Normal thyroid activity undergoes significant changes throughout pregnancy. At the first trimester, there may be transient increases in free T4 (fT4) levels with the suppression of thyroid stimulating hormone (TSH) suppression depending on human chorionic gonadotropin (hCG) stimulation. Following that period, fT4 concentration decreases slightly (10-15% on an average) and serum TSH levels return to normal (1). Throughout pregnancy, according to the gestational age, fT4 and TSH reference levels can change. Therefore, commenting on the thyroid function of pregnant patients according to the reference range for those who are not pregnant can create diagnostic errors (2,3). The fetus is unable to have thyroid hormone production until the 18-20 week of pregnancy. Until fetal hormone secretion starts, fetal development depends on the level of thyroxin in the circulation from the mother (4). The literature of the last few decades provides evidence that any decrease in thyroid hormone levels during pregnancy can prove harmful for both, the mother and the fetus (5,6,7). Isolated maternal hypothyroxinemia is characterized by low serum fT4 but normal serum TSH concentrations (6,7). Even though there are studies (8,9,10) showing that maternal hypothyroxinemia can lead to adverse fetal outcomes, no such effect is noted in any current publication (11). Since there are no established criteria for the diagnosis of isolated maternal hypothyroxinemia, it is not easy to detect the real incidence. In studies from areas without an iodine deficiency isolated hypothyroxinemia (IH) occurs in a frequency of 1.3-2.3% (12,13,14), whereas it occurs in a frequency of 25-30% in areas with a mild to moderate iodine deficiency (15,16). To date, there has been no study investigating the frequency of IH in Turkey. Thus, we planned to develop a study in order to determine the maternal-fetal effects of IH and the frequency of IH.
We included 196 pregnant women aged 18 years and older who had no previous thyroid disease, had live singleton fetus, became pregnant spontaneously, were on their 4-12 weeks of pregnancy, and attended our gynecology and obstetric outpatient clinic for the first routine obstetric controls between 2009 and 2011. We obtained approval from the ethics committee. Six patients did not complete the study due to abortion during the first trimester. All the subjects were euthyroid. Hypothyroidism was detected in three and hyperthyroidism was detected in 2 pregnant women, who were excluded from the study. Free T3 (fT3), fT4, TSH, anti-thyroid peroxidase antibody (anti-TPO), anti-thyroglobuline antibody (anti-TG), and urinary iodine measurements were performed in the remaining 185 pregnant women during the three trimesters. The delivery methods, gestational age and the weights of all infants were recorded.
The Abbott Architect 2000 device and chemiluminescent microparticle immunassay device was used to measure fT3, fT4 and TSH levels. Thyroid function tests were interpreted according to reference range that was determined for pregnants. Anti-TPO and anti-TG were studied with Roche Elecsys 2010 device and electrochemiluminescence immunoassay method. Subjects with serum fT4 values below the lower limit of the trimester-specific reference range and TSH concentrations within the trimester-specific reference range were diagnosed with IH (6,7). Since there are no FT4 reference levels available for pregnant women in Turkey, the manufacturer’s recommended reference ranges were used in this study. Subjects with serum TSH concentration above the upper limit of the trimester-specific reference range (1st trimester: 0.1-2.5 mIU/L, 2nd trimester: 0.2-3.0 mIU/L and 3rd trimester: 0.3-3.0 mIU/L) with a normal free T4 were diagnosed with subclinical hypothyroidism (SH) (17). 24-hour urine was collected, the urinary iodine concentrations (UIC) was determined with a colorimetric method based on the Sandell-Kolthoff reaction as recommended by WHO and ICCIDD (18) using the spectrophotometric method (Shimatzu mini spectrophometer). A recent WHO/ICDIDD expert group defined epidemiological criteria for assessing iodine nutrition based on the median or range in UIC of pregnant women. Based on these ranges, iodine intake was accepted as follows: insufficient: UIC <150 μg/L; adequate: 150-249 μg/L; more than adequate: 250-499 μg/L; and excessive: >500 μg/L (18).
The analysis used in the study was made via SPSS for Windows ver. 15.0 (Chicago, IL). We used The Kolmogorov-Smirnov test and the Shapiro-Wilk test for the analysis of convenience of the data for normal distribution, student’s t-test and the Mann-Whitney test for the analysis of continuous variables, and Pearson’s chi-Square and Fisher’s exact tests for the analysis of categorical variables. The correlations between the continuous variables were evaluated with the Pearson and Spearman correlation tests. The variables that fitted the normal distribution were determined with average and standard deviations, and the variables not fitting the normal distribution were determined through the median and interquartile ranges. A p value of less than 0.05 was considered statistically significant.
The average age was 25.7±5.2 years (range 20-41). The clinical and biochemical features of our study population at presentation are reported in Table 1.
IH was detected in 72 pregnant patients out of 185 (38%). When the evaluation was performed for each trimester individually, no patients with IH were detected during the first trimester. At the second trimester, 59 pregnant patients out of 185 (32%), and at the third trimester, 50 pregnant patients out of 185 (27%) were noted to have IH (Figure 1). Thirteen (26%) patients detected in the third trimester had new-onset IH, whereas IH was present even during the second trimester in 37 (74%) patients.
Treatment was not administered to the patients with IH. The comparison of laboratory parameters of the patients with or without IH and other features are given in Table 2.
There was no relationship of fT4 levels (0.94 cut-off rate) with delivery method (vaginal or cesarean), infant birth weight, and complications during the first trimester (p=0.337, 0.588, 0.386, respectively).
There was no significant relationship of fT4 levels (0.75 cut-off rate) with delivery method (vaginal or cesarean), infant birth weight, and complications during the second trimester (p=0.855, 0.390, 0.551, respectively).
No significant relationship of fT4 levels (0.65 cut-off rate) with delivery method, and complications at the third trimester was found (p=0.653 and 1.000, respectively). During the third trimester, the birth weights of infants with IH were higher (3200 vs 3600) (p=0.029).
While the UIC in 59.5% of pregnant patients were less than 150 mcg/l during the first trimester, these levels were lower in 51.7% of pregnant patients during the second trimester. In the third trimester, 60% of pregnant patients were noted to have lower urinary iodine levels.
In all trimesters, no relationship was detected between fT4 and UIC (p=0.469, p=0.897 and p=0.223 for the first, second and third trimesters, respectively). Additionally, no relationship was detected between TSH levels and UIC during any of the trimesters (p=0.303, p=0.561 and p=0.333 for the first, second and third trimesters, respectively).
During the second trimester, SH was detected in 9 (4.9%) pregnant patients and in 6 (3.2%) patients during the third trimester, and 1-thyroxin replacement was started accordingly. Anti-TPO and anti-TG levels were positive in three patients with SH during the second trimester and in 3 patients with SH during the third trimester.
50% of 50 patients with IH returned for their postpartum visits, and their thyroid function was noted to have returned to normal.
Although the underlying cause of IH is not fully understood, iodine deficiency during pregnancy appears to be a responsible factor. Different rates of IH incidence are reported in different studies depending on the sufficiency of iodine in the geographic locations in which the studies are performed. While the frequency of IH in iodine-sufficient ares has been reported to be between 1.3% (12) and 2.3% (13), this rate has been recorded between 25-30% in areas of mild-to-moderate iodine deficiency. Indeed, in conditions of mild-moderate iodine deficiency, thyroid stimulation by hCG, which occurs over the 1st trimester, leads to the preferential output of T3 over T4. In these women, T4 secretion soon becomes inappropriately low relative to the increasing T4-binding globulin (TBG) concentrations. This leads to the progressive desaturation of TBG by T4, ultimately resulting in steadily declining fT4 concentrations (6,19). In iodine- sufficient areas, the cause of IH is not fully understood, however, pregnant patients with IH in these areas may be consuming less iodine (below the recommended 250 μg/day) than required for normal thyroid function and production of thyroid hormones. In this study, we detected IH in 38% of pregnant patients in our region, and 59.5% (urinary iodine <150 mcg/L) of them were suffering from iodine deficiency. At the beginning of the study, the median UIC was 117.5 mcg/L. In Turkey, after salt iodization, the median UIC increased to 87 μg/L in 2002 and to 117 μg/L in 2004 (20). In 2007, the median UIC in school-age children reached 130 μg/L, suggesting sufficient iodine intake in the general population (21). These follow-up monitoring studies demonstrated that iodine deficiency was eliminated in most urban areas, including Ankara, the capital city of Turkey. However, iodine status among pregnant women is a still debated issue in our country. A study conducted in Ankara has shown that the median UIC in pregnant women was 80.5 μg/L (22). In another study with first-trimester pregnant women, almost half of the subjects were below the WHO, United Nations Children’s Fund, and International Council for the Control of Iodine Deficiency Disorders lower median reference limits of 150 μg/L (23). Despite mandatory iodination, the fact that the iodine deficiency rate is still high in our region can explain high frequency of IH. In the group with IH, although iodine deficiency was higher, the difference was not statistically significant. This suggests that iodine deficiency is not the only element in IH pathogenesis. When the evaluation was made separately for each trimester, we did not have any patient with IH detected at the first trimester. During the second trimester, IH was detected in 59 of 185 patients (32%), and in 50 of 185 patients (27%) in their third trimester. While 13 (26%) patients detected at the last trimester had new onset IH, in 37 (74%) patients, IH was present even in the 2nd trimester. Same as our results, in a study by Moleti et al. (16), IH was detected in 25% of pregnant patients in an iodine-deficient region and the frequency of IH was highest in the second trimester, and was lower (3.2%) in the early weeks of pregnancy.
In our study, anti-TPO was detected in 40% of the pregnant patients with subclinical hypothyroidism. This result supports the notion that SH can occur due to autoimmune thyroiditis, which often causes progressive thyroid failure (24). Anti TPO levels in our patients with IH were similar to that in normal pregnant patients in compliance with the previous studies (16,24). These results suggest that autoimmune thyroiditis does not play a role in the pathogenesis of IH. According to the recent ATA guidelines proposals, treatment is not recommended (25), Current ETA guideline does not recommend any therapy in the 2nd and 3rd trimesters for IH cases (26), and thus, in our study, treatment was not administered to patients with IH. WHO, ATA and ETA guidelines recommend 250 mcg daily intake of iodine for pregnant women (18,25,26). In studies from some mild and moderate iodine-deficient European countries, it was observed that iodine supplementation for pregnant women did not prevent decrement in fT4 (27,28). In such places as our region, with oral intake, a total amount must be 250 mcg/day. Thus, 100-150 mcg/day iodine supplementation should be given. Therefore, it should be emphasized that the goal of iodine supplementation should not be the inhibition of fT4 drop, it should be given for the increased requirement in pregnancy, to suppress enlargement of mother’s thyroid gland and to prevent iodine deficiency disorders in babies.
The levels of fT4 in patients with IH were significantly lower when compared to the group without IH during the first and the second trimesters, while TSH levels were significantly higher. The difference between these groups disappeared during the third trimester. As noted from previous studies, the need for iodine during pregnancy increases significantly. In patients from regions of iodine deficiency, fT4 levels decrease later in gestation and TSH levels increase. We assume that the reason for the decrease in fT4 levels that are within the normal range in the group without IH and disappearance of the difference between the groups is due to the deficiency of iodine in our region.
Demographic data of patients with and without IH were similar. No obstetric complication occurred in patients with IH, and their cesarean section rates were similar to that of the group without IH. Supporting the results of a previous study, there was not any relationship between IH and excessive adverse pregnancy outcome (24). During the first and the second trimester, no relationship was detected between T4 levels and infant birth weights, but during the third trimester, birth weight of patients with IH was higher. Pre-pregnancy weight of patients with IH was greater than that of patients without IH, but this difference was not statistically significant. The difference in infant weights may be related to the different pre-pregnancy weights of the mothers.
The Endocrine Society (17) and the latest ATA (25) guidelines propose a thyroid function test in pregnancy, with the aim of identifying high-risk pregnant women. However, no recommendation is available for follow-up during late pregnancy.
It has been reported that pregnant women can have subclinical or apparent hypothyroidism although their thyroid function tests are normal at the beginning of the pregnancy and, hypothyroidism can be underdiagnosed in 40% of pregnant women when thyroid function tests are performed only in the early gestational weeks (16). Supporting these findings, in our study, we found SH in 15 pregnant women whose thyroid function tests that were done in the first trimester were normal. We assume that large population studies are needed in order to evaluate whether there is a need for thyroid function tests during pregnancy in women living in regions where iodine deficiency is still a problem.
In conclusion, in our study, we found out that IH is not related with adverse obstetric outcomes. In the second or three trimesters, we did not encounter any pregnancy complications in patients with IH. Our findings support the updated guidelines which suggest that providing therapy to patients with IH is not required (25).
Conflicts of Interest
There are no conflicts of interest.
1. Glinoer D. The regulation of thyroid functions in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404-433.
2. Vaidya B, Anthony S, Bilous M, Shields B, Drury J, Hutchison S, Bilous R. Detection of thyroid dysfunction in early pregnancy: Universal screening or targeted high-risk case finding? J Clin Endocrinol Metab 2007;92:203-207.
3. Shan ZY, Chen YY, Teng WP, Yu XH, Li CY, Zhou WW, Gao B, Zhou JR, Ding B, Ma Y, Wu Y, Liu Q, Xu H, Liu W, Li J, Wang WW, Li YB, Fan CL, Wang H, Guo R, Zhang HM. A study for maternal thyroid hormone deficiency during the first half of pregnancy in China. Eur J Clin Invest 2009;39:37-42.
4. de Escobar GM, Obregón MJ, del Rey FE. Maternal thyroid hormones early in pregnancy and fetal brain development. Best Pract Res Clin Endocrinol Metab 2004;18:225-248.
5. Glinoer D, Delange F. The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the progeny. Thyroid 2000;10:871-887.
6. Morreale de Escobar G, Obregón MJ, Escobar del Rey F. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 2000;85:3975-3987.
7. Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Role of thyroid hormone during early brain development. Eur J Endocrinol 2004;151:25-37.
8. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf) 2003;59:282-288.
9. Li Y, Shan Z, Teng W, Yu X, Li Y, Fan C, Teng X, Guo R, Wang H, Li J, Chen Y, Wang W, Chawinga M, Zhang L, Yang L, Zhao Y, Hua T. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25–30 months. Clin Endocrinol (Oxf) 2010;72:825-829.
10. Henrichs J, Bongers-Schokking JJ, Schenk JJ, Ghassabian A, Schmidt HG, Visser TJ, Hooijkaas H, de Muinck Keizer- Schrama, SM, Hofman A, Jaddoe VV, Visser W, Steegers EA, Verhulst FC, de Rijke YB, Tiemeier H. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the Generation R Study. J Clin Endocrinol Metab 2010;95:4227-4234.
11. Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, Chiusano E, John R, Guaraldo V, George LM, Perona M, Dall’Amico D, Parkes AB, Joomun M, Wald NJ. Antenatal thyroid screening and childhood cognitive function. N Engl J Med 2012;366:493-501.
12. Casey BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, Cunningham GF. Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol 2007;109:1129-1135.
13. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, Sullivan L, Canick J, Porter TF, Luthy D, Gross S, Bianchi DW, D’Alton ME. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 2008;112:85-92.
14. Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev 2010;31:702-755.
15. Berbel P, Mestre JL, Santamaría A, Palazón I, Franco A, Graells M, González-Torga A, de Escobar GM. Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: the importance of early iodine supplementation. Thyroid 2009;19:511-119.
16. Moleti M, Lo Presti VP, Mattina F, Mancuso A, De Vivo A, Giorgianni G, Di Bella B, Trimarchi F, Vermiglio F. Gestational thyroid function abnormalities in conditions of mild iodine deficiency: early screening versus continuous monitoring of maternal thyroid status. Eur J Endocrinol 2009;160:611-117.
17. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, Eastman CJ, Lazarus JH, Luton D, Mandel SJ, Mestman J, Rovet J, Sullivan S. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2543-2565.
18. World Health Organization, United Nations Children’s Fund, International Council for the Control of Iodine Deficiency Disorders. Assessment of Iodine Deficiency Disorders and Monitoring Their Elimination: A Guide for Programme Managers, 3rd edn. World Health Organization, Geneva, 2007.
19. Pedraza PE, Obregon MJ, Escobar-Morreale H.F, del Rey FE, de Escobar GM. Mechanisms of adaptation to iodine deficiency in rats: thyroid status is tissue specific. Its relevance for man. Endocrinology 2006;147:2098-2108.
20. Erdogan MF, Demir O, Emral R, Kamel AN, Erdogan G. More than a decade of iodine prophylaxis is needed to eradicate goiter among school age children in a moderately iodine-deficient region. Thyroid 2009;19:265-268.
21. Erdogan MF, Agbaht K, Altunsu T, Ozbas S, Yücesan F, Tezel B, Sargın C, Ilbeg I, Artık N, Köse R, Erdogan G. Current iodine status in Turkey. Journal of Endocrinological Investigation 2009;32:617-622.
22. Oguz Kutlu A, Kara C. Iodine deficiency in pregnant women in the apparently iodine-sufficient capital city of Turkey. Clin Endocrinol (Oxf) 2012;77:615-620.
23. Kut A, Gursoy A, Senbayram S, Bayraktar N, Budakoglu II, Akgün HS. Iodine intake is still inadequate among pregnant women eight years after mandatory iodination of salt in Turkey. Journal of Endocrinological Investigation 2010;33:461-464.
24. Casey BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, Cunningham GF. Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol 2007;109:1129-1135.
25. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S, Wiersinga W. American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081-1125.
26. Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European Thyroid Association Guidelines for the Management of Subclinical Hypothyroidism in Pregnancy and in Children. Eur Thyroid J 2014;3:76-94.
27. Brucker-Davis F, Panaïa-Ferrari P, Gal J, Fénichel P, Hiéronimus S. Iodine Supplementation throughout Pregnancy Does Not Prevent the Drop in FT4 in the Second and Third Trimesters in Women with Normal Initial Thyroid Function. Eur Thyroid J 2013;2:187-194.
28. Zimmermann MB. The effects of iodine deficiency in pregnancy and infancy. Paed Perinatal Epidemiol 2012;26:108-117.