Iodine status of pregnant Haitian-American women

Transcription

1 Boston University OpenBU Theses & Dissertations Boston University Theses & Dissertations 2014 Iodine status of pregnant Haitian-American women Segal, Amanda Rachel Boston University

2 BOSTON UNIVERSITY SCHOOL OF MEDICINE Thesis IODINE STATUS OF PREGNANT HAITIAN-AMERICAN WOMEN by AMANDA RACHEL SEGAL B.Sc., McGill University, 2011 Submitted in partial fulfillment of the requirements for the degree of Master of Science 2014

3 2014 by AMANDA SEGAL All rights reserved

4 Approved by First Reader Elizabeth N. Pearce, M.D., M.Sc. Section of Endocrinology, Diabetes, and Nutrition Associate Professor of Medicine Second Reader Hee-Young Park, Ph.D. Professor of Dermatology

5 ACKNOWLEDGMENTS First and foremost, thank you to Dr. Pearce whose extensive knowledge and guidance helped me shape the content of my thesis. I would like sincerely to thank Roodgy St. Jean for her collaboration on the project and Dr. Myrlene Jeudy and Dr. Linda Heffner for her tremendous direction and support throughout this process. I would finally like to thank Dr. Park for not only advising and helping me throughout my journey, yet for being a wonderful mentor and friend. Lastly, a thank you to my family for supporting me over the years and providing endless love and support. iv

6 IODINE STATUS OF PREGNANT HAITIAN-AMERICAN WOMEN AMANDA RACHEL SEGAL ABSTRACT Iodine is an essential element for the production of thyroid hormone, which is required for fetal cognitive development during pregnancy. Changes in maternal metabolism and physiology increase iodine requirements, and even mild iodine deficiency may lead to adverse effects on fetal neurodevelopment. While overall iodine intake in the United States is considered to be sufficient, there have been recent concerns about mild deficiency among women of childbearing years. Potentially exacerbating this issue amongst Haitian-American women is the known occurrence of iodine deficiency in Haiti. Attempts to supplement iodized salt by UNICEF have been unsuccessful due to Haiti s current political climate. Haitian immigrant women living in the United States may be at particular risk for iodine deficiency during pregnancy due to their unique dietary patterns. We conducted a cross-sectional study of 21 pregnant Haitian women living in the Boston area in order to determine if they are ingesting adequate dietary iodine. Our subjects included women with singleton pregnancies, who were not taking any thyroid hormone or anti-thyroid medication, and who were recruited at the Antenatal Clinic at Boston Medical Center. We obtained spot urine iodine concentrations, as well as information pertaining to iodine-containing prenatal vitamin use. To date, this has been the only such study carried out in this particularly vulnerable ethnic group and this study provides information of public health importance. v

7 TABLE OF CONTENTS TITLE...i COPYRIGHT PAGE...ii READER APPROVAL PAGE..iii ACKNOWLEDGMENTS... iv ABSTRACT... v TABLE OF CONTENTS... vi LIST OF TABLES... vii LIST OF FIGURES... viii LIST OF ABBREVIATIONS... ix INTRODUCTION... 1 METHODS RESULTS DISCUSSION REFERENCES CURRICULUM VITAE vi

8 LIST OF TABLES Table Title Page 1 Iodine content of composites of food categories 4 2 Recommendations for iodine intake by age or population 8 3 Epidemiological criteria from the WHO for assessment of iodine nutrition in a population based on median or range of urinary iodine 10 4 Effects of inadequate maternal iodine status on cognitive outcomes in their children 16 5 Study Population 27 vii

9 LIST OF FIGURES Figure Title Page 1 Iodine Pathway in the Thyroid Cell 2 2 Image of a Goiter 6 3 Scatterplot of thyroglobulin concentrations vs. UIC 7 4 TRH-thyrotropin axis during pregnancy 13 5 Median urinary iodine concentration for participants older than 6 years old and women of childbearing age 19 6 Iodine nutrition based on the median urinary iodine concentration 21 7 Average recovery of iodine from biological matter 24 8 Urinary iodine concentrations in 100 Boston 29 area pregnant women viii

10 LIST OF ABBREVIATIONS AI... Adequate Intake BMC... Boston Medical Center BU... Boston University BUMC... Boston University Medical Center D2... Type 2 Iodothyronine Deiodinase D3... Type 3 Iodothyronine Deiodinase DIT... Diiodotyrosine EAR... Estimated Average Requirement FDA... Food and Drug Administration hcg... Human Chorionic Gonadotropin IOM... Institute of Medicine IRB... Institutional Review Board NCS... National Children s Study NHANES... National Health and Nutritional Examination Survey NIS... Sodium Iodide Symporter RDA... Recommended Dietary Allowance RNI... Recommended Nutrient Intake rt3... Reverse Triiodothyronine T3... Triiodothyronine T4... Thyroxine ix

11 TBG... Thyroxine-Binding Globulin TRH... Thyroid Releasing Hormone TSH... Thyroid Stimulating Hormone UI... Urinary Iodine UIC... Urinary Iodine Concentration WHO... World Health Organization x

12 INTRODUCTION Thyroid Hormone Production and Regulation Low thyroid hormone levels stimulate the hypothalamus, which is located at the base of the brain, to release thyroid releasing hormone (TRH), which positively stimulates the anterior pituitary gland to release thyroid stimulating hormone (TSH). TSH then stimulates the thyroid gland to produce the thyroid hormones Thyroxine (T4) and Triiodothyronine (T3). High levels of thyroid hormone negatively signal both the hypothalamus and anterior pituitary, thereby controlling the release of TRH and TSH and creating a negative feedback loop. Thyroid hormone production, which requires an adequate consumption of iodine, a crucial micronutrient provided through diet, is essential for fetal neurodevelopment. Adequate intake of dietary iodine is needed to minimize thyroid dysfunction in the population. Once consumed, up to 80% of absorbed iodide is taken up by the thyroid gland (1). Both TSH and plasma iodine levels regulate thyroidal iodine uptake. The active process of transporting iodine from the blood into the thyroid gland is accomplished by the sodium-iodine symporter (NIS), a protein located on the basolateral membrane of the thyroid epithelial cells (2). Upon entering the thyroid gland, iodine is used to iodinate tyrosine residues on thyroglobulin, thus forming both monoiodotyrosine (MIT) and diiodotyrosine (DIT). The thyroid hormones T4 and T3 are generated through the coupling of 2 DITs or 1 DIT and 1 MIT together through the formation of diether bridges (3 & 4). While T3 is the active form of the thyroid hormone, the thyroid gland 1

13 produces a much higher proportion of T4, which is converted to T3 in the peripheral tissues. Within the thyroid gland, mature thyroglobulin contains 0.1-1% of its mass in iodine and is stored extracellularly in the luminal colloid of the follicle. Following endocytosis, lysosomal and endosomal proteases digest the thyroglobulin, thus releasing T3 and T4 into the bloodstream. Since T4 binds to the thyroxine-binding globulin (TBG) more tightly than T3, it has a longer half-life in circulation. TBG is synthesized in the liver and has a single iodothyronine-binding site. The metabolism of thyroid hormone via deiodinases causes the released iodine to either be recycled by the thyroid gland or be released into the urine through the kidneys (5). The kidneys ultimately excrete 90% of the iodine consumed (5). Figure 1: Iodine Pathway in the Thyroid Cell, taken from Trumpff et al. (6) 2

14 Sources of Iodine Iodine is widely but unevenly distributed throughout the world, with its majority being found in oceans. Foods of marine origin, therefore, contain a relatively high concentration of natural iodine. Iodine, which is oxidized in the seawater from iodide, is volatile and enters the earth s atmosphere, where it is returned to the soil via rain (7). However, in several regions of the world (including Haiti), iodine cycling is not sufficient and results in iodine-depleted soil and water. Agricultural crops and animals raised in these regions, therefore, will be low in iodine levels. Populations living in these regions will experience iodine deficiency unless iodine is supplemented through dietary sources. The spraying of commercial salt with iodide may reverse iodine deficiency in populations, and the iodization of salt continues to be the main strategy to eliminate iodine deficiency in the world (8). 3

15 Table 1: Iodine content of composites of food categories, taken from Vought et al. (9) In the United States, the median daily intake of iodine in was determined to be around µg/d in males and µg/d in females (11). A major source of dietary iodine is through salt fortified with iodine. Salt iodization is a useful, effectively distributed and inexpensive way to ensure iodine sufficiency in a population. Approximately 120 countries around the world have implemented the use of iodized salt as a public health effort (12). The U.S. Food and Drug Administration (FDA) recommends mg KI/kg salt, which is equivalent to mg I/kg salt (12). However, salt iodization had never been mandated in the United States and the majority of salt consumed is not iodized. Another source of iodine in the U.S. is some bread, due to the use of iodate conditioners (13 & 14). The dairy industry utilizes iodophor cleansers and supplements cattle feed with iodine. Although these practices are not done for public 4

16 health purposes, currently dairy products are the major U.S. dietary source of iodine (14). While variable amounts of iodine are found in meat and seafood, it has been established by the FDA that the main US non-salt dietary iodine sources are found in bread and dairy products (15). Assessing Population Iodine Status Other than urinary iodine concentration measurements as a biomarker for iodine intake, both thyroglobulin and goiter ultrasounds serve as indicators of adequate iodine intake. Serum thyroglobulin is elevated during times of iodine deficiency, mainly due to high levels of circulating TSH and thyroidal hyperplasia (17). The prevalence of a goiter is an indicator of the severity of iodine deficiency disorders in a population (18). Inspection and palpation of the goiter are typically used to classify the goiter, however in areas of mild-to-moderate iodine deficiency, the measurement of thyroid volume through ultrasound is the preferred method (8). This method of examination is desirable since it is noninvasive, quick and can be performed in remote areas; however it requires valid references from iodine-sufficient populations in order for screening to be accurate. The results of a thyroid ultrasound are subjective since the measurements and findings of thyroid size and diameter require judgment an experience and different ultrasound techniques may produce interobserver errors of the Thyroid volume as high as 26% (19). In order to improve the reliability of thyroid volume measurements through ultrasounds, it is important to standardize the process worldwide. 5

17 Figure 2: Image of a goiter, taken from Zimmerman (2) Serum thyroglobulin is a sensitive measurement of both iodine deficiency and iodine excess (20). Zimmerman et al. demonstrated that there is a significant greater amount of thyroglobulin present in children with iodine-deficiency (with a UIC of less than 100 mcg/l) and in children with iodine excess (with a UIC of greater than 300 mcg/l) (20). Therefore, it was shown that over the range of severely deficient to excess iodine intake, the thyroglobulin concentrations demonstrate a U-shaped graph. This study further concluded that a median thyroglobulin amount of <13 µg/l indicates iodine sufficiency in a population. 6

18 Figure 3: Scatterplot of thyroglobulin concentrations vs. UIC of children age 6-12 years from 12 countries (20) The estimated iodine requirement by age and population group is presented in Table 2 below from the U.S. Institute of Medicine (IOM) (16). 7

19 Table 2. Recommendations for iodine intake (µg /d) by age or population group Age or population group Infants 0-12 months Children 1-8 years Children 9-13 years Adults 14 Institute of Medicine s EAR Institute of Medicine s RDA Age or population group * Children 0-5 years Children 6-12 years Adults > years years Pregnancy Pregnancy 250 Lactation Lactation 250 * AI for infants since an RDA has not been defined for this group World Health Organization s RNI 90 (Table 2) Recommendations for iodine intake (µg /d) by age and population group. From U.S. Institute of Medicine (16); and World Health Organization (8) 120 The estimated average requirement (EAR) is defined as the daily intake of iodine that is sufficient for half of the individuals of a certain age group and is used to assess groups and not individuals (16). The recommended dietary allowance (RDA) is the average daily intake of iodine that meets the requirement of 97-98% of healthy individuals of a particular population group and is used to assess the daily iodine intake of an individual (16). The adequate intake (AI) is provided only if there is insufficient data to calculate the EAR and is assumed to meet or exceed the concentration of iodine required in all of the participants in a certain group, and may be used as an aim for individual intake (16). According to World Health Organization (WHO) standards, the recommended nutrient 8

20 intake (RNI) is the daily dietary intake of iodine that sufficiently meets the needs of basically all of the individuals of a group (8). There are several methods that can effectively measure the iodine status of a population. Since >90% of iodine consumed eventually enters the urine, median spot urinary iodine concentrations (UIC) serve as an indicator for recent population dietary iodine intake (18). Urinary median thresholds are used to identify urinary dietary iodine sufficiency in populations yet cannot be used to measure the status of individuals due to large variation in individuals daily iodine intake (19). Because of this day-to-day fluctuation, approximately ten repeat spot urine collections are required in order to accurately measure individual iodine intake (23 and 24). Table 2 is adapted from WHO criteria for assessing iodine nutrition in a population based on the median urinary iodine values (8). 9

21 Table 3. Epidemiological criteria from the WHO for assessment of iodine nutrition (8) Urinary Iodine (µg/liter) Iodine Intake Iodine Status School aged children <20 Insufficient Severe iodine deficiency Insufficient Moderate iodine deficiency Insufficient Mild iodine deficiency Adequate Optimal More than adequate Risk of iodine-induced hyperthyroidism >300 Excessive Risk of adverse health consequences Pregnant Women <150 Insufficient Adequate More than adequate 500 Excessive Lactating women <100 Insufficient 100 Adequate Children less than 2 years old <100 Insufficient 100 Adequate 10

22 Iodine requirements during pregnancy Starting in the first trimester, maternal thyroid hormone production increases by around 50%. Early in gestation, both TSH and human chorionic gonadotropin (hcg) stimulate the thyroid gland. hcg is a hormone produced by the syncitioblast of the developing embryo during the first trimester and its alpha subunit binds to and stimulates the TSH receptor (24). During pregnancy, this hcg-induced stimulation of the thyroid gland is responsible for the rapid increase in thyroxine production near the end of the first trimester (25). This, in turn, activates the negative feedback on the pituitary gland and decreases TSH concentrations. Pregnancy is also associated with an increase in serum thyroxine-binding globulin (26). Elevated levels of estrogen during pregnancy cause an increase in the sialylation of thyroxine-binding globulin, thereby reducing hepatic clearing of TBG and resulting in an increased its concentration in the circulation. Due to the increase in the binding protein, the levels of total T3 and T4 increase by 50% during pregnancy. Another result of pregnancy is the modification of metabolism of thyroid hormone due to elevated deiodination activity within the placenta. The iodothyronine deiodinases expressed in the placenta are type 3 (D3), which converts T4 to rt3, and type 2 (D2), which generates inactive T2 from T3 (27). The placental deiodinases, thus, deactivates the thyroid hormone, thereby protecting the fetus from excessive hormone exposure. The overall increase in thyroid hormone degradation in the placenta contributes to the increased demand of maternal thyroid hormone synthesis. 11

23 Starting early in gestation, there is a significant increase in urinary iodine loss due to the increase in glomerular filtration rate (26). Since iodine is excreted passively, the increased maternal renal glomerular filtration causes a higher renal clearance of ingested iodine (28). By weeks of gestation, the fetal thyroid gains the ability to accumulate iodine, yet is unable to organify the iodine (i.e. to produce thyroid hormone) until about the 16 th -20 th week (29). Prior to this point, maternal thyroid hormone production must be adequate in order to meet the fetal metabolic requirements. Once thyroid function is established in the fetus, its iodine turnover is much higher than that of adults (30 & 31). As a result of the increase in the production of thyroid hormone, increased urinary iodine loss, and fetal iodine requirements, dietary iodine intake must be higher during pregnancy than in non-pregnant adults. The World Health Organization recommends an intake of 250mcg/day of iodine, in comparison to 150 mcg/day for non-pregnant adults (8). 12

24 Figure 4. TRH-thyrotropin axis during pregnancy, taken from Karaca et al. (32) Effects of Iodine Deficiency During Pregnancy Thyroid hormone, which is dependent on the consumption of adequate iodine, is crucial for fetal neurodevelopment and physical growth during pregnancy (33). Since the fetus is unable to synthesize its own thyroid hormone until weeks of gestation, in early gestation it is entirely dependent on the low concentrations of maternal thyroid hormone that cross the placenta. Women with sufficient iodine intake prior and throughout pregnancy will have an adequate amount of iodine within the thyroid gland and will be able to adapt to the increased demand for thyroid hormone production during 13

25 gestation. However, women living in iodine-deficient areas are unable to compensate or adapt. Even minimally low maternal T4 levels during pregnancy may result in higher rates of miscarriages, congenital abnormalities, and mental impairment (8, 34, 35, 40, 41). Iodine deficiency is the leading cause of preventable mental retardation worldwide, as it affects 38% of the global population (36). Thyroid hormone affects neuronal migration, myelination of axons, synaptic transmission, and plasticity throughout neurodevelopment (37 and 38). It plays a crucial role in the timing of the differentiation of oligodendrocytes and regulates the expression of enzymes involved in the formation of lipids and in the expression of proteins found in the structure of myelin (38). The consequences of hypothyroidism and iodine deficiency on fetal neuronal development depend upon timing and the severity of the hypothyroxinemia. Even mild maternal hypothyroidism during pregnancy may cause disrupted neuronal migration in the fetus, resulting in ectopic neurons in different cortical layers of the brain (39). Severe maternal iodine deficiency may result in several negative effects on the fetus, including: decreased intelligence, congenital anomalies and neurological cretinism (22). The characteristic features of cretinism are severe mental retardation with squint, deaf mutism, and motor spasticity (15). The results of mild-to-moderate iodine deficiency during pregnancy are not as well characterized as those of severe iodine deficiency. A study by Bath et al. examined the effect of mild iodine deficiency in UK pregnant women and its effect of the cognitive development in their children (40). They measured the UIC of pregnant women in their first trimester and then measured the IQ of their children at 8 years old. It was found that 14

26 offspring of women with an iodine-to-creatine ratio of less than 150 µg/g were more likely to have scores in the lowest quartile for verbal IQ, reading accuracy, and reading comprehension than women with ratios of 150 µg/g or more (40). Another recent study by Hynes et al. examined mild iodine deficiency in pregnant women and the standardized test performance outcomes of their 9-year-old children (41). It was demonstrated that children of women who were mildly iodine deficient in pregnancy (UIC < 150 µg/l) had score reductions of 10% in spelling, 7.6% in grammar, and 5.7% in English literature performance in comparison to children of mothers with normal iodine levels (41). Both studies, therefore, provide evidence that even mild iodine deficiency during pregnancy may result in long-term adverse neurocognitive effects on the child. 15

27 Table 4. Effects of inadequate maternal iodine status on cognitive outcomes in their children, results taken from Bath et al. on the (40) Potential Effects of Thiocyanate Exposure Thiocyanate acts as a competitive inhibitor of the sodium/iodine symporter (NIS), and therefore decreases thyroidal iodine uptake. Environmental exposure, therefore, may disrupt thyroid function (42). Thiocyanate is derived mainly from certain foods and from cigarette smoke. Thiocyanate is metabolized both from cigarette smoke within the body, and is also a metabolite of cyanogenic glucosides which are found in certain plant foods, like cabbage, broccoli, cassava and rapeseed oil (43). Exposure to thiocyanate has been shown to increase the risk of the development of goiter in populations with moderate-tosevere iodine deficiency (44). Studies have shown that maternal smoking throughout pregnancy is associated with changes in fetal and maternal thyroid function; including: lower T4 levels, increased serum TSH levels, and thyroid enlargement (45 & 46). FT4 16

28 levels were lower in smokers during the first trimester of pregnancy than in nonsmokers, which may potentially be linked to thiocyanate exposure (47). Vanderver et al. reported that smoking in women in childbearing years is correlated with a higher rate of hypothyroxinemia, yet this is only present in women with the highest urinary iodine concentrations (48). Chanoine et al. reported that in regions of borderline low iodine intake, smoking throughout pregnancy was significantly correlated with the presence of goiters and elevated amounts of serum thyroglobulin in infants (49). It has also been shown that the thiocyanate found in cigarette smoke competitively inhibits the NIS responsible for the transport of iodide in the lactating mammary gland. Lauberg et al. demonstrated that smoking while breastfeeding reduced the amount of iodine transferred through breast milk, thereby potentially increasing the risk of impaired neurodevelopment of the infant (49). Iodine Status in the US Since the 1940s, dietary iodine in the United States has been adequate overall, even though the adult median urinary concentration dropped from 320 mcg/l when the first National Health and Nutrition Examination Survey (NHANES I) was done in the 1970s to 145 mcg/l at the time of NHANES III in the early 1990s (50). What is particularly alarming is the fact that the prevalence of urinary iodine concentration values of <50 mcg/l among women of childbearing age almost quadrupled from 4% to 15% over these 20 years. The most recent examination of the iodine status of the United States, from NHANES , demonstrated that the population median UIC was 144 µg /L, 17

29 which is significantly lower than the median value of 164 µg /L from NHANES (51). The median UIC for all women was 134 µg /L, and the UI for women of childbearing years, ages years, was 124 µg /L. The UI concentration for women of childbearing years has been consistently lower than the general population since 2001 (51) (Figure 5). The median UI for pregnant women recorded in NHANES was 135 µg /L, suggesting mild iodine deficiency. NHANES data from indicated that 37.3% of nonpregnant women of childbearing years have median UI concentrations less than 100 µg /L, while 55.8% of pregnant women have UI concentrations less than 150 ug/l. 18

30 Figure 5: Median urinary iodine concentration for participants older than 6 years old and women of childbearing age based on NHANES , from Caldwell et al. (52) Due to the concern about mild iodine deficiency in pregnant women in the US, there have been public health recommendations for iodine supplementation, for women planning a pregnancy, during pregnancy, and during lactation. The American Thyroid Association, Endocrine Society, and Teratology Society have recommended that all pregnant women and women planning a pregnancy should receive dietary supplementation containing 150 µg /day of iodine and that all US prenatal vitamins should contain 150 µg of iodine daily (53, 54, 55). However, iodine content of prenatal vitamins is not mandated in the US. Only 51% of the types of prenatal vitamins available 19

31 in the United States contain iodine and only 20% of US pregnant women surveyed from reported routinely taking iodine-containing supplements (56 & 57). Iodine Deficiency in Haiti Located only 500 miles from Florida, Haiti has a population of 8 million people, including 1 million newborns annually who are potentially at risk for iodine-deficiency (58). There are currently 29,000 Haitian children each year born each year with cretinism and mental impairment as a result of iodine deficiency (59). Despite decades of international public health efforts, the household consumption of iodized salt has decreased from 11% in 2000 to 3% in 2005, making it the lowest in the Western Hemisphere (60). UNICEF Haiti has attempted to supply the equipment for salt iodization, yet their efforts could not be completed due to social and political barriers. We postulate that Haitian immigrant women living in the US may have unique dietary patterns and also may frequently travel back and forth to Haiti and therefore may be particularly at risk for iodine deficiency during pregnancy. 20

32 Figure 6: Iodine nutrition based on the median urinary iodine concentration, by country; taken from Zimmermann et al. (60) The purpose of this study is to determine the iodine status of a cohort of pregnant Haitian-American women living the Boston-area. This is the first study to specifically examine the relationships among iodine and cigarette smoking on urinary iodine levels during pregnancy in this population. 21

33 METHODS Subjects The study population included pregnant Haitian women seeking prenatal care at the Boston Medical Center (BMC) Antenatal clinic. About 2,600 women per year deliver at BMC, of whom 40% receive their prenatal care there and the rest at affiliated community health clinics. Approximately 14% of the patients who routinely attend the BMC Obstetrics clinic are of Haitian ethnicity. Haitian women receiving prenatal care at the Antenatal clinic at BMC were eligible to participate. Inclusion criteria included fluency in either English or Haitian Creole. Women carrying two or more fetuses were excluded from the study. Women with a history of thyroid disease or those taking thyroid hormone or anti-thyroid medications were excluded. Women who had undergone any radiologic studies with iodinated intravenous contrast agents within six months were also excluded. Written informed consent was obtained from all participants. The BUMC IRB approved the study. Study Measures: Participants completed a questionnaire regarding their age, ethnicity, smoking behavior (do they smoke or live with people that smoke), whether or not they take prenatal vitamins, if they drink milk each day (and if so, how many glasses), and when was their last visit to Haiti that exceeded 6 months. In order to determine if the women were taking iodine-containing prenatal supplements, they were asked to describe the brand, type (prescription vs. nonprescription) and the frequency of use. Spot urine 22

34 specimens were obtained from all women in order to measure the concentrations of iodine. Sample Size We relied on the model determined by Andersen et al. which calculated that spot urine samples from 125 individuals are required in order to estimate the iodine level of a population with 95% confidence within a precision range of ±10% (18). Study results thus far are only preliminary, and more participants need to be enrolled in order to reach the target sample size. Laboratory Measures: All of the laboratory measurements on the urine specimens were performed at the Boston University Iodine, Perchlorate and Thyroid Function Test Research Laboratory. Prior to the iodine analysis, all urine samples were stored at -80º C. The total urinary iodine content was measured spectrophotometrically by a modification of the method of Benotti et al. (61). This procedure required a minimum number of reagents, and therefore reduces the chance of reagent contamination. The cost of this method is lower than other methods for iodine determination and recovers the iodine accurately and well (61). The assay required the addition of 0.5 ml of chloric acid to 0.1 ml of urine. After the sample was digested for 20 minutes, 2.1 ml of arsenious acid was added and then put through automated analysis. Since only 0.1 ml of urine is used for the screening, it is possible to accurately measure the content of the iodine in it (61). 23

35 Figure 7: Average recovery of iodine from biological matter, taken from Benotti et al. (61). Statistical Analysis Descriptive statistics were provided for each outcome measure. The statistics for continuous variables included mean, standard deviation, median and range. Categorical variables were described by frequency. Median urinary iodine values were compared to the threshold values provided by the World Health Organization in order to determine 24

36 whether the population was iodine-sufficient. According to WHO guidelines, median urinary iodine concentrations of mcg/l in pregnant women were considered iodine-sufficient. 25

37 RESULTS Population: The majority of the sample population, which consisted of 21 women, was born in Haiti and had returned to Haiti for at least 6 months within the last 5 years. The age of participants ranged from 21 to 36 years old, with an average age of 31.6 ± 4.5. None of the women reported smoking, nor were they living with someone that smoked. Eightysix percent of the women were taking prenatal vitamins, of which most were prescribed by the physician and obtained at the pharmacy in the Boston Medical Center, which stocks only one brand supplemented with 150 µg of iodine out of 6 brands. The majority of the women (around 90%) reported drinking milk daily throughout their pregnancy, with an average of 1.3 glasses per day ± Ninety percent of the women reported that they were born in Haiti, while the other 10% are second-generation Haitian Americans living in the Boston area. All of the women have reported having spent at least 6 months in Haiti, with 38% of them having travelled there within the last 2 years. 26

38 Table 5. Study Population Age (Mean ± SD) Born in Haiti # (%) Spent 6 months or more in Haiti within the last 2 years # (%) Reported Yes to smoking # (%) Glasses of milk/day Mean ± SD Reported Yes to taking prenatal vitamins # (%) Urinary iodine concentration (mcg/l) Median (range) 31.6 ± (90%) 8 (38%) 0 (0%) 1.3 ± (86%) ( ) Urinary Iodine Concentrations The median urinary iodine level was mcg/l, and iodine concentrations ranged from 52.7 to The lower 95% confidence interval was mcg/l and the upper 95% confidence interval was mcg/l. According to WHO standards for iodine status during pregnancy, the median value of mcg/l is considered to be iodine sufficient. Given that none of the women enrolled thus far reported cigarette smoke exposure, we are unable to determine whether UIC differed in women who smoked or had secondhand smoke exposure. 27

39 DISCUSSION Because iodine is critically important for adequate thyroid hormone production and normal neurodevelopment of the fetus, pregnant women are the most vulnerable population to iodine deficiency. In our Boston-area sample of pregnant Haitian American, we found a median urinary iodine value of mcg/l. These data, although preliminary, suggest that the dietary intake of iodine in this group is sufficient according to WHO standards, since the median exceeds 150 mcg/l. This is the first study of its kind to look at the iodine status of this population. Additional analyses are needed in order to look at predictors of iodine status and thyroid function in pregnancy in this subgroup of women. Comparison of Results to Previous Studies A study performed in 2004 examined the urinary iodine concentrations of 100 Boston-area pregnant women at BMC and found a marginal median urinary iodine level of 149 mcg/l (62). The median urinary iodine value found in our study is slightly higher than the 2004 study. 28

40 Figure 8: Urinary iodine concentrations in 100 Boston area pregnant women (62) Another recent study in Toronto, Canada evaluated the iodine status of pregnant women who presented for routine antenatal care (63). One hundred forty-two women were recruited at the clinics in Toronto where they completed a questionnaire and provided spot urine specimens to measure urinary iodine concentration (UIC). The mean maternal age was 33.8 ± 4.3 years and the median UIC was 221µg/L. Six women (4.2 %) had iodine levels that were less than 50 µg/l, and 36 women (25.4%) had levels between 50 and 150 µg/l. This study included mainly Caucasian, well-educated and affluent Canadian women. Dietary and lifestyle factors were likely quite different from the Haitian American women in the present study. 29

41 In the NHANES study of , it was found that the median urinary iodine concentration for pregnant U.S. women was 135 µg/l (52). Among these women, approximately 55.8% had a urinary iodine concentration of less than 150 mcg, suggesting inadequate iodine (52). When comparing this data to the data found in our study, it was shown that only 38% of the pregnant population at the BMC Antenatal Clinic had a median urinary iodine concentration of less than 150 mcg. Pregnant women in the third trimester participating in the National Children s Study (NCS) had a median urinary iodine concentration of 167 µg/l, while the median UIC for women in their third trimester in NHANES was 172 µg/l (52). Of the women that participated in the NCS study, 45.3% had median urinary iodine concentrations of less than 150 µg/l (52). Strengths and Limitations This study was novel because we were able to examine a population that has never previously been studied. We were able to gather information about potential predictors of iodine deficiency in the Haitian American pregnant population living in Boston. These predictors will be used in multivariable statistical models when the full study sample has been enrolled. Another strength was that the questionnaire was in Haitian Creole and we were able to communicate with the women in their own language. Urinary iodine concentrations are a reliable biomarker for iodine status. The main weakness of this study was that the data are preliminary and numbers are small, so we therefore need to await completion of the study in order to reach a more 30

42 definitive conclusion about the iodine status of this population. We relied on self-report when the patients answered the questionnaires, which may have resulted in some misclassification. We didn t measure thyroid function. We did not assess exposure to perchlorate, thiocyanate and other potential environmental thyroid disruptors. Since we only gathered urine at one time point during pregnancy, we were unable to assess possible variations in iodine concentrations throughout pregnancy. Lastly, the targeted population was slightly heterogeneous since some individuals were born in Haiti and others grew up in US. 31

43 CONCLUSION In conclusion, the preliminary data from this study are reassuring, suggesting that this Haitian American pregnant population in the Boston area is likely iodine sufficient. Further studies could include an examination of the iodine status of pregnant women living in Haiti, a comparison of thyroid function in Haitian women living in the US versus those living in Haiti, and could explore environmental goitrogens and their effect on thyroid function in both groups. 32

44 REFERENCES 1. Degroot, LJ. (1966). Kinetic analysis of iodine metabolism. The Journal of Clinical Endocrinology & Metabolism/26: Zimmerman, MB. (2009). Iodine deficiency. Endocrinology Review/30: Dunn, JT. (1995). Thyroglobulin, hormone synthesis and thyroid disease. European Journal of endocrinology/140: Dunn, JT., Dunn, AD. (2001). Update on intrathyroidal iodine metabolism. Thyroid/11: Oppenheimer, JH., Schwartz, HL., Surks, MI. (1975). Determination of common parameters of iodothyronine metabolism and distribution in man by noncompartmental analysis. The Journal of Clinical Endocrinology and Metabolism/41: Trumpff, C., De Schepper, J., Tafforeau, J., Van Oyen, H., Vanderfaeillie, J., Vandevijvere, S. (2013). Mild iodine deficiency in pregnancy in Europe and its consequences for cognitive and psychomotor development of children: a review. Journal of Trace Elements in Medicine and Biology/27: Goldschmidt, VW. (1954). Geochemistry. Oxford, UK: Oxford University Press 8. World Health Organization, United Nations Children s Fund, International Council for the Control of Iodine Deficiency Disorders. (2007). Assessment of iodine deficiency disorders and monitoring their elimination. 3 rd ed. Geneva 9. Vought, RL., London, WT. (1964). Dietary sources of iodine. The American Journal of Clinical Nutrition/14: Food and Nutrition Board, Institute of Medicine. Dietary reference intakes. Washington, D.C.: National Academy Press; 2006; pp Murray, CW., Egan, SK., Kim, H., Beru, N., Bolger, PM. (2008). UF Food and Drug Administration s Total Diet Study: dietary intake of perchlorate and iodine. Journal of Exposure Science and Environmental Epidemiology/18:

45 12. Dasgupta, PK., Liu, Y., Dyke, JV. (2008). Iodine nutrition: Iodine content of iodized salt in the United States. Environmental Science and Technology/42: London, WT., Vought, RL., Brown, FA. (1966). Bread-dietary sources of large quantities of iodine. New England Journal of Medicine/223: Pearce, EN., Pino, S., He, X., et al. (2004). Sources of dietary iodine: bread, cows milk, and infant formula in the Boston area. The Journal of Clinical Endocrinology and Metabolism/89: Murray, CM., Egan, SK., Kim, H., et al. (2008). US Food and Drug Administrations Total Diet Study: dietary intake of perchlorate and iodine. Journal of Exposure Science and Environmental Epidemiology/ Institute of Medicine, Academy of Sciences. (2001). Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC:National Academy Press 17. Knudsen, N., Bulow, I., Jorgensen, T., Perrild, H., Ovesen, L., Laurberg, P. (2001). Serum Tg: a sensitive marker of thyroid abnormalities and endocrine deficiency in epidemiological studies. Journal of Clinical Endocrinology and Metabolism/86(8): Zimmermann, MB., Hess, SH., Molinari, L., de Benoist, B., Delange, F., Braverman, LE., Fujieda, K., Ito, Y., Jooste, PL., Moosa, K., Pearce, EN., Pretell, EA., Shishiba, Y. (2004). New reference values for thyroid volume by ultrasound in iodine-sufficient schoolchildren: a World Health Organization/Nutrition for Health and Development Iodine Deficiency Study Group Report. American Journal of Clinical Nutrition/79: Zimmermann, MB., Molinari, L., Spehl, M. (2001). Toward a consensus on reference values for thyroid volume in iodine-replete schoolchildren: results of a workshop on interobserver and interequipment variation in sonographic measurement of thyroid volume. European Journal of Endocrinology/144: Zimmermann, MB., Aeberli, I., Andersson, M., Assey, V., Jara Yorg, JA., Jooste, P., Jukic, T., Kartono, D., Kusic, Z., Pretell, E., San Luis, TOL., Untoro, J., Timmer, A. (2013). Thyroglobulin is a sensitive measure of both deficient and excess iodine intakes in children and indicates no adverse effects on thyroid function in the UIC range of µg/l: a UNICEF/ICCIDD study group report. Journal of Endocrinology and Metabolism/98(3):

46 21. Zimmermann, MB., Andersson, M. (2012). Assessment of iodine nutrition in populations: past, present, and future. Nutritional Review/70: Konig, F., Andersson, M., Hotz, K., Aeberli, I., Zimmermann, MB. (2011). Ten repeat collections for urinary iodine from spot samples or 24-hour samples are needed to reliably estimate individual iodine status in women. Journal of Nutrition/141: Andersen, S., Karmisholt, J., Pedersen, KM., Laurberg, P. (2008). Reliability of studies of iodine intake and recommendations for number of samples in groups and in individuals. British Journal of Nutrition/99: Hershman, JM. (2004). Physiological and pathological aspects of the effect of human chorionic gonadotropin on the thyroid. Best Practice & Research Clinical Endocrinology & Metabolism/18: Yoshimura, M., Hershman, JM. (1995). Thyrotropic action of human chorionic gonadotropin. Thyroid/5: Moleti, M., Trimarchi, F., Vermiglio, F. (2013) Thyroid physiology in pregnancy. Endocrine Practice/ Chan, SY., Vasilopoulou, E., Kilby, MD. (2009). The role of the placenta in thyroid hormone delivery to the fetus. Nature Clinical Practice Endocrinology & Metabolism/5: Dafnis, E., Sabatini, S. (1992). The effect of pregnancy on renal function: physiology and pathophysiology. The American Journal of the Medical Sciences/303: Burrow, GN., Fisher, DA., Larsen, PR. (1994). Maternal and fetal thyroid function. New England Journal of Medicine/331: Delange, F., Bourdoux, P., Chanoine, JP. (1986). Physiopathology of iodine nutrition during pregnancy, lactation, and early post-natal life. Vitamins and Minerals in Pregnancy and Laction. Nestle Nutrition Workshop Series, Vol. 16. New York: Nestec Ltd.; Beckers, C. (1991). Iodine economy in and around pregnancy. In: Beckers C, Reinwein D. The Thyroid and Pregnancy. Stuttgart:Schattauer/ Karaca, Z., Tanriverdi, F., Unluhicaci, K., Kelestimur, F. (2010). Pregnancy and pituitary disorders. European Journal of Endocrinology/162:

47 33. Glinoer, D., De Nayer, P., Delange, F., Lemone, M., Toppet, V., Spehl, M., Grun, JP. (1995). A randomized trial for the treatment of mild iodine deficiency during pregnancy: maternal and neonatal effects. Journal of Clinical Endocrinology & Metabolism/80: Hertzel, BS., Delange, F., Dunn, JT., Ling, J., Mannar, V., Pandav, C. (2004). Towards the global elimination of brain damage due to iodine deficiency 35. De Escobar, GM., Obregon, MJ., Del Rey, FE. (2007). Iodine deficiency and brain development in the first half of pregnancy. Public Health Nutrition/1-: Pearce, EN., Andersson, M., Zimmermann, MB. (2013). Global iodine nutrition: where do we stand in 2013? Thyroid/23(5): Younes-Rapozo, V., Berendonk, J., Savignon, T. et al. (2006). Thyroid hormone deficiency changes the distribution of oligodendrocyte/myelin markers during oligodendroglial differentiation in vitro. International Journal of Developmental Neuroscience/24: Auso, E., Lavado-Autric, R., Vuevas, E., et al. (2004). A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology/145: Haddow, JE., Palomaki, GE., Allan, WC., Williams, JR., Knight, GJ., Gagnon, J., O Heir, CE., Mitchell, ML., Hermos, RJ., Waisbren, SE., Faix, JD., Klein, Rz. (1999). Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. New England Journal of Medicine/341: Bath, SC., Steer, CD., Goldring, J., Emmett, P., Rayman, MP. (2013). Effects 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/382(9889): Hynes, KL., Otahal, P., Hay, I., Burgess, JR. (2013). Mild iodine deficiency during pregnancy is associated with reduced educational outcomes in the offspring: 9-year follow-up of the gestational iodine cohort. Journal of Clinical Endocrinology & Metabolism/98(5): Tonacchera, M., Pinchera, A., Dimida, A,. et al. (2004). Relative potencies and additivity of Perchlorate, Thiocyanate, nitrate, and iodide on the inhibition of 36

48 radioactive iodide uptake by the Human Sodium Iodide Symporter. Thyroid/14: Dorea, JG. (2004). Maternal thiocyanate and thyroid status during breast-feeding. The Journal of the American College of Nutrition/23: Brauer, VF., Below, H., Kramer, A., Fuhrer, D., Paschke, R. (2006). The role of thiocyanate in the etiology of goiter in an industrial metropolitan area. European Journal of Endocrinology/154: Meberg, A., Marstein, S. (1986). Smoking during pregnancy: effects on the fetal thyroid function. Acta Paediatrica Scand/75: Chanoine, JP., Toppet, V., Bourdoux, P., Spehl, M., Delange, F. (1991). Smoking during pregnancy: a significant cause of neonatal thyroid enlargement. British Journal of Obstetrics and Gynecology/98: Pearce, EN., Oken, E., Gillman, MW., Lee, SL., Magnani, B., Platek, D., Braverman, LE., (2008). Association of first-trimester thyroid function test values with thyroperoxidase antibody status, smoking, and multivitamin use. Endocrine Practice/14: Vnderver, GB., Engel, A., Lamm, S. (2007). Cigarette smoking and iodine as hypothyroxinemic stressors in U.S. women of childbearing age: a NHANES III analysis 49. Laurberg, P., Nohr, SB., Pedersen, KM., Fuglsang, E. (2004). Iodine nutrition in breast-fed infants is impaired by maternal smoking. Journal of Clinical Endocrinology & Metabolism/89: Hollowell, JG., Staehling, NW., Hannon, WH., et al. (1998). Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III ( and ). Journal of Clinical Endocrinology and Metabolism/83(10): Makhmudov, A., Ely, E., Jones, RL., Wang, RY. (2011). Iodine status of the US population, National Health and Nutrition Examination Survey, and Thyroid/21: Caldwell, KL., Pan, Y., Mortensen, ME., Makhmudov, A., Merill, L., Moye, J. (2013). Iodine status in pregnant women in the national children s study and in U.S. women (15-44 years), National Health and Nutrition Examination Survey Thyroid/23.8:

49 53. De Groot, L., Abalovich, M., Alexander, EK., Amino, N., Barbour, L., Cobin, RH., Eastman, CJ., Lazarus, JH., Luton, D., Mandel, SJ., Mestman, J., Rovet, J., Sullivan, S. (2012). Management of thyroid dysfunction during pregnancy and postpartum: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism/97.8: Stagnaro-Green, A., Abalovich, M., Alexander, E., Azizi, F., Mestman, J., Negro, R., Nixon, A., Pearce, EN., Soldin, OP., Sullivan, S., Wiersinga, W., American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. (2011). Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid/21(10): Obican, SG., Jahnke, GD., Soldin, OP., Scialli, AR. (2012). Teratology public affairs committee position paper: iodine deficiency in pregnancy. Birth Defects Res (Part A): Clinical Molecular Teratology/94: Gregory, CO., Serdula, MK., Sullivan, KM. (2009). Use of Supplements with and without iodine in women of childbearing age in the United States. Thyroid/19(9): Leung, AM., Pearce, EN., Braverman, LE. (2009). Iodine content of prenatal multivitamins in the United States. New England Journal of Medicine/360(9): Tenpenny, KE., Trent, CJ., Sutherland, PA., Van Middlesworth, L., Williams- Cleaves, B., Braverman, LE. (2009). Evidence of endemic goiter and iodine deficiency in a mountainous area of Haiti. Endocrine Practice: United Nations Children s Fund and Micronutrient Initiative. Vitamin and Mineral Deficiency: A Global Damage Assessment Report. New Yrok, NY: UNICEF: Zimmermann, MB., Jooste, PL., Pandav, CS. (2008). The iodine deficiency disorders, Lancet/372: Benotti, J., Benotti, N., Pino, S., Gardyna, H. (1965). Determination of total iodine in urine, stool, diets and tissue. Clinical Chemistry/11: Pearce, EN., Bazrafshan, HR., He, X., Pino, S., Braverman, LE. (2004), Dietary iodine in pregnant women from the Boston, Massachusetts area. Thyroid/4:

50 63. Katz, PM., Leung, AM., Braverman, LE., Pearce, EN., Tomlinson, G., He, X., Vertes, J., Okun, N., Walfish, PG., Feig, DS. (2013). Iodine nutrition during pregnancy in Toronto, Canada. Endocrine Practice/19(2):

51 CURRICULUM VITAE AMANDA RACHEL SEGAL Year of Birth: 1989 Languages: English, French & Italian HIGHLIGHTS OF QUALIFICATIONS Highly analytical with excellent problem solving abilities Great interpersonal skills Strong work ethic Focused on teamwork EDUCATION MCGILL SCHOOL OF MEDICINE, Montreal MD, MCDM BOSTON UNIVERSITY SCHOOL OF MEDICINE, Boston MSc in Medical Science MCGILL UNIVERSITY, Montreal 2011 BS in Anatomy and Cell Biology DAWSON COLLEGE, Montreal 2008 DEC in Health Sciences Deans Honor List PROFESSIONAL EXPERIENCE BOSTON UNIVERSITY SCHOOL OF MEDICINE, Boston Research in Obstetrics Iodide Deficiency in Pregnancy BOSTON UNIVERSITY SCHOOL OF MEDICINE, Boston Teaching Fellowship Histology Teaching Assistant / Tutor Physiology 40 Current Current