using a 7.5-MHz linear transducer. Subjects were examined in the supine position with the neck hyperextended. To determine the volume of the nodules and thyroid lobes, the formula for an ellipsoid {pi}/6 x (width x length x thickness) was applied. The volume of the normal tissue was obtained by subtracting the total volume of the nodules from that of the thyroid gland. All ultrasound studies were performed by three ultrasonographers who were blinded to the previous ultrasound reports of the subjects. The in vivo intra- and interpersonal coefficient of variations obtained from five repeated measurements of the thyroid volume on three healthy volunteers was 5.6% and 7.8%, respectively. Similarly, the intra- and interpersonal coefficient of variations obtained from five repeated measurement on three thyroid nodules was 6.8% and 10.3%, respectively.

Statistics

Comparisons within the group were done by repeated-measures ANOVA, and comparison between groups were by ANOVA or {chi}-square test using an SPSS program (SPSS, Inc., Chicago, IL) . Bonferroni correction was applied to adjust for multiple comparisons. Results are presented as mean plus or minus SD or median (interquartile range), depending on their distribution.

Results

The mean age of the subjects was 30.8 ± 4.8 yr, and on average they were pregnant for the second time (gravidity 2.0 ± 1.1). All had normal fT3 and fT4 levels during recruitment, and their mean urinary iodine excretion was 102 ± 59 nmol/mmol Cr. Among these women, eight had nodules greater than 1 cm that were clinically palpable. Ultrasound study revealed the presence of thyroid nodules in another 26 subjects, giving a TND prevalence of 15.3%. Twelve (5.4%) subjects had more than one nodule, with seven having two nodules and five having three or more nodules (Table 1Go). Among these 34 single or dominant nodules, 16 were less than 5 mm, 10 were between 5 and 10 mm, and 8 were greater than 10 mm. The ultrasound appearance of the single or dominant nodules was hypoechoic in 22, heterogenous in six, cystic in three, solid in one, and semisolid cystic in two.


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  		Table 1. Characteristics of thyroid nodules detected at first trimester of pregnancy

 
The size of the single/dominant nodules of these 34 subjects was assessed in two ways, its maximum diameter and volume. The median value for the maximum diameter of these nodules were as follows: first trimester 5.1 (range 2–32) mm; second trimester 5.1 (range 2–39) mm, third trimester 5.5 (range 2.5–38) mm, 6 wk postpartum 8.0 (range 2.5–38) mm; and 3 months postpartum 7.1 (range 2–35) mm (ANOVA, P = NS). Although there was no significant change in the maximum diameter of these nodules, the volume showed significant enlargement during pregnancy and remained so even at 3 months after delivery [first trimester: 60 (14–344) mm3; second trimester: 65 (26–410) mm3; third trimester: 65 (26–472) mm3; 6 wk postpartum: 103 (25–461) mm3; 3 months postpartum: 73 (22–344) mm3; median (interquartile range), ANOVA P < 0.05; Fig. 1Go]. When the nodules were analyzed separately, the increase in volume reached statistical significance only in those lesions between 5 and 10 mm (Table 2Go). The volume of the nodules was correlated with the total thyroid gland volume at all time points (P all < 0.05) but not with the volume of the normal nonnodular thyroid tissue. Among these 34 subjects, the nodules became undetectable in two subjects during the study period (one at third trimester and one at 6 wk postpartum). On the other hand, four subjects with solitary nodule developed additional nodules during the study period.



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  		Figure 1. Serial changes in the volume of the single/dominant nodule detected at various stages of pregnancy: first (T1), second (T2), and third (T3) trimester of pregnancy and 6 wk and 3 months postpartum (pp). The box represents 25th and 75th quartile range; the middle line represents the median value. *P < 0.05, **P < 0.02, ***P < 0.01 vs. T1.

 

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  		Table 2. Changes in the diameter and volume of the thyroid nodules during and after pregnancy

 
Among the women without preexisting nodules, appearance of new nodules was detected in 25 (11.3%) women as pregnancy advanced (8 women at second trimester, 10 at third trimester, 5 at 6 wk postpartum, and 2 at 3 months postpartum, Fig. 2Go). At 3 months postpartum, thyroid nodules were present in 54 subjects, giving an incidence of 24.4% (P < 0.02 vs. first trimester). The volume of these nodules at first detection was 24 (11–43) mm3 at second trimester, 11 (5–22) mm3 at third trimester, and 14 (10–59) mm3 at 6 wk postpartum, respectively, with a median diameter of 3.6 mm, 2.8 mm, and 3.0 mm, respectively. Apart from the three nodules that were cystic in appearance, all other newly developed nodules were hypoechoic in nature. Three of these newly developed lesions resolved by 3 months postpartum. None of these newly developed nodules were clinically palpable throughout the study. Apart from the five nodules that resolved, 10 other nodules showed a reduction in size, compared with the measurements obtained at the third trimester.



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  		Figure 2. The number of thyroid nodules at each stage of pregnancy: first (T1), second (T2), and third (T3) trimester of pregnancy and 6 wk and 3 months postpartum (pp). The open bar represents a preexisting nodule; the hatched bar represents a newly discovered nodule. *, P < 0.05; **, P < 0.02.

 
Women with detectable thyroid nodules at first trimester were older (32.6 ± 4.5 vs. 30.0 ± 4.7 yr, P < 0.01) and had higher gravidity (2.8 ± 1.0 vs. 2.0 ± 11, P < 0.02), compared with women having no thyroid nodules throughout gestation. They also had lower serum TSH levels (0.26 [0.12–2.71] vs. 0.48 [0.08–2.03] mIU/liter, median [range], P = 0.03) and higher Tg levels (5.2 [2.8–43.7] vs. 4.4 [1.6–57.2] mg/liter, median [range], P < 0.05) throughout pregnancy, compared with those without nodules. Overall, 13 subjects had subnormal TSH levels at first trimester, but only one patient had persistently low TSH level throughout pregnancy. The fT4, fT3, and T3/T4 ratio were, however, similar between the two groups.

Overall, we observed an increase in urinary loss of iodine in these women as pregnancy progressed. Compared with those with no detectable nodules, subjects who developed new nodules had significantly higher urinary iodine excretion throughout pregnancy and during the postpartum period (Table 3Go). However, the TSH and Tg levels as well as other parameters of thyroid function test were similar in subjects with or without new nodule formation throughout the study (data not shown).


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  		Table 3. Urinary iodine excretion in subjects with new thyroid nodule formation vs. those without nodules throughout pregnancy

 
To document the nature of these nodules, fine-needle aspiration (FNA) under ultrasonographic guidance was performed on nodules that were greater than 5 mm in diameter 3 months after delivery. Twenty-one nodules were biopsied, with a median diameter of 11 (range 5.6–35) mm. Among these nodules, three yielded only cystic fluid during FNA. The rest all showed features consistent with nodular hyperplasia or colloid nodules. There was no case of thyroid malignancy encountered.

Discussion

This is the first prospective ultrasonographic study on the behavior of thyroid nodules in healthy women during pregnancy. The incidence of TND increased from 15.3% at first trimester to 24.4% 3 months post delivery.

The cause for the higher incidence of TND in women is unclear, although it was speculated to be related to pregnancy (18). There is a general impression that TND is discovered quite often during pregnancy. However this may only reflect the fact that women often seek medical care for the first time when they are pregnant, and there has been no evidence so far to demonstrate that pregnancy will induce thyroid nodule formation. The present study documented an increase in size as well as the number of the thyroid nodules over a period of 10–12 wk apart each trimester of pregnancy. This behavior is unlike that seen in nonpregnant subjects. Experience in nonpregnant subjects shows that thyroid nodules tend to grow slowly, and their increase in size may be evident only after several years even by modern ultrasonographic technique. Follow-up of subjects participating in the Framingham Study shows a 15-yr palpable thyroid nodule incidence rate of less than 2% in female and male subjects (1). The incidence of new nodules detected clinically was 0.09%/yr. Tan et al. (21) reported that among 19 patients with a documented solitary nodule by ultrasound examination, seven developed new nodules on follow-up scan 1–3 yr later. Unfortunately, we did not have a control group in this study to compare the rate of new nodule formation in nonpregnant women.

The reasons for the increase in number and size of thyroid nodules during pregnancy are unclear. One of the possible causes is iodine insufficiency. Although Hong Kong is a nongoitrous area, a previous population study revealed that the dietary iodine intake of healthy adults is borderline sufficient (22) and that the intake may become inadequate at times of stress such as during pregnancy. We observed that subjects with new nodule formation had higher urine iodine excretion throughout pregnancy, suggesting that they had negative iodine balance because of increased renal clearance. The hallmark of iodine restriction in the pregnancy state is goiter formation. Previous report on the thyroid volume of this same cohort showed a significant increase in gland size during pregnancy of up to 30% (23). The serum TSH level of these women doubled toward term, and the change in thyroid volume during pregnancy correlated positively with the change in Tg and negatively with urinary iodine concentration (23). Other studies conducted in areas with restricted iodine supply documented an increment in glandular size of similar magnitude (24), and the hyperplastic gland often failed to regress after delivery (25). However, these studies did not report on the incidence of TND during pregnancy. Histological studies on endemic goiter showed that pure hyperplasia was found mainly in children and seldom in adults (26).

Nodules of variable size are often encountered on thyroid sections of adults with endemic goiters. Because pregnancy may be associated with a negative iodine balance, even in iodine sufficient areas, it is not surprising to observe a high incidence of TND during pregnancy. The reason for thyroid hyperplasia associated with negative iodine balance is believed to be because of thyroidal stimulation by the elevated TSH in these subjects (26). However, the pathological mechanism for TND is unclear. In our present study, we failed to observe any difference in the serum TSH and Tg levels of those subjects with new nodule formation during pregnancy, despite a difference in urinary iodine excretion. It is possible that the number of subjects with new nodule formation are too small to reach statistical power or that the magnitude of urinary iodine loss in these women was not sufficient enough to cause significant differences in the serum TSH or Tg levels. For those women with preexisting nodules detected during the first trimester of pregnancy, their serum TSH levels were lower than those without thyroid nodules. Suppressed serum TSH levels associated with thyroid nodules have been well reported, and this phenomenon is also observed in subjects residing in iodine deficient areas (15).

The pathogenesis of nodular goitre has been extensively studied over the past decades. Classically, it was thought that elevation of TSH levels, albeit small, is the main stimulus leading to thyrocyte proliferation and diffuse goiter formation. Subsequently, nodules appeared as the patient aged, finally leading to a multinodular goiter. Recently, this concept is being challenged. Studer et al. and Studer and Derwall (27, 28) provided evidence that the growth of multinodular goiters is essentially TSH independent. They observed a natural heterogeneity among follicular cells, probably because of the embryological polyclonal nature of the thyroid gland. This is thought to result in thyroid follicles that are very heterogeneous in their growth capacity as well as in their sensitivity and response to TSH. Thus, uniform and chronic exposure of the thyroid gland with time may lead to a multinodular pattern. Hence, any condition leading to chronic stimulation of TSH receptor can augment the development of multinodularity (e.g. in situations of iodine deficiency); mutations in the TSH receptor, CG stimulation during pregnancy, and growth factors such as IGF-I and epidermal growth factor can also stimulate follicular growth (29). Because a number of these stimulatory factors may coexist during pregnancy, it is understandable why pregnancy may predispose to nodule formation.

Interestingly, we noticed that despite the average size of the nodules was still larger than that at first presentation, some of the nodules were already smaller at 3 months postpartum, suggesting that with longer follow-up some of these nodules may resolve when the causative stimulants associated with pregnancy were removed.

FNA of the nodules was done only 3 months after delivery to evaluate the natural course of the nodules during and after pregnancy and to avoid the effect of FNA in altering the size of the nodule (30). The results of FNA revealed that the incidence of malignancy among the nodules diagnosed during pregnancy was low. We did not detect any case of thyroid malignancy in the present report. This contrasted with previous cross-sectional studies reporting a high prevalence rate of 30–40% of thyroid malignancy in women presenting with clinically palpable thyroid nodules during pregnancy (31, 32), despite evidence suggesting that pregnancy has no adverse effect on thyroid cancer. However, the median diameters of the nodules reported from these cross-sectional studies were in general bigger than that reported in the present study, with a median diameter of greater than 2 cm (31, 32). Also, a recent report from a thyroid cancer registry revealed that only 4.4% of thyroid cancers in young women were diagnosed during pregnancy (33). This incidence is similar to the 5% malignancy rate among all thyroid nodules observed in the general population.

In conclusion, we demonstrated that pregnancy is associated with an increase in the size of preexisting thyroid nodules as well as the number of newly developed thyroid nodules. This may predispose to subsequent multinodular goiter in later life.

Acknowledgments

We thank S. P. Kwong, L. Y. Ngan, S. H. Cheung, Y. Y. Sha, M. Shi, T. Cheung, and K. S. Lau for technical support; S. Yeung for statistical assistance; and K. Yu for typing the manuscript.

Footnotes

This work was supported by Hong Kong Research Grant Council.

Abbreviations: FNA, Fine-needle aspiration; fT3, serum-free T3; fT4, serum-free T4; TND, thyroid nodular disease.

Received August 31, 2001.

Accepted November 14, 2001.

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