Abstract
Background: Iodine is an essential micronutrient for thyroid hormone production. Adequate iodine intake and normal thyroid function are important during early development, and breastfed infants rely on maternal iodine excreted in breast milk for their iodine nutrition. The proportion of women in the United States of childbearing age with urinary iodine concentration (UIC) <50 μg/L has been increasing, and a subset of lactating women may have inadequate iodine intake. UIC may also be influenced by environmental exposure to perchlorate and thiocyanate, competitive inhibitors of iodine transport into thyroid, and lactating mammary glands. Data regarding UIC in U.S. lactating women are limited. To adequately assess the iodine sufficiency of lactating women and potential associations with environmental perchlorate and thiocyanate exposure, we conducted a multicenter, cross-sectional study of urinary iodine, perchlorate, and thiocyanate concentrations in healthy U.S. lactating women.
Methods: Lactating women ≥18 years of age were recruited from three U.S. geographic regions: California, Massachusetts, and Ohio/Illinois from November 2008 to June 2016. Demographic information and multivitamin supplements use were obtained. Iodine, perchlorate, and thiocyanate levels were measured from spot urine samples. Correlations between urinary iodine, perchlorate, and thiocyanate levels were determined using Spearman's rank correlation. Multivariable regression models were used to assess predictors of urinary iodine, perchlorate, and thiocyanate levels, and UIC <100 μg/L.
Results: A total of 376 subjects (≥125 from each geographic region) were included in the final analyses [mean (SD) age 31.1 (5.6) years, 37% white, 31% black, and 11% Hispanic]. Seventy-seven percent used multivitamin supplements, 5% reported active cigarette smoking, and 45% were exclusively breastfeeding. Median urinary iodine, perchlorate, and thiocyanate concentrations were 143 μg/L, 3.1 μg/L, and 514 μg/L, respectively. One-third of women had UIC <100 μg/L. Spot urinary iodine, perchlorate, and thiocyanate levels all significantly positively correlated to each other. No significant predictors of UIC, UIC <100 μg/L, or urinary perchlorate levels were identified. Smoking, race/ethnicity, and marital status were significant predictors of urinary thiocyanate levels.
Conclusion: Lactating women in three U.S. geographic regions are iodine sufficient with an overall median UIC of 143 μg/L. Given ubiquitous exposure to perchlorate and thiocyanate, adequate iodine nutrition should be emphasized, along with consideration to decrease these exposures in lactating women to protect developing infants.
Keywords: : iodine nutrition, iodine in breastfeeding, lactation, iodine, perchlorate, thiocyanate
Introduction
Iodine is an essential micronutrient necessary for thyroid hormone production. Adequate iodine intake and normal thyroid function are especially important during early development. Breastfed infants rely on maternal iodine excreted in breast milk for the production of thyroid hormones necessary for normal neurodevelopment (1,2). Therefore, dietary iodine requirements are higher for lactating women than they are for nonlactating adults. The U.S. Institute of Medicine's Recommended Dietary Allowance for iodine is 290 μg/day for lactating women, compared with 150 μg/day recommended for nonpregnant adults (3).
Since the 1920s, U.S. dietary iodine consumption has been considered adequate, initially due to the introduction of iodized salt. Population iodine sufficiency, based on a sample size of at least 125 individuals (4), is defined by the World Health Organization (WHO) as median urinary iodine concentrations (UIC) ≥100 μg/L in lactating adults (5). A recent systematic review of UIC in lactating women based on the presence of mandatory or voluntary iodine fortification program reported the mean or median UIC was >100 μg/L in more than 50% of countries with mandatory iodine fortification programs, in contrast to less than 33% of countries with voluntary iodine fortification programs (6). The U.S. has never had a mandatory iodine fortification program. Although the UIC of the general population is currently deemed adequate at 164 μg/L (7), the median UIC in U.S. adults decreased by over 50% from the early 1970s to the early 1990s, according to data from the National Health and Nutrition Examination Survey (NHANES) (8). Of particular concern is that the prevalence of UIC <50 μg/L among women of childbearing age increased by almost four-fold, from 4% to 15%, during this period. Among pregnant women in large U.S. national datasets during 2005–2010, only third-trimester women were iodine sufficient, while first- and second-trimester women had median urinary iodine concentrations that categorized them in the mildly iodine insufficient range (9). While the overall U.S. adult population remains iodine sufficient by WHO standards, a subset of lactating women may have inadequate dietary iodine intake (10).
Sources of iodine in the diet of U.S. adults have been difficult to identify because there are a wide variety of potential sources, there is a wide amount of variation in the iodine content of some common foods, and food iodine content is not listed on packaging. In addition, UIC thresholds have been identified for populations, but not for individual patients. For this reason, a public health approach to iodine supplementation in the United States has been advocated, particularly for women of childbearing age. The American Thyroid Association has recommended that all women receive dietary supplements containing 150 μg iodine daily during preconception, pregnancy, and lactation and that all prenatal vitamins contain 150 μg of iodine (11). This position is also supported by the Endocrine Society (12), the Teratology Society (13), and the American Academy of Pediatrics (14) but has not yet been widely adopted in current clinical practice. In the United States, iodine is not a required component of prenatal vitamins, and a study in 2009 revealed that only 51% of U.S.-marketed prenatal multivitamins contain iodine, and the iodine content is often lower than listed and highly variable (15). In early 2015, the Council for Responsible Nutrition, the U.S. trade group for supplement manufacturers, recommended that all manufacturers include at least 150 μg of iodine per daily dose of supplements intended for pregnant or lactating women (16). However, as this remains a voluntary measure, there was only a modest increase to 61% in the proportion of U.S. prenatal vitamins with iodine in a recent study (17). In a U.S. survey of 275 obstetricians and 199 midwives, providers answered that they at best “rarely recommended” iodine-containing prenatal multivitamins for women planning pregnancy (68% and 70%, respectively), for pregnant women (66% and 67%), or for lactating women (68% and 72%) (18).
Urinary iodine content may be influenced by factors other than maternal dietary iodine intake. The thyroidal effects of low-level environmental perchlorate and thiocyanate exposures have recently been controversial. In particular, perchlorate exposure has been adversely associated with thyroid dysfunction in some studies. Perchlorate is formed by natural processes and is a byproduct from airbag inflation systems, matches, fertilizers, road flares, solid rocket fuel, munitions, and fireworks (19). Perchlorate is highly soluble and can persist in groundwater for decades. In the U.S., perchlorate is ubiquitous and has been detected in food supplies including baby food, dairy products, eggs, fruits, grains, and vegetables; in crops such as tobacco; in vitamins (20–25); and in river water following a July fourth fireworks celebration (26). It is a competitive inhibitor of the sodium-iodide symporter (NIS), which actively transports iodine into thyroid and lactating mammary cells (27). When given in pharmacological doses, perchlorate decreases the active transport of iodine into the thyroid and possibly breast milk (27). Low-level environmental perchlorate exposure appears to be ubiquitous in the U.S. population. In the NHANES 2001–2002 survey, perchlorate was detected in all 2820 spot urine samples (median urine perchlorate concentration 3.6 μg/L) (28) and was a significant negative predictor of total thyroxine and a positive predictor of thyrotropin values in women, primarily those with UIC <100 μg/L (29). NIS expression is upregulated in the lactating breast and concentrates iodine from the circulation to a degree similar to the thyroid (30). Given perchlorate's high affinity for NIS, breastmilk is a direct source of perchlorate exposure in the breastfeeding infant.
Cigarette smoke contains cyanide that is metabolized to thiocyanate, which can also decrease the uptake of iodine into the thyroid and breastmilk by competitively inhibiting NIS, although thiocyanate is a less potent NIS competitor than perchlorate (31). One study in Denmark concluded that cigarette smoking decreases breastmilk iodine concentrations (32), and we demonstrated the same effect in a small cohort of Boston-area lactating women (33). Cigarette smoke exposure may thus exacerbate the effects of environmental perchlorate exposure on thyroid function. Thiocyanate is also naturally present in certain foods, such as cauliflower, broccoli, kale, bamboo shoots, and Brussels sprouts.
There are limited data regarding median UICs among U.S. lactating women. We previously reported that the median UIC of 56 Boston-area lactating women was 114 μg/L (range 25–920 μg/L) (33), similar to that (104 μg/L; range 13–528 μg/L) of 97 Boston-area women in the immediate postpartum period (34). Others have shown that median urinary iodine levels fluctuate in the immediate postpartum period, ranging from 36–63 μg/L at 3–10 days after delivery (35). However, there is a lack of studies of U.S. lactating women with a sample size large enough to make an inference regarding population level iodine sufficiency. We conducted a multicenter, cross-sectional observational study of urinary iodine, perchlorate, and thiocyanate concentrations in 376 healthy lactating U.S. mothers to adequately determine the iodine sufficiency of this particularly susceptible population and assess whether this may be associated with low-level environmental perchlorate and thiocyanate exposures.
Materials and Methods
A multicenter, cross-sectional study of dietary habits and UIC of 378 lactating women in the U.S. was conducted from November 2008 through June 2016 (in Massachusetts [MA] from November 2008 through September 2015; in California [CA] from March 2011 through June 2016; and in Ohio [OH] and Illinois [IL] from June 2011 through December 2015). Institutional Review Board approval for the study was obtained from the Boston University Medical Campus and Boston Medical Center (BMC), Boston, MA; University of California Los Angeles (UCLA) Medical Center, Los Angeles, CA; University of Southern California, Los Angeles, CA; Ohio State University (OSU) Medical Center, Columbus, OH; and NorthShore University Health System, Evanston, IL, where subject recruitment and urine sample collection occurred.
Study subjects and measures
Breastfeeding women at least 18 years of age were recruited from obstetric and pediatric clinics and through advertisements in the local community. Women who were postpartum for any length of time if delivered vaginally or who were at least two months postpartum if delivered by cesarean section at BMC were eligible because of the use of topical iodine-containing cleaners for Foley catheter insertion for cesarean section at BMC. Women who were at least three weeks postpartum at UCLA and OSU medical centers were eligible because of the routine use of topical iodine-containing cleaners at delivery at these sites. The differences in the duration after birth for eligibility for each site were partly due to changing information during the course of the study. Spanish-speaking women at OSU were eligible for recruitment. Otherwise, non-English speaking women and women with history of or current known thyroid disease, use of thyroid hormones or anti-thyroidal medications, or use of amiodarone within 24 months were excluded. Women who had undergone radiologic studies with intravenous iodine-containing contrast agents within three months were also excluded.
Subject demographic information, including age, race/ethnicity, marital status, education level, smoking behavior, present exposure to passive smoke, and any family history of thyroid disorders was obtained through a questionnaire. Use of iodine-containing prenatal or other multivitamin supplements (MVI) was also assessed. However, iodine content of MVI was not known for most subjects, and therefore, we could not differentiate iodine-containing and non-iodine-containing MVI. Spot urine samples were collected from all participants for measurements of iodine, perchlorate, and thiocyanate.
A total of 378 lactating women from three U.S. geographic locations were recruited: 126 from Boston, MA; 125 from Los Angeles, CA; and 127 combined from Columbus, OH and Evanston, IL. Two participants from IL were unable to provide urine samples following informed consent, and thus were excluded from analyses. Therefore, a total of 376 subjects (126 from MA; 125 from CA; and 125 from OH and IL) were included in the final analyses. Spot UIC cannot be used as an individual biomarker of iodine nutritional status due to its fluctuation from recent iodine intake, and median spot UIC in at least 125 subjects is used instead to assess population level iodine sufficiency (4).
Laboratory methods
Urine samples were frozen upon collection and stored at −80°C until measurement. Samples from sites outside of Boston were shipped on dry ice to Boston University Iodine Research Laboratory for measurements. Levels of spot urinary iodine, perchlorate, and thiocyanate were measured by ion-chromatography mass spectrometry. The limit of detection for iodine is 0.5 μg/L, and the interassay coefficient of variation for iodine measurement in our laboratory is 2.2–7.6%. The limit of detection for perchlorate is 0.05 μg/L, and the interassay coefficient of variation for perchlorate measurement in our laboratory ranges from 2.2% to 5.9%. The limit of detection for thiocyanate is 0.05 μg/L, and the interassay coefficient of variation for thiocyanate measurement in our laboratory is <5%.
Statistical analyses
Descriptive statistics are reported as mean ± standard deviation or median (range). Kruskal-Wallis tests and ANOVA were used to compare characteristics among the three geographical sites for categorical variables and continuous variables, respectively. Spearman's rank correlation was used to determine univariate associations between urinary perchlorate, iodine, and thiocyanate. The univariate associations between urinary perchlorate, iodine, and thiocyanate levels were further assessed for only those with urinary iodine concentration (UIC) less than 100 μg/L, the WHO-recommended cutoff for population level iodine sufficiency in lactating women (5). Wilcoxon rank sum tests were used to determine univariate associations between MVI use and urinary iodine levels and between smoking and urinary thiocyanate levels.
Multivariable linear regression models were used to assess predictors of urinary iodine, urinary perchlorate, and urinary thiocyanate levels. Multivariable logistic regression models were used to assess predictors of UIC <100 μg/L. The covariates included in all multivariable analyses were selected based on potential biological or clinical significance related to outcome, and included race/ethnicity, mother's age, marital status, highest education level, MVI use, smoking, and use of formula supplementation for baby. Mother's age was entered as a continuous variable in years. The following were entered as categorical variables; race/ethnicity (white, black, Latino, Asian, Native American, and others), marital status (never married, married, divorced, widowed, other), highest education level (high school or below, vocation/trade school, two-year college, four-year college, grad school or higher), MVI use (yes, no), smoking (yes, no). Use of formula supplementation for baby was categorized in two different ways: a dichotomous variable of yes/no or a categorical variable of none/<12 ounces/day/≥12 ounces/day. For assessment of predictors of urinary perchlorate level, urinary thiocyanate level was included as a covariate. For assessment of predictors of urinary thiocyanate level, urinary perchlorate level was included as a covariate.
All statistical analyses were performed using SAS version 9.3 (SAS institute, Cary, NC). Results were considered statistically significant if the two-tailed p-value was <0.05.
Results
A total of 376 subjects (125 from CA, 126 from MA, and 125 from OH/IL) were included in the analyses. Demographic subject characteristics are presented in Table 1. The distribution of lactating women who were smoking was significantly different among regions, likely because of the difference between CA and OH/IL (2 and 9 subjects, respectively), although the overall proportion of women who were active cigarette smokers was small. Use of MVI or supplemental baby formula use when assessed as yes/no was not significantly different among sites.
Table 1.
Subject Characteristics Among Three U.S. Geographic Regions
| All (N = 376) | CA (N = 125) | MA (N = 126) | OH/IL (N = 125) | Comparison (p-value) | |
|---|---|---|---|---|---|
| n (%) | |||||
| Race/ethnicity | <0.001 | ||||
| Non-Hispanic white | 137 (37%) | 43 (34%) | 23 (18%) | 71 (29%) | |
| Non-Hispanic black | 114 (31%) | 13 (10%) | 80 (63%) | 21 (18%) | |
| Hispanic | 39 (11%) | 18 (14%) | 7 (6%) | 14 (12%) | |
| Asian | 60 (16%) | 45 (36%) | 9 (7%) | 6 (5%) | |
| Native American | 6 (2%) | 1 (1%) | 5 (4%) | 0 | |
| Other | 15 (4%) | 5 (4%) | 2 (2%) | 8 (7%) | |
| Birthplace | <0.001 | ||||
| US | 221 (59%) | 72 (58%) | 53 (42%) | 96 (78%) | |
| Other | 153 (41%) | 53 (42%) | 73 (58%) | 27 (22%) | |
| Marital status | <0.001 | ||||
| Never married | 89 (24%) | 13 (11%) | 48 (38%) | 28 (23%) | |
| Married | 237 (64%) | 74 (60%) | 75 (60%) | 88 (72%) | |
| Divorced | 36 (10%) | 32 (26%) | 2 (2%) | 2 (2%) | |
| Widowed | 2 (1%) | 1 (1%) | 0 | 1 (1%) | |
| Other | 8 (2%) | 3 (2%) | 1 (1%) | 4 (3%) | |
| Highest education | <0.001 | ||||
| High school or below | 62 (17%) | 8 (7%) | 24 (19%) | 30 (24%) | |
| Vocation/trade school | 71 (19%) | 26 (21%) | 39 (31%) | 6 (5%) | |
| 2-yr college | 42 (11%) | 7 (6%) | 17 (13%) | 18 (15%) | |
| 4-yr college | 82 (22%) | 22 (18%) | 23 (18%) | 37 (30%) | |
| Grad or higher | 114 (31%) | 59 (48%) | 23 (18%) | 32 (26%) | |
| MVI use | 0.53 | ||||
| Yes | 285 (77%) | 99 (80%) | 93 (74%) | 93 (76%) | |
| No | 87 (23%) | 25 (20%) | 33 (26%) | 29 (24%) | |
| Smoking | 0.03 | ||||
| Yes | 19 (5%) | 2 (2%) | 6 (5%) | 11 (9%) | |
| No | 354 (95%) | 122 (98%) | 120 (95%) | 112 (91%) | |
| Use of supplemental baby formula by category | 0.04 | ||||
| None | 168 (45%) | 59 (48%) | 48 (38%) | 61 (50%) | |
| <12 ounces/day | 159 (43%) | 56 (45%) | 53 (42%) | 50 (41%) | |
| ≥12 ounces/day | 43 (12%) | 9 (7%) | 24 (19%) | 10 (8%) | |
| Dichotomous supplemental baby formula use | 0.03 | ||||
| Yes | 202 (45%) | 65 (52%) | 77 (62%) | 60 (50%) | |
| No | 168 (55%) | 59 (48%) | 48 (38%) | 61 (50%) | |
| Mean (SD) or Median (range) | |||||
| Mother's age (years) | 31.1 (5.6) | 32.7 (5.0) | 29.5 (5.8) | 31.1 (5.6) | <0.001 |
| GA at birth (weeks) | 38.6 (2.5) | 38.9 (2.4) | 39.3 (1.2) | 37.6 (3.3) | <0.001 |
| Baby age at enrollment (days) | 45.5 (6–1868) | 49.5 (12–1868) | 43.5 (10–672) | 44.5 (6–428) | <0.001 |
CA, subjects recruited in California; IL, subjects recruited in Illinois; GA, gestational age; MA, subjects recruited in Massachusetts; MVI, multivitamin supplements; OH, subjects recruited in Ohio; SD, standard deviation.
The laboratory measurements of spot urinary iodine, perchlorate, and thiocyanate levels, as well as the proportions of women with UIC less than 100 μg/L, are presented in Table 2. Overall median UIC was 143 μg/L (range 6–2140 μg/L), and median UICs were not significantly different between geographic regions (p = 0.18). The median UIC in all three regions were adequate (159 μg/L in CA, 131 μg/L in MA, and 154 μg/L in OH/IL), per the World Health Organization recommendation of UIC ≥100 μg/L in lactating women (5). There were no significant differences of the median urinary iodine, perchlorate, or thiocyanate levels between regions. There were also no significant differences in proportion of women with UIC <100 μg/L between regions.
Table 2.
Laboratory Measurements and Comparison of Distribution by Region
| All (n = 376) | CA (n = 125) | MA (n = 126) | OH/IL (n = 125) | Comparison (p-value) | |
|---|---|---|---|---|---|
| Median (range) | |||||
| Urinary iodine concentration (μg/L) | 143 (6–2140) | 159 (16.9–720) | 131 (10.6–595) | 154 (6–2140) | 0.18 |
| Urinary perchlorate concentration (μg/L) | 3.1 (0.2–94.5) | 2.8 (0.2–94.5) | 3.2 (0.2–22.4) | 3.5 (0.2–31.7) | 0.70 |
| Urinary thiocyanate concentration (μg/L) | 514 (12.3–4250) | 565 (43.2–2020) | 450.8 (31.1–2755) | 525.5 (12.3–4250) | 0.16 |
| N (%) | |||||
| UIC <100 μg/L | 125 (33%) | 37 (30%) | 44 (35%) | 44 (35%) | 0.54 |
UIC, urinary iodine concentration.
Correlations between spot urinary iodine, perchlorate, and thiocyanate levels in all subjects, and in subjects with UIC <100 μg/L are presented in Table 3. Spot urinary iodine, perchlorate, and thiocyanate levels were all significantly positively correlated with each other. MVI use and spot UIC were not significantly correlated (p = 0.095). Smoking and thiocyanate level was significantly positively correlated (p < 0.001). Among those with UIC <100 μg/L, only perchlorate and iodine levels and thiocyanate and iodine levels were significantly correlated to each other.
Table 3.
Correlations Between Spot Urinary Iodine, Perchlorate, and Thiocyanate Concentrations
| All subjects | |||
|---|---|---|---|
| Iodine | Perchlorate | Thiocyanate | |
| Iodine | ——– | Correlation coefficient = 0.284 p < 0.001 |
Correlation coefficient = 0.364 p < 0.001 |
| Perchlorate | Correlation coefficient = 0.284 p < 0.001 |
——– | Correlation coefficient = 0.186 p < 0.001 |
| Thiocyanate | Correlation coefficient = 0.364 p < 0.001 |
Correlation coefficient = 0.186 p < 0.001 |
——– |
| Subjects with UIC <100μg/L only | |||
|---|---|---|---|
| Iodine | Perchlorate | Thiocyanate | |
| Iodine | ——– | Correlation coefficient = 0.257 p = 0.004 |
Correlation coefficient = 0.447 p < 0.001 |
| Perchlorate | Correlation coefficient = 0.257 p = 0.004 |
——– | Correlation coefficient = 0.138 p = 0.12 |
| Thiocyanate | Correlation coefficient = 0.447 p < 0.001 |
Correlation coefficient = 0.138 p = 0.12 |
——– |
The multivariable models predicting UIC were not statistically significant (p = 0.32, R2 = 0.054 when supplemental baby formula use was assessed as a dichotomous variable and p = 0.24, R2 = 0.061 when supplemental baby formula use was assessed as a categorical variable). The multivariable model predicting UIC <100 μg/L was not statistically significant when supplemental baby formula use was assessed as a dichotomous variable (p = 0.060, R2 = 0.075). However, the multivariable model predicting UIC <100 μg/L was statistically significant when supplemental baby formula use was assessed as a categorical variable (p = 0.012, R2 = 0.094), with race/ethnicity as the only significant predictor (p = 0.02). In the post hoc subgroup analyses, Asian race/ethnicity was significantly associated with 0.75 times lower risk of UIC <100 μg/L compared with white race/ethnicity (log estimate −0.287, p = <0.001). The multivariable models predicting spot urine perchlorate levels were not statistically significant (p = 0.30, R2 = 0.058 when supplemental baby formula use was assessed as a dichotomous variable and p = 0.30, R2 = 0.061 when supplemental baby formula use was assessed as a categorical variable). The multivariable models predicting spot urine thiocyanate levels were statistically significant (Tables 4, 5). When supplemental baby formula use was assessed as a dichotomous variable, the model was statistically significant, with p < 0.001 and R2 = 0.22. Among the covariates assessed, race/ethnicity, marital status, and smoking were statistically significant predictors (p-values of 0.013, 0.025, and <0.001, respectively). In the post hoc subgroup analyses, black race/ethnicity was significantly associated with lower thiocyanate level by 213.68 μg/L compared with white race/ethnicity (p- = 0.001), married status was associated with lower thiocyanate level by 200.19 μg/L compared with never married status (p = 0.002), and not smoking was associated with lower thiocyanate level by 807.08 μg/L compared with smoking (p < 0.001). When supplemental baby formula use was assessed as a categorical variable, the model was statistically significant with a p < 0.001 and R2 = 0.22. Among the covariates assessed, race/ethnicity, marital status, and smoking status were statistically significant (p-values of 0.013, 0.026, and <0.001, respectively). In the post hoc subgroup analyses, black race/ethnicity was significantly associated with lower thiocyanate level by 213.70 μg/L compared with white race/ethnicity (p = 0.001), married status was associated with lower thiocyanate level by 199.98 μg/L compared with never married status (p = 0.002), and not smoking was associated with lower thiocyanate level by 806.77 μg/L compared with smoking (p = <0.001).
Table 4.
Multivariable Regression Analysis Predicting Spot Urine Thiocyanate Levels Using Supplemental Baby Formula as a Categorical Variable (p < 0.0001, R2 = 0.22)
| Covariates | Estimate (SE) | p-Value |
|---|---|---|
| Intercept | 1609.5 (175.7) | <0.0001 |
| Race/ethnicity | 0.013 | |
| Black | −213.7 (65.1) | 0.001 |
| Hispanic | −129.9 (86.8) | 0.14 |
| Asian | −20.5 (77.3) | 0.79 |
| Native American | −279.0 (188.2) | 0.14 |
| Other | −227.1 (118.5) | 0.06 |
| Mother's age | 0.37 (4.76) | 0.94 |
| Marital status | 0.03 | |
| Married | −200.0 (64.6) | 0.002 |
| Divorced | −119.7 (102.0) | 0.24 |
| Widowed | −387.2 (438.9) | 0.38 |
| Other | −333.5 (180.0) | 0.06 |
| Highest education level | 0.98 | |
| Vocation/trade school | −45.0 (82.2) | 0.58 |
| 2-year college | −44.6 (93.6) | 0.63 |
| 4-year college | −32.6 (84.8) | 0.70 |
| Graduate school or higher | −23.5 (83.9) | 0.78 |
| MVI use – no | 90.6 (57.2) | 0.12 |
| Smoking – no | −806.8 (144.7) | <0.0001 |
| Supplemental baby formula use | 1.00 | |
| <12 ounces/day | −2.5 (53.8) | 0.96 |
| ≥12 ounces/day | 0.69 (82.1) | 0.99 |
| Spot urine perchlorate level | 5.7 (3.7) | 0.12 |
White race/ethnicity, never married marital status, highest education level of high school or less, MVI use, smoking, and no baby formula use were used as the reference groups.
Table 5.
Multivariable Regression Analysis Predicting Spot Urine Thiocyanate Levels Using Supplemental Baby Formula as a Dichotomous Variable (p < 0.0001, R2 = 0.22)
| Covariates | Estimate (SE) | p-Value |
|---|---|---|
| Intercept | 1608.1 (169.6) | <0.0001 |
| Race/ethnicity | 0.013 | |
| Black | −213.7 (65.0) | 0.001 |
| Hispanic | −130.0 (86.6) | 0.13 |
| Asian | −20.9 (76.5) | 0.78 |
| Native American | −277.7 (185.0) | 0.13 |
| Other | −227.5 (117.9) | 0.05 |
| Mother's age | −0.003 (0.004) | 0.94 |
| Marital status | 0.03 | |
| Married | −200.2 (64.3) | 0.002 |
| Divorced | −119.6 (101.8) | 0.24 |
| Widowed | −387.8 (438.0) | 0.38 |
| Other | −333.1 (179.5) | 0.06 |
| Highest education level | 0.98 | |
| Vocation/trade school | −45.0 (82.1) | 0.58 |
| 2-year college | −44.4 (93.3) | 0.63 |
| 4-year college | −32.5 (84.6) | 0.70 |
| Graduate school or higher | −23.3 (83.7) | 0.78 |
| MVI use – no | 90.6 (57.1) | 0.11 |
| Smoking – no | −807.1 (114.3) | <0.0001 |
| Supplement baby formula use – no | 1.86 (51.5) | 0.97 |
| Spot urine perchlorate level | 5.7 (3.7) | 0.12 |
White race/ethnicity, never married marital status, highest education level of high school or less, MVI use, smoking, and no baby formula use were used as the reference groups.
Discussion
The data presented here show that U.S. lactating women from three distinct geographic regions are iodine sufficient, with an overall median UIC of 143 μg/L, above the WHO recommended threshold for iodine sufficiency in lactating women of 100 μg/L. The proportion of women with UIC <100 μg/L were similar among all regions, ranging from 30% to 35%. This is similar to the proportion of U.S. pregnant women with a UIC <100 μg/L in NHANES data (7). Although two-thirds of women were taking a MVI, there was no correlation between MVI use and UIC, although most women were unsure whether their MVI contained iodine. A recent study of U.S. prenatal multivitamin supplements showed only 61% contained iodine according to the product labeling (17).
U.S. lactating women are overall iodine sufficient. However, approximately one-third of our subjects have spot UICs <100 μg/L. The median perchlorate level in our sample was slightly higher than the mean perchlorate level in U.S. adults over 20 years of age in 2013–2014 reported by the Center for Disease Control and Prevention (CDC) (3.1 μg/L vs. 2.53 μg/L) (36). The median thiocyanate level in our sample was almost one-half of the mean thiocyanate level in U.S. adults over 20 years of age in 2013–2014 reported by the CDC (514 μg/L vs. 1060 μg/L) (36). This is likely because of the small number of smokers in our sample, and our mean is more in line with the mean thiocyanate level of 773 μg/L (0.773 mg/L) found in nonsmoking adults in 2013–2014 by the CDC.
Spot urine iodine, perchlorate, and thiocyanate concentrations were all significantly positively correlated with each other, likely due to co-contamination from common exposure routes. Interestingly, the correlation between thiocyanate and iodine became stronger when assessed in the subset of lactating women with UIC <100 μg/L. There may be underlying behavioral differences affecting the correlations between UIC and urinary thiocyanate levels. For example, one subject had a very high UIC of 2140 μg/L and a high urinary thiocyanate level of 2230 μg/L, suggesting a possible unifying environmental exposure or possibly due to concentration of urine.
There were no significant predictors for UIC, although race/ethnicity was a significant predictor of UIC <100 μg/L in one multivariable analysis. There were no significant predictors of urinary perchlorate levels. Smoking was one of the significant predictors of urinary thiocyanate levels in our multivariable analyses, as expected. As perchlorate and thiocyanate are inhibitors of NIS, they were not included in the multivariable models predicting UIC or low UIC. Normal UICs do not exclude the possibility that perchlorate or thiocyanate may still impair iodine uptake into the thyroid gland leading to thyroid dysfunction (29), or into lactating mammary glands leading to inadequate iodine nutrition for breastfed infants (32,33). In the presence of underlying iodine deficiency with low thyroidal iodine storage, the effects of perchlorate or thiocyanate exposure on thyroid function or breastmilk iodine content may be greater. Given the findings of an increasing proportion of women of reproductive age with UIC <50 μg/L (7) and high proportions of pregnant or lactating women with UIC <100 μg/L as seen in the NHANES data (7) and in the present study, U.S. pregnant or lactating women and breastfed infants remain particularly vulnerable to the adverse effects of low-level environmental perchlorate and thiocyanate exposures.
Limitations of this study include a lack of information regarding dietary habits and thyroidal iodine saturation status. A spot UIC does not reflect thyroidal iodine status since the thyroid may have adequate iodine storage even though UIC is low. However, obtaining a nuclear scan to assess thyroidal iodine uptake would have been extremely difficult, as our subjects were all lactating mothers. Therefore, we used UIC to assess population-level iodine sufficiency using the threshold recommended by the WHO. Another limitation of this study is lack of measurement of urinary creatinine levels as a marker of urine dilution. However, UIC without correction with urinary creatinine level is deemed to be sufficient in assessing population-level iodine status by the WHO and we measured iodine, perchlorate, and thiocyanate from the same urine sample to minimize potential confounding by dilution. Strengths include the sample size and the ethnic diversity of our study population, with 37% non-Hispanic whites, 31% non-Hispanic blacks, and 11% Hispanic.
In summary, this study provides novel data assessing the current status of iodine nutrition among U.S. lactating women, in direct line with one of the charges by the recent American Thyroid Association guidelines for the diagnosis and management of thyroid disease in pregnancy and the postpartum period (10). These findings show that population-level iodine sufficiency was demonstrated from three distinct U.S. geographic regions, and iodine nutrition among U.S. lactating women is comparable across these regions. Median urinary perchlorate and thiocyanate concentrations were similar among the three sites. Although the U.S. Environmental Protection Agency announced in February 2011 that perchlorate regulation of drinking water will be considered (37), such measures have not yet been implemented, and discussions to do so continue to be in progress (38). Given ubiquitous exposure to low-level environmental perchlorate and thiocyanate in our sample population, adequate iodine nutrition should be emphasized in lactating women to provide optimal iodine nutrition for their breastfed infants.
Acknowledgments
This research was supported by U.S. National Institutes of Health grants NIH K23HD068552 (A.M.L.) and NIH T32DK007201-37 (S.Y.L.), and The Chicago Lying-In Hospital Board of Directors, Helen Johnson Babies Alumni Fund (A.M.M.).
Author Disclosure Statement
No competing financial interests exist.
References
- 1.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. N Engl J Med 341:549–555 [DOI] [PubMed] [Google Scholar]
- 2.Henrichs J, Ghassabian A, Peeters RP, Tiemeier H. 2013. Maternal hypothyroxinemia and effects on cognitive functioning in childhood: how and why? Clin Endocrinol (Oxf) 79:152–162 [DOI] [PubMed] [Google Scholar]
- 3.Institute of Medicine (U.S.) Panel on Micronutrients 2001 Dietary reference intakes for vitamin a, vitamin k, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. National Academies Press, Washington DC: Available at: www.ncbi.nlm.nih.gov/books/NBK222310 (accessed February1, 2015) [PubMed] [Google Scholar]
- 4.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. Br J Nutr 99:813–818 [DOI] [PubMed] [Google Scholar]
- 5.WHO, UNICEF, ICCIDD 2007. Assessment of iodine deficiency disorders and monitoring their elimination: a guide for programme managers. Third edition. Available at: http://whqlibdoc.who.int/publications/2007/9789241595827_eng.pdf (accessed February1, 2015)
- 6.Nazeri P, Mirmiran P, Shiva N, Mehrabi Y, Mojarrad M, Azizi F. 2015. Iodine nutrition status in lactating mothers residing in countries with mandatory and voluntary iodine fortification programs: an updated systematic review. Thyroid 25:611–620 [DOI] [PubMed] [Google Scholar]
- 7.Caldwell KL, Makhmudov A, Ely E, Jones RL, Wang RY. 2011. Iodine status of the U.S. population, national health and nutrition examination survey, 2005–2006 and 2007–2008. Thyroid 21:419–427 [DOI] [PubMed] [Google Scholar]
- 8.Hollowell JG, Staehling NW, Hannon WH, Flanders DW, Gunter EW, Maberly GF, Braverman LE, Pino S, Miller DT, Garbe PL, DeLozier DM, Jackson RJ. 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 (1971–1974 and 1988–1994). J Clin Endocrinol Metab 83:3401–3408 [DOI] [PubMed] [Google Scholar]
- 9.Caldwell KL, Pan Y, Mortensen ME, Makhmudov A, Merrill 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 2005–2010. Thyroid 23:927–937 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Leung AM, Braverman LE, Pearce EN. 2012. History of U.S. iodine fortification and supplementation. Nutrients 4:1740–1746 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, Grobman W, Laurberg P, Lazarus JH, Mandel SJ, Peeters R, Sullivan S. 2017. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 27:315–389 [DOI] [PubMed] [Google Scholar]
- 12.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. J Clin Endocrinol Metab 97:2543–2565 [DOI] [PubMed] [Google Scholar]
- 13.Obican SG, Jahnke GD, Soldin OP, Scialli AR. 2012. Teratology public affairs committee position paper: iodine deficiency in pregnancy. Birth Defects Res A Clin Mol Teratol 94:677–682 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Council on Environmental Health, Rogan WJ, Paulson JA, Baum C, Brock-Utne AC, Brumberg HL, Campbell CC, Lanphear BP, Lowry JA, Osterhoudt KC, Sandel MT, Spanier A, Trasande L. 2014. Iodine deficiency, pollutant chemicals, and the thyroid: new information on an old problem. Pediatrics 133:1163–1166 [DOI] [PubMed] [Google Scholar]
- 15.Leung AM, Pearce EN, Braverman LE. 2009. Iodine content of prenatal multivitamins in the United States. N Engl J Med 360:939–940 [DOI] [PubMed] [Google Scholar]
- 16.Council for Responsible Nutrition 2015 Recommended guidelines: iodine quantity in multivitamin/mineral supplements for pregnancy and lactation. Available at: www.crnusa.org/pdfs/CRNRecommendedGuidelinesIodine_Final.pdf (accessed May4, 2016)
- 17.Lee SY, Stagnaro-Green A, MacKay D, Wong AW, Pearce EN. 2016. Iodine contents in prenatal vitamins in the U.S. Thyroid 26(S1): A–159 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.De Leo S, Pearce EN, Braverman LE. 2017. Iodine supplementation in women during preconception, pregnancy, and lactation: current clinical practice by U.S. obstetricians and midwives. Thyroid 27:434–439 [DOI] [PubMed] [Google Scholar]
- 19.Leung AM, Pearce EN, Braverman LE. 2014. Environmental perchlorate exposure: potential adverse thyroid effects. Curr Opin Endocrinol Diabetes Obes 21:372–376 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Leung AM, Pearce EN, Braverman LE. 2010. Perchlorate, iodine and the thyroid. Best Pract Res Clin Endocrinol Metab 24:133–141 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Calderón R, Godoy F, Escudey M, Palma P. 2017. A review of perchlorate (ClO4(−)) occurrence in fruits and vegetables. Environ Monit Assess 189:82. [DOI] [PubMed] [Google Scholar]
- 22.Kirk AB, Martinelango PK, Tian K, Dutta A, Smith EE, Dasgupta PK. 2005. Perchlorate and iodide in dairy and breast milk. Environ Sci Technol 39:2011–2017 [DOI] [PubMed] [Google Scholar]
- 23.Murray CW, Egan SK, Kim H, Beru N, Bolger PM. 2008. U.S. Food and Drug Administration's Total Diet Study: dietary intake of perchlorate and iodine. J Expo Sci Environ Epidemiol 18:571–580 [DOI] [PubMed] [Google Scholar]
- 24.Renner R. 2006. Perchlorate found in vitamins and elsewhere. Environ Sci Technol 40:2498–2499 [PubMed] [Google Scholar]
- 25.Ellington JJ, Wolfe NL, Garrison AW, Evans JJ, Avants JK, Teng Q. 2001. Determination of perchlorate in tobacco plants and tobacco products. Environ Sci Technol 35:3213–3218 [DOI] [PubMed] [Google Scholar]
- 26.Leung AM, He X, Pearce EN, Braverman LE. 2013. Perchlorate concentrations in Boston's Charles River after the July 4th fireworks spectacular. Thyroid 23:378–379 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Dohán O, Carrasco N. 2003. Advances in Na(+)/I(−) symporter (NIS) research in the thyroid and beyond. Mol Cell Endocrinol 213:59–70 [DOI] [PubMed] [Google Scholar]
- 28.Blount BC, Valentin-Blasini L, Osterloh JD, Mauldin JP, Pirkle JL. 2007. Perchlorate exposure of the U.S. Population, 2001–2002. J Expo Sci Environ Epidemiol 17:400–407 [DOI] [PubMed] [Google Scholar]
- 29.Blount BC, Pirkle JL, Osterloh JD, Valentin-Blasini L, Caldwell KL. 2006. Urinary perchlorate and thyroid hormone levels in adolescent and adult men and women living in the United States. Environ Health Perspect 114:1865–1871 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Dohán O, Portulano C, Basquin C, Reyna-Neyra A, Amzel LM, Carrasco N. 2007. The Na+/I symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate. Proc Natl Acad Sci U S A 104:20250–20255 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Tonacchera M, Pinchera A, Dimida A, Ferrarini E, Agretti P, Vitti P, Santini F, Crump K, Gibbs J. 2004. Relative potencies and additivity of perchlorate, thiocyanate, nitrate, and iodide on the inhibition of radioactive iodide uptake by the human sodium iodide symporter. Thyroid 14:1012–1019 [DOI] [PubMed] [Google Scholar]
- 32.Laurberg P, Nøhr SB, Pedersen KM, Fuglsang E. 2004. Iodine nutrition in breast-fed infants is impaired by maternal smoking. J Clin Endocrinol Metab 89:181–187 [DOI] [PubMed] [Google Scholar]
- 33.Pearce EN, Leung AM, Blount BC, Bazrafshan HR, He X, Pino S, Valentin-Blasini L, Braverman LE. 2007. Breast Milk Iodine and Perchlorate Concentrations in Lactating Boston-Area Women. J Clin Endocrinol Metab 92:1673–1677 [DOI] [PubMed] [Google Scholar]
- 34.Leung AM, Pearce EN, Hamilton T, He X, Pino S, Merewood A, Braverman LE. 2009. Colostrum iodine and perchlorate concentrations in Boston-area women: a cross-sectional study. Clin Endocrinol (Oxf) 70:326–330 [DOI] [PubMed] [Google Scholar]
- 35.Smyth PPA, Smith DF, Sheehan S, Higgins M, Burns R, O'Herlihy C. 2007. Short-term changes in maternal and neonatal urinary iodine excretion. Thyroid 17:219–222 [DOI] [PubMed] [Google Scholar]
- 36.U.S. Department of Health and Human Services, Centers for Disease Control and Prevention 2017 Fourth national report on human exposure to environmental chemicals, updated tables, January 2017, Volume One. Available at: www.cdc.gov/biomonitoring/pdf/FourthReport_UpdatedTables_Volume1_Jan2017.pdf (accessed February21, 2017)
- 37.Environmental Protection Agency 2011 Drinking water: regulatory determination on perchlorate. Federal Register. Available at: www.federalregister.gov/documents/2011/02/11/2011-2603/drinking-water-regulatory-determination-on-perchlorate (accessed September20, 2017)
- 38.Environmental Protection Agency 2017 Perchlorate peer review report final 032917. Supporting & Related Material document. Available at: www.regulations.gov/document?D=EPA-HQ-OW-2016-0439-0006 (accessed September20, 2017)