Journal of Perinatology (2014) 34, 594–598 © 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
ORIGINAL ARTICLE
Effects of maternal iodine supplementation during pregnancy and lactation on iodine status and neonatal thyroid-stimulating hormone D Sukkhojaiwaratkul1, P Mahachoklertwattana1, P Poomthavorn1, P Panburana2, La-or Chailurkit3, P Khlairit1 and S Pongratanakul1 OBJECTIVE: To determine the iodine status in pregnant and lactating women, as well as neonatal thyroid-stimulating hormone (TSH) concentration. STUDY DESIGN: Pregnant women cared at our hospital, the University Hospital in Bangkok, had routinely received 200 μg iodine tablet daily since October 2010. Urinary iodine concentrations (UICs) of 1508 pregnant and 87 lactating women and 76 offspring and breast milk iodine concentration (BMIC) (n = 57) were measured. Cord serum TSH levels from hypothyroidism screening were analyzed. RESULT: Median UIC levels of pregnant and lactating women were 170.6 and 138.0 μg l–1, respectively. Median BMIC and infants’ UIC at 2-month postpartum in iodine-supplemented group were higher than the respective values of non-supplemented group. Median cord serum TSH level obtained before iodine supplementation (n = 8332) was higher than that obtained after supplementation (n = 5181; 7.3 vs 5.2 mU l–1). CONCLUSION: Maternal iodine supplementation improved iodine nutrition in their breast-fed offspring. A trend toward declining in cord serum TSH values after iodine supplementation indicates improvement of iodine status during pregnancy. Journal of Perinatology (2014) 34, 594–598; doi:10.1038/jp.2014.62; published online 17 April 2014
INTRODUCTION Thyroid hormone is essential for neurological development, particularly in the developing brain. Iodine is an essential constituent of thyroid hormone. Its requirement during pregnancy is increased. Thus, pregnant women and their offspring who reside in iodine-deficient areas have a greater risk of iodine deficiency than those who reside in iodine-sufficient areas. Iodine deficiency in pregnant women increases risks of low birth weight, mortality, neuromotor and cognitive impairment in their offspring.1 The study conducted during the years 2000 to 2003 in 15 provinces of Thailand demonstrated that median urinary iodine concentration (UIC) in 1182 pregnant women was 103 μg l–1, which indicated mild iodine deficiency.2 Similarly, our previous unpublished studies in Bangkok during the years 1990 to 1992 and 1999 to 2000 demonstrated that median UICs in pregnant women were 56 μg l–1 (n = 341) and 85 μg l–1 (n = 209), respectively, which indicated mild-to-moderate iodine deficiency. In addition, the study from the south of Thailand during the years 2006 to 2007 in 272 pregnant women demonstrated that median UIC was 78 μg l–1.3 These data indicated that inadequate iodine nutrition in pregnant women had been prevalent in Thailand. The previous Italian study in mild-to-moderate iodine-deficient areas demonstrated that iodine supplementation with 200 μg of iodine tablet daily increased UIC from 91 to 230 μg g Cr–1.4 Similarly, in the United States, the National Health and Nutrition Examination Survey in the years 1988 to 1994 demonstrated that
median UIC in pregnant women without iodine supplementation (n = 234) was slightly lower than those supplemented with 150 μg of iodine tablet daily (n = 100; 141 vs 169 μg l–1).5 In addition to median UIC, neonatal thyroid-stimulating hormone (TSH) is another sensitive indicator of iodine status in pregnant women.6 Serum neonatal TSH levels are higher in maternal iodine deficiency as compared with those of iodinesufficient mothers. Moreover, the decline of high neonatal TSH level following iodized salt supplementation indicated an improvement of iodine nutrition in the population.7 Lactating women are vulnerable to iodine deficiency.8 This is due to high iodine content secreted into breast milk by increasing expression of sodium/iodide symporter during lactation.9 In iodine-sufficient areas, breast milk iodine concentration (BMIC) is in the range of 150 to 180 μg l–1,10 which is considered adequate for infants’ requirement. Therefore, in iodine-deficient areas, BMIC may not be adequate for the need of the infant. Several studies demonstrated higher BMIC in iodine-supplemented mothers compared with non-supplemented mothers.11,12 Since October 2010, there has been a Thai National Iodine Supplementation Program by giving a daily iodine tablet to all pregnant women throughout their gestation in order to improve maternal iodine status. In addition, universal salt iodization has been strengthened and implemented. However, iodine tablet supplementation has been an inconsistent practice in our hospital. Whether iodine tablet supplementation improves iodine status in our pregnant population has not been investigated.
1 Department of Pediatrics, Division of Endocrinology and Metabolism, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 2Department of Obstetrics and Gynecology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand and 3Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Correspondence: Professor P Mahachoklertwattana, Division of Endocrinology and Metabolism, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama 6 Road, Bangkok 10400 Thailand. E-mail: [email protected] Received 30 October 2013; revised 23 February 2014; accepted 6 March 2014; published online 17 April 2014
Iodine status in pregnancy and neonatal TSH D Sukkhojaiwaratkul et al
595 We, therefore, aimed to determine the effects of maternal iodine tablet supplementation on iodine status of pregnant and lactating women and their infants as well as neonatal TSH levels. METHODS This study had been conducted during the years 2011 to 2013 at Ramathibodi Hospital, a University Hospital in Bangkok, Thailand. The study was approved by the institute’s ethics committee and written informed consent was obtained from all participants. A total of 1508 pregnant women who attended the antenatal care clinic were enrolled (Figure 1a). Urine samples were collected for UIC measurement throughout the gestations. There were 1646 urine samples collected. There were 138 (9%) pregnant women who provided two urine samples in both the first and second trimesters and 1370 (91%) pregnant women provided only one urine sample. Urine samples obtained at first trimester of gestation were collected at the first visit of antenatal care. Thus, all the first trimester urine samples were obtained before iodine tablet supplementation. Although iodine tablet supplementation has been implemented since October 2010, the coverage of the supplementation has not been completed. After the first visit of antenatal care, 51% of pregnant women were given multivitamin tablet, containing 200 μg of iodine. The percentages of iodine tablet supplementation were estimated from the prescription in the medical records. Medication adherence was not directly assessed. Lactating women and their offspring’s UICs and BMIC were measured at 2-month postpartum as summarized in Figure 1b. Medication adherence in iodine-supplemented lactating women was 92%. Urine and breast milk samples were frozen at –20 °C until the analysis. The iodine concentrations of urine and breast milk samples were measured by Sandell–Kolthoff reaction. Based on WHO population criteria, a median UIC of o 150 μg l–1 for pregnant women and o100 μg l–1 for lactating women and infants were used to define iodine deficiency.13 Cord serum TSH levels obtained from routine neonatal screening for congenital hypothyroidism during the years 2005 to 2013 were retrospectively reviewed and comparisons of the levels between the pre- and post-iodine supplementation program (January 2005 to October 2010 vs November 2011 to May 2013) were made. Cord serum TSH level
was measured by electrochemiluminescence immunoassay kit (Abbot Laboratories, Chicago, IL, USA). The detection limit of TSH assay was 0.0025 mU l–1.
RESULTS UIC in pregnant women There were 833, 597 and 162 samples obtained during the first, second and third trimesters of gestation, respectively. The respective median (range) UIC values in each trimester were 166.3 (7.7 to 1299.1), 167.9 (11.5 to 1499.3) and 204.6 (28.6 to 1045.8) μg l–1. The overall median (range) UIC was 170.6 (7.7 to 1499.3) μg l–1 (Figure 2). These findings indicated adequate iodine status throughout gestation in this population. A total of 488 urine samples from second and third trimesters were then categorized into two groups, iodine-supplemented (n = 218) and non-supplemented (n = 270) (Figure 1a). The former had significantly higher median (range) UIC than the latter (196.5 (11.5 to 1173.9) vs 161.1 (14.5 to 1045.8) μg l–1, P o0.01). However, both values are in iodine sufficiency range for pregnant women (>150 μg l–1). UIC in lactating women and their infants Eighty-seven lactating women were enrolled at 2-month postpartum. Their median (range) UIC was 138.0 (26.8 to 735.8) μg l–1, which indicated adequate iodine nutrition. Thirty-four subjects (39%) received iodine tablet supplementation. Median (range) UIC of lactating women in iodine-supplemented group (n = 34) tended to be higher than that of non-supplemented group (n = 53) but without statistical significance (198.8 (31.4 to 735.8) vs 119.8 (26.7 to 620.8) μg l–1, P = 0.079). Urine samples of 76 infants at the age of 2 months were obtained. The median (range) UIC was 219.4 (76.2 to 1066.8) μg l–1. Infants were divided into three groups according to their feedings
Figure 1. (a) Protocol flow chart of pregnant women enrolled in the study; supplemented group = iodine tablet supplementation. (b) Protocol flow chart of 2-month-old infants and their mothers at Well Baby Clinic, Ramathibodi Hospital, Bangkok, Thailand; supplemented mothers = lactating mothers receiving iodine tablet supplementation, BMIC, breast milk iodine concentration; UIC, urinary iodine concentration. © 2014 Nature America, Inc.
Journal of Perinatology (2014), 594 – 598
Iodine status in pregnancy and neonatal TSH D Sukkhojaiwaratkul et al
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Figure 2. Urinary iodine concentration (UIC) (median and interquartile range) of pregnant women throughout gestation and lactating mothers at 2-month postpartum; *median UIC in the third trimester was significantly higher than those of the first trimester (P = 0.012) and second trimester (P = 0.013).
Figure 4. Maternal urinary iodine concentration (UIC) (circle) and percentage of cord serum thyroid-stimulating hormone (TSH) of >10 mU l–1 (triangle) in the years 1993, 2000 and 2013 at Ramathibodi Hospital. Straight lines through each time point represent the trend changes overtime.
Eighty-one percent (n = 6749) of neonates in group 1 but only 54% (n = 2798) in group 2 had cord serum TSH of >5 mU l–1 (P o0.001). Similarly, 26% (n = 2166) of neonates in group 1 but only 11.7% (n = 606) in group 2 had cord serum TSH of >10 mU l–1 (P o 0.001). Data from the previous2 and present studies at Ramathibodi Hospital demonstrated the reciprocal trend changes overtime of percentage of high cord serum TSH (>10 mU l–1) and maternal median UIC (Figure 4).
Figure 3. Urinary iodine concentration of 2-month-old infants (n = 25), comparing between infants with maternal iodine supplementation and infants without maternal iodine supplementation. Box plot represents median and interquatile range.
as exclusive breast milk (n = 25), exclusive formula (n = 40) and combination (n = 11) (Figure 1b). The respective median (range) UIC values were 260.9 (106.6 to 1066.1), 191.4 (45.0 to 1042.0) and 127.7 (76.2 to 301.1) μg l–1 but no significant difference. Infant formulas contain approximately 70 to 100 μg iodine per litre. Exclusively breast-fed infants whose mothers received iodine supplementation (n = 11) had greater median (range) UIC than those of non-supplemented mothers (n = 14) (380.8 (164.0 to 668.7) vs 215.8 (106.6 to 1066.1) μg l–1, P = 0.017; Figure 3). Breast milk iodine concentration Breast milk samples were collected from 57 lactating women. Their median (range) BMIC was 90.8 (0 to 311.5) μg l–1. There were 33 subjects (65%) who received iodine tablet supplementation. In iodine-supplemented mothers, their median BMIC was significantly higher than that of non-supplemented mothers (108.6 (8.8 to 311.5) vs 69.5 (0.0 to 172.4) μg l–1, P = 0.032). Neonatal cord serum TSH concentration Neonates born before October 2010 were classified as pre-iodine supplementation group (group 1) while those born after October 2010 were in the post-iodine supplementation group (group 2). Cord serum TSH values were obtained from 13 513 neonates, 8332 in group 1 and 5181 in group 2. Median (range) cord serum TSH level in group 1 was significantly higher than that of the group 2 (7.3 (0.01 to 87.7) vs 5.2 (0.01 to 35.1) mU l–1, P o0.001). Journal of Perinatology (2014), 594 – 598
DISCUSSION Salt iodization is the most effective strategy to eradicate iodine deficiency.13 The Thai National Iodine Deficiency Disorder (IDD) Control Project on household and industrial salt iodization has been established since 1989. However, the national survey in the years 2000 to 2006 demonstrated that Thai pregnant women remained iodine deficient.14 This is partly due to incomplete coverage of iodized salt. Therefore, strategies to improve iodized salt coverage have been implemented. In the mean time, rapid improvement of iodine nutrition in pregnant women by giving iodine tablet supplementation has been implemented since October 2010. This study demonstrated that iodine nutrition in pregnant women was improved following iodine tablet supplementation program, which is in agreement with previous studies.4,5,15 Moreover, iodine tablet supplementation was shown to be more effective than iodized salt supplementation in improving iodine status in pregnant women.16,17 Thus, the American Thyroid Association recommends 150 μg daily iodine intake during pregnancy and lactation.18 Interestingly, the median UIC in the first trimester in our study was adequate before iodine tablet supplementation. This result could be the result of an increase in iodized salt coverage in Thailand up to 94% in the year 2011 (Department of Health of Thailand), as compared with only 47% coverage in the year 2009.19 Regarding trimester-specific changes of UIC, the previous study in iodine-sufficient areas demonstrated a trend of decline in urinary iodine excretion with advanced gestation.20–22 On the contrary, this study demonstrated that median UIC collected during the third trimester was significantly higher than those collected during the first and second trimesters. This finding is likely a result of the effect of iodine tablet supplementation up to 62% in the third trimester as compared with 0% and 51% in the first and second trimesters, respectively. This study demonstrated a trend toward higher median UIC in iodine-supplemented lactating women as compared with nonsupplemented women, albeit no statistical significance. As a result, © 2014 Nature America, Inc.
Iodine status in pregnancy and neonatal TSH D Sukkhojaiwaratkul et al
the infants of the supplemented mothers also had higher median UIC as compared with those of the non-supplemented mothers. These findings are consistent with the previous study.23 Median BMIC in this study was in suboptimal level for infants’ requirement according to the Institute of Medicine recommendation for daily iodine intake of 110 μg.24 Median BMIC was significantly higher in iodine-supplemented mothers as compared with non-supplemented mothers. Taken together, increased BMIC and infants’ UIC indicated the direct effect of iodine tablet supplementation in lactating women. This finding is in agreement with the previous reports in lactating women who received 100 to 200 μg daily of iodine supplementation.11,12,23 There was a trend toward declining of cord serum TSH values after iodine supplementation during pregnancy. This finding is consistent with the previous studies in iodine-deficient areas.7,25 Hence, a trend toward declining of neonatal TSH levels is likely one of the indicators of improvement of iodine nutrition in pregnant women. Percentage of blood spot neonatal TSH values >5.0 mU l–1 of >3% has been used as an index of iodine deficiency.6 This numerical value was derived from older than 72-h-old neonates who were born in iodine-sufficient areas. Thus, TSH concentrations obtained from cord blood are not equivalent to those obtained from the blood spots of 72-h-old neonates. Therefore, the percentage of neonates who had cord blood TSH concentrations of >10 mU l–1 is 11.7%, which may suggest iodine deficiency by the above criterion, while maternal median UIC is 170.6 μg l–1 (Figure 4), which indicates adequate iodine nutrition. This discrepancy supports the notion that the neonatal TSH criterion may not be a reliable monitoring tool for iodine deficiency as suggested by Smyth and Li in the previous reports.26,27 This study demonstrated iodine sufficiency during pregnancy and lactation in study population despite iodine tablet coverage was only about 50 to 60%. This is likely due to an improvement of iodized salt coverage at the present time. However, mild elevation of neonatal TSH values and UIC o 150 μg l–1 in pregnant women were still present. These findings indicate mild iodine insufficiency. Recent evidences suggested that mild iodine deficiency during pregnancy was associated with reduced cognitive and educational outcomes in the offspring.28,29 Therefore, intervention with iodine tablet supplementation in our study is likely to be effective in improving maternal iodine nutrition and thus could prevent adverse impacts on fetal neurocognitive function. This study demonstrated the long-term trend toward an improvement of iodine status in pregnant women who have resided in Bangkok. However, our study has some limitations, which include small sample size in lactating woman and infant groups, incompleteness of iodine supplementation and no assessment of medication adherence in pregnant woman group. In addition, lack of randomization of urine samples collection may cause selection bias. In conclusion, this study demonstrated that universal iodine tablet supplementation during pregnancy and lactation improved iodine nutrition in mothers and their offspring, and thus could prevent neonatal hyperthyrotropinemia or subclinical hypothyroidism in early infancy. Therefore, in mildly iodine-deficient areas, iodine tablet supplementation in pregnant and lactating women is an effective strategy to rapidly improve iodine nutrition in the high-risk population. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS This study was supported by a research grant (no. MURA2012/50) from the Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand. We thank Professor Rajata Rajatanavin for the constructive critique of the manuscript.
© 2014 Nature America, Inc.
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REFERENCES 1 Zimmermann MB. Iodine deficiency. Endocr Rev 2009; 30: 376–408. 2 Rajatanavin R. Iodine deficiency in pregnant women and neonates in Thailand. Public Health Nutr 2007; 10: 1602–1605. 3 Jaruratanasirikul S, Sangsupawanich P, Koranantakul O, Chavitan P, Ruanengrairatanaroj P, Sriplung H et al. Maternal iodine status and neonatal thyroid-stimulating hormone concentration: a community survey in Songkhla, southern Thailand. Public Health Nutr 2009; 12: 2279–2284. 4 Antonangeli L, Maccherini D, Cavaliere R, Di Giulio C, Reinhardt B, Pinchera A et al. Comparison of two different doses of iodide in the prevention of gestational goiter in marginal iodine deficiency: a longitudinal study. Eur J Endocrinol 2002; 147: 29–34. 5 Lamm SH, Chen R, Engel A, Hollowell JG. Effect of iodine supplementation on urine iodine in iodine-sufficient population-pregnant US women [Abstract]. Thyroid 2005; 15: S-171. 6 WHO, UNICEF, ICCIDD. Indicators for Assessing Iodine Deficiency Disorders and Their Control through Salt Iodization . World Health Organization, WHO/NUT/94.6: Geneva, Switzerland, 1994; 1–55. 7 Oltarzewski M, Szymborski J. Neonatal hypothyroid screening in monitoring of iodine deficiency and iodine supplementation in Poland. J Endocrinol Invest 2003; 26: 27–31. 8 Chan SS, Hams G, Wiley VT, Wilcken B, McElduff A. Postpartum maternal iodine status and the relationship to neonatal thyroid function. Thyroid 2003; 13: 873–876. 9 Spitzweg C, Joba W, Eisenmenger W, Heufelder AE. Analysis of human sodium iodide symporter gene expression in extrathyroidal tissues and cloning of its complementary deoxyribonucleic acids from salivary gland, mammary gland, and gastric mucosa. J Clin Endocrinol Metab 1998; 83: 1746–1751. 10 Delange F. Iodine requirements during pregnancy, lactation and the neonatal period and indicators of optimal iodine nutrition. Public Health Nutr 2007; 10: 1571–1580. 11 Pedersen KM, Laurberg P, Iversen E, Knudsen PR, Gregersen SE, Rasmussen OS et al. Amelioration of some pregnancy-associated variations in thyroid function by iodine supplementation. J Clin Endocrinol Metab 1993; 77: 1078–1083. 12 Glinoer D, De Nayer P, Delange F, Lemone M, Toppet V, Spehl M et al. A randomized trial for the treatment of mild iodine deficiency during pregnancy: maternal and neonatal effects. J Clin Endocrinol Metab 1995; 80: 258–269. 13 WHO, UNICEF, ICCIDD. Assessment of the Iodine Deficiency Disorders and Monitoring Their Elimination. WHO/NHD/01.1 World Health Organization: Geneva Switzerland, 2007. 14 Division of Nutrition, Ministry of Public Health. Surveillance System for ‘Tracking Progress Towards the Sustainable Elimination of Iodine Deficiency Disorders in Thailand: Result of 2000–2004’. Division of Nutrition, Ministry of Public Health: Bangkok, 2005. 15 Nøhr SB, Laurberg P. Opposite variations in maternal and neonatal thyroid function induced by iodine supplementation during pregnancy. J Clin Endocrinol Metab 2000; 85: 623–627. 16 Mezosi E, Molnar I, Jakab A, Balogh E, Karanyi Z, Nagy P et al. Prevalence of iodine deficiency and goitre during pregnancy in East Hungary. Eur J Endocrinol 2000; 143: 479–483. 17 Smyth PP. Variation in iodine handling during normal pregnancy. Thyroid 1999; 9: 637–642. 18 Public Health Committee of the American Thyroid Association: Becker DV, Braverman LE, Delange F, Dunn JT, Franklyn JA et al. Iodine supplementation for pregnancy and lactation-United States and Canada: recommendations of the American Thyroid Association. Thyroid 2006; 16: 949–951. 19 International Council for the Control of Iodine Deficiency Disorders (ICCIDD). Tracking progress towards sustainable elimination of iodine deficiency disorders in Thailand. External Review of the IDD Elimination Program in Thailand. ICCIDD: Ottawa, Canada, 2009. 20 Smyth PP, Hetherton AM, Smith DF, Radcliff M, O’Herlihy C. Maternal iodine status and thyroid volume during pregnancy: correlation with neonatal iodine intake. J Clin Endocrinol Metab 1997; 82: 2840–2843. 21 Brander L, Als C, Buess H, Haldimann F, Harder M, Hanggi W et al. Urinary iodine concentration during pregnancy in an area of unstable dietary iodine intake in Switzerland. J Endocrinol Invest 2003; 26: 389–396. 22 Fuse Y, Ohashi T, Yamaguchi S, Yamaguchi M, Shishiba Y, Irie M. Iodine status of pregnant and postpartum Japanese women: effect of iodine intake on maternal and neonatal thyroid function in an iodine-sufficient area. J Clin Endocrinol Metab 2001; 96: 3846–3854. 23 Mulrine HM, Skeaff SA, Ferguson EL, Gray AR, Valeix P. Breast-milk iodine concentration declines over the first 6 mo postpartum in iodine-deficient women. Am J Clin Nutr 2001; 92: 849–856.
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598 24 Institute of Medicine, Academy of Sciences, USA. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium and Zinc. National Academy Press: Washington, DC, 2001. 25 Tylek-Lemańska D, Rybakowa M, Kumorowicz-Kopiec M, Dziatkowiak H, Ratajczak R. Iodine deficiency disorders incidence in neonates based on the experience with mass screening for congenital hypothyroidism in southeast Poland in the years 1985–2000. J Endocrinol Invest 2003; 26: 32–38. 26 Burns R, Mayne PD, O’Herlihy C, Smith DF, Higgins M, Staines A et al. Can neonatal TSH screening reflect trends in population iodine intake? Thyroid 2008; 18: 883–888.
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27 Li M, Eastman CJ. Neonatal TSH screening: is it a sensitive and reliable tool for monitoring iodine status in populations? Best Pract Res Clin Endocrinol Metab 2010; 24: 63–75. 28 Hynes KL, Otahal P, Hay I, Burgess JR. Mild iodine deficiency during pregnancy is associated with reduced educational outcomes in the offspring: 9-year follow-up of the gestational iodine cohort. J Clin Endocrinol Metab 2013; 98: 1954–1963. 29 Bath SC, Steer CD, Golding J, Emmett P, Rayman MP. Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Lancet 2013; 382: 331–337.
© 2014 Nature America, Inc.
ORIGINAL ARTICLE
Effects of maternal iodine supplementation during pregnancy and lactation on iodine status and neonatal thyroid-stimulating hormone D Sukkhojaiwaratkul1, P Mahachoklertwattana1, P Poomthavorn1, P Panburana2, La-or Chailurkit3, P Khlairit1 and S Pongratanakul1 OBJECTIVE: To determine the iodine status in pregnant and lactating women, as well as neonatal thyroid-stimulating hormone (TSH) concentration. STUDY DESIGN: Pregnant women cared at our hospital, the University Hospital in Bangkok, had routinely received 200 μg iodine tablet daily since October 2010. Urinary iodine concentrations (UICs) of 1508 pregnant and 87 lactating women and 76 offspring and breast milk iodine concentration (BMIC) (n = 57) were measured. Cord serum TSH levels from hypothyroidism screening were analyzed. RESULT: Median UIC levels of pregnant and lactating women were 170.6 and 138.0 μg l–1, respectively. Median BMIC and infants’ UIC at 2-month postpartum in iodine-supplemented group were higher than the respective values of non-supplemented group. Median cord serum TSH level obtained before iodine supplementation (n = 8332) was higher than that obtained after supplementation (n = 5181; 7.3 vs 5.2 mU l–1). CONCLUSION: Maternal iodine supplementation improved iodine nutrition in their breast-fed offspring. A trend toward declining in cord serum TSH values after iodine supplementation indicates improvement of iodine status during pregnancy. Journal of Perinatology (2014) 34, 594–598; doi:10.1038/jp.2014.62; published online 17 April 2014
INTRODUCTION Thyroid hormone is essential for neurological development, particularly in the developing brain. Iodine is an essential constituent of thyroid hormone. Its requirement during pregnancy is increased. Thus, pregnant women and their offspring who reside in iodine-deficient areas have a greater risk of iodine deficiency than those who reside in iodine-sufficient areas. Iodine deficiency in pregnant women increases risks of low birth weight, mortality, neuromotor and cognitive impairment in their offspring.1 The study conducted during the years 2000 to 2003 in 15 provinces of Thailand demonstrated that median urinary iodine concentration (UIC) in 1182 pregnant women was 103 μg l–1, which indicated mild iodine deficiency.2 Similarly, our previous unpublished studies in Bangkok during the years 1990 to 1992 and 1999 to 2000 demonstrated that median UICs in pregnant women were 56 μg l–1 (n = 341) and 85 μg l–1 (n = 209), respectively, which indicated mild-to-moderate iodine deficiency. In addition, the study from the south of Thailand during the years 2006 to 2007 in 272 pregnant women demonstrated that median UIC was 78 μg l–1.3 These data indicated that inadequate iodine nutrition in pregnant women had been prevalent in Thailand. The previous Italian study in mild-to-moderate iodine-deficient areas demonstrated that iodine supplementation with 200 μg of iodine tablet daily increased UIC from 91 to 230 μg g Cr–1.4 Similarly, in the United States, the National Health and Nutrition Examination Survey in the years 1988 to 1994 demonstrated that
median UIC in pregnant women without iodine supplementation (n = 234) was slightly lower than those supplemented with 150 μg of iodine tablet daily (n = 100; 141 vs 169 μg l–1).5 In addition to median UIC, neonatal thyroid-stimulating hormone (TSH) is another sensitive indicator of iodine status in pregnant women.6 Serum neonatal TSH levels are higher in maternal iodine deficiency as compared with those of iodinesufficient mothers. Moreover, the decline of high neonatal TSH level following iodized salt supplementation indicated an improvement of iodine nutrition in the population.7 Lactating women are vulnerable to iodine deficiency.8 This is due to high iodine content secreted into breast milk by increasing expression of sodium/iodide symporter during lactation.9 In iodine-sufficient areas, breast milk iodine concentration (BMIC) is in the range of 150 to 180 μg l–1,10 which is considered adequate for infants’ requirement. Therefore, in iodine-deficient areas, BMIC may not be adequate for the need of the infant. Several studies demonstrated higher BMIC in iodine-supplemented mothers compared with non-supplemented mothers.11,12 Since October 2010, there has been a Thai National Iodine Supplementation Program by giving a daily iodine tablet to all pregnant women throughout their gestation in order to improve maternal iodine status. In addition, universal salt iodization has been strengthened and implemented. However, iodine tablet supplementation has been an inconsistent practice in our hospital. Whether iodine tablet supplementation improves iodine status in our pregnant population has not been investigated.
1 Department of Pediatrics, Division of Endocrinology and Metabolism, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 2Department of Obstetrics and Gynecology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand and 3Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Correspondence: Professor P Mahachoklertwattana, Division of Endocrinology and Metabolism, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama 6 Road, Bangkok 10400 Thailand. E-mail: [email protected] Received 30 October 2013; revised 23 February 2014; accepted 6 March 2014; published online 17 April 2014
Iodine status in pregnancy and neonatal TSH D Sukkhojaiwaratkul et al
595 We, therefore, aimed to determine the effects of maternal iodine tablet supplementation on iodine status of pregnant and lactating women and their infants as well as neonatal TSH levels. METHODS This study had been conducted during the years 2011 to 2013 at Ramathibodi Hospital, a University Hospital in Bangkok, Thailand. The study was approved by the institute’s ethics committee and written informed consent was obtained from all participants. A total of 1508 pregnant women who attended the antenatal care clinic were enrolled (Figure 1a). Urine samples were collected for UIC measurement throughout the gestations. There were 1646 urine samples collected. There were 138 (9%) pregnant women who provided two urine samples in both the first and second trimesters and 1370 (91%) pregnant women provided only one urine sample. Urine samples obtained at first trimester of gestation were collected at the first visit of antenatal care. Thus, all the first trimester urine samples were obtained before iodine tablet supplementation. Although iodine tablet supplementation has been implemented since October 2010, the coverage of the supplementation has not been completed. After the first visit of antenatal care, 51% of pregnant women were given multivitamin tablet, containing 200 μg of iodine. The percentages of iodine tablet supplementation were estimated from the prescription in the medical records. Medication adherence was not directly assessed. Lactating women and their offspring’s UICs and BMIC were measured at 2-month postpartum as summarized in Figure 1b. Medication adherence in iodine-supplemented lactating women was 92%. Urine and breast milk samples were frozen at –20 °C until the analysis. The iodine concentrations of urine and breast milk samples were measured by Sandell–Kolthoff reaction. Based on WHO population criteria, a median UIC of o 150 μg l–1 for pregnant women and o100 μg l–1 for lactating women and infants were used to define iodine deficiency.13 Cord serum TSH levels obtained from routine neonatal screening for congenital hypothyroidism during the years 2005 to 2013 were retrospectively reviewed and comparisons of the levels between the pre- and post-iodine supplementation program (January 2005 to October 2010 vs November 2011 to May 2013) were made. Cord serum TSH level
was measured by electrochemiluminescence immunoassay kit (Abbot Laboratories, Chicago, IL, USA). The detection limit of TSH assay was 0.0025 mU l–1.
RESULTS UIC in pregnant women There were 833, 597 and 162 samples obtained during the first, second and third trimesters of gestation, respectively. The respective median (range) UIC values in each trimester were 166.3 (7.7 to 1299.1), 167.9 (11.5 to 1499.3) and 204.6 (28.6 to 1045.8) μg l–1. The overall median (range) UIC was 170.6 (7.7 to 1499.3) μg l–1 (Figure 2). These findings indicated adequate iodine status throughout gestation in this population. A total of 488 urine samples from second and third trimesters were then categorized into two groups, iodine-supplemented (n = 218) and non-supplemented (n = 270) (Figure 1a). The former had significantly higher median (range) UIC than the latter (196.5 (11.5 to 1173.9) vs 161.1 (14.5 to 1045.8) μg l–1, P o0.01). However, both values are in iodine sufficiency range for pregnant women (>150 μg l–1). UIC in lactating women and their infants Eighty-seven lactating women were enrolled at 2-month postpartum. Their median (range) UIC was 138.0 (26.8 to 735.8) μg l–1, which indicated adequate iodine nutrition. Thirty-four subjects (39%) received iodine tablet supplementation. Median (range) UIC of lactating women in iodine-supplemented group (n = 34) tended to be higher than that of non-supplemented group (n = 53) but without statistical significance (198.8 (31.4 to 735.8) vs 119.8 (26.7 to 620.8) μg l–1, P = 0.079). Urine samples of 76 infants at the age of 2 months were obtained. The median (range) UIC was 219.4 (76.2 to 1066.8) μg l–1. Infants were divided into three groups according to their feedings
Figure 1. (a) Protocol flow chart of pregnant women enrolled in the study; supplemented group = iodine tablet supplementation. (b) Protocol flow chart of 2-month-old infants and their mothers at Well Baby Clinic, Ramathibodi Hospital, Bangkok, Thailand; supplemented mothers = lactating mothers receiving iodine tablet supplementation, BMIC, breast milk iodine concentration; UIC, urinary iodine concentration. © 2014 Nature America, Inc.
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Figure 2. Urinary iodine concentration (UIC) (median and interquartile range) of pregnant women throughout gestation and lactating mothers at 2-month postpartum; *median UIC in the third trimester was significantly higher than those of the first trimester (P = 0.012) and second trimester (P = 0.013).
Figure 4. Maternal urinary iodine concentration (UIC) (circle) and percentage of cord serum thyroid-stimulating hormone (TSH) of >10 mU l–1 (triangle) in the years 1993, 2000 and 2013 at Ramathibodi Hospital. Straight lines through each time point represent the trend changes overtime.
Eighty-one percent (n = 6749) of neonates in group 1 but only 54% (n = 2798) in group 2 had cord serum TSH of >5 mU l–1 (P o0.001). Similarly, 26% (n = 2166) of neonates in group 1 but only 11.7% (n = 606) in group 2 had cord serum TSH of >10 mU l–1 (P o 0.001). Data from the previous2 and present studies at Ramathibodi Hospital demonstrated the reciprocal trend changes overtime of percentage of high cord serum TSH (>10 mU l–1) and maternal median UIC (Figure 4).
Figure 3. Urinary iodine concentration of 2-month-old infants (n = 25), comparing between infants with maternal iodine supplementation and infants without maternal iodine supplementation. Box plot represents median and interquatile range.
as exclusive breast milk (n = 25), exclusive formula (n = 40) and combination (n = 11) (Figure 1b). The respective median (range) UIC values were 260.9 (106.6 to 1066.1), 191.4 (45.0 to 1042.0) and 127.7 (76.2 to 301.1) μg l–1 but no significant difference. Infant formulas contain approximately 70 to 100 μg iodine per litre. Exclusively breast-fed infants whose mothers received iodine supplementation (n = 11) had greater median (range) UIC than those of non-supplemented mothers (n = 14) (380.8 (164.0 to 668.7) vs 215.8 (106.6 to 1066.1) μg l–1, P = 0.017; Figure 3). Breast milk iodine concentration Breast milk samples were collected from 57 lactating women. Their median (range) BMIC was 90.8 (0 to 311.5) μg l–1. There were 33 subjects (65%) who received iodine tablet supplementation. In iodine-supplemented mothers, their median BMIC was significantly higher than that of non-supplemented mothers (108.6 (8.8 to 311.5) vs 69.5 (0.0 to 172.4) μg l–1, P = 0.032). Neonatal cord serum TSH concentration Neonates born before October 2010 were classified as pre-iodine supplementation group (group 1) while those born after October 2010 were in the post-iodine supplementation group (group 2). Cord serum TSH values were obtained from 13 513 neonates, 8332 in group 1 and 5181 in group 2. Median (range) cord serum TSH level in group 1 was significantly higher than that of the group 2 (7.3 (0.01 to 87.7) vs 5.2 (0.01 to 35.1) mU l–1, P o0.001). Journal of Perinatology (2014), 594 – 598
DISCUSSION Salt iodization is the most effective strategy to eradicate iodine deficiency.13 The Thai National Iodine Deficiency Disorder (IDD) Control Project on household and industrial salt iodization has been established since 1989. However, the national survey in the years 2000 to 2006 demonstrated that Thai pregnant women remained iodine deficient.14 This is partly due to incomplete coverage of iodized salt. Therefore, strategies to improve iodized salt coverage have been implemented. In the mean time, rapid improvement of iodine nutrition in pregnant women by giving iodine tablet supplementation has been implemented since October 2010. This study demonstrated that iodine nutrition in pregnant women was improved following iodine tablet supplementation program, which is in agreement with previous studies.4,5,15 Moreover, iodine tablet supplementation was shown to be more effective than iodized salt supplementation in improving iodine status in pregnant women.16,17 Thus, the American Thyroid Association recommends 150 μg daily iodine intake during pregnancy and lactation.18 Interestingly, the median UIC in the first trimester in our study was adequate before iodine tablet supplementation. This result could be the result of an increase in iodized salt coverage in Thailand up to 94% in the year 2011 (Department of Health of Thailand), as compared with only 47% coverage in the year 2009.19 Regarding trimester-specific changes of UIC, the previous study in iodine-sufficient areas demonstrated a trend of decline in urinary iodine excretion with advanced gestation.20–22 On the contrary, this study demonstrated that median UIC collected during the third trimester was significantly higher than those collected during the first and second trimesters. This finding is likely a result of the effect of iodine tablet supplementation up to 62% in the third trimester as compared with 0% and 51% in the first and second trimesters, respectively. This study demonstrated a trend toward higher median UIC in iodine-supplemented lactating women as compared with nonsupplemented women, albeit no statistical significance. As a result, © 2014 Nature America, Inc.
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the infants of the supplemented mothers also had higher median UIC as compared with those of the non-supplemented mothers. These findings are consistent with the previous study.23 Median BMIC in this study was in suboptimal level for infants’ requirement according to the Institute of Medicine recommendation for daily iodine intake of 110 μg.24 Median BMIC was significantly higher in iodine-supplemented mothers as compared with non-supplemented mothers. Taken together, increased BMIC and infants’ UIC indicated the direct effect of iodine tablet supplementation in lactating women. This finding is in agreement with the previous reports in lactating women who received 100 to 200 μg daily of iodine supplementation.11,12,23 There was a trend toward declining of cord serum TSH values after iodine supplementation during pregnancy. This finding is consistent with the previous studies in iodine-deficient areas.7,25 Hence, a trend toward declining of neonatal TSH levels is likely one of the indicators of improvement of iodine nutrition in pregnant women. Percentage of blood spot neonatal TSH values >5.0 mU l–1 of >3% has been used as an index of iodine deficiency.6 This numerical value was derived from older than 72-h-old neonates who were born in iodine-sufficient areas. Thus, TSH concentrations obtained from cord blood are not equivalent to those obtained from the blood spots of 72-h-old neonates. Therefore, the percentage of neonates who had cord blood TSH concentrations of >10 mU l–1 is 11.7%, which may suggest iodine deficiency by the above criterion, while maternal median UIC is 170.6 μg l–1 (Figure 4), which indicates adequate iodine nutrition. This discrepancy supports the notion that the neonatal TSH criterion may not be a reliable monitoring tool for iodine deficiency as suggested by Smyth and Li in the previous reports.26,27 This study demonstrated iodine sufficiency during pregnancy and lactation in study population despite iodine tablet coverage was only about 50 to 60%. This is likely due to an improvement of iodized salt coverage at the present time. However, mild elevation of neonatal TSH values and UIC o 150 μg l–1 in pregnant women were still present. These findings indicate mild iodine insufficiency. Recent evidences suggested that mild iodine deficiency during pregnancy was associated with reduced cognitive and educational outcomes in the offspring.28,29 Therefore, intervention with iodine tablet supplementation in our study is likely to be effective in improving maternal iodine nutrition and thus could prevent adverse impacts on fetal neurocognitive function. This study demonstrated the long-term trend toward an improvement of iodine status in pregnant women who have resided in Bangkok. However, our study has some limitations, which include small sample size in lactating woman and infant groups, incompleteness of iodine supplementation and no assessment of medication adherence in pregnant woman group. In addition, lack of randomization of urine samples collection may cause selection bias. In conclusion, this study demonstrated that universal iodine tablet supplementation during pregnancy and lactation improved iodine nutrition in mothers and their offspring, and thus could prevent neonatal hyperthyrotropinemia or subclinical hypothyroidism in early infancy. Therefore, in mildly iodine-deficient areas, iodine tablet supplementation in pregnant and lactating women is an effective strategy to rapidly improve iodine nutrition in the high-risk population. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS This study was supported by a research grant (no. MURA2012/50) from the Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand. We thank Professor Rajata Rajatanavin for the constructive critique of the manuscript.
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