- Email: [email protected]
Iodine status in Danish pregnant and breastfeeding women including studies of some challenges in urinary iodine status evaluation
Journal of Trace Elements in Medicine and Biology 31 (2015) 285–289
Contents lists available at ScienceDirect
Journal of Trace Elements in Medicine and Biology journal homepage: www.elsevier.com/locate/jtemb
INVITED REVIEW
Iodine status in Danish pregnant and breastfeeding women including studies of some challenges in urinary iodine status evaluation Stine Linding Andersen a,b,c,∗ , Louise Kolding Sørensen a , Anne Krejbjerg a,b , Margrethe Møller d , Ditte Marie Klitbo e , Susanne Backman Nøhr f , Klaus Michael Pedersen g , Peter Laurberg a,b a
Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark Department of Clinical Medicine, Aalborg University, Aalborg, Denmark c Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark d Department of Obstetrics and Gynecology, Aalborg University Hospital, Aalborg, Denmark e Department of Endocrinology, Bispebjerg Hospital, Bispebjerg, Denmark f Department of Postgraduate Education, Aalborg University Hospital, Aalborg, Denmark g Department of Internal Medicine, Vejle Hospital, Vejle, Denmark b
a r t i c l e
i n f o
Article history: Received 1 October 2014 Accepted 14 November 2014 Keywords: Iodine Pregnancy Breastfeeding Urinary iodine concentration Urinary creatinine concentration
a b s t r a c t Denmark was previously iodine deficient with regional differences. Moderate iodine deficiency appeared in West Denmark and mild iodine deficiency in East Denmark and also Danish pregnant and breastfeeding women suffered from iodine deficiency. The Danish mandatory iodine fortification of salt was introduced in the year 2000 and has increased iodine intake in the Danish population. However, median urinary iodine concentration in the general population and in pregnant and breastfeeding women is still below the level recommended, corresponding to mild iodine deficiency. Certain characteristics may challenge the evaluation of urinary iodine status in pregnancy and during breastfeeding. This review also addresses methodological challenges related to spot urine sampling conditions and the use of iodine supplement and discusses the use of non-pregnant population groups as a proxy for iodine intake in pregnant women. © 2014 Elsevier GmbH. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iodine status before the iodine fortification of salt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iodine status after the iodine fortification of salt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methodological challenges in evaluation of urinary iodine status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Location and time of spot urine sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iodine supplement intake and spot urine sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iodine metabolism in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-pregnant population groups as a proxy for iodine status in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author at: Department of Endocrinology, Aalborg University Hospital, Sdr. Skovvej 15, 9000 Aalborg, Denmark. Tel.: +45 99 66 36 85. E-mail address: [email protected] (S.L. Andersen). http://dx.doi.org/10.1016/j.jtemb.2014.11.004 0946-672X/© 2014 Elsevier GmbH. All rights reserved.
286 286 286 287 287 287 288 288 289 289 289
286
S.L. Andersen et al. / Journal of Trace Elements in Medicine and Biology 31 (2015) 285–289
Introduction
Median UIC (µg/liter)
Iodine is required for the synthesis of thyroid hormones and the crucial role of thyroid hormones during early brain development makes adequate iodine intake in pregnant and breastfeeding women imperative [1]. Monitoring of population iodine status is important worldwide, and suboptimal iodine status has been shown both in developed and developing countries [2]. The recommended method to assess iodine status in a population is to collect spot urine samples for measurement of urinary iodine concentration (UIC) and calculation of median UIC [3]. According to the World Health Organization (WHO), the United Nations Children’s Fund (UNICEF), and the International Council for the Control of Iodine Deficiency Disorders (ICCIDD) [3], a median UIC in the range from 50 to 99 g/L corresponds to mild iodine deficiency, from 20 to 49 g/L is moderate iodine deficiency and severe iodine deficiency is when the median UIC is below 20 g/L. Efforts to prevent iodine deficiency include universal food fortification programs and/or the recommendation of individual iodine supplementation. The Danish population previously suffered from mild to moderate iodine deficiency and a mandatory iodine fortification of salt was introduced in the year 2000 [4]. Iodine status in the general Danish population and in pregnant and breastfeeding women specifically has been evaluated both before and after the iodine fortification was introduced. In this review we describe urinary iodine status in Danish pregnant and breastfeeding women before and after the iodine fortification of salt and compare the urinary iodine status in these subgroups with that of the general population. Historically, iodine status in a population was evaluated from the collection of spot urine samples in schoolchildren and it has been considered whether data on non-pregnant population groups can be used as a proxy for iodine status in pregnant women [5]. However, the conclusion has often been that a median UIC indicating sufficient iodine intake in schoolchildren may not indicate sufficient iodine intake in pregnant women [6]. The evaluation of iodine status from spot urine samples is challenging and many methodological details may influence the results [7]. In this review we also focus on some of the challenges related to the evaluation of iodine status in pregnant and breastfeeding women and we speculate whether disparities in results of urinary iodine status in different population groups may in part be explained by different urine sampling conditions.
150
Iodine status before the iodine fortification of salt Denmark was previously iodine deficient with regional difference caused by different levels of iodine in drinking water [8]. Divided by the Great Belt, East Denmark had mild iodine deficiency and as illustrated in Fig. 1 West Denmark had moderate iodine deficiency with a median UIC below 50 g/L. Iodine status in Danish pregnant and breastfeeding women had been examined before the introduction of the iodine fortification of salt. The investigations [9–13] were mainly performed in West Denmark with previously most pronounced iodine deficiency. As illustrated in Fig. 1, the iodine intake in pregnant and breastfeeding women in this part of Denmark was inadequate with a median UIC on the border of mild to moderate iodine deficiency. Examination of pregnant women showed signs of thyroidal stress with increasing thyroid volume and serum TSH, and high levels of serum thyroglobulin (Tg) [10]. At this time, 35% of Danish pregnant women reported intake of iodine containing supplements when they arrived for delivery [11] approximating the frequency of iodine supplement intake in the Danish population in general [14]. The inadequate iodine status
Lower recommended level pregnant women
General population Pregnant women
125
Breastfeeding women
100
Iodine supplement
Lower recommended level non-pregnant adults
No iodine supplement
75
No iodine supplement
50
25
0 1997
~1990 ~1990
Before iodine fortification
2008
2012
2012
2008
2012
2012
After iodine fortification
Fig. 1. Median urinary iodine concentration (UIC) observed in various studies in the general population as well as in pregnant and breastfeeding women living in West Denmark. Results were stratified by time of examination (before/after the introduction of the mandatory iodine fortification of salt introduced in the year 2000) and iodine supplement intake. Source: Data from [15,16] for the general population, [10,13] for pregnant and breastfeeding women before the iodine fortification, and [17,18] for pregnant and breastfeeding women after the iodine fortification. Data for pregnant and breastfeeding women before the iodine fortification were averaged from two investigations with data collection from 1987 [10] and from 1994 [13].
in Danish pregnant women led to intervention studies with iodine supplement in pregnancy [10,13]. Pregnant women taking iodine supplement had higher median UIC and the changes in thyroid volume, serum TSH and serum Tg were ameliorated [10]. One concern about iodine supplement intake has been the possible risk of aggravation of thyroid autoimmunity in the postpartum period. However, in a Danish randomized controlled trial, iodine supplement intake in pregnancy was not associated with a higher frequency or more severe postpartum thyroid dysfunction [13]. Iodine status after the iodine fortification of salt A voluntary iodine fortification of salt was introduced in Denmark in 1998, but the voluntary approach turned out to be insufficient, and a mandatory iodine fortification of household salt and salt used for commercial production of bread was implemented in the year 2000 [4]. The Danish investigation of iodine intake and thyroid disease (DanThyr) has monitored iodine status in East and West Denmark before and after the mandatory iodine fortification of salt. In both regions, iodine intake had increased after the introduction of the mandatory iodine fortification of salt and the combined median UIC (East and West Denmark) was 101 g/L in 2005 [14]. A follow-up study of the same individuals before and after iodine fortification also showed a significant increase in median UIC from 1997 to 2008 [15,16] as depicted for no iodine supplement users in West Denmark in Fig. 1. The combined median
S.L. Andersen et al. / Journal of Trace Elements in Medicine and Biology 31 (2015) 285–289
287
Median 200
Hospital sample (median 10 am) Home sample (median 6 pm)
175
p = 0.8 Hospital
150
Home
p = 0.002
125
Home
100 Hospital
75 50 25 0 Urinary iodine concentration (µg/liter)
24-hour estimated urinary iodine excretion (µg)
Fig. 2. Median urinary iodine concentration and estimated 24-h urinary iodine excretion in 66 pregnant women who made a spot urine sample non-fasting in the hospital and another day at home. p-values are results of the Wilcoxon signed-rank test. Source: Data from [19].
UIC (East and West Denmark) was 83 g/L at the last follow-up examination in 2008 [15]. Iodine status in Danish pregnant and breastfeeding women after the introduction of the mandatory iodine fortification of salt has been examined in the year 2012 in the North Denmark Region located in West Denmark [17,18] (Fig. 1). Median UIC had increased in pregnant and breastfeeding women compared with previous studies, and the overall median UIC was 101 g/L. The median UIC was below the level recommended in pregnancy both in iodine supplement users and in non-users, but considerably lower in the group of pregnant women with no use of iodine supplement. In Denmark, no official recommendations exist for iodine supplement intake in pregnancy and during breastfeeding. In our recent investigation [17], the use of iodine supplement in pregnancy had considerably increased compared with the previous study (∼85% vs. previously 35%). The majority of women took iodine supplement containing 175 g iodine/day and they all obtained iodine from a multivitamin pill. In pregnancy, Danish recommendations exist for the intake of iron, folic acid and vitamin D which are often combined in a multivitamin pill. On the other hand, no recommendations exist for supplement intake during breastfeeding as reflected by a lower frequency of iodine supplement intake during breastfeeding (∼50%) in our recent Danish investigation [18]. Methodological challenges in evaluation of urinary iodine status Certain characteristics may challenge the evaluation of urinary iodine status from spot urine samples in pregnant and breastfeeding women. Our most recent investigations of iodine status in Danish pregnant and breastfeeding women were extended to include not only evaluation of urinary iodine status by the ‘classical’ approach, but also to investigate methodological challenges. Location and time of spot urine sampling In studies of pregnant women, study inclusion often takes place during a routine hospital visit for obstetric ultrasound. Such hospital visits are often in the morning or in the afternoon and it can be speculated if a spot urine sample obtained in the hospital is representative for a sample which was instead obtained at home during daily living. In our recent investigation of Danish pregnant women,
66 participants delivered a spot urine sample both in the hospital at the time of inclusion and another day at home [19]. Median UIC was significantly higher in the home sample than in the hospital sample (Fig. 2). Urinary creatinine concentration was measured as a proxy for maternal fluid intake and we used this measurement and the 24-h urinary iodine excretion previously measured in a group of Danish pregnant women [9] to calculate the estimated 24-h urinary iodine excretion [19]. When UIC was adjusted by urinary creatinine concentration, no difference between the hospital and the home sample was observed (Fig. 2). The time of spot urine sampling in the hospital was always in the morning (non-fasting) at a median 10 am. The time of spot urine sampling at home was not prespecified, but the pregnant women were instructed to sample urine at the same time as their household members. It turned out that the majority of families managed to sample urine in the afternoon or evening at median 6 pm. When stratified by time of sampling at home (before vs. at or after 5 pm), UIC was only significantly higher in the home sample when sampling at home was at or after 5 pm. Thus, UIC was influenced by time of sampling but when urinary creatinine concentration was used to calculate the estimated 24-h urinary iodine excretion the time dependent difference leveled out. The significance of spot urine sampling time is in line with other reports [20,21] and it can be speculated if the evening meal or different fluid intake led to a higher UIC in the evening samples. Further studies are needed and studies with prespecified and similar time of urine sampling in both locations are necessary to further evaluate the possible influence by sampling location. However, the results stress the importance of reporting and considering location and time of spot urine sampling in studies of pregnant women. Iodine supplement intake and spot urine sampling Iodine supplement intake is often recommended to ensure adequate iodine intake of the mother, the fetus and the breastfed infant. The relationship between iodine intake and urinary excretion of iodine was illustrated by use of radioiodine in 1947 [22]. Keating et al. [22] investigated urinary iodine excretion after oral ingestion of radioiodine in four healthy men. Approximately 2/3 of the dose appeared in the urine within 48 h and 50% was excreted within 6 h. Considering this, it can be speculated if the time of most recent iodine supplement intake prior to spot urine and
288 150
S.L. Andersen et al. / Journal of Trace Elements in Medicine and Biology 31 (2015) 285–289 Median (µg/liter)
125
MIC
100
UIC in pregnancy
p < 0.001 p < 0.001
75 UIC during breastfeeding
p = 0.3
50
25
0 The same day
The day before
Several days ago/non-user
Intake of iodine supplement prior to spot urine sampling
Fig. 3. Urinary iodine concentration (UIC) in pregnancy and during breastfeeding and breast milk iodine concentration (MIC) in 127 Danish women stratified by time of most recent iodine supplement intake prior to sampling. p-values are results of the Kruskal–Wallis test. Source: Data from [18].
breast milk sampling could influence results. In our recent Danish investigations, the participants were asked if most recent iodine supplement intake was the same day prior to spot urine sampling, the day before, several days ago, or non-user [18,19]. As depicted in Fig. 3, a significant trend was observed for UIC and breast milk iodine concentration (MIC) with the highest median value when iodine supplement intake was the same day prior to sampling. On the other hand, UIC during breastfeeding was not significantly influenced by most recent iodine supplement intake (Fig. 3). The transport of iodide into breast milk leads to changes in iodine metabolism in the breastfeeding mother as 40–45% of her dietary iodine intake is excreted into breast milk [23]. When urinary creatinine concentration was used as a proxy for maternal fluid intake, UIC, but not MIC, was influenced by maternal fluid intake [18]. Thus, when maternal fluid intake is increased to compensate for the fluid loss into breast milk, UIC is expected to be lower during breastfeeding compared to pregnancy. This is also reflected by the lower recommended level for UIC during breastfeeding (100 g/L) despite increased iodine requirements [3]. In a study with acute high dietary iodine intake, MIC increased with a peak after 6 h, whereas UIC remained stable during the 8 h of observation [24] compatible with our results for iodine supplement intake (Fig. 3). Further studies are needed to evaluate the influence of iodine supplement intake on results of spot urine sampling, but the results stress the importance of reporting and considering time of most recent iodine supplement intake prior to spot urine sampling. Iodine metabolism in pregnancy Physiological changes in iodine metabolism occur in pregnancy. There is a ∼50% increase in the production of thyroid hormones which requires an increased uptake of iodide in the thyroid gland [25]. There is also an increased metabolism of thyroid hormones due to the increased activity of type-3 deiodinase in placenta [26] and finally the glomerular filtration rate increases in early pregnancy and is maintained ∼50% higher throughout pregnancy leading to an increased renal excretion of iodide [27].
The physiological changes in iodine metabolism during pregnancy was investigated in 1964 by Aboul-Khair et al. [28] who performed intravenous injection of radioiodine in 13 pregnant women and 13 controls. They observed [28] that the increased renal clearance of iodide led to a decrease in the plasma inorganic iodide (PII) concentration. The absolute uptake of iodide in the thyroid gland was increased by 50%, but the thyroid clearance of iodide was 3–4 times higher in pregnancy suggesting that the thyroid gland had to work harder to obtain sufficient iodide due to the lower PII. The study was based on indirect measurement of PII and performed in an area with iodine deficiency [28]. In a study with direct measurement of PII, no changes in PII were observed during pregnancy, but the women investigated in this study had a more than adequate iodine intake [29]. The main determinants of UIC are the dietary iodine intake and the fluid intake. It can be speculated whether the physiological changes in iodine metabolism in pregnancy may alter the determinants of UIC. The increased maternal thyroid hormone production due to TBG increase, maternal tissue expansion and the need for transport of T4 as well as iodide across the placenta to the fetus will lead to some iodine retention, but it can be calculated that this iodine retention represent only a few g iodine per day. Thus, when iodine intake is as recommended or even less than this, the daily iodine retention is a very small fraction, but it will constitute a relatively larger fraction in case of very low iodine intake. In the kidneys, there is an increased renal excretion of iodide starting from early pregnancy, but this is counteracted by a decreased PII concentration and then a new steady state for the renal clearance of iodide is established. Thus, in pregnancy as well as in non-pregnant adults, the main determinants of UIC appear to be the dietary iodine intake and the fluid intake. Non-pregnant population groups as a proxy for iodine status in pregnancy Historically, schoolchildren were used for assessment of iodine status in a population [5]. Thus, in some populations data on pregnant women may be sparse or not available. The use of nonpregnant population groups as a proxy for iodine status in pregnant women has been considered, but the conclusion has mainly been that adequate iodine status of schoolchildren or non-pregnant women may not indicate adequate iodine status in pregnant women [6]. Considering the methodological challenges in evaluation of urinary iodine status from spot urine samples, it can be speculated if differences in urine sampling conditions could partly explain the conclusions e.g. the pregnant women sampling in the morning and the schoolchildren sampling in another location at another time of the day. In our recent investigation of iodine intake in Danish pregnant women we included pregnant women and members of their household (male partners and children) and the family members were instructed to perform non-fasting spot urine samples at home at the same time [19]. Using this approach, we observed no difference in median UIC between the pregnant women, the male partners, and the children (Fig. 4) with similar results when stratified by iodine supplement intake. The most striking difference was that iodine supplement intake was much more frequent in pregnant women (87%) than in male partners (15%) and children (25%). When we compared individual pairs of pregnant women and male partner, as expected UIC was higher in the pregnant woman than the male partner when only she used iodine supplement. When none or both used iodine supplement no difference in UIC was observed [19]. In Danish families it did not seem as if the pregnant women had changed their diet or fluid intake to a considerably different level, but studies in different populations are needed to clarify the use of non-pregnant groups as a proxy for iodine status in pregnant
S.L. Andersen et al. / Journal of Trace Elements in Medicine and Biology 31 (2015) 285–289 Median UIC (µg/liter) 200 175 150
p = 0.1
125 100 75 50 25 0 Pregnant women n = 68
Male partners n = 67
Children n = 51
Fig. 4. Median urinary iodine concentration in pregnant women, male partners and children. All family members sampled a spot urine sample at home at the same time. p-value is result of the Kruskal–Wallis test. Iodine supplement use in pregnant women: 87%, male partners: 15%, and children: 25%. Median UIC (pregnant women vs. male partners vs. children) in iodine supplement users: 136 g/L vs. 136 g/L vs. 151 g/L (p = 0.5), in iodine supplement non-users: 98 g/L vs. 110 g/L vs. 121 g/L (p = 0.4). Source: Data from [19].
women. Results stress the importance of standardizing spot urine sampling conditions for comparison of different population groups. Perspective Urinary iodine status in Danish pregnant and breastfeeding women living in an area of Denmark with previously moderate iodine deficiency is still inadequate more than 10 years after the introduction of the Danish iodine fortification. Combined with the most recent data on iodine status in the Danish population in general, the results may call for a modest increase in the level of iodide added to salt in Denmark. The frequency of iodine supplement intake during pregnancy had increased and was high while lower during breastfeeding. Urinary iodine status was better when the women used iodine supplement, and iodine supplement should be officially recommended during pregnancy and breastfeeding in Denmark. Certain characteristics about studies in pregnant and breastfeeding women may challenge the interpretation of urinary iodine status, and further studies are needed to ascertain methodological aspects in more detail including the use of non-pregnant population groups as a proxy for iodine status in pregnant women. Future studies should optimally consider and report: time and location of spot urine sampling, time of most recent iodine supplement intake prior to spot urine sampling, and urinary creatinine concentration. Conflict of interest The authors declare no conflict of interest. References [1] Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 2000;8511:3975–87.
289
[2] Pearce EN, Andersson M, Zimmermann MB. Global iodine nutrition: where do we stand in 2013? Thyroid 2013;235:523–8. [3] WHO, UNICEF, ICCIDD. Assessment of iodine deficiency disorders and monitoring their elimination. A guide for programme managers, vol. 3. World Health Organisation; 2007. p. 1–98. [4] Laurberg P, Jorgensen T, Perrild H, Ovesen L, Knudsen N, Pedersen IB, et al. The Danish investigation on iodine intake and thyroid disease, DanThyr: status and perspectives. Eur J Endocrinol 2006;1552:219–28. [5] Zimmermann MB. Iodine deficiency. Endocr Rev 2009;304:376–408. [6] Wong EM, Sullivan KM, Perrine CG, Rogers LM, Pena-Rosas JP. Comparison of median urinary iodine concentration as an indicator of iodine status among pregnant women, school-age children, and nonpregnant women. Food Nutr Bull 2011;323:206–12. [7] Skeaff SA. Assessing iodine intakes in pregnancy and strategies for improvement. J Trace Elem Med Biol 2012;262–263:141–4. [8] Pedersen KM, Laurberg P, Nohr S, Jorgensen A, Andersen S. Iodine in drinking water varies by more than 100-fold in Denmark. Importance for iodine content of infant formulas. Eur J Endocrinol 1999;1405:400–3. [9] Pedersen KM, Borlum KG, Knudsen PR, Hansen ES, Johannesen PL, Laurberg P. Urinary iodine excretion is low and serum thyroglobulin high in pregnant women in parts of Denmark. Acta Obstet Gynecol Scand 1988;675:413–6. [10] Pedersen KM, Laurberg P, Iversen E, Knudsen PR, Gregersen HE, Rasmussen OS, et al. Amelioration of some pregnancy-associated variations in thyroid function by iodine supplementation. J Clin Endocrinol Metab 1993;774:1078–83. [11] Nohr SB, Laurberg P, Borlum KG, Pedersen KM, Johannesen PL, Damm P, et al. Iodine deficiency in pregnancy in Denmark, regional variations and frequency of individual iodine supplementation. Acta Obstet Gynecol Scand 1993;725:350–3. [12] Nohr SB, Laurberg P, Borlum KG, Pedersen KM, Johannesen PL, Damm P, et al. Iodine status in neonates in Denmark: regional variations and dependency on maternal iodine supplementation. Acta Paediatr 1994;836:578–82. [13] Nohr SB, Jorgensen A, Pedersen KM, Laurberg P. Postpartum thyroid dysfunction in pregnant thyroid peroxidase antibody-positive women living in an area with mild to moderate iodine deficiency: is iodine supplementation safe. J Clin Endocrinol Metab 2000;859:3191–8. [14] Rasmussen LB, Carle A, Jorgensen T, Knudsen N, Laurberg P, Pedersen IB, et al. Iodine intake before and after mandatory iodization in Denmark: results from the Danish investigation of iodine intake and thyroid diseases (DanThyr) study. Br J Nutr 2008;1001:166–73. [15] Rasmussen LB, Jorgensen T, Perrild H, Knudsen N, Krejbjerg A, Laurberg P, et al. Mandatory iodine fortification of bread and salt increases iodine excretion in adults in Denmark – a 11-year follow-up study. Clin Nutr 2014;33:1033–40. [16] Krejbjerg A, Bjergved L, Pedersen IB, Carle A, Jorgensen T, Perrild H, et al. Iodine fortification may influence the age-related change in thyroid volume: a longitudinal population-based study (DanThyr). Eur J Endocrinol 2014;1704:507–17. [17] Andersen SL, Sorensen LK, Krejbjerg A, Moller M, Laurberg P. Iodine deficiency in Danish pregnant women. Dan Med J 2013;607:A4657. [18] Andersen SL, Moller M, Laurberg P. Iodine concentrations in milk and in urine during breastfeeding are differently affected by maternal fluid intake. Thyroid 2014;244:764–72. [19] Andersen SL, Sørensen LK, Krejbjerg A, Møller M, Laurberg P. Challenges in the evaluation of urinary iodine status in pregnancy: the importance of iodine supplement intake and time of sampling. Eur Thyroid J 2014;33:179–88. [20] Rasmussen LB, Ovesen L, Christiansen E. Day-to-day and within-day variation in urinary iodine excretion. Eur J Clin Nutr 1999;535:401–7. [21] Als C, Helbling A, Peter K, Haldimann M, Zimmerli B, Gerber H. Urinary iodine concentration follows a circadian rhythm: a study with 3023 spot urine samples in adults and children. J Clin Endocrinol Metab 2000;854:1367–9. [22] Keating FR, Power MH, Berkson J, Haines SF. The urinary excretion of radioiodine in various thyroid states. J Clin Invest 1947;266:1138–51. [23] Laurberg P, Andersen SL. Nutrition: Breast milk – a gateway to iodinedependent brain development. Nat Rev Endocrinol 2014;103:134–5. [24] Leung AM, Braverman LE, He X, Heeren T, Pearce EN. Breastmilk iodine concentrations following acute dietary iodine intake. Thyroid 2012;2211:1176–80. [25] Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR. Timing and magnitude of increases in Levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004;3513:241–9. [26] Roti E, Fang SL, Green K, Emerson CH, Braverman LE. Human placenta is an active site of thyroxine and 3,3’5-triiodothyronine tyrosyl ring deiodination. J Clin Endocrinol Metab 1981;533:498–501. [27] Davison JM, Hytten FE. Glomerular filtration during and after pregnancy. J Obstet Gynaecol Br Commonw 1974;818:588–95. [28] Aboul-Khair SA, Crooks J, Turnbull AC, Hytten FE. The physiological changes in thyroid function during pregnancy. Clin Sci 1964;27:195–207. [29] Liberman CS, Pino SC, Fang SL, Braverman LE, Emerson CH. Circulating iodide concentrations during and after pregnancy. J Clin Endocrinol Metab 1998;8310:3545–9.
Contents lists available at ScienceDirect
Journal of Trace Elements in Medicine and Biology journal homepage: www.elsevier.com/locate/jtemb
INVITED REVIEW
Iodine status in Danish pregnant and breastfeeding women including studies of some challenges in urinary iodine status evaluation Stine Linding Andersen a,b,c,∗ , Louise Kolding Sørensen a , Anne Krejbjerg a,b , Margrethe Møller d , Ditte Marie Klitbo e , Susanne Backman Nøhr f , Klaus Michael Pedersen g , Peter Laurberg a,b a
Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark Department of Clinical Medicine, Aalborg University, Aalborg, Denmark c Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark d Department of Obstetrics and Gynecology, Aalborg University Hospital, Aalborg, Denmark e Department of Endocrinology, Bispebjerg Hospital, Bispebjerg, Denmark f Department of Postgraduate Education, Aalborg University Hospital, Aalborg, Denmark g Department of Internal Medicine, Vejle Hospital, Vejle, Denmark b
a r t i c l e
i n f o
Article history: Received 1 October 2014 Accepted 14 November 2014 Keywords: Iodine Pregnancy Breastfeeding Urinary iodine concentration Urinary creatinine concentration
a b s t r a c t Denmark was previously iodine deficient with regional differences. Moderate iodine deficiency appeared in West Denmark and mild iodine deficiency in East Denmark and also Danish pregnant and breastfeeding women suffered from iodine deficiency. The Danish mandatory iodine fortification of salt was introduced in the year 2000 and has increased iodine intake in the Danish population. However, median urinary iodine concentration in the general population and in pregnant and breastfeeding women is still below the level recommended, corresponding to mild iodine deficiency. Certain characteristics may challenge the evaluation of urinary iodine status in pregnancy and during breastfeeding. This review also addresses methodological challenges related to spot urine sampling conditions and the use of iodine supplement and discusses the use of non-pregnant population groups as a proxy for iodine intake in pregnant women. © 2014 Elsevier GmbH. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iodine status before the iodine fortification of salt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iodine status after the iodine fortification of salt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methodological challenges in evaluation of urinary iodine status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Location and time of spot urine sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iodine supplement intake and spot urine sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iodine metabolism in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-pregnant population groups as a proxy for iodine status in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author at: Department of Endocrinology, Aalborg University Hospital, Sdr. Skovvej 15, 9000 Aalborg, Denmark. Tel.: +45 99 66 36 85. E-mail address: [email protected] (S.L. Andersen). http://dx.doi.org/10.1016/j.jtemb.2014.11.004 0946-672X/© 2014 Elsevier GmbH. All rights reserved.
286 286 286 287 287 287 288 288 289 289 289
286
S.L. Andersen et al. / Journal of Trace Elements in Medicine and Biology 31 (2015) 285–289
Introduction
Median UIC (µg/liter)
Iodine is required for the synthesis of thyroid hormones and the crucial role of thyroid hormones during early brain development makes adequate iodine intake in pregnant and breastfeeding women imperative [1]. Monitoring of population iodine status is important worldwide, and suboptimal iodine status has been shown both in developed and developing countries [2]. The recommended method to assess iodine status in a population is to collect spot urine samples for measurement of urinary iodine concentration (UIC) and calculation of median UIC [3]. According to the World Health Organization (WHO), the United Nations Children’s Fund (UNICEF), and the International Council for the Control of Iodine Deficiency Disorders (ICCIDD) [3], a median UIC in the range from 50 to 99 g/L corresponds to mild iodine deficiency, from 20 to 49 g/L is moderate iodine deficiency and severe iodine deficiency is when the median UIC is below 20 g/L. Efforts to prevent iodine deficiency include universal food fortification programs and/or the recommendation of individual iodine supplementation. The Danish population previously suffered from mild to moderate iodine deficiency and a mandatory iodine fortification of salt was introduced in the year 2000 [4]. Iodine status in the general Danish population and in pregnant and breastfeeding women specifically has been evaluated both before and after the iodine fortification was introduced. In this review we describe urinary iodine status in Danish pregnant and breastfeeding women before and after the iodine fortification of salt and compare the urinary iodine status in these subgroups with that of the general population. Historically, iodine status in a population was evaluated from the collection of spot urine samples in schoolchildren and it has been considered whether data on non-pregnant population groups can be used as a proxy for iodine status in pregnant women [5]. However, the conclusion has often been that a median UIC indicating sufficient iodine intake in schoolchildren may not indicate sufficient iodine intake in pregnant women [6]. The evaluation of iodine status from spot urine samples is challenging and many methodological details may influence the results [7]. In this review we also focus on some of the challenges related to the evaluation of iodine status in pregnant and breastfeeding women and we speculate whether disparities in results of urinary iodine status in different population groups may in part be explained by different urine sampling conditions.
150
Iodine status before the iodine fortification of salt Denmark was previously iodine deficient with regional difference caused by different levels of iodine in drinking water [8]. Divided by the Great Belt, East Denmark had mild iodine deficiency and as illustrated in Fig. 1 West Denmark had moderate iodine deficiency with a median UIC below 50 g/L. Iodine status in Danish pregnant and breastfeeding women had been examined before the introduction of the iodine fortification of salt. The investigations [9–13] were mainly performed in West Denmark with previously most pronounced iodine deficiency. As illustrated in Fig. 1, the iodine intake in pregnant and breastfeeding women in this part of Denmark was inadequate with a median UIC on the border of mild to moderate iodine deficiency. Examination of pregnant women showed signs of thyroidal stress with increasing thyroid volume and serum TSH, and high levels of serum thyroglobulin (Tg) [10]. At this time, 35% of Danish pregnant women reported intake of iodine containing supplements when they arrived for delivery [11] approximating the frequency of iodine supplement intake in the Danish population in general [14]. The inadequate iodine status
Lower recommended level pregnant women
General population Pregnant women
125
Breastfeeding women
100
Iodine supplement
Lower recommended level non-pregnant adults
No iodine supplement
75
No iodine supplement
50
25
0 1997
~1990 ~1990
Before iodine fortification
2008
2012
2012
2008
2012
2012
After iodine fortification
Fig. 1. Median urinary iodine concentration (UIC) observed in various studies in the general population as well as in pregnant and breastfeeding women living in West Denmark. Results were stratified by time of examination (before/after the introduction of the mandatory iodine fortification of salt introduced in the year 2000) and iodine supplement intake. Source: Data from [15,16] for the general population, [10,13] for pregnant and breastfeeding women before the iodine fortification, and [17,18] for pregnant and breastfeeding women after the iodine fortification. Data for pregnant and breastfeeding women before the iodine fortification were averaged from two investigations with data collection from 1987 [10] and from 1994 [13].
in Danish pregnant women led to intervention studies with iodine supplement in pregnancy [10,13]. Pregnant women taking iodine supplement had higher median UIC and the changes in thyroid volume, serum TSH and serum Tg were ameliorated [10]. One concern about iodine supplement intake has been the possible risk of aggravation of thyroid autoimmunity in the postpartum period. However, in a Danish randomized controlled trial, iodine supplement intake in pregnancy was not associated with a higher frequency or more severe postpartum thyroid dysfunction [13]. Iodine status after the iodine fortification of salt A voluntary iodine fortification of salt was introduced in Denmark in 1998, but the voluntary approach turned out to be insufficient, and a mandatory iodine fortification of household salt and salt used for commercial production of bread was implemented in the year 2000 [4]. The Danish investigation of iodine intake and thyroid disease (DanThyr) has monitored iodine status in East and West Denmark before and after the mandatory iodine fortification of salt. In both regions, iodine intake had increased after the introduction of the mandatory iodine fortification of salt and the combined median UIC (East and West Denmark) was 101 g/L in 2005 [14]. A follow-up study of the same individuals before and after iodine fortification also showed a significant increase in median UIC from 1997 to 2008 [15,16] as depicted for no iodine supplement users in West Denmark in Fig. 1. The combined median
S.L. Andersen et al. / Journal of Trace Elements in Medicine and Biology 31 (2015) 285–289
287
Median 200
Hospital sample (median 10 am) Home sample (median 6 pm)
175
p = 0.8 Hospital
150
Home
p = 0.002
125
Home
100 Hospital
75 50 25 0 Urinary iodine concentration (µg/liter)
24-hour estimated urinary iodine excretion (µg)
Fig. 2. Median urinary iodine concentration and estimated 24-h urinary iodine excretion in 66 pregnant women who made a spot urine sample non-fasting in the hospital and another day at home. p-values are results of the Wilcoxon signed-rank test. Source: Data from [19].
UIC (East and West Denmark) was 83 g/L at the last follow-up examination in 2008 [15]. Iodine status in Danish pregnant and breastfeeding women after the introduction of the mandatory iodine fortification of salt has been examined in the year 2012 in the North Denmark Region located in West Denmark [17,18] (Fig. 1). Median UIC had increased in pregnant and breastfeeding women compared with previous studies, and the overall median UIC was 101 g/L. The median UIC was below the level recommended in pregnancy both in iodine supplement users and in non-users, but considerably lower in the group of pregnant women with no use of iodine supplement. In Denmark, no official recommendations exist for iodine supplement intake in pregnancy and during breastfeeding. In our recent investigation [17], the use of iodine supplement in pregnancy had considerably increased compared with the previous study (∼85% vs. previously 35%). The majority of women took iodine supplement containing 175 g iodine/day and they all obtained iodine from a multivitamin pill. In pregnancy, Danish recommendations exist for the intake of iron, folic acid and vitamin D which are often combined in a multivitamin pill. On the other hand, no recommendations exist for supplement intake during breastfeeding as reflected by a lower frequency of iodine supplement intake during breastfeeding (∼50%) in our recent Danish investigation [18]. Methodological challenges in evaluation of urinary iodine status Certain characteristics may challenge the evaluation of urinary iodine status from spot urine samples in pregnant and breastfeeding women. Our most recent investigations of iodine status in Danish pregnant and breastfeeding women were extended to include not only evaluation of urinary iodine status by the ‘classical’ approach, but also to investigate methodological challenges. Location and time of spot urine sampling In studies of pregnant women, study inclusion often takes place during a routine hospital visit for obstetric ultrasound. Such hospital visits are often in the morning or in the afternoon and it can be speculated if a spot urine sample obtained in the hospital is representative for a sample which was instead obtained at home during daily living. In our recent investigation of Danish pregnant women,
66 participants delivered a spot urine sample both in the hospital at the time of inclusion and another day at home [19]. Median UIC was significantly higher in the home sample than in the hospital sample (Fig. 2). Urinary creatinine concentration was measured as a proxy for maternal fluid intake and we used this measurement and the 24-h urinary iodine excretion previously measured in a group of Danish pregnant women [9] to calculate the estimated 24-h urinary iodine excretion [19]. When UIC was adjusted by urinary creatinine concentration, no difference between the hospital and the home sample was observed (Fig. 2). The time of spot urine sampling in the hospital was always in the morning (non-fasting) at a median 10 am. The time of spot urine sampling at home was not prespecified, but the pregnant women were instructed to sample urine at the same time as their household members. It turned out that the majority of families managed to sample urine in the afternoon or evening at median 6 pm. When stratified by time of sampling at home (before vs. at or after 5 pm), UIC was only significantly higher in the home sample when sampling at home was at or after 5 pm. Thus, UIC was influenced by time of sampling but when urinary creatinine concentration was used to calculate the estimated 24-h urinary iodine excretion the time dependent difference leveled out. The significance of spot urine sampling time is in line with other reports [20,21] and it can be speculated if the evening meal or different fluid intake led to a higher UIC in the evening samples. Further studies are needed and studies with prespecified and similar time of urine sampling in both locations are necessary to further evaluate the possible influence by sampling location. However, the results stress the importance of reporting and considering location and time of spot urine sampling in studies of pregnant women. Iodine supplement intake and spot urine sampling Iodine supplement intake is often recommended to ensure adequate iodine intake of the mother, the fetus and the breastfed infant. The relationship between iodine intake and urinary excretion of iodine was illustrated by use of radioiodine in 1947 [22]. Keating et al. [22] investigated urinary iodine excretion after oral ingestion of radioiodine in four healthy men. Approximately 2/3 of the dose appeared in the urine within 48 h and 50% was excreted within 6 h. Considering this, it can be speculated if the time of most recent iodine supplement intake prior to spot urine and
288 150
S.L. Andersen et al. / Journal of Trace Elements in Medicine and Biology 31 (2015) 285–289 Median (µg/liter)
125
MIC
100
UIC in pregnancy
p < 0.001 p < 0.001
75 UIC during breastfeeding
p = 0.3
50
25
0 The same day
The day before
Several days ago/non-user
Intake of iodine supplement prior to spot urine sampling
Fig. 3. Urinary iodine concentration (UIC) in pregnancy and during breastfeeding and breast milk iodine concentration (MIC) in 127 Danish women stratified by time of most recent iodine supplement intake prior to sampling. p-values are results of the Kruskal–Wallis test. Source: Data from [18].
breast milk sampling could influence results. In our recent Danish investigations, the participants were asked if most recent iodine supplement intake was the same day prior to spot urine sampling, the day before, several days ago, or non-user [18,19]. As depicted in Fig. 3, a significant trend was observed for UIC and breast milk iodine concentration (MIC) with the highest median value when iodine supplement intake was the same day prior to sampling. On the other hand, UIC during breastfeeding was not significantly influenced by most recent iodine supplement intake (Fig. 3). The transport of iodide into breast milk leads to changes in iodine metabolism in the breastfeeding mother as 40–45% of her dietary iodine intake is excreted into breast milk [23]. When urinary creatinine concentration was used as a proxy for maternal fluid intake, UIC, but not MIC, was influenced by maternal fluid intake [18]. Thus, when maternal fluid intake is increased to compensate for the fluid loss into breast milk, UIC is expected to be lower during breastfeeding compared to pregnancy. This is also reflected by the lower recommended level for UIC during breastfeeding (100 g/L) despite increased iodine requirements [3]. In a study with acute high dietary iodine intake, MIC increased with a peak after 6 h, whereas UIC remained stable during the 8 h of observation [24] compatible with our results for iodine supplement intake (Fig. 3). Further studies are needed to evaluate the influence of iodine supplement intake on results of spot urine sampling, but the results stress the importance of reporting and considering time of most recent iodine supplement intake prior to spot urine sampling. Iodine metabolism in pregnancy Physiological changes in iodine metabolism occur in pregnancy. There is a ∼50% increase in the production of thyroid hormones which requires an increased uptake of iodide in the thyroid gland [25]. There is also an increased metabolism of thyroid hormones due to the increased activity of type-3 deiodinase in placenta [26] and finally the glomerular filtration rate increases in early pregnancy and is maintained ∼50% higher throughout pregnancy leading to an increased renal excretion of iodide [27].
The physiological changes in iodine metabolism during pregnancy was investigated in 1964 by Aboul-Khair et al. [28] who performed intravenous injection of radioiodine in 13 pregnant women and 13 controls. They observed [28] that the increased renal clearance of iodide led to a decrease in the plasma inorganic iodide (PII) concentration. The absolute uptake of iodide in the thyroid gland was increased by 50%, but the thyroid clearance of iodide was 3–4 times higher in pregnancy suggesting that the thyroid gland had to work harder to obtain sufficient iodide due to the lower PII. The study was based on indirect measurement of PII and performed in an area with iodine deficiency [28]. In a study with direct measurement of PII, no changes in PII were observed during pregnancy, but the women investigated in this study had a more than adequate iodine intake [29]. The main determinants of UIC are the dietary iodine intake and the fluid intake. It can be speculated whether the physiological changes in iodine metabolism in pregnancy may alter the determinants of UIC. The increased maternal thyroid hormone production due to TBG increase, maternal tissue expansion and the need for transport of T4 as well as iodide across the placenta to the fetus will lead to some iodine retention, but it can be calculated that this iodine retention represent only a few g iodine per day. Thus, when iodine intake is as recommended or even less than this, the daily iodine retention is a very small fraction, but it will constitute a relatively larger fraction in case of very low iodine intake. In the kidneys, there is an increased renal excretion of iodide starting from early pregnancy, but this is counteracted by a decreased PII concentration and then a new steady state for the renal clearance of iodide is established. Thus, in pregnancy as well as in non-pregnant adults, the main determinants of UIC appear to be the dietary iodine intake and the fluid intake. Non-pregnant population groups as a proxy for iodine status in pregnancy Historically, schoolchildren were used for assessment of iodine status in a population [5]. Thus, in some populations data on pregnant women may be sparse or not available. The use of nonpregnant population groups as a proxy for iodine status in pregnant women has been considered, but the conclusion has mainly been that adequate iodine status of schoolchildren or non-pregnant women may not indicate adequate iodine status in pregnant women [6]. Considering the methodological challenges in evaluation of urinary iodine status from spot urine samples, it can be speculated if differences in urine sampling conditions could partly explain the conclusions e.g. the pregnant women sampling in the morning and the schoolchildren sampling in another location at another time of the day. In our recent investigation of iodine intake in Danish pregnant women we included pregnant women and members of their household (male partners and children) and the family members were instructed to perform non-fasting spot urine samples at home at the same time [19]. Using this approach, we observed no difference in median UIC between the pregnant women, the male partners, and the children (Fig. 4) with similar results when stratified by iodine supplement intake. The most striking difference was that iodine supplement intake was much more frequent in pregnant women (87%) than in male partners (15%) and children (25%). When we compared individual pairs of pregnant women and male partner, as expected UIC was higher in the pregnant woman than the male partner when only she used iodine supplement. When none or both used iodine supplement no difference in UIC was observed [19]. In Danish families it did not seem as if the pregnant women had changed their diet or fluid intake to a considerably different level, but studies in different populations are needed to clarify the use of non-pregnant groups as a proxy for iodine status in pregnant
S.L. Andersen et al. / Journal of Trace Elements in Medicine and Biology 31 (2015) 285–289 Median UIC (µg/liter) 200 175 150
p = 0.1
125 100 75 50 25 0 Pregnant women n = 68
Male partners n = 67
Children n = 51
Fig. 4. Median urinary iodine concentration in pregnant women, male partners and children. All family members sampled a spot urine sample at home at the same time. p-value is result of the Kruskal–Wallis test. Iodine supplement use in pregnant women: 87%, male partners: 15%, and children: 25%. Median UIC (pregnant women vs. male partners vs. children) in iodine supplement users: 136 g/L vs. 136 g/L vs. 151 g/L (p = 0.5), in iodine supplement non-users: 98 g/L vs. 110 g/L vs. 121 g/L (p = 0.4). Source: Data from [19].
women. Results stress the importance of standardizing spot urine sampling conditions for comparison of different population groups. Perspective Urinary iodine status in Danish pregnant and breastfeeding women living in an area of Denmark with previously moderate iodine deficiency is still inadequate more than 10 years after the introduction of the Danish iodine fortification. Combined with the most recent data on iodine status in the Danish population in general, the results may call for a modest increase in the level of iodide added to salt in Denmark. The frequency of iodine supplement intake during pregnancy had increased and was high while lower during breastfeeding. Urinary iodine status was better when the women used iodine supplement, and iodine supplement should be officially recommended during pregnancy and breastfeeding in Denmark. Certain characteristics about studies in pregnant and breastfeeding women may challenge the interpretation of urinary iodine status, and further studies are needed to ascertain methodological aspects in more detail including the use of non-pregnant population groups as a proxy for iodine status in pregnant women. Future studies should optimally consider and report: time and location of spot urine sampling, time of most recent iodine supplement intake prior to spot urine sampling, and urinary creatinine concentration. Conflict of interest The authors declare no conflict of interest. References [1] Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 2000;8511:3975–87.
289
[2] Pearce EN, Andersson M, Zimmermann MB. Global iodine nutrition: where do we stand in 2013? Thyroid 2013;235:523–8. [3] WHO, UNICEF, ICCIDD. Assessment of iodine deficiency disorders and monitoring their elimination. A guide for programme managers, vol. 3. World Health Organisation; 2007. p. 1–98. [4] Laurberg P, Jorgensen T, Perrild H, Ovesen L, Knudsen N, Pedersen IB, et al. The Danish investigation on iodine intake and thyroid disease, DanThyr: status and perspectives. Eur J Endocrinol 2006;1552:219–28. [5] Zimmermann MB. Iodine deficiency. Endocr Rev 2009;304:376–408. [6] Wong EM, Sullivan KM, Perrine CG, Rogers LM, Pena-Rosas JP. Comparison of median urinary iodine concentration as an indicator of iodine status among pregnant women, school-age children, and nonpregnant women. Food Nutr Bull 2011;323:206–12. [7] Skeaff SA. Assessing iodine intakes in pregnancy and strategies for improvement. J Trace Elem Med Biol 2012;262–263:141–4. [8] Pedersen KM, Laurberg P, Nohr S, Jorgensen A, Andersen S. Iodine in drinking water varies by more than 100-fold in Denmark. Importance for iodine content of infant formulas. Eur J Endocrinol 1999;1405:400–3. [9] Pedersen KM, Borlum KG, Knudsen PR, Hansen ES, Johannesen PL, Laurberg P. Urinary iodine excretion is low and serum thyroglobulin high in pregnant women in parts of Denmark. Acta Obstet Gynecol Scand 1988;675:413–6. [10] Pedersen KM, Laurberg P, Iversen E, Knudsen PR, Gregersen HE, Rasmussen OS, et al. Amelioration of some pregnancy-associated variations in thyroid function by iodine supplementation. J Clin Endocrinol Metab 1993;774:1078–83. [11] Nohr SB, Laurberg P, Borlum KG, Pedersen KM, Johannesen PL, Damm P, et al. Iodine deficiency in pregnancy in Denmark, regional variations and frequency of individual iodine supplementation. Acta Obstet Gynecol Scand 1993;725:350–3. [12] Nohr SB, Laurberg P, Borlum KG, Pedersen KM, Johannesen PL, Damm P, et al. Iodine status in neonates in Denmark: regional variations and dependency on maternal iodine supplementation. Acta Paediatr 1994;836:578–82. [13] Nohr SB, Jorgensen A, Pedersen KM, Laurberg P. Postpartum thyroid dysfunction in pregnant thyroid peroxidase antibody-positive women living in an area with mild to moderate iodine deficiency: is iodine supplementation safe. J Clin Endocrinol Metab 2000;859:3191–8. [14] Rasmussen LB, Carle A, Jorgensen T, Knudsen N, Laurberg P, Pedersen IB, et al. Iodine intake before and after mandatory iodization in Denmark: results from the Danish investigation of iodine intake and thyroid diseases (DanThyr) study. Br J Nutr 2008;1001:166–73. [15] Rasmussen LB, Jorgensen T, Perrild H, Knudsen N, Krejbjerg A, Laurberg P, et al. Mandatory iodine fortification of bread and salt increases iodine excretion in adults in Denmark – a 11-year follow-up study. Clin Nutr 2014;33:1033–40. [16] Krejbjerg A, Bjergved L, Pedersen IB, Carle A, Jorgensen T, Perrild H, et al. Iodine fortification may influence the age-related change in thyroid volume: a longitudinal population-based study (DanThyr). Eur J Endocrinol 2014;1704:507–17. [17] Andersen SL, Sorensen LK, Krejbjerg A, Moller M, Laurberg P. Iodine deficiency in Danish pregnant women. Dan Med J 2013;607:A4657. [18] Andersen SL, Moller M, Laurberg P. Iodine concentrations in milk and in urine during breastfeeding are differently affected by maternal fluid intake. Thyroid 2014;244:764–72. [19] Andersen SL, Sørensen LK, Krejbjerg A, Møller M, Laurberg P. Challenges in the evaluation of urinary iodine status in pregnancy: the importance of iodine supplement intake and time of sampling. Eur Thyroid J 2014;33:179–88. [20] Rasmussen LB, Ovesen L, Christiansen E. Day-to-day and within-day variation in urinary iodine excretion. Eur J Clin Nutr 1999;535:401–7. [21] Als C, Helbling A, Peter K, Haldimann M, Zimmerli B, Gerber H. Urinary iodine concentration follows a circadian rhythm: a study with 3023 spot urine samples in adults and children. J Clin Endocrinol Metab 2000;854:1367–9. [22] Keating FR, Power MH, Berkson J, Haines SF. The urinary excretion of radioiodine in various thyroid states. J Clin Invest 1947;266:1138–51. [23] Laurberg P, Andersen SL. Nutrition: Breast milk – a gateway to iodinedependent brain development. Nat Rev Endocrinol 2014;103:134–5. [24] Leung AM, Braverman LE, He X, Heeren T, Pearce EN. Breastmilk iodine concentrations following acute dietary iodine intake. Thyroid 2012;2211:1176–80. [25] Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR. Timing and magnitude of increases in Levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004;3513:241–9. [26] Roti E, Fang SL, Green K, Emerson CH, Braverman LE. Human placenta is an active site of thyroxine and 3,3’5-triiodothyronine tyrosyl ring deiodination. J Clin Endocrinol Metab 1981;533:498–501. [27] Davison JM, Hytten FE. Glomerular filtration during and after pregnancy. J Obstet Gynaecol Br Commonw 1974;818:588–95. [28] Aboul-Khair SA, Crooks J, Turnbull AC, Hytten FE. The physiological changes in thyroid function during pregnancy. Clin Sci 1964;27:195–207. [29] Liberman CS, Pino SC, Fang SL, Braverman LE, Emerson CH. Circulating iodide concentrations during and after pregnancy. J Clin Endocrinol Metab 1998;8310:3545–9.