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Iodine Nutrition in Breast-Fed Infants Is Impaired by Maternal Smoking

Departments of Endocrinology and Medicine (P.L., K.M.P.) and Gynaecology and Obstetrics (S.B.N.), Aalborg Hospital, DK-9000 Aalborg; and Ringkoebing Hospital (E.F.), DK-6950 Ringkoebing, Denmark

Address all correspondence and requests for reprints to: Peter Laurberg, Department of Endocrinology and Medicine, Aalborg Hospital, DK-9000 Aalborg, Denmark. E-mail: laurberg{at}aas.nja.dk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Lack of iodine for thyroid hormone formation during the fetal stage and/or the first years of life may lead to developmental brain damage. During the period of breastfeeding, thyroid function of the infant depends on iodine in maternal milk.

We studied healthy, pregnant women admitted for delivery and their newborn infants. Cotinine in urine and serum was used to classify mothers as smokers (n = 50) or nonsmokers (n = 90).

Smoking and nonsmoking mothers had identical urinary iodine on d 5 after delivery, but smoking was associated with reduced iodine content in breast milk (smokers 26.0 µg/liter vs. nonsmokers 53.8 µg/liter; geometric mean, P < 0.001) and in the infants’ urine (smokers 33.3 µg/liter, vs. nonsmokers 50.4 µg/liter, P = 0.005). Results were consistent in multivariate linear models and by logistic regression analysis. The odds ratio for smoking vs. nonsmoking mothers to have lower breast milk than urinary iodine content was 8.4 (95% confidence interval, 3.5–20.1). In smokers, iodine transfer into breast milk correlated negatively to urinary cotinine concentration. Smoking mothers had significantly higher serum levels of thiocyanate, which may competitively inhibit the sodium-iodide symporter responsible for iodide transport in the lactating mammary gland.

Smoking during the period of breastfeeding increases the risk of iodine deficiency-induced brain damage in the child. Women who breastfeed should not smoke, but if they do, an extra iodine supplement should be considered.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
IODINE IS ESSENTIAL for thyroid hormone synthesis and, accordingly, is required for normal development, growth, and metabolism. Lack of thyroid hormone for more than a few weeks during brain development in utero or the first years of life may permanently harm brain function. Worldwide, iodine deficiency is a main cause of preventable brain damage and mental retardation (1, 2). Major progress has been made toward elimination of iodine deficiency (3). However, in the year 2001, an estimated 50 million children were born in areas without protection against iodine deficiency disorders (4).

Thyroid hormones governing brain development in early fetal life are of maternal origin. The fetal thyroid contributes increasingly from the second trimester of pregnancy to fully cover the needs of hormone after birth (5, 6). The thyroid gland of the neonatal infant very actively accumulates iodide, with a rapid turnover, to meet the demands of thyroid hormone formation and secretion (7). The mammary glands of the breastfeeding mother concentrate iodide from blood and excrete it into milk (8). To safely cover the needs of the infant, a relatively high iodine intake for lactating mothers has been advocated (9).

The transport protein responsible for iodide accumulation in the mammary gland has recently been characterized and is identical with the sodium-iodide symporter of the thyroid gland (10, 11). A number of chemicals may competitively inhibit the function of this transporter. One such compound is thiocyanate (11, 12), which accumulates in the blood and tissues of smokers (13, 14, 15). We assessed the risk of iodine deficiency in breast-fed infants associated with maternal smoking.

	Subjects and Methods

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Study population

Healthy pregnant women were recruited consecutively when admitted for delivery after uncomplicated pregnancy in departments of obstetrics in Denmark (Copenhagen, n = 30; Aarhus, n = 30; Ringkoebing, n = 30; Randers, n = 29; and Aalborg, n = 33; total, n = 152). After informed consent and following ethical regulations, detailed information was obtained on intake of iodine supplements. The women were instructed to continue any supplement intake during the puerperal period to keep iodine intake relatively stable. Six women with intermittent intake of iodine supplements were excluded from the study. As described later, another six women were excluded due to ambiguous classification of smoking habits. All women intended to breastfeed their newborn child. All were Caucasian, and none had visible goitre or previous thyroid disease. None of the women had a history of recent exposure to excess iodine, and iodine-containing disinfectants were not used. Samples were collected before the recent introduction of salt iodization in Denmark (16). Hence, the population had, in general, mild to moderate iodine deficiency (17). The majority of the women investigated lived in areas of moderate iodine deficiency (smokers, 74%; nonsmokers, 81%; P = 0.32).

Sampling for analyses

Blood samples were taken from the mother by standard cubital phlebotomy shortly after admission for labor. Closure of the umbilical cord was performed within the first minute after delivery, and mixed cord blood was sampled from the placental part shortly after. After sampling, blood was centrifuged, and serum was stored at -20 C until analyses.

On d 5 after delivery, we collected a morning spot urine and breast milk sample from the mothers and a urine sample from the neonates. Neonatal urine was collected in a small self-adhesive plastic bag (Coloplast baby urine collector; Coloplast, Espergærde, Denmark). Urine samples were kept at -20 C. Urine was available from all 140 mothers included in the final analyses. There were 135 urine samples from neonates, 136 samples of milk, 138 serum samples from mothers, and 133 cord serum samples.

Assessment of smoking and iodine nutrition

Smoking status was assessed by measurements of the nicotine metabolite cotinine in serum and urine (18, 19). Cotinine in serum from the mothers before delivery and from cord blood was measured by immunoassay (Immulite 2000 Nicotine Metabolite Assay; Diagnostic Products Corporation, Los Angeles, CA). Analytical sensitivity was 5 µg/liter, and a cutoff of 25 µg/liter has been found to distinguish smokers. In the present set-up, the measurement range was from 5–600 µg/liter. At the cutoff level, the intraassay and interassay coefficients of variation were 9.6 and 12.3%, respectively. Cotinine in urine from the mothers and the neonatal infants was measured by a double antibody RIA (Diagnostic Products Corporation). Analytical sensitivity was 9 µg/liter, and the cutoff for smoking was 500 µg/liter. Intra- and interassay coefficients of variation around the cutoff were 5.3 and 6.8%, respectively. Cotinine 1 µg/liter corresponds to 5.68 nmol/liter.

The iodine nutrition of mothers and infants was studied by measurements of iodine in urine. In nonlactating women, around 90% of iodine is excreted in urine (20, 21), and urinary iodine parallels intake when intake and metabolism of iodine is in a steady state. Milk iodine content was measured to evaluate the effect of smoking on iodide transport in the mammary gland and on the balance between iodine intake and urinary iodine excretion in the infants. Iodine was measured by the colorimetric method of the Sandell-Koltkoff reaction after alkaline ashing, as previously described (22). The analytical sensitivity was 2 µg/liter. The coefficient of variation in the range investigated was less than 5%, and the recovery of added iodine was more than 95%. Iodine 1 µg/liter corresponds to 7.88 nmol/liter. Thiocyanate in serum was measured by the manual method described by Degiampietro et al. (23). Analytical sensitivity was 10 µmol/liter. Intra- and interassay coefficients of variation were 5.9 and 3.9%, respectively. TSH in serum was measured by immunoluminometric assay (Berilux; Behring Werke, Marburg, Germany; detection limit, 0.01 mU/liter; reference range, 0.4–4.0 mU/liter), as previously described (24).

Statistical analysis

The hypothesis of this study was that smoking would be associated with reduced iodine content in mother’s milk and infant’s urine, whereas mother’s urinary iodine excretion would be slightly higher. Iodine contents of urine and milk and serum TSH showed log normal distribution, which is the usual finding in population studies. All calculations using TSH and iodine concentrations or ratios between iodine concentrations were performed using logarithmically transformed data. The study had 80% power to detect a difference in iodine content of 15–20% at a 5% level of significance. We did statistical analyses with SPSS version 10.0 (SPSS Denmark, Holte, Denmark). Results from smokers and nonsmokers were compared using the independent sample t test, Mann-Whitney test, or ² test for contingency tables as appropriate. Continual measures were analyzed in univariate and multivariate linear models, and dichotomous variables were analyzed using logistic regression analysis as indicated.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Characteristics of smoking and nonsmoking mothers

Smoking status was evaluated by the measurement of the nicotine metabolite cotinine in serum from the mothers when admitted for labor and in urine on d 5 after delivery. Furthermore, we measured cotinine in serum from mixed cord blood and in urine from the infants on d 5. In general, either high or low levels of cotinine were found in a mother-child set of samples. In two mothers, inconsistent results were obtained. Four mothers had borderline positive serum samples when admitted for labor and negative urine samples on d 5 after delivery, suggesting moderate smoking before delivery with cessation of smoking after delivery. All were excluded from further analysis. Levels of cotinine in serum and urine are shown in Table 1. Figure 1 illustrates the distributions of urinary cotinine in mothers classified as smokers and nonsmokers.

View larger version (35K): [in this window] [in a new window]   FIG. 1. Frequency distributions of urinary cotinine concentrations in mothers classified as smokers and nonsmokers. Cotinine 1 µg/liter corresponds to 5.68 nmol/liter.

Average levels of iodine in mother’s urine and breast milk and in infant’s urine on d 5 after delivery are shown in Fig. 2. Even if smoking and nonsmoking mothers had similar levels of urinary iodine, breast-milk iodine was much reduced in smoking mothers (geometric mean milk iodine in smokers, 26.0 µg/liter; SEM range, 23.2–29.1 µg/liter, vs. nonsmokers, 53.8 µg/liter; SEM range, 49.4–58.5 µg/liter; P < 0.001, independent sample t test). In the infants, the low milk iodine supply from smoking mothers gave a low urinary iodine excretion (geometric mean urinary iodine in infant with smoking mothers, 33.3 µg/liter; SEM range, 29.9–37.2 µg/liter, vs. infants with nonsmoking mothers, 50.4 µg/liter; SEM range, 46.0–55.1 µg/liter; P = 0.005). We evaluated the balance between iodine nutrition of individual pairs of mothers and infants by calculating the ratio between iodine in mother’s breast milk and mother’s urine as depicted in Fig. 3. Smoking mothers had a much lower breast-milk iodine content and their infants had a lower urinary iodine content than expected from the mother’s urinary iodine excretion.

View larger version (25K): [in this window] [in a new window]   FIG. 2. Comparison of urinary and breast-milk iodine contents in smoking and nonsmoking mothers. Morning samples of urine and breast milk from mothers and urine from breast-fed infants were collected on d 5 after delivery. For calculation of geometric mean values and statistical comparisons (independent sample t test), logarithmically transformed data were used. Iodine 1 µg/liter corresponds to 7.88 nmol/liter.

View larger version (24K): [in this window] [in a new window]   FIG. 3. Breast-milk iodine is expressed as fraction of the mother’s urinary iodine concentration (nonsmokers vs. smokers: mean ratio, 1.16; SEM, 1.08–1.25 vs. mean, 0.57; SEM, 0.52–0.61), and infant’s urinary iodine content is expressed as fraction of the mother’s urinary iodine concentration (nonsmokers vs. smokers: mean ratio, 1.22; SEM, 1.11–1.34 vs. mean, 0.84; SEM, 0.76–0.92). Both are measures of iodine transfer from mother to child during breastfeeding. Infant’s urinary iodine content expressed as a fraction of milk iodine content (mean ratio, 0.92; SEM, 0.85–1.01 vs. mean, 1.28; SEM, 1.15–1.42) is an inverse measure of iodine retention in the infant. For calculation of geometric mean values and for statistical comparisons (independent sample t test), logarithmically transformed data were used to normalize distributions.

To evaluate possible confounders, the various measures of iodine intake in mothers and infants were studied in multiple linear regression models including the mother’s smoking habits, intake of iodine supplements, mother’s age, parity, gestational age, living in mild or moderate iodine deficiency regions, and birth weight. The models confirmed the findings of the univariate analyses; smoking showed no association with mother’s urinary iodine excretion but was negatively associated with milk iodine content (P < 0.001), infant’s urinary iodine content (P = 0.004), ratio of mother’s breast-milk iodine to mother’s urinary iodine (P < 0.001), and ratio of infant’s urinary iodine to mother’s urinary iodine (P = 0.004) and positively associated with the ratio of infant’s urinary iodine to milk iodine (P = 0.022). Intake of iodine supplements was, as expected, positively associated with mother’s urinary iodine and breast-milk iodine as well as infant’s urinary iodine content (P < 0.001).

Risk of iodine deficiency

We studied the risk of having iodine concentrations in mother’s urine and breast milk and in infant’s urine that might be associated with iodine deficiency. The limit used was an iodine concentration of 50 µg/liter, which depicts populations at increased risk of iodine deficiency disorders (1). Furthermore, we previously observed signs of substrate-dependent insufficient thyroid hormone synthesis when the average daily urinary iodine excretion was less than 50 µg (25). The odds ratio for smokers having such low values in breast milk and infant’s urine was high, as depicted in Fig. 4. On the other hand, smoking was not associated with a low maternal urinary iodine excretion.

View larger version (22K): [in this window] [in a new window]   FIG. 4. Odds ratios for signs of iodine deficiency or low iodine transfer from mother to child in smoking vs. nonsmoking mothers. Horizontal lines indicate 95% confidence intervals. The multivariate logistic regression models included mother’s smoking, intake of iodine supplements, mother’s age and parity.

Dose dependence of the effect of smoking on iodine transfer from mother to child

We calculated correlations between mother’s urinary cotinine concentrations and iodine variables in smokers and nonsmokers. In the smokers, maternal urinary cotinine concentrations correlated negatively to iodine in breast milk (Spearman’s , -0.459; P = 0.001) and iodine in infant’s urine (Spearman’s , -0.383; P = 0.007), with no correlation to iodine in mother’s urine (Spearman’s , 0.012; P = 0.93). The negative correlation (Spearman’s , -0.497; P < 0.001) between maternal urinary cotinine and the ratio of iodine in infant’s urine to mother’s urine as a measure of iodine transfer from mother to child is shown in Fig. 5. In the nonsmokers, neither breast milk nor infant’s urinary iodine showed any correlation to urinary cotinine in the mothers (data not shown).

View larger version (24K): [in this window] [in a new window]   FIG. 5. Correlation between cotinine in urine from smoking mothers on d 5 after delivery and the ratio between iodine in infant’s urine and mother’s urine. Equation for fit (regression) line: log iodine in infant’s urine/mother’s urine = 1.47 - 0.45 x log cotinine in mother’s urine. Cotinine 1 µg/liter corresponds to 5.68 nmol/liter.

The correlations between thiocyanate in mother’s and cord sera at the time of delivery and iodine in mother’s urine and milk and neonate’s urine collected on d 5 after delivery are shown in Table 3. A significant correlation was present between maternal and cord serum thiocyanate (Pearson’s correlation, r = 0.66; P < 0.001), and no major differences were observed between correlations to iodine values (Table 3). Serum thiocyanate did not correlate to mother’s urinary iodine concentration, whereas negative correlations to iodine in mother’s milk and borderline negative correlations to iodine in neonate’s urine were observed. Transfer of iodine into milk evaluated by the ratio between iodine in milk and urine in mothers correlated negatively to serum thiocyanate. On the other hand, the fraction of iodine intake of the neonate excreted in urine evaluated by the ratio between iodine in neonate’s urine and mother’s breast milk correlated positively to serum thiocyanate.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our study aimed to clarify the association between maternal smoking and the transfer of iodine from the breastfeeding mother to her infant. Recently, we reviewed the literature on thiocyanate-rich feeding to domestic animals (26). Thiocyanate had a major inhibitory effect on milk iodine excretion, which in some studies was associated with impaired thyroid function and disturbed development of the offspring (27).

Tobacco smoking is a major source of thiocyanate in humans (13, 14, 15, 23), and as suspected, we now observed impaired iodine transport into breast milk if the mother was a smoker. Smoking during the period of breastfeeding dose-dependently reduced breast-milk iodine content to about half and, consequently, exposes the infant to increased risk of iodine deficiency.

The iodine intake from natural diet is low in many parts of the world, and widespread iodine supplementation programs have been introduced. The primary aim is to reduce the risk of developmental brain damage induced by iodine deficiency during the fetal period and the first years of infant life (1, 2). Still, many children are born without sufficient protection against iodine deficiency (4).

Another major risk to global health is tobacco smoking [World Health Organization (WHO), Tobacco Free Initiative, http://www.WHO.int/tobacco]. Smoking is declining in some countries, but this is often less so in young females. In many developing countries, smoking has been infrequent among women, but this may be increasing (28). Even if smoking during pregnancy is known to result in a variety of adverse health effects in the child, it is often difficult for the women to stop smoking during pregnancy (28). We classified women as smokers according to the levels of the nicotine metabolite cotinine in serum and urine. Smoking may be underreported during pregnancy, and cotinine is a more precise indicator of smoking status (29, 30). All the women classified as smokers and their infants had consistently high levels of cotinine in blood and urine, indicating regular smoking during pregnancy and lactation.

Thiocyanate levels were high in serum from smoking mothers and their neonatal infants, confirming previous studies on the effects of smoking (13, 14, 15, 23). Thiocyanate inhibits competitively the function of the sodium-iodide symporter localized in the basolateral membrane of the thyroid gland (31, 32). This transporter accumulates iodide in the thyroid for hormone synthesis, and partial inhibition of iodide transport by thiocyanate is probably the main reason for the increase in risk of goitre and thyroid nodules in smokers (33, 34, 35). Chanoine et al. (36) reported that, in an area with borderline low iodine intake, smoking during pregnancy was a significant cause of thyroid enlargement and elevated serum thyroglobulin in the newborn.

Our results are consistent with thiocyanate inhibition of the function of the iodide transporter in the lactating mammary gland in smokers, although it cannot be excluded that other chemicals from smoke are involved. In addition, we found that urinary iodine excretion of the infants was less reduced than breast-milk iodine content when the mother was a smoker. This might be another effect of thiocyanate generated in the smoking mother. Thiocyanate crosses the placenta and is, to some extent, excreted in milk in the rat (37), the sow (27), and the dairy cow (38). Vanderpas et al. (39) measured thiocyanate (mean ± SEM, 57 ± 3 µmol/liter) in breast milk from mothers living in Central Africa and having a high thiocyanate intake from cassava. Thiocyanate was higher than in the breast milk in a group of Belgian mothers (45 ± 3 µmol/liter). During the early days of life, the infant thyroid very actively accumulates iodide for thyroid hormone synthesis (7). Thiocyanate from the mother may divert part of the iodine in the infant from thyroid uptake to renal excretion, as observed in domestic animals during thiocyanate feeding (38). Therefore, maternal smoking may impair the ability of the infant thyroid to produce hormone even more than indicated by the low urinary iodine excretion of the infant.

A pertinent question is whether thiocyanate from diet may also impair iodine transport into mother’s milk. Substantial evidence supports that this occurs in domestic animals and may cause developmental damage in the offspring (26). In the present study, we found no evidence for significant effects of thiocyanate from diet in Denmark because there was no correlation between iodine in milk and serum thiocyanate in nonsmokers. However, dietary intake of thiocyanate may be much higher in some populations, leading to various abnormalities including cretinism when combined with low iodine intake (40). Typically, cretinism observed in such areas is predominantly myxoedematous cretinism (40), with brain damage developing during the first years of life (41).

The exact mechanism behind the postnatal hypothyroidism leading to myoedematous cretinism has not been clarified. Thyroid atrophy has been ascribed to concomitant selenium deficiency (42, 43). However, the involution of the thyroid seems to be a relatively late phenomenon (44) and, therefore, of little importance for the irreversible mental retardation. Furthermore, the epidemiological link between selenium deficiency and myxoedematous cretinism has been called into question (45). Possibly, thiocyanate in the diet may impair not only the thyroid of the mother, the fetus, and the infant after ingestion (40) but also induce severe postnatal iodine deficiency by blocking iodine transport into mother’s milk. This might be an important mechanism involved in the postnatal brain damage of myxoedematous cretinism.

Thiocyanate inhibition of iodide transport into milk being a cause for developmental damage is supported by animal studies. Thiocyanate feeding of lactating sows gave a pattern of high serum thiocyanate in the sows, moderately elevated thiocyanate in sow’s milk, slightly elevated serum thiocyanate in the piglets, and very low milk iodine content. Under these circumstances, serum T₄ was unaffected in the sows but was reduced to half in the 28-d-old piglets (46). Hypothyroidism in piglets was prevented by iodine supplementation of the sows (46).

In the study by Vanderpas et al. (39), serum thiocyanate in neonates from Central Africa at the time of birth was around 130 µmol/liter, and in Belgian controls, it was < 70 µmol/liter. These values are not much different from those observed in neonates born of smoking vs. nonsmoking mothers in the present study, and Delange et al. (47) reported that Belgian smokers had serum thiocyanate in the range found in Central Africa. This underscores the potential importance of thiocyanate from smoking tobacco as a factor involved in the development of iodine deficiency disorders in the breast-fed infant.

Reduction of tobacco smoking (WHO Framework Convention on Tobacco Control, via Tobacco Free Initiative, http://www.WHO.int/tobacco) and sustained eradication of brain damage due to iodine deficiency (1) are both major issues on the agenda of WHO. A further global campaign of WHO is to reinforce thriving and health of infants by promoting breastfeeding (WHO Nutrition: Infant and Young Children Feeding Practices, http://www.WHO.int/nut/#inf). Our results indicate that these goals are interdependent. If the mother has an insufficient iodine intake and if she is a smoker, then breastfeeding may involve a considerable risk of iodine deficiency-induced disorders in the infant.

Breastfeeding mothers should not smoke, but if they do, it is important that they obtain sufficient iodine from diet or from iodine-containing supplements.

	Acknowledgments

 
We gratefully acknowledge our colleagues Karl-Gerhard Børlum, Peter L. Johannesen, Peter Dam, and Allan Johansen for help with recruiting participants and collecting data.

Received May 13, 2003.

Accepted October 1, 2003.

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