NEWS & VIEWS NUTRITION
Breast milk—a gateway to iodinedependent brain development Peter Laurberg and Stine Linding Andersen
Iodine from the diet is fundamental for brain development. Via milk, infants receive 40–45% of the iodine in their mother’s diet during breastfeeding; however, it is unclear to what extent depot iodine supplements (that is, iodized oil) given to iodine-deficient breastfeeding mothers compares with direct supplementation of the infants. Laurberg, P. & Andersen, S. L. Nat. Rev. Endocrinol. 10, 134–135 (2014); published online 28 January 2014; doi:10.1038/nrendo.2014.3
In large areas of the world, and especially in mountainous regions, the iodine content of food that is not fortified is not sufficient to meet the needs of pregnant and breastfeeding women, which can lead to irreversible brain damage in the child.1 Salt iodization could solve the problem, but daily supplements should be given to pregnant and breastfeed‑ ing women if salt iodization has not been implemented. If daily supplementation is not possible, iodized oil given as a depot to the mother covers their iodine needs for a long period of time,1 depending on the dose, preparation and type of administration. 2 Bouhouch and colleagues recently pub‑ lished a comprehensive and difficult study addressing some aspects of the practical use of iodized oil for providing infants with ade‑ quate iodine.3 The results provide evidence in a field in which guidance has mostly been based on extrapolation. The results also highlight the importance of exploring in more detail what level of iodine deficiency involves a risk of developmental damage.
Iodine is a substrate for the production of thyroid hormones, which are indispen‑ sable regulators of development (particu‑ larly of the brain).1 Joint guidelines have been published by the WHO, the United Nations Children’s Fund (UNICEF) and the International Council for the Control of Iodine Deficiency Disorders (ICCIDD) in an effort to prevent iodine deficiency disorders.1 To cover the requirements for iodine, both for the breastfeeding mother and for her breastfed infant, the guidelines recommend that the mother has a daily intake of 250 μg iodine.1 If this is not pos‑ sible, a 400 mg depot of orally administered iodized oil is recommended for the mother.1 If breastfeeding is not possible and the infant’s diet is suspected to have insufficient iodine content, the guidelines recommend giving 200 mg of iodine orally (as iodized oil) directly to the infant.1 These recommendations were studied in detail by Bouhouch and colleagues in 241 women with moderate iodine deficiency in
Mother
65 μg per day Iodine intake 250 μg per day
Child
Extrathyroidal iodide pool
Urine 120 μg per day ~115 μg/l (1.05 l per day)
30 μg per day
65 μg per day Milk (40–45%) 110 μg per day ~135 μg/l
Faeces and sweat 20 μg per day
Intake 110 μg per day
Urine 90 μg per day ~225 μg/l (0.40 l per day)
20 μg per day
Extrathyroidal iodide pool
Faeces and sweat 10 μg per day
Figure 1 | A model illustrating the estimated iodine balance in a breastfeeding mother with recommended iodine intake and her child, based on data from several studies. 1,4,5 Calculated values are rounded to the nearest 5 μg. Maternal dietary iodine intake is set to 250 μg per day, as recommended.1
134 | MARCH 2014 | VOLUME 10
a mountainous area of Morocco.3 Breast feeding mothers and their infants were ran‑ domly assigned to receive either 400 mg of iodine (as iodized oil) orally to the mother or 100 mg orally to the infant. Unexpectedly, infant urinary iodine levels were higher after maternal supplementation than after infant supplementation. Median urinary iodine excretion in groups of people is the most important tool to monitor daily iodine intake in a given popu lation, as ~90% of dietary iodine intake is excreted in urine.1 Ideally, iodine should be measured in all urine excreted over 24 h, but for practical reasons spot urine samples (one sample taken at a random time point) are generally used for monitoring iodine status.1 However, this method introduces a degree of uncertainty to the measurement, because the concentration of iodine depends not only on the average iodine intake, but also on the average urine production over 24 h.4 Evaluation of iodine intake in breastfeed‑ ing women differs to that in people who are not lactating, as fluid is also excreted via milk, which might result in a variant 24 h diuresis. In addition, a large proportion of iodine is excreted in the milk. Therefore, urinary levels of iodine in lactating women represent much less than 90% of intake (which is the case in people who are not lactating). Evaluating iodine status in breast fed infants is also different in comparison to adults because they have a positive iodine balance and a diuresis different to that of adults. To understand the results of Bouhouch and colleagues, we set up a model of iodine balance in a breastfeeding mother and her child on the basis of other studies (Figure 1).1,4,5 Over a wide range of iodine intake,4,6 the breastfeeding mother delivers 40–45% of her dietary iodine intake to her infant 4 (this is equivalent to 110 μg per day in the example depicted in Figure 1). An exception is mothers with high blood levels of thiocyanate from their diet or smok ing, which dose-dependently might reduce levels of iodine in the milk to less than half that seen in mothers with normal levels of thiocyanate.7 Bouhouch and colleagues did not specify whether or not their study parti cipants smoked. However, on the basis of the reported iodine concentrations in the maternal milk and urine, thioc yanate did not influence the results of their study.3 The model shown in Figure 1 might explain the main finding of the study—that infant urinary iodine concentrations were higher www.nature.com/nrendo
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS (area under curve ~70% higher) after giving mothers 400 mg iodine than after 100 mg iodine given directly to the infants. According to this model, 400 mg iodine to the mother would deliver 160–180 mg iodine to the infant via breast milk. If Bouhouch and colleagues had used the 200 mg iodine dose to infants recommended by the WHO (rather than 100 mg),1 their results might have been the opposite of those reported. Notably, giving the iodine to the mother is preferable, as this method benefits both the mother and the infant.
‘‘
Bouhouch and co-workers have provided very important new information on the use of iodized oil…
’’
An interesting finding in the study by Bouhouch and colleagues is that iodine given to the mother resulted in infant, but not maternal, urinary iodine concentra‑ tions above the lower limit of sufficiency (100 μg/l) given by the WHO, UNICEF and ICCIDD joint guidelines.1 According to the model (Figure 1), the main reason for this finding is that infant urine generally has an iodine concentration twice as high as maternal urine. Many studies have documented that iodized oil at the doses used by Bouhouch and colleagues has remarkably few adverse effects.2,3 A small caveat is that the group of infants with the highest iodine supply (administration of 400 mg iodine to their mother) had a reduced increase in body
length after 9 months, and their mothers had higher depression scores after 12 months, than the mother–infant pairs in which the supplement was given directly to the infant.3 No differences were observed in many other outcomes measured in this study of women with moderate iodine deficiency.3 The study did not include an unsupple‑ mented control group. Still, the findings are at striking variance with the results of a pre‑ vious controlled study in pregnant women in Algeria who were severely iodine-deficient.8 In this study, iodized oil (240 mg iodine) given before or in early pregnancy resulted in better thyroid function in the mother and neonate, fewer pregnancy complications and higher birth weight compared with a control group of unsupplemented mothers. Bouhouch and co-workers have provided very important new information on the use of iodized oil, with results that corroborate models of iodine balance in breastfeeding mothers and their children (Figure 1). Simi lar carefully controlled studies are needed to more exactly conclude which level of iodine deficiency results in brain develop ment being at risk, as has been highlighted in an article published in 2013.9 Similarly, the possible importance of small deviations in maternal thyroid function in early pregnancy is to be investigated in controlled studies.10 Department of Endocrinology, Mølleparkvej 4, Aalborg University Hospital, 9000 Aalborg, Denmark (P. Laurberg, S. L. Andersen). Correspondence to: P. Laurberg [email protected] Competing interests The authors declare no competing interests.
NATURE REVIEWS | ENDOCRINOLOGY
1.
WHO, UNICEF, ICCIDD. Assessment of iodine deficiency disorders and monitoring their elimination. A guide for programme managers. World Health Organisation, 1–99 [online], http://whqlibdoc.who.int/publications/2007/ 9789241595827_eng.pdf (2007). 2. Wolff, J. Physiology and pharmacology of iodized oil in goiter prophylaxis. Medicine 80, 20–36 (2001). 3. Bouhouch, R. R. et al. Direct iodine supplementation of infants versus supplementation of their breastfeeding mothers: a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. http://dx.doi. org/10.1016/S2213-8587(13)70155-4. 4. Andersen, S. L., Møller, M. & Laurberg, P. Iodine concentrations in milk and in urine during breastfeeding are differently affected by maternal fluid intake. Thyroid http://dx.doi.org/ 10.1089/thy.2013.0541. 5. van den Hove, M. F., Beckers, C., Devlieger, H., de Zegher, F. & De Nayer, P. Hormone synthesis and storage in the thyroid of human preterm and term newborns: effect of thyroxine treatment. Biochimie 81, 563–570 (1999). 6. Moon, S. & Kim, J. Iodine content of human milk and dietary iodine intake of Korean lactating mothers. Int. J. Food Sci. Nutr. 50, 165–171 (1999). 7. Laurberg, P., Nøhr, S. B., Pedersen, K. M. & Fuglsang, E. Iodine nutrition in breast-fed infants is impaired by maternal smoking. J. Clin. Endocrinol. Metab. 89, 181–187 (2004). 8. Chaouki, M. L. & Benmiloud, M. Prevention of iodine deficiency disorders by oral administration of lipiodol during pregnancy. Eur. J. Endocrinol. 130, 547–551 (1994). 9. Zhou, S. J., Anderson, A. J., Gibson, R. A. & Makrides, M. Effect of iodine supplementation in pregnancy on child development and other clinical outcomes: a systematic review of randomized controlled trials. Am. J. Clin. Nutr. 98, 1241–1254 (2013). 10. Laurberg, P., Andersen, S. L., Pedersen, I. B., Andersen, S. & Carlé, A. Screening for overt thyroid disease in early pregnancy may be preferable to searching for small aberrations in thyroid function tests. Clin. Endocrinol. (Oxf.) 79, 297–304 (2013).
VOLUME 10 | MARCH 2014 | 135 © 2014 Macmillan Publishers Limited. All rights reserved
Breast milk—a gateway to iodinedependent brain development Peter Laurberg and Stine Linding Andersen
Iodine from the diet is fundamental for brain development. Via milk, infants receive 40–45% of the iodine in their mother’s diet during breastfeeding; however, it is unclear to what extent depot iodine supplements (that is, iodized oil) given to iodine-deficient breastfeeding mothers compares with direct supplementation of the infants. Laurberg, P. & Andersen, S. L. Nat. Rev. Endocrinol. 10, 134–135 (2014); published online 28 January 2014; doi:10.1038/nrendo.2014.3
In large areas of the world, and especially in mountainous regions, the iodine content of food that is not fortified is not sufficient to meet the needs of pregnant and breastfeeding women, which can lead to irreversible brain damage in the child.1 Salt iodization could solve the problem, but daily supplements should be given to pregnant and breastfeed‑ ing women if salt iodization has not been implemented. If daily supplementation is not possible, iodized oil given as a depot to the mother covers their iodine needs for a long period of time,1 depending on the dose, preparation and type of administration. 2 Bouhouch and colleagues recently pub‑ lished a comprehensive and difficult study addressing some aspects of the practical use of iodized oil for providing infants with ade‑ quate iodine.3 The results provide evidence in a field in which guidance has mostly been based on extrapolation. The results also highlight the importance of exploring in more detail what level of iodine deficiency involves a risk of developmental damage.
Iodine is a substrate for the production of thyroid hormones, which are indispen‑ sable regulators of development (particu‑ larly of the brain).1 Joint guidelines have been published by the WHO, the United Nations Children’s Fund (UNICEF) and the International Council for the Control of Iodine Deficiency Disorders (ICCIDD) in an effort to prevent iodine deficiency disorders.1 To cover the requirements for iodine, both for the breastfeeding mother and for her breastfed infant, the guidelines recommend that the mother has a daily intake of 250 μg iodine.1 If this is not pos‑ sible, a 400 mg depot of orally administered iodized oil is recommended for the mother.1 If breastfeeding is not possible and the infant’s diet is suspected to have insufficient iodine content, the guidelines recommend giving 200 mg of iodine orally (as iodized oil) directly to the infant.1 These recommendations were studied in detail by Bouhouch and colleagues in 241 women with moderate iodine deficiency in
Mother
65 μg per day Iodine intake 250 μg per day
Child
Extrathyroidal iodide pool
Urine 120 μg per day ~115 μg/l (1.05 l per day)
30 μg per day
65 μg per day Milk (40–45%) 110 μg per day ~135 μg/l
Faeces and sweat 20 μg per day
Intake 110 μg per day
Urine 90 μg per day ~225 μg/l (0.40 l per day)
20 μg per day
Extrathyroidal iodide pool
Faeces and sweat 10 μg per day
Figure 1 | A model illustrating the estimated iodine balance in a breastfeeding mother with recommended iodine intake and her child, based on data from several studies. 1,4,5 Calculated values are rounded to the nearest 5 μg. Maternal dietary iodine intake is set to 250 μg per day, as recommended.1
134 | MARCH 2014 | VOLUME 10
a mountainous area of Morocco.3 Breast feeding mothers and their infants were ran‑ domly assigned to receive either 400 mg of iodine (as iodized oil) orally to the mother or 100 mg orally to the infant. Unexpectedly, infant urinary iodine levels were higher after maternal supplementation than after infant supplementation. Median urinary iodine excretion in groups of people is the most important tool to monitor daily iodine intake in a given popu lation, as ~90% of dietary iodine intake is excreted in urine.1 Ideally, iodine should be measured in all urine excreted over 24 h, but for practical reasons spot urine samples (one sample taken at a random time point) are generally used for monitoring iodine status.1 However, this method introduces a degree of uncertainty to the measurement, because the concentration of iodine depends not only on the average iodine intake, but also on the average urine production over 24 h.4 Evaluation of iodine intake in breastfeed‑ ing women differs to that in people who are not lactating, as fluid is also excreted via milk, which might result in a variant 24 h diuresis. In addition, a large proportion of iodine is excreted in the milk. Therefore, urinary levels of iodine in lactating women represent much less than 90% of intake (which is the case in people who are not lactating). Evaluating iodine status in breast fed infants is also different in comparison to adults because they have a positive iodine balance and a diuresis different to that of adults. To understand the results of Bouhouch and colleagues, we set up a model of iodine balance in a breastfeeding mother and her child on the basis of other studies (Figure 1).1,4,5 Over a wide range of iodine intake,4,6 the breastfeeding mother delivers 40–45% of her dietary iodine intake to her infant 4 (this is equivalent to 110 μg per day in the example depicted in Figure 1). An exception is mothers with high blood levels of thiocyanate from their diet or smok ing, which dose-dependently might reduce levels of iodine in the milk to less than half that seen in mothers with normal levels of thiocyanate.7 Bouhouch and colleagues did not specify whether or not their study parti cipants smoked. However, on the basis of the reported iodine concentrations in the maternal milk and urine, thioc yanate did not influence the results of their study.3 The model shown in Figure 1 might explain the main finding of the study—that infant urinary iodine concentrations were higher www.nature.com/nrendo
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS (area under curve ~70% higher) after giving mothers 400 mg iodine than after 100 mg iodine given directly to the infants. According to this model, 400 mg iodine to the mother would deliver 160–180 mg iodine to the infant via breast milk. If Bouhouch and colleagues had used the 200 mg iodine dose to infants recommended by the WHO (rather than 100 mg),1 their results might have been the opposite of those reported. Notably, giving the iodine to the mother is preferable, as this method benefits both the mother and the infant.
‘‘
Bouhouch and co-workers have provided very important new information on the use of iodized oil…
’’
An interesting finding in the study by Bouhouch and colleagues is that iodine given to the mother resulted in infant, but not maternal, urinary iodine concentra‑ tions above the lower limit of sufficiency (100 μg/l) given by the WHO, UNICEF and ICCIDD joint guidelines.1 According to the model (Figure 1), the main reason for this finding is that infant urine generally has an iodine concentration twice as high as maternal urine. Many studies have documented that iodized oil at the doses used by Bouhouch and colleagues has remarkably few adverse effects.2,3 A small caveat is that the group of infants with the highest iodine supply (administration of 400 mg iodine to their mother) had a reduced increase in body
length after 9 months, and their mothers had higher depression scores after 12 months, than the mother–infant pairs in which the supplement was given directly to the infant.3 No differences were observed in many other outcomes measured in this study of women with moderate iodine deficiency.3 The study did not include an unsupple‑ mented control group. Still, the findings are at striking variance with the results of a pre‑ vious controlled study in pregnant women in Algeria who were severely iodine-deficient.8 In this study, iodized oil (240 mg iodine) given before or in early pregnancy resulted in better thyroid function in the mother and neonate, fewer pregnancy complications and higher birth weight compared with a control group of unsupplemented mothers. Bouhouch and co-workers have provided very important new information on the use of iodized oil, with results that corroborate models of iodine balance in breastfeeding mothers and their children (Figure 1). Simi lar carefully controlled studies are needed to more exactly conclude which level of iodine deficiency results in brain develop ment being at risk, as has been highlighted in an article published in 2013.9 Similarly, the possible importance of small deviations in maternal thyroid function in early pregnancy is to be investigated in controlled studies.10 Department of Endocrinology, Mølleparkvej 4, Aalborg University Hospital, 9000 Aalborg, Denmark (P. Laurberg, S. L. Andersen). Correspondence to: P. Laurberg [email protected] Competing interests The authors declare no competing interests.
NATURE REVIEWS | ENDOCRINOLOGY
1.
WHO, UNICEF, ICCIDD. Assessment of iodine deficiency disorders and monitoring their elimination. A guide for programme managers. World Health Organisation, 1–99 [online], http://whqlibdoc.who.int/publications/2007/ 9789241595827_eng.pdf (2007). 2. Wolff, J. Physiology and pharmacology of iodized oil in goiter prophylaxis. Medicine 80, 20–36 (2001). 3. Bouhouch, R. R. et al. Direct iodine supplementation of infants versus supplementation of their breastfeeding mothers: a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. http://dx.doi. org/10.1016/S2213-8587(13)70155-4. 4. Andersen, S. L., Møller, M. & Laurberg, P. Iodine concentrations in milk and in urine during breastfeeding are differently affected by maternal fluid intake. Thyroid http://dx.doi.org/ 10.1089/thy.2013.0541. 5. van den Hove, M. F., Beckers, C., Devlieger, H., de Zegher, F. & De Nayer, P. Hormone synthesis and storage in the thyroid of human preterm and term newborns: effect of thyroxine treatment. Biochimie 81, 563–570 (1999). 6. Moon, S. & Kim, J. Iodine content of human milk and dietary iodine intake of Korean lactating mothers. Int. J. Food Sci. Nutr. 50, 165–171 (1999). 7. Laurberg, P., Nøhr, S. B., Pedersen, K. M. & Fuglsang, E. Iodine nutrition in breast-fed infants is impaired by maternal smoking. J. Clin. Endocrinol. Metab. 89, 181–187 (2004). 8. Chaouki, M. L. & Benmiloud, M. Prevention of iodine deficiency disorders by oral administration of lipiodol during pregnancy. Eur. J. Endocrinol. 130, 547–551 (1994). 9. Zhou, S. J., Anderson, A. J., Gibson, R. A. & Makrides, M. Effect of iodine supplementation in pregnancy on child development and other clinical outcomes: a systematic review of randomized controlled trials. Am. J. Clin. Nutr. 98, 1241–1254 (2013). 10. Laurberg, P., Andersen, S. L., Pedersen, I. B., Andersen, S. & Carlé, A. Screening for overt thyroid disease in early pregnancy may be preferable to searching for small aberrations in thyroid function tests. Clin. Endocrinol. (Oxf.) 79, 297–304 (2013).
VOLUME 10 | MARCH 2014 | 135 © 2014 Macmillan Publishers Limited. All rights reserved
