Low Iodine Content in the Diets of Hospitalized Preterm Infants

Abstract

Context:

Iodine is critical for normal thyroid hormone synthesis and brain development during infancy, and preterm infants are particularly vulnerable to the effects of both iodine deficiency and excess. Use of iodine-containing skin antiseptics in intensive care nurseries has declined substantially in recent years, but whether the current dietary iodine intake meets the requirement for hospitalized preterm infants is unknown.

Objective:

The aim of the study was to measure the iodine content of enteral and parenteral nutrition products commonly used for hospitalized preterm infants and estimate the daily iodine intake for a hypothetical 1-kg infant.

Methods:

We used mass spectrometry to measure the iodine concentration of seven preterm infant formulas, 10 samples of pooled donor human milk, two human milk fortifiers (HMF) and other enteral supplements, and a parenteral amino acid solution and soy-based lipid emulsion. We calculated the iodine provided by typical diets based on 150 ml/kg · d of formula, donor human milk with or without HMF, and parenteral nutrition.

Results:

Preterm formula provided 16.4–28.5 μg/d of iodine, whereas unfortified donor human milk provided only 5.0–17.6 μg/d. Adding two servings (six packets) of Similac HMF to human milk increased iodine intake by 11.7 μg/d, whereas adding two servings of Enfamil HMF increased iodine intake by only 0.9 μg/d. The other enteral supplements contained almost no iodine, nor did a parenteral nutrition-based diet.

Conclusions:

Typical enteral diets for hospitalized preterm infants, particularly those based on donor human milk, provide less than the recommended 30 μg/d of iodine, and parenteral nutrition provides almost no iodine. Additional iodine fortification should be considered.

Iodine is a trace element required for the synthesis of T₄ and T₃, which are critical for normal neurodevelopment in the neonatal period. Worldwide, iodine deficiency resulting in hypothyroidism is the most important preventable cause of cognitive impairment in children (1). However, iodine excess can also be harmful, causing decreased thyroid hormone production and secretion in susceptible individuals (2). Optimal iodine intake provides adequate substrate for thyroid hormone production while avoiding the potential for decreasing thyroid hormone synthesis.

Over 12% of all births in the United States are preterm (<37 completed wk gestation) (3), and preterm infants are a particularly vulnerable population with respect to iodine nutrition. Preterm infants have lower iodine and thyroid hormone stores relative to full-term infants (4) and require relatively more iodine than full-term infants and older children to maintain a positive iodine balance (5, 6), so they are at risk for deficiency without adequate dietary intake. However, hospitalized preterm infants are also susceptible to iodine excess from frequent exposure to iodine-containing skin cleansers such as povidine-iodine, due to immaturity of the preterm skin and resultant high cutaneous absorption. In addition, the ability to escape from the acute thyroid-suppressing effects of iodine (the Wolff-Chaikoff effect) does not mature until 36 wk gestation (7, 8).

After previous studies demonstrated that the use of iodinated skin cleansers in neonatal intensive care unit (NICU) patients was associated with markedly elevated urinary iodine levels (9) and transient hypothyroidism (10, 11), many NICUs in the United States and elsewhere responded by discontinuing the use of povidine-iodine for routine skin cleansing. In these NICUs, dietary iodine is the sole source of iodine for hospitalized infants. Other studies have reported a low iodine content of preterm infant formulas (12) and some samples of human milk (13), but there is little evidence regarding the iodine content of diets used currently for hospitalized preterm infants, particularly diets based on parenteral nutrition and donor human milk, the use of which is on the rise in the United States (14) and is widespread in other countries (15).

The aims of our study were: 1) to measure the iodine content of commercial enteral and parenteral nutrition products and donor human milk typically fed to hospitalized preterm infants; 2) to estimate the total daily dietary iodine intake for a hypothetical 1-kg preterm infant; and 3) to compare our estimates with the recommended daily intake of 30 μg/kg · d.

Materials and Methods

Measurement of iodine content in enteral and parenteral nutrition products

We used ion chromatography-mass spectrometry (16) to measure the iodine content of seven commercially available preterm infant formulas; two commercial human milk fortifiers (HMF); the enteral nutritional supplements medium chain triglyceride (MCT) oil (Mead Johnson Nutrition, Glenview, IL), Beneprotein (Nestle HealthCare Nutrition, Florham Park, NJ), and Polycose (Abbott Nutrition, Columbus, OH); a parenteral amino acid solution (Trophamine; B. Braun Medical Inc., Bethlehem, PA); and soy-based 20% lipid emulsion (Intralipid; Fresenius Kabi, Schaumburg, IL). We also measured the iodine content of 10 samples of donor human milk. Each sample was constituted from three to five different anonymous donors, Holder pasteurized, and frozen according to published guidelines (17).

Calculation of iodine intake for typical hospitalized preterm infant

Using typical enteral (formula and human milk-based) and parenteral diets for preterm infants (Table 1), we calculated the total iodine intake from each component of the diet for a hypothetical 1-kg infant with 150 ml/kg · d of total fluid intake. To estimate the total daily iodine intake, we then summed the daily iodine intake from each component of the diet. For the human milk-based diets, we calculated the total daily iodine intake based on milk with the lowest, median, and highest iodine content.

Table 1.

Typical diets for hospitalized preterm infants

Enteral

Preterm formula (20, 24, or 30 kcal/oz)

Transitional formula (22 kcal/oz)

Human milk

Unfortified (approximately 20 kcal/oz)

Fortified

22 kcal/oz (2 packets HMF per 100 ml)

24 kcal/oz (4 packets HMF per 100 ml)

26 kcal/oz (4 packets HMF + 0.87 ml MCT oil per 100 ml)

27 kcal/oz (4 packets HMF + 0.87 ml MCT oil + 1 g Beneprotein per 100 ml)

29 kcal/oz (4 packets HMF + 0.87 ml MCT oil + 1 g Beneprotein + 3 g Polycose per 100 ml)

Parenteral

Amino acid solution + dextrose + lipid emulsion

Results

Table 2 shows the iodine content in the seven commercial formulas and parenteral nutrition products and the daily iodine intake based on a 1-kg infant with a total fluid intake of 150 ml/kg · d. The iodine content of preterm and transitional formulas ranged from 109.0 to 190.0 μg/liter, and daily intake for the hypothetical 1-kg infant ranged from 16 to 29 μg/d. Iodine intake from the parenteral amino acid solution and lipid emulsion was negligible.

Table 2.

Iodine content and typical daily iodine intake from commercial infant formula and parenteral nutrition products

Product	Iodine content (μg/liter)	Typical daily intake (μg/kg · d)a
Enteral
Preterm formula
Premature Enfamil
20 kcal/oz	157	24
24 kcal/oz	172	26
Similac Special Care
20 kcal/oz	115	17
24 kcal/oz	109	16
30 kcal/oz	160	24
Transitional formula
Enfacare	190	29
Neosure	118	18
Parenteral
Trophamine amino acid solution	2.5	0.3
Intralipid lipid emulsion	15.1	0.2

^aBased on a hypothetical 1-kg infant with total fluid intake of 150 ml/kg · d.

The iodine content in the 10 donor human milk samples ranged from 33.3 to 117.5 μg/liter (Fig.1), with a mean (sd) of 59.5 (28.7) and a median of 46.0 μg/liter. Similac HMF contained 2.2 μg/g of iodine, whereas Enfamil HMF contained almost none (Table 3). The iodine content of other human milk additives is also listed in Table 3; these products also contain very little iodine. Table 4 shows the iodine content in donor human milk-based diets, using the recipes shown in Table 1 and donor human milk with the minimum, median, and maximum iodine content. Without fortification with HMF, donor human milk with the maximum iodine content provided only 17.6 μg/kg · d of iodine. Even with fortification, only human milk with the maximum iodine content (117.5 μg/liter) fortified with Similac HMF (four packets/100 ml) provided close to the recommended 30 μg/kg · d of iodine; all the other human milk-based diets provided less than the recommended amount.

Fig. 1.

Iodine content in 10 samples of donor human milk. Each sample was pooled by the milk bank from three to five different donors, Holder pasteurized, and frozen according to published guidelines (17). To provide the recommended 30 μg/d for preterm infants, human milk would need to contain 200 μg/liter of iodine; all 10 samples had less than this amount.

Table 3.

Iodine content of breast milk additives

Product	Iodine content
HMF
Enfamil HMF	0.2 μg/g
Similac HMF	2.2 μg/g
Other enteral additives
MCT oil	2.6 μg/liter
Beneprotein	0.1 μg/g
Polycose	0.0 μg/g

Table 4.

Daily iodine intake from breast milk-based diets

Diet	Iodine content (μg/liter)	Iodine intake (μg/kg · d)a
Breast milk with minimum iodine
Unfortified	33.3	5.0
22 kcal/oz
Similac HMF	72.7	10.9
Enfamil HMF	36.7	5.5
≥24 kcal/oz
Similac HMF	111.3	16.7
Enfamil HMF	39.3	5.9
Breast milk with median iodine
Unfortified	59.3	9.0
22 kcal/oz
Similac HMF	85.3	12.8
Enfamil HMF	49.3	7.4
≥24 kcal/oz
Similac HMF	124.0	18.6
Enfamil HMF	52.0	7.8
Breast milk with maximum iodine
Unfortified	117.5	17.6
22 kcal/oz
Similac HMF	156.7	23.5
Enfamil HMF	120.7	18.1
≥24 kcal/oz
Similac HMF	196.0	29.4
Enfamil HMF	123.3	18.5

^aBased on a hypothetical 1-kg infant with total fluid intake of 150 ml/kg · d.

Discussion

We found that typical enteral formula-based diets for preterm neonates provided considerably less iodine than the recommended minimum of 30 μg/kg · d (6, 18). In general, donor human milk provided less iodine than commercial infant formulas, and parenteral nutrition provided almost no iodine. In the past, hospitalized preterm neonates were exposed to large amounts of iodine through povidine-iodine used to clean skin for invasive procedures. Our results suggest that a shift to equally effective noniodinated skin cleansers, while preventing the adverse effects of iodine excess, may have unintended consequences, increasing the risk for negative iodine balance and iodine deficiency, particularly in infants receiving banked donor human milk-based diets or prolonged parenteral nutrition.

None of the donor human milk samples we tested would provide the recommended iodine intake for a growing preterm infant. Our results also demonstrate substantial variability in the iodine content of donor human milk, despite the fact that each of our samples was pooled from three to five different donors. Our results with donor human milk differ from several previous studies that reported a substantially higher iodine content of preterm breast milk; for example, Spanish (12) and Scottish (19) studies of milk provided by lactating mothers of preterm infants of less than 30 wk gestation both reported a mean iodine content of approximately 100 μg/liter, almost twice the mean content of 60 μg/liter in our study. Similarly, a U.S. study (13) of 57 lactating women reported a median breast milk iodine content of 155 μg/liter (range, 2.7 to 1968), also considerably higher than our study and with even greater variability. In another U.S. study, Kirk et al. (20) reported a mean breast milk iodine content of 63.3 μg/liter (range, 4.5 to 184.5), similar to our findings.

The reason for the variability of iodine content of human milk may relate to differences in maternal dietary intake from foods and supplements. Although the United States is a generally iodine-sufficient region, according to the 2005–2008 U.S. National Health and Nutrition Examination Survey, 57% of pregnant women had urinary iodine levels below 150 μg/liter (21). Our results suggest that iodine may be inadequate in the diets of women who donate their milk to milk banks and support recommendations of national and international organizations that all lactating women—including milk donors—take a daily multivitamin containing at least 150 μg of iodine; of note, many prenatal vitamins in the United States contain little iodine (22). It is also possible that Holder pasteurization of the donor milk decreases its iodine content; future studies should examine this possibility.

Our findings suggest that preterm infants receiving prolonged parenteral nutrition do not receive enough iodine. Parenteral nutrition is recommended for all preterm infants born weighing less than 1500 g (23), and many infants—particularly sicker and less mature infants—do not receive full enteral feedings until several weeks after birth. U.S. and European organizations recommend adding only 1 μg/kg · d of iodine to parenteral nutrition, far below the 30 μg/kg · d required to maintain positive iodine balance, but these recommendations assume a substantial degree of skin absorption of topical iodine-containing antiseptics (18). A study (19) of parenterally fed preterm infants of 30 wk gestation or less who were not exposed to iodine-containing skin disinfectants demonstrated evidence of iodine deficiency (low urinary iodine levels) and a negative iodine balance from birth, which reversed by approximately 2 wk of age with the establishment of enteral feeding, suggesting that inadequate iodine in parenteral nutrition has meaningful clinical consequences.

Severe iodine deficiency leads to neurodevelopmental impairment through decreased synthesis of thyroid hormones, which are critical for normal brain development in infancy. The prevalence of postnatal hypothyroxinemia is higher among preterm vs. full-term infants, with estimates ranging from 10% to over 30% in infants of less than 32 wk gestation and/or less than 1500 g (24–27). The phenomenon of lower T₄ levels in preterm infants is referred to as the transient hypothyroxinemia of prematurity. Several studies (25, 28, 29) have reported that transient hypothyroxinemia in preterm infants is associated with poorer long-term cognitive and motor outcomes including cerebral palsy, although underlying physiological immaturity and critical illness are also likely to contribute to later neurological impairments (26, 30).

The extent to which iodine status underlies transient hypothyroxinemia of prematurity is unclear. A Spanish study (31) estimated that iodine deficiency accounted for approximately 30% of hypothyroxinemia seen in enterally fed preterm infants of 27–30 wk gestation, in addition to other factors such as immaturity of the hypothalamic-pituitary-thyroid axis, acute prematurity-related illness (e.g. surfactant deficiency, sepsis), and medications such as dopamine. Although a randomized trial (32) of 40–50 vs. 12–16 μg/kg · d iodine supplementation in infant formula in 121 preterm infants of less than 33 wk gestation did not demonstrate a beneficial effect of the higher iodine supplementation on T₄ or TSH levels, the extent of participants' exposure to povidine-iodine was not reported. Additionally, only four infants in the trial received predominantly their mothers' own milk, and none received donor human milk. Neurodevelopmental outcomes were not evaluated. In a phase I trial of thyroid hormone supplementation for preterm infants with transient hypothyroxinemia, control infants treated with 30 μg/d of iodine had thyroid hormone levels similar to infants who received the vehicle control (33). Further studies are needed to delineate the impact of iodine nutrition on thyroid function and neurodevelopment in the current era of neonatal intensive care, in populations unexposed to povidine-iodine and fed predominantly human milk.

Our study examined sources of iodine in the preterm diet, but we did not directly measure the iodine status of individual infants fed different diets, nor did we examine the effects of diet on results of newborn screening for congenital hypothyroidism. In the past, rising rates of congenital hypothyroidism detected by newborn screening led to a recognition of iodine overload as an underlying causal factor (34, 35). Of note, the incidence of congenital hypothyroidism has been rising in the United States (27), although the extent to which declining iodine intake relates to this observation is unclear.

In summary, we found that both enteral and parenteral diets for hospitalized preterm infants are low in iodine. Hospitalized preterm infants may be at risk for iodine deficiency, particularly without exposure to iodinated skin cleansers. Ensuring that all lactating women follow recommendations to take a daily multivitamin containing at least 150 μg of iodine is likely to increase the iodine content in human milk. Adding more iodine to parenteral nutrition and commercial HMF may also be warranted.