http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–4 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.982530
ORIGINAL ARTICLE
Vitamin D status and thyroid autoimmunity in Korean pregnant women Hee-Won Moon1, Hee-Jung Chung2, Mina Hur1, and Yeo-Min Yun1 Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea and 2Department of Laboratory Medicine, Cheil General Hospital and Women’s Healthcare Center, Kwandong University College of Medicine, Seoul, Republic of Korea
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Abstract
Keywords
Objective: There is increasing interest in the role of vitamin D (vitD) during pregnancy. We prospectively evaluated the vitD status in Korean pregnant women and evaluated the levels of vitD according to thyroid-specific autoimmunity during pregnancy. Methods: We included pregnant 531 women who visited for prenatal care and 238 agematched, non-pregnant women as a control population. The levels of thyrotropin, FT4, thyroid peroxidase (TPO), thyroglobulin (Tg) antibody (Ab) and 25-hydroxy vitamin D [25(OH)D] were measured by electrochemiluminescence immunoassays. Results: The mean levels of 25(OH)D at trimester 1, 2 and 3 were 13.6, 15.6 and 19.3 ng/mL, respectively; and the prevalence of vitD insufficiency was 83.6%, 75.1% and 55.9%, respectively. The mean 25(OH)D levels were not significantly different between Tg and TPO Ab-positive and negative pregnant women (14.9 versus 16.1, and 14.9 versus 16.1 ng/mL, respectively). Conclusions: vitD insufficiency was exceptionally high, especially in the first trimester, in Korean pregnant women. The mean 25(OH)D levels were not significantly different according to autoimmunity. Further studies on this relationship could provide important information to assess the vitD status in patients with thyroid autoimmunity during pregnancy.
Autoimmunity, pregnancy, thyroid, vitamin D
Introduction Vitamin D (vitD) has an important role in the skeletal system, and recently nonskeletal role of vitD has been also suggested in many conditions including cancers, autoimmune diseases, cardiovascular disease and diabetes [1–4]. Immunomodulation is mediated through the vitD receptor, and activation of this receptor in immune cells leads to transcription of gene products that initiate a cascade of anti-proliferative and immuneregulatory processes [5,6]. A few recent studies evaluated the relation between vitD insufficiency and autoimmune thyroid diseases, but showed conflicting results [7–10]. Recently, there has been increasing interest in the role of vitD during pregnancy, and many studies have evaluated the association between low vitD level and adverse pregnancy outcomes including preeclampsia, preterm birth and gestational diabetes [11,12]. Although a recent systemic review concluded that the association of vitD level and pregnancy outcome is inconclusive and needs further investigation [11], the evidence regarding physiologic role of vitD in reproductive outcomes is still strong [12]. Maternal thyroid hormones play an important role in fetal development and thyroid dysfunction is associated with pregnancy complications and
Address for correspondence: Yeo-Min Yun, MD, PhD, Department of Laboratory Medicine, Konkuk University Hospital, 120-1, Neungdongro, Gwangjin-gu, Seoul, Republic of Korea. Fax: 82-2-2030-5587. E-mail: [email protected]
History Received 13 August 2014 Accepted 28 October 2014 Published online 28 November 2014
adverse perinatal outcomes [13–15]. Autoimmune thyroiditis associated with thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody (Ab) is the main cause of hypothyroidism during pregnancy [16] and is more common than generally acknowledged [17]. In Korea, there is sparse data on vitD status and thyroid-specific autoimmunity in pregnant women. In this study, we evaluated the vitD status in pregnant Korean women and compared the levels of vitD according to thyroid-specific autoimmunity during pregnancy.
Subjects and methods Subjects We included pregnant women who visited the Department of Obstetrics and Gynecology of Konkuk University Medical Center and Cheil General Hospital and Women’s Healthcare Center for prenatal care from April 2012 to December 2012. After exclusion for lack of data, the study population comprised 531 pregnant women (147 at first, 241 at second and 143 at third trimester). The mean age of the study population was 32.8 ± 3.5 years, ranging from 24–45 years. For comparison with non-pregnant population, we included 238 age-matched, non-pregnant women whose mean age was 32.0 ± 4.2 years (range, 20–42 years). General characteristics of the study population are listed in Table 1. The mean age and prevalence of TPO Ab of each group (first, second and third trimester and non-pregnant) were not significantly different, and the prevalence of Tg Ab was significantly
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Table 1. Baseline characteristics of the study population. Pregnant Trimester N Age Tg antibody positive (%) TPO antibody positive (%)
First
Second
Third
Non-pregnant
p*
147 32.7 ± 3.3 18 (12.2) 17 (11.6)
241 32.6 ± 3.6 13 (5.4) 20 (8.3)
143 33.0 ± 3.4 7 (4.9) 6 (4.2)
238 32.0 ± 4.2 27 (11.3) 16 (6.7)
0.062 0.014 0.111
Values are presented as mean ± SD unless indicated otherwise. *p value when compared between four groups by ANOVA and chi-square test. Tg, thyroglobulin and TPO, thyroid peroxidase.
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Table 2. The vitamin D level in Korean pregnant and non-pregnant women. Pregnant Trimester N 25(OH)D, ng/mL Prevalence of vitamin D insufficiency
First
Second
Third
Total
Non-pregnant
p*
147 13.6 ± 6.3 83.6%
241 15.6 ± 6.8 75.1%
143 19.3 ± 8.5 55.9%
531 16.0 ± 7.5 72.3%
238 19.1 ± 6.1 63.0%
50.001 0.010
Values are presented as mean (SD) unless indicated otherwise. p value compared between pregnant and non-pregnant group by Student’s t-test and chi-square test, respectively. Between first, second and third trimester, there was a significant diffrence in 25(OH)D level (p50.001 by ANOVA) and significant rise from first to third trimester (p50.001 by Pearson’s correlation). The prevalences of vitamin D insufficiency using the 20 ng/mL cut off were significantly different between first, second and third trimester (p50.001 by the chi-square test). 25(OH)D, 25-hydroxy vitamin D.
different between groups. The patient population from this study overlaps with that of another study (excluding Abpositive subjects) on estimation of reference interval of TSH and FT4 in pregnant women. vitD insufficiency was defined as serum 25-hydroxy vitamin D [25(OH)D] 520 ng/mL (50 nmol/L) [18,19]. Background data including age, parity, obstetric history and previous disease were obtained from medical record review. The study protocol was approved by the Institutional Review Boards of Konkuk University Medical Center and Cheil General Hospital and Women’s Healthcare Center. Determination of TSH, FT4, TPO, TG Ab and 25(OH)D The levels of TSH, FT4, TPO and Tg Ab were quantified by electrochemiluminescence immunoassay (ECL) using automated modular analyzer (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s recommendations. TPO and Tg Ab were taken as positive if the levels were 435 IU/mL and 4115 IU/mL, respectively, as specified by the manufacturer. The status of vitD was assessed by measuring serum 25(OH)D level using the Elecsys vitD Total Assay (Roche Diagnostics). The assay is a competitive, ECL that detects both 25(OH)D2 and 25(OH)D3. Statistical analyses Relationships between the continuous variables of the different groups were analyzed using Student’s t-test, Mann– Whitney test and ANOVA. The significance of categorical variables was assessed by the chi-square test. Statistical analysis was performed using SPSS software, version 12.0 (SPSS, Chicago, IL) and MedCalc Statistical software 9.3.9.0
(Mariakerke, Belgium). The p values were considered to be statistically significant.
Results VitD level in Korean pregnant and non-pregnant women The mean level of 25(OH)D in the first, second and third trimester was 13.6, 15.6 and 19.3 ng/mL, respectively (Table 2). There was a significant rise in 25(OH)D level from the first to third trimester (p50.001 by ANOVA and Pearson’s correlation). The mean 25(OH)D level of agematched non-pregnant women was 19.1 ng/mL, which was significantly higher than that of pregnant women (16.0 ng/ mL, p50.001 by Student’s t-test). The prevalence of vitD insufficiency using the 20-ng/mL cut off at the first, second and third trimester was 83.6%, 75.1% and 55.9%, respectively (p50.001 by the chi-square test). The prevalence of vitD insufficiency was significantly lower in non-pregnant women than in pregnant women (63.0% versus 72.3%, p ¼ 0.010 by the chi-square test). VitD level according to autoimmunity in pregnancy The mean 25(OH)D levels were not significantly different between Tg and TPO Ab-positive and negative pregnant women (14.9 versus 16.1, and 14.9 versus 16.1 ng/mL, respectively). When we analyzed separately in each trimester, there are also no significant differences of mean 25(OH)D levels according to the autoantibody positivity in each trimester (Table 3). There were no significant correlation between
Vitamin D and thyroid autoimmunity
DOI: 10.3109/14767058.2014.982530
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Table 3. The vitamin D level according to positivity of TPO and Tg antibody in each trimester and non-pregnancy. Antibody positivity Tg Population First trimester Second trimester Third trimester Non-pregnant
Positive 13.3 ± 6.1 16.7 ± 3.8 15.9 ± 6.1 18.4 ± 6.8
(n ¼ 18) (n ¼ 13) (n ¼ 7) (n ¼ 27)
TPO Negative 13.6 ± 6.3 15.5 ± 6.9 19.4 ± 8.6 19.2 ± 6.0
(n ¼ 129) (n ¼ 228) (n ¼ 136) (n ¼ 211)
p* 0.8173 0.5319 0.2767 0.5510
Positive 11.8 ± 5.5 16.7 ± 6.2 18.2 ± 8.6 18.7 ± 6.0
(n ¼ 17) (n ¼ 20) (n ¼ 6) (n ¼ 16)
Negative 13.8 ± 6.3 13.8 ± 6.3 19.3 ± 8.6 19.1 ± 6.0
(n ¼ 130) (n ¼ 221) (n ¼ 137) (n ¼ 222)
p* 0.2341 0.4427 0.7462 0.8090
Values are the levels of 25(OH)D (ng/mL) presented as mean ± SD. *p value when compared between antibody positive and negative individuals by Student’s t-test. Tg, thyroglobulin; TPO, thyroid peroxidase; and 25(OH)D, 25-hydroxy vitamin D.
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25(OH)D level and the Tg nor TPO Ab levels (p ¼ 0.4878 and 0.0980, respectively).
Discussion Since 25(OH)D crosses the placenta, adequate vitD status of the mother is important for the health of mother and child [20]. There are significant regional and ethnic differences in the prevalence of vitD insufficiency, and the reported prevalence of vitD insufficiency in pregnancy varies markedly, ranging from 18 to 84% [20–24]. A study in multiethnic pregnant women reported that the prevalence of vitD insufficiency (25(OH)D550 nmol/L) was 13% in Whites, 45% in Hispanics and 80% in black pregnant women [20]. In our study, the prevalence of vitD insufficiency in Korean pregnant women was very high (72.3%), and the prevalence during the first trimester (83.6%) was similar to those of black women in the United States and northern India [20,22]. Considering that our study population was not a risk group, but comprised healthy pregnant women, the prevalence was higher than expected. Moreover, the Korean pregnant women showed a higher prevalence of vitD insufficiency than age-matched nonpregnant women, which was not observed in a previous study that included pregnant and non-pregnant women [20]. During the progress of pregnancy, the mean serum level of 25(OH)D increased from the first trimester (13.6 ng/mL) to the third trimester (19.3 ng/mL). Accordingly, the prevalence of vitD insufficiency was highest in the first trimester (83.6%) and lowest in the third trimester (55.9%). Although the rise of 25(OH)D from the first trimester to the third trimester has been also observed in other studies [20,25], a contrary result was also reported [26]. Since many pregnant women took vitamin supplements during pregnancy, this trend of 25(OH)D concentration needs to be evaluated further. Recent studies reported the relationship between vitD insufficiency and Hashimoto’s thyroiditis, in which TPO and Tg Ab are involved in non-pregnant population [8–10,27,28]. However, there is also a study that showed no relation between vitD insufficiency and thyroid autoimmunity [7]. There are sparse data concerning the relationship between vitD status and thyroid autoimmunity in pregnancy. In our study, prevalence of Tg and TPO Ab is highest in first trimester (Table 1). Although there is sparse on the prevalence of thyroid-related autoantibody during pregnancy, the highest prevalence of TPO-Ab in first trimester was also reported in previous studies [29,30]. For evaluation of vitD status according to thyroid-related autoimmunity, important factors could be age and gestational
age of each sub-group. Mean age of each group was not significantly different. However, the prevalence of vitD insufficiency and prevalence of positive thyroid-related autoantibody were highest in the first trimester in this study. Therefore, Ab-positive groups include more pregnant women at first trimester and could affect the lower vitD level in this group. Thus, we analyzed the vitD level in auto Ab-positive and negative group in each trimester separately. There are no significant differences of mean 25(OH)D levels according to the autoantibody positivity in each trimester. Since the prevalence of Tg and TPO Ab positivity was low (7% and 8% in pregnant and 11.3% and 6.3% in non-pregnant women) in our study compared to those of other studies, statistical power could be low. This statistical insignificance might be due to small number of Ab-positive women; a study with a larger population would be conclusive. Of note, cut off is another important factor for prevalence of Tg and TPO Ab positivity. The cut off is various according to manufacturers and need to be standardized for accurate assessment [30]. Our study has some limitations. The 25(OH)D level was not measured serially during pregnancy, thus could not assess the change of 25(OH)D level in each individual. Second, data were not collected of vitD supplementation, and calcium or phosphorus level. In general, many pregnant Korean women take multi-vitamin supplements, but the status of vitD was not optimal in a considerable portion of pregnant women despite supplement use. Finally, we did not include postpartum lactating women, who could develop postpartum thyroiditis. The optimal vitD level in lactating period is also important and assessment of vitD level in postpartum thyroiditis would be very valuable. In conclusion, we assessed the vitD status in pregnant Korean women and showed very high incidence of vitD insufficiency, especially in the first trimester, in pregnant Korean women. There is no significant difference of 25(OH)D level between individuals with and without thyroid-specific autoantibodies. Further studies investigating this relationship could provide important information to assess the vitD status in patients with thyroid dysfunction during pregnancy.
Acknowledgements This study was supported by Konkuk University.
Declaration of interest Authors do not have any conflict of interest to disclose.
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References 1. Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451–9. 2. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008;117:503–11. 3. Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and metaanalysis. J Clin Endocrinol Metab 2007;92:2017–29. 4. Choi HS, Oh HJ, Choi H, et al. Vitamin D insufficiency in Korea – a greater threat to younger generation: the Korea National Health and Nutrition Examination Survey (KNHANES) 2008. J Clin Endocrinol Metab 2011;96:643–51. 5. Di Rosa M, Malaguarnera M, Nicoletti F, Malaguarnera L. Vitamin D3: a helpful immuno-modulator. Immunology 2011;134:123–39. 6. Hewison M. Vitamin D and the immune system: new perspectives on an old theme. Rheum Dis Clin North Am 2012;38:125–39. 7. Effraimidis G, Badenhoop K, Tijssen JG, Wiersinga WM. Vitamin D deficiency is not associated with early stages of thyroid autoimmunity. Eur J Endocrinol 2012;167:43–8. 8. Kivity S, Agmon-Levin N, Zisappl M, et al. Vitamin D and autoimmune thyroid diseases. Cell Mol Immunol 2011;8:243–7. 9. Tamer G, Arik S, Tamer I, Coksert D. Relative vitamin D insufficiency in Hashimoto’s thyroiditis. Thyroid 2011;21:891–6. 10. Bozkurt NC, Karbek B, Ucan B, et al. The association between severity of vitamin D deficiency and Hashimoto’s thyroiditis. Endocr Pract 2013;19:479–84. 11. Nassar N, Halligan GH, Roberts CL, et al. Systematic review of first-trimester vitamin D normative levels and outcomes of pregnancy. Am J Obstet Gynecol 2011;205:208.e1–7. 12. Urrutia RP, Thorp JM. Vitamin D in pregnancy: current concepts. Curr Opin Obstet Gynecol 2012;24:57–64. 13. Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005;105:239–45. 14. Allan WC, Haddow JE, Palomaki GE, et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 2000;7:127–30. 15. Abalovich M, Gutierrez S, Alcaraz G, et al. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002;12:63–8. 16. Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92:S1–47.
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17. Blatt AJ, Nakamoto JM, Kaufman HW. National status of testing for hypothyroidism during pregnancy and postpartum. J Clin Endocrinol Metab 2012;97:777–84. 18. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81. 19. Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin Proc 2011;86:50–60. 20. Ginde AA, Sullivan AF, Mansbach JM, Camargo Jr CA. Vitamin D insufficiency in pregnant and nonpregnant women of childbearing age in the United States. Am J Obstet Gynecol 2010;202: 436.e431–8. 21. van der Meer IM, Karamali NS, Boeke AJ, et al. High prevalence of vitamin D deficiency in pregnant non-Western women in The Hague, Netherlands. Am J Clin Nutr 2006;84:350–3; quiz 468–9. 22. Sachan A, Gupta R, Das V, et al. High prevalence of vitamin D deficiency among pregnant women and their newborns in northern India. Am J Clin Nutr 2005;81:1060–4. 23. Mulligan ML, Felton SK, Riek AE, Bernal-Mizrachi C. Implications of vitamin D deficiency in pregnancy and lactation. Am J Obstet Gynecol 2010;202:429.e421–9. 24. Li W, Green TJ, Innis SM, et al. Suboptimal vitamin D levels in pregnant women despite supplement use. Can J Public Health 2011; 102:308–12. 25. Milman N, Hvas AM, Bergholt T. Vitamin D status during normal pregnancy and postpartum. A longitudinal study in 141 Danish women. J Perinat Med 2011;40:57–61. 26. Ardawi MS, Nasrat HA, BA’Aqueel HS. Calcium-regulating hormones and parathyroid hormone-related peptide in normal human pregnancy and postpartum: a longitudinal study. Eur J Endocrinol 1997;137:402–9. 27. Camurdan OM, Doger E, Bideci A, et al. Vitamin D status in children with Hashimoto thyroiditis. J Pediatr Endocrinol Metab 2012;25:467–70. 28. Goswami R, Marwaha RK, Gupta N, et al. Prevalence of vitamin D deficiency and its relationship with thyroid autoimmunity in Asian Indians: a community-based survey. Br J Nutr 2009;102: 382–6. 29. Smyth PP, Wijeyaratne CN, Kaluarachi WN, et al. Sequential studies on thyroid antibodies during pregnancy. Thyroid 2005;15: 474–7. 30. Panesar NS, Chan KW, Li CY, Rogers MS. Status of anti-thyroid peroxidase during normal pregnancy and in patients with hyperemesis gravidarum. Thyroid 2006;16:481–4.
ORIGINAL ARTICLE
Vitamin D status and thyroid autoimmunity in Korean pregnant women Hee-Won Moon1, Hee-Jung Chung2, Mina Hur1, and Yeo-Min Yun1 Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea and 2Department of Laboratory Medicine, Cheil General Hospital and Women’s Healthcare Center, Kwandong University College of Medicine, Seoul, Republic of Korea
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Abstract
Keywords
Objective: There is increasing interest in the role of vitamin D (vitD) during pregnancy. We prospectively evaluated the vitD status in Korean pregnant women and evaluated the levels of vitD according to thyroid-specific autoimmunity during pregnancy. Methods: We included pregnant 531 women who visited for prenatal care and 238 agematched, non-pregnant women as a control population. The levels of thyrotropin, FT4, thyroid peroxidase (TPO), thyroglobulin (Tg) antibody (Ab) and 25-hydroxy vitamin D [25(OH)D] were measured by electrochemiluminescence immunoassays. Results: The mean levels of 25(OH)D at trimester 1, 2 and 3 were 13.6, 15.6 and 19.3 ng/mL, respectively; and the prevalence of vitD insufficiency was 83.6%, 75.1% and 55.9%, respectively. The mean 25(OH)D levels were not significantly different between Tg and TPO Ab-positive and negative pregnant women (14.9 versus 16.1, and 14.9 versus 16.1 ng/mL, respectively). Conclusions: vitD insufficiency was exceptionally high, especially in the first trimester, in Korean pregnant women. The mean 25(OH)D levels were not significantly different according to autoimmunity. Further studies on this relationship could provide important information to assess the vitD status in patients with thyroid autoimmunity during pregnancy.
Autoimmunity, pregnancy, thyroid, vitamin D
Introduction Vitamin D (vitD) has an important role in the skeletal system, and recently nonskeletal role of vitD has been also suggested in many conditions including cancers, autoimmune diseases, cardiovascular disease and diabetes [1–4]. Immunomodulation is mediated through the vitD receptor, and activation of this receptor in immune cells leads to transcription of gene products that initiate a cascade of anti-proliferative and immuneregulatory processes [5,6]. A few recent studies evaluated the relation between vitD insufficiency and autoimmune thyroid diseases, but showed conflicting results [7–10]. Recently, there has been increasing interest in the role of vitD during pregnancy, and many studies have evaluated the association between low vitD level and adverse pregnancy outcomes including preeclampsia, preterm birth and gestational diabetes [11,12]. Although a recent systemic review concluded that the association of vitD level and pregnancy outcome is inconclusive and needs further investigation [11], the evidence regarding physiologic role of vitD in reproductive outcomes is still strong [12]. Maternal thyroid hormones play an important role in fetal development and thyroid dysfunction is associated with pregnancy complications and
Address for correspondence: Yeo-Min Yun, MD, PhD, Department of Laboratory Medicine, Konkuk University Hospital, 120-1, Neungdongro, Gwangjin-gu, Seoul, Republic of Korea. Fax: 82-2-2030-5587. E-mail: [email protected]
History Received 13 August 2014 Accepted 28 October 2014 Published online 28 November 2014
adverse perinatal outcomes [13–15]. Autoimmune thyroiditis associated with thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody (Ab) is the main cause of hypothyroidism during pregnancy [16] and is more common than generally acknowledged [17]. In Korea, there is sparse data on vitD status and thyroid-specific autoimmunity in pregnant women. In this study, we evaluated the vitD status in pregnant Korean women and compared the levels of vitD according to thyroid-specific autoimmunity during pregnancy.
Subjects and methods Subjects We included pregnant women who visited the Department of Obstetrics and Gynecology of Konkuk University Medical Center and Cheil General Hospital and Women’s Healthcare Center for prenatal care from April 2012 to December 2012. After exclusion for lack of data, the study population comprised 531 pregnant women (147 at first, 241 at second and 143 at third trimester). The mean age of the study population was 32.8 ± 3.5 years, ranging from 24–45 years. For comparison with non-pregnant population, we included 238 age-matched, non-pregnant women whose mean age was 32.0 ± 4.2 years (range, 20–42 years). General characteristics of the study population are listed in Table 1. The mean age and prevalence of TPO Ab of each group (first, second and third trimester and non-pregnant) were not significantly different, and the prevalence of Tg Ab was significantly
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Table 1. Baseline characteristics of the study population. Pregnant Trimester N Age Tg antibody positive (%) TPO antibody positive (%)
First
Second
Third
Non-pregnant
p*
147 32.7 ± 3.3 18 (12.2) 17 (11.6)
241 32.6 ± 3.6 13 (5.4) 20 (8.3)
143 33.0 ± 3.4 7 (4.9) 6 (4.2)
238 32.0 ± 4.2 27 (11.3) 16 (6.7)
0.062 0.014 0.111
Values are presented as mean ± SD unless indicated otherwise. *p value when compared between four groups by ANOVA and chi-square test. Tg, thyroglobulin and TPO, thyroid peroxidase.
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Table 2. The vitamin D level in Korean pregnant and non-pregnant women. Pregnant Trimester N 25(OH)D, ng/mL Prevalence of vitamin D insufficiency
First
Second
Third
Total
Non-pregnant
p*
147 13.6 ± 6.3 83.6%
241 15.6 ± 6.8 75.1%
143 19.3 ± 8.5 55.9%
531 16.0 ± 7.5 72.3%
238 19.1 ± 6.1 63.0%
50.001 0.010
Values are presented as mean (SD) unless indicated otherwise. p value compared between pregnant and non-pregnant group by Student’s t-test and chi-square test, respectively. Between first, second and third trimester, there was a significant diffrence in 25(OH)D level (p50.001 by ANOVA) and significant rise from first to third trimester (p50.001 by Pearson’s correlation). The prevalences of vitamin D insufficiency using the 20 ng/mL cut off were significantly different between first, second and third trimester (p50.001 by the chi-square test). 25(OH)D, 25-hydroxy vitamin D.
different between groups. The patient population from this study overlaps with that of another study (excluding Abpositive subjects) on estimation of reference interval of TSH and FT4 in pregnant women. vitD insufficiency was defined as serum 25-hydroxy vitamin D [25(OH)D] 520 ng/mL (50 nmol/L) [18,19]. Background data including age, parity, obstetric history and previous disease were obtained from medical record review. The study protocol was approved by the Institutional Review Boards of Konkuk University Medical Center and Cheil General Hospital and Women’s Healthcare Center. Determination of TSH, FT4, TPO, TG Ab and 25(OH)D The levels of TSH, FT4, TPO and Tg Ab were quantified by electrochemiluminescence immunoassay (ECL) using automated modular analyzer (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s recommendations. TPO and Tg Ab were taken as positive if the levels were 435 IU/mL and 4115 IU/mL, respectively, as specified by the manufacturer. The status of vitD was assessed by measuring serum 25(OH)D level using the Elecsys vitD Total Assay (Roche Diagnostics). The assay is a competitive, ECL that detects both 25(OH)D2 and 25(OH)D3. Statistical analyses Relationships between the continuous variables of the different groups were analyzed using Student’s t-test, Mann– Whitney test and ANOVA. The significance of categorical variables was assessed by the chi-square test. Statistical analysis was performed using SPSS software, version 12.0 (SPSS, Chicago, IL) and MedCalc Statistical software 9.3.9.0
(Mariakerke, Belgium). The p values were considered to be statistically significant.
Results VitD level in Korean pregnant and non-pregnant women The mean level of 25(OH)D in the first, second and third trimester was 13.6, 15.6 and 19.3 ng/mL, respectively (Table 2). There was a significant rise in 25(OH)D level from the first to third trimester (p50.001 by ANOVA and Pearson’s correlation). The mean 25(OH)D level of agematched non-pregnant women was 19.1 ng/mL, which was significantly higher than that of pregnant women (16.0 ng/ mL, p50.001 by Student’s t-test). The prevalence of vitD insufficiency using the 20-ng/mL cut off at the first, second and third trimester was 83.6%, 75.1% and 55.9%, respectively (p50.001 by the chi-square test). The prevalence of vitD insufficiency was significantly lower in non-pregnant women than in pregnant women (63.0% versus 72.3%, p ¼ 0.010 by the chi-square test). VitD level according to autoimmunity in pregnancy The mean 25(OH)D levels were not significantly different between Tg and TPO Ab-positive and negative pregnant women (14.9 versus 16.1, and 14.9 versus 16.1 ng/mL, respectively). When we analyzed separately in each trimester, there are also no significant differences of mean 25(OH)D levels according to the autoantibody positivity in each trimester (Table 3). There were no significant correlation between
Vitamin D and thyroid autoimmunity
DOI: 10.3109/14767058.2014.982530
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Table 3. The vitamin D level according to positivity of TPO and Tg antibody in each trimester and non-pregnancy. Antibody positivity Tg Population First trimester Second trimester Third trimester Non-pregnant
Positive 13.3 ± 6.1 16.7 ± 3.8 15.9 ± 6.1 18.4 ± 6.8
(n ¼ 18) (n ¼ 13) (n ¼ 7) (n ¼ 27)
TPO Negative 13.6 ± 6.3 15.5 ± 6.9 19.4 ± 8.6 19.2 ± 6.0
(n ¼ 129) (n ¼ 228) (n ¼ 136) (n ¼ 211)
p* 0.8173 0.5319 0.2767 0.5510
Positive 11.8 ± 5.5 16.7 ± 6.2 18.2 ± 8.6 18.7 ± 6.0
(n ¼ 17) (n ¼ 20) (n ¼ 6) (n ¼ 16)
Negative 13.8 ± 6.3 13.8 ± 6.3 19.3 ± 8.6 19.1 ± 6.0
(n ¼ 130) (n ¼ 221) (n ¼ 137) (n ¼ 222)
p* 0.2341 0.4427 0.7462 0.8090
Values are the levels of 25(OH)D (ng/mL) presented as mean ± SD. *p value when compared between antibody positive and negative individuals by Student’s t-test. Tg, thyroglobulin; TPO, thyroid peroxidase; and 25(OH)D, 25-hydroxy vitamin D.
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25(OH)D level and the Tg nor TPO Ab levels (p ¼ 0.4878 and 0.0980, respectively).
Discussion Since 25(OH)D crosses the placenta, adequate vitD status of the mother is important for the health of mother and child [20]. There are significant regional and ethnic differences in the prevalence of vitD insufficiency, and the reported prevalence of vitD insufficiency in pregnancy varies markedly, ranging from 18 to 84% [20–24]. A study in multiethnic pregnant women reported that the prevalence of vitD insufficiency (25(OH)D550 nmol/L) was 13% in Whites, 45% in Hispanics and 80% in black pregnant women [20]. In our study, the prevalence of vitD insufficiency in Korean pregnant women was very high (72.3%), and the prevalence during the first trimester (83.6%) was similar to those of black women in the United States and northern India [20,22]. Considering that our study population was not a risk group, but comprised healthy pregnant women, the prevalence was higher than expected. Moreover, the Korean pregnant women showed a higher prevalence of vitD insufficiency than age-matched nonpregnant women, which was not observed in a previous study that included pregnant and non-pregnant women [20]. During the progress of pregnancy, the mean serum level of 25(OH)D increased from the first trimester (13.6 ng/mL) to the third trimester (19.3 ng/mL). Accordingly, the prevalence of vitD insufficiency was highest in the first trimester (83.6%) and lowest in the third trimester (55.9%). Although the rise of 25(OH)D from the first trimester to the third trimester has been also observed in other studies [20,25], a contrary result was also reported [26]. Since many pregnant women took vitamin supplements during pregnancy, this trend of 25(OH)D concentration needs to be evaluated further. Recent studies reported the relationship between vitD insufficiency and Hashimoto’s thyroiditis, in which TPO and Tg Ab are involved in non-pregnant population [8–10,27,28]. However, there is also a study that showed no relation between vitD insufficiency and thyroid autoimmunity [7]. There are sparse data concerning the relationship between vitD status and thyroid autoimmunity in pregnancy. In our study, prevalence of Tg and TPO Ab is highest in first trimester (Table 1). Although there is sparse on the prevalence of thyroid-related autoantibody during pregnancy, the highest prevalence of TPO-Ab in first trimester was also reported in previous studies [29,30]. For evaluation of vitD status according to thyroid-related autoimmunity, important factors could be age and gestational
age of each sub-group. Mean age of each group was not significantly different. However, the prevalence of vitD insufficiency and prevalence of positive thyroid-related autoantibody were highest in the first trimester in this study. Therefore, Ab-positive groups include more pregnant women at first trimester and could affect the lower vitD level in this group. Thus, we analyzed the vitD level in auto Ab-positive and negative group in each trimester separately. There are no significant differences of mean 25(OH)D levels according to the autoantibody positivity in each trimester. Since the prevalence of Tg and TPO Ab positivity was low (7% and 8% in pregnant and 11.3% and 6.3% in non-pregnant women) in our study compared to those of other studies, statistical power could be low. This statistical insignificance might be due to small number of Ab-positive women; a study with a larger population would be conclusive. Of note, cut off is another important factor for prevalence of Tg and TPO Ab positivity. The cut off is various according to manufacturers and need to be standardized for accurate assessment [30]. Our study has some limitations. The 25(OH)D level was not measured serially during pregnancy, thus could not assess the change of 25(OH)D level in each individual. Second, data were not collected of vitD supplementation, and calcium or phosphorus level. In general, many pregnant Korean women take multi-vitamin supplements, but the status of vitD was not optimal in a considerable portion of pregnant women despite supplement use. Finally, we did not include postpartum lactating women, who could develop postpartum thyroiditis. The optimal vitD level in lactating period is also important and assessment of vitD level in postpartum thyroiditis would be very valuable. In conclusion, we assessed the vitD status in pregnant Korean women and showed very high incidence of vitD insufficiency, especially in the first trimester, in pregnant Korean women. There is no significant difference of 25(OH)D level between individuals with and without thyroid-specific autoantibodies. Further studies investigating this relationship could provide important information to assess the vitD status in patients with thyroid dysfunction during pregnancy.
Acknowledgements This study was supported by Konkuk University.
Declaration of interest Authors do not have any conflict of interest to disclose.
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